CN101208085A

CN101208085A - Mofified release 1-[(3-hydroxy-adamant-1-ylamino)-acetyl]-pyrrolidine-2(s)-carbonitrile formulation

Info

Publication number: CN101208085A
Application number: CNA2006800205753A
Authority: CN
Inventors: J·科瓦尔斯基; J·P·拉克什曼; A·T·M·塞拉尤迪恩; Y·乔希
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2005-06-10
Filing date: 2006-06-08
Publication date: 2008-06-25
Anticipated expiration: 2026-06-08
Also published as: ZA200709499B; CN101208085B

Abstract

Abstract of the Disclosure The subject invention provides a pharmaceutical tablet formulation comprising per unit dosage form e.g. per tablet the following ingredients: (a) a compound as an active ingredient, wherein the compound has a formula: [Chemical formula should be inserted here as it appears on Abstract in paper form] wherein R is substituted adamantyl and n is an integer from 0 to 3 or a pharmaceutically acceptable salt thereof; (b) a hydroxypropyl methylcellulose with an apparent viscosity of 80,000 cP to 120,000 cP (nominal value 100,000 cP) when present in a 1% solution; (c) a microcrystalline cellulose; and (d) a magnesium stearate.

Description

1-[(3-hydroxyl-adamantyl-1-base is amino)-acetyl group]-the accent release formulation of pyrrolidinyl-2 (s)-nitrile

Background of invention

The present invention relates to be used to prevent or treat the slow releasing preparation that comprises inhibitors of dipeptidyl IV (DPP-IV) of diabetes, non-insulin-dependent diabetes mellitus, obesity, arthritis, osteoporosis and other diseases.

DPP-IV is the useful medicine that is used for the treatment of diabetes, non-insulin-dependent diabetes mellitus, obesity, arthritis, osteoporosis and other diseases, because it is suppressed at the inactivation of the glucagon-like peptide-I (GLP-I) in the blood plasma, and (WO 02/062 to increase its endocrine effect, 764, WO01/55105, WO 02/02560).

But, as detailed below, in live body the active strong inhibition of DPP-IV on, the situation that some is always insuitable.

For example, there is report DPP-IV inhibitor to improve vasorelaxation action by material O and the active raising of DPP-IV when treating chronic sinusitis, because have negative correlativing relation (for example between the density of the inflammatory cell at the DPP-IV of chronic sinusitis patient's nasal mucosa on the active and nasal mucosa, FASEB J., 2002,16:1132-1134).Therefore, think the DPP-IV activity of the diabetics that do not need to suppress consumingly concurrent chronic inflammatory disease, because it can cause the inflammation aggravation.

It is important to the glucose homeostasis that report selective DPP-IV activity is arranged, because metabolite GLP-I (9-36) amide of GLP-I and DPP-IV reduces blood glucose levels (Am.J.Physiol.Endocrinol.Metab., 2002,282:E873-E879).

In addition, have in the treatment that is reported in the hepatitis C patients that uses interferon-' alpha ', the order of severity depressed and anxiety relevant with the active decline of serum DPP-IV (for example, Mol.Psychiatry, 2001,6:475-480).

Seen that by current situation always suitable to the live body situation of the active strong inhibition of DPP-IV in some bodies is arranged, the inventor thinks and is necessary to develop that suitably to suppress DPP-IV active and have the outstanding convenience and the preparation of compliance equally.

For these purposes, the inventor is in that to herein disclosed is 1-[(3-hydroxyl-adamantyl-1-base amino)-acetyl group]-pyrrolidinyl-2 (s)-nitrile (being also referred to as LAF237 or row spit of fland, Victor (vildagliptin) (INN)) transfers and releases/slow releasing preparation.The accent that comprises row spit of fland, Victor releases/and the exploitation of slow release (MR) preparation is necessary to improving by treatment patient's therapeutic quality.Row spit of fland, Victor is the inhibitors of dipeptidyl IV of Orally active that is applicable to the improvement of type ii diabetes glycemic control.

LAF237 is specifically open in the embodiment 1 of WO 00/34241.LAF237 can according among the WO00/34241 or the description among the international patent application No.EP2005/000400 (application number) prepare.

Because row spit of fland, Victor is to moisture-sensitive, be the stability of product at one of main emphasis of listing preparation (MF) exploitation.Hydrolysis is the main degradation pathway in row spit of fland, Victor.The stability in row spit of fland, known Victor is subjected to moisture initial in the tablet, have figuration dosage (drug loading %) influence that exists in the excipient of high inherent moisture and the tablet.Row spit of fland, the Victor preparation of current checking is DC (directly compacting) sheet that 25% drug loading is arranged.

Consider the water sensitivity in row spit of fland, Victor, clinical service preparation (CSF) and the development plan of listing preparation (MF) concentrate on the technology that does not need to make water, for example the direct compression technology.

Therefore row spit of fland, Victor need not the special operation of handling by being categorized as the II class.

Row spit of fland, Victor crude drug (DS) is to moisture-sensitive.Need very airtight packing.Being 25 ℃ the current date of inspection again stored 30 months.

Well-known patient adheres to relevantly with administration frequency indirectly to drug administration, promptly compares with twice administration every day (BID) scheme, can see once a day that (OD) is easier to adhere to.Most of data in row spit of fland, current Victor are based on that the research of rapid release (IR) preparation that row spit of fland, Victor BID gives obtains.

Transfer with OD and to release dosage and substitute 50mg IR BID dosage and will provide the patient to take medicine convenient and to the dual benefits of the OD product of patient's innovation for the treatment of.

The invention provides and to be pressed, preferably directly to be suppressed into enough hardness/friabilities, acceptable disintegration time, hyposensitivity, the stability of improvement, acceptable stripping kenel and by the medicinal tablet of the tablet of the pharmaco-kinetic properties of improving among the patient who treats moisture.Medicinal tablet can also be used for for example capsule, tablet, compressed tablet, direct compressed tablet, granule.

Summary of the invention

The invention provides the per unit dosage form for example the per unit tablet comprise the medicinal tablet of following composition:

(a) compound or pharmaceutically acceptable salt thereof of following formula is as active component:

Wherein R is the adamantyl that replaces, and n is from 0 to 3 integer;

(b) when existing, have 80 with 1% solution, 000cP to 120, (scale value is 100 to the apparent viscosity of 000cP, hydroxypropyl emthylcellulose 000cP);

(c) microcrystalline Cellulose; With

(d) magnesium stearate

The present invention also provides the tablet of every 400mg to comprise the medicinal tablet of following composition:

(a) row spit of fland, Victor or its officinal salt of about 100mg amount;

(b) hydroxypropyl emthylcellulose of about 160mg amount, the apparent viscosity when wherein hydroxypropyl emthylcellulose exists with 1 solution is 80,000cP to 120,000cP (sign value 100,000cP);

(c) microcrystalline Cellulose of 120mg amount;

(d) lactose of the amount of about 16mg; With

(e) magnesium stearate of 4mg amount.

The present invention also provides for example every medicinal tablet that comprises following composition of per unit dosage form:

Wherein R is the adamantyl that replaces, and n is from 0 to 3 integer; And

(b) when existing, have apparent viscosity 80 with 1% solution, 000cP to 120, (the sign value is 100 to 000cP, hydroxypropyl emthylcellulose 000cP).

Description of drawings

Fig. 1. method flow diagram.This figure has shown the manufacture method of selecting.

Fig. 2.Fast with the stripping curve that discharges at a slow speed.

Fig. 3.The compaction curve of row spit of fland, Victor MR 100mg sheet that contains the CSF preparation of 40%HPMC.

Fig. 4.The friability of row spit of fland, Victor MR 100mg sheet that contains the CSF preparation of 40%HPMC.

Fig. 5.Roll-in and hold the pressure time to 30%HPMC, the influence of 100mg sheet.Estimate 30%HPMC and improved compaction curve.Estimated the influence of holding the pressure time at speed tablet from 40 to 80rpm the time simultaneously.

Fig. 6.Roll-in is to the influence of 100mg sheet hardness.With the middle powder mixture that does not add magnesium stearate, when press power increases, Fitzpatrick (Chilsonator, model IR220) is estimated.

Fig. 7.Roll-in is to the influence of 150mg sheet hardness.With the middle powder mixture that does not add magnesium stearate, when compression force increases, Fitzpatrick (Chilsonator, model IR220) is estimated.

Fig. 8.Roll-in is to the influence of 100mgMR dissolution characteristic.Studied the influence of roll-in with 40%HPMC K100M, and compared with the dissolution characteristic of clinical lot number to dissolution characteristic.

Fig. 9.Roll-in is to the influence of 150mgMR dissolution characteristic.Studied the influence of roll-in with 40%HPMC K100M, and compared with the dissolution characteristic of clinical lot number to dissolution characteristic.

Figure 10.Use the influence of Bepex roll squeezer roll-in to row spit of fland, Victor 100mg sheet hardness.Studied the influence that increases compression force.

Figure 11.Use the influence of Bepex roll squeezer roll-in to row spit of fland, Victor 150mg sheet.Studied the influence that increases compression force.

Figure 12.Roll-in is to the influence of 100mg sheet.Fitzpatrick (Chilsonator.modelIR220) roll squeezer is in compression force influence to the mixture of powders that comprises 40%HPMC from 500 to 10000lb/in the time.

Figure 13.Roll-in is to the influence of 150mg sheet.Fitzpatrick (Chilsonator, modelIR220) roll squeezer is in compression force from 500 to 10, during 000lb/in to the influence of the mixture of powders that comprises 40%HPMC.

Figure 14.Roll-in is to the influence of 100mg sheet friability.The compaction curve of the tablet that roller pressure is produced during greater than 5000lb/in (or 43.75KN) does not have the poorer of roll-in or precompressed than CSF.

Figure 15.Roll-in is to the HPMC concentration and the influence of holding the pressure time of 100mg sheet.

Figure 16.Roll-in is to the HPMC concentration and the influence of holding the pressure time of 150mg sheet.

Figure 17.The stripping curve of 100mg sheet.

Figure 18.The stripping curve of 150mg sheet.

Figure 19.Roll-in is to the influence of screen analysis.

Figure 20.Roll-in is to the influence of screen analysis.

Detailed Description Of The Invention

Term

" DPP-IV inhibitor " means to suppress DPP-IV and (classified by IUBMB: the compound of enzymatic activity EC3.4.14.5). Compound may be peptidyl peptidyl or non-. As long as the DPP-IV inhibitor keeps it and suppresses active, use the form that enters before or after the live body can be different. In the name, the DPP-IV inhibitor can have DPP-IV to suppress active " active metabolite " after live body changes by the metabolism recurring structure. In addition, the DPP-IV inhibitor can be " prodrug " that becomes in vivo the activation form under the physiological condition by the reactions change of enzyme, hydrochloric acid in gastric juice etc. In addition, DPP-IV suppresses activity can be by utilizing, such as the people's such as Raymond method confirm (Diabetics, 1998,47:1253-1258).

The specific embodiment of DPP-IV inhibitor comprises

(1) following formula: compound of describing among the WO 02/062764:

(wherein encircle A and be can be substituted 5-to 10-unit aromatic ring; R¹And R²Can be identical or different separately and can be the alkyl that replaces, maybe may be the heterocyclic group that replaces; X be valence link ,-O-,-S-,-SO-,-SO₂-or-NR³-(R ³Be hydrogen atom or can substituted alkyl); And L is divalent hydrocarbyl mission).

The compound of formula (I) expression can be anhydrous or water substance and prodrug are arranged.

The suitable embodiment of the compound of formula (I) expression comprises following compound.

Compound I-a

Wherein encircling A is that 1 or 2 compound that is selected from the substituent phenyl ring of following group can be arranged:

1) cyano group;

2) can be respectively by the C of carbamoyl group or carboxylic group replacement_1-10Alkyl group (preferably, ethyl) or C_2-10Kiki alkenyl group (preferably, vinyl);

3) 1 to 3 alkoxycarbonyl groups that is selected from carbamoyl group, a carboxylic group and 2-5 C can be arranged (preferably, methoxycarbonyl) substituent can substituted hydroxyl (preferably, the alkoxy base of 1-10 C (preferably, methoxyl group, isopropoxy); Oh group; The aralkoxy group of 7-13 C (preferably, benzyloxy)) (more preferably carbamyl ylmethoxy);

4) carboxyl groups (preferably, C_1-6Alkyl-carbonyl (preferably acetyl group), carbamoyl, list-or two-(can there be 1 to 3 to be selected from halogen atom and C_1-6The substituent C of alkoxyl-carbonyl_1-6Alkyl)-carbamoyl (preferably, methylamino formoxyl, ethylamino formoxyl, propyl group carbamoyl, formyl-dimethylamino, trifluoroethyl carbamoyl, ethoxy carbonyl methylamino formoxyl etc.). C_3-10Cycloalkyl-carbamoyl (preferably, cyclopropylamino formoxyl), C_7-13Aralkyl-carbamoyl (preferably, benzyl carbamoyl), nitrogen heterocyclic ring-carbonyl (preferably, pyrrolidinyl carbonyl, piperidino carbonyl), the C that can be replaced by hydroxyl_1-6Alkyl sulphonyl (preferably, methyl sulphonyl), C_1-6Alkyl sulphinyl (preferably, methylsulfinyl), carboxyl, C_1-6Alkoxyl-carbonyl (preferably, methoxycarbonyl) and thiocarbamoyl);

5) can substituted amino (preferably, carbamoyl is amino);

6) sulfydryl (alkylthio group (being preferably methyl mercapto) of 1-10 the C that preferably, can be replaced by the carbamoyl group;

7) be respectively can substituted heterocyclic group (aromatic heterocycle group (preferably, furyl, thienyl,  azoles base,  di azoly, thiazolyl, tetrazole radical, pyridine radicals, pyrrole radicals, triazolyl) or the nonaromatic heterocycles group is (preferably, dioxo iso-indoles, 5-oxo  diazole-3-base, 5-oxothiaxialole-3-yl), it can have 1 or 2 substituting group that preferably is selected from following group: can be by the C of 1 to 3 halogen atom replacement_1-6The alkoxy carbonyl (preferably, ethoxy carbonyl) of alkyl group (preferably, methyl, trifluoromethyl), carboxylic group, a 2-8 C, cyano group, carbamoyl group, amino group, list-or two-C_2-10Alkanoylamino group (for example, the acetylamino isovaleryl is amino), C_1-10Alkoxyl-carbonylamino group (for example, methoxycarbonyl amino), carbamoyl amino group, list-or two-C_1-10Alkyl-carbamoyl amino group (for example, the methylamino formoxyl is amino, formyl-dimethylamino amino), C_6-14Aryl-carbonylamino group (for example, benzoyl-amido), C_3-10Cycloalkyl-carbonylamino group, C_7-13Alkoxy aryl-carbonylamino, dimethyl methyl acylamino-), single-or two-C_1-10The amino group of alkyl sulfonyl (for example, methyl sulphonyl amino, diethyl sulfonamido), C_6-14Arenesulfonyl amino group and C_1-6Alkoxyl-carbamoyl amino group (for example, the methoxyl group carbamoyl is amino);

8) 1 or 2 substituent phenyl ring that is selected from following group can be arranged: amidino groups; R¹The alkyl group (preferably, isobutyl group, neopentyl) of 4-10 C or the cycloalkyl-alkyl group (preferably, cyclopropyl methyl) of 4-10 C; R²To have 1 or 2 to be selected from halogen atom (preferably, fluorine, chlorine) and C_1-6The aromatic yl group (being preferably phenyl) of substituent 6-14 C of alkyl (being preferably methyl); X is valence link; And L is C_1-10Alkylidene (is preferably-CH₂-)。

Compound I-b

Its medium ring A can have 1 or 2 chemical compound that is selected from the substituent phenyl ring of following groups:

1) being respectively can be by the C of the alkoxycarbonyl groups of 2-8 C (preferably, ethoxy carbonyl) or the replacement of carbamoyl group _1-10Alkyl group (preferably, ethyl) or C _2-10Kiki alkenyl group (preferably, vinyl);

2) can substituted oh group (preferably, the alkoxyl of 1-10 C (preferred methoxyl group), alkoxyl can be replaced by carbamoyl; More preferably, carbamyl ylmethoxy);

3) carboxyl groups (preferably, carbamoyl, thiocarbamoyl, carboxyl);

4) can substituted heterocyclic group (the fragrant heterocyclic radical group (preferably, furyl, thienyl,  azoles base,  di azoly, thiazolyl, tetrazole radical, pyridine radicals, pyrrole radicals, triazolyl) or the nonaromatic heterocycles base is (preferably, 5-oxo  diazole-3-yl), it can have 1 or 2 substituent group that preferably is selected from following group: C _1-6The alkoxycarbonyl groups (preferably, ethoxy carbonyl) of alkyl (preferably, methyl), carboxylic group, a 2-8 C, cyano group, carbamoyl group, amino group, list-or two-C _2-10Alkanoylamino group (for example, acetylamino, isovaleryl amino), C _1-10Alkoxycarbonyl amino group (for example, methoxycarbonyl amino), carbamoyl amino group, list-or two-C _1-10Alkyl-carbamoyl amino group (for example, methylamino formoxyl amino, formyl-dimethylamino amino group), C _6-14Aryl-carbonylamino group (for example, benzoyl-amido), C _3-10Cycloalkyl-carbonylamino group (for example, methyl sulphonyl amino, dimethyl methyl acyl amino), C _6-14Arlysulfonylamino group and C _1-6Alkoxyl-carbamoyl amino group (for example, methoxyl group carbamoyl amino)); R ¹Be the alkyl group (preferably, isobutyl group, neopentyl) of 4-10 C or the cycloalkyl-alkyl group (preferably, cyclopropyl methyl) of 4-10 C; R ²Be can be by the alkyl group (preferably, butyl) of 1-10 C of 1 to 3 halogen atom replacement; X is-O-; And L is C _1-10Alkylidene (preferably-CH ₃-).

In the chemical compound of formula (I) expression, preferred especially 1-[2-[(5-is cyanopyridine-based-the 2-yl) amino] ethylamino] acetyl group-2-cyano group (S)-ketopyrrolidine; 1-[(3-hydroxyl-adamantyl-1-base is amino)-acetyl group]-pyrrolidine-2 (S)-nitrile; 2-[3-(amino methyl)-4-butoxy-2-isobutyl group-1-oxo-1,2-dihydro-6-isoquinolyl-1,3-thiazoles-4-nitrile; 2-[3-(amino methyl)-4-butoxy-2-isobutyl group-1-oxo-1,2-dihydro-6-isoquinolyl-1,3-thiazoles-4-formic acid; 2-[3-(amino methyl)-4-butoxy-2-isobutyl group-1-oxo-1,2-dihydro-6-isoquinolyl-1,3-thiazoles-4-Methanamide; 2-[3-(amino methyl)-4-butoxy-2-isobutyl group-1-oxo-1,2-dihydro-6-isoquinolyl]-1,3-thiazoles-4-Ethyl formate; (E) 3-[3-(amino methyl)-4-butoxy-2-isobutyl group-1-oxo-1,2-dihydro-6-isoquinolyl]-the 2-acrylamide; (E)-and 3-[3-(amino methyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl]-the 2-acrylamide; 3-(amino methyl)-2-isobutyl group-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolin Methanamide; 2-{[3-(amino methyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] the oxygen base } acetamide.

(2) chemical compound represented of following formula

(wherein f is 1 or 2; G is 0,1 or 2; X is-CH ₂-,-O-,-S-,-SO-,-SO ₂-or-NR ₃-(R ³Be hydrogen atom or C _1-6Alkyl group); R be hydrogen atom, cyano group ,-CHO ,-B (OH) ₂, P (O) (O-R ³), CC-R ⁴, or CH=N-R ⁵(R ⁴Be hydrogen atom, fluorine atom, C _1-6Alkyl group, cyano group, nitryl group ,-OR ³,-CO ₂R ³, or-COR ³(R ³Represent meaning same as above); R ⁵Be phenyl group, oh group ,-OR ³,-OCOR ³, or benzyloxy group (R ³Represent meaning same as above); And what A represented to be described in WO95/15309 etc. can substituted amino acid residue).

In formula, R ³The C of expression _1-6Alkyl group for example comprises, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, 1-ethyl propyl, hexyl, isohesyl, 1,1-dimethyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethyl-butyl etc.

Amino acid residue among " can substituted amino acid residue " who represents with A comprises forms α-or group of removing from these aminoacid of the hydroxyl of the carboxylic group of beta-amino acids.

The a-amino acid here for example comprises, alanine, arginine, asparagine, Aspartic Acid, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, betanin, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, ornithine, homocysteine etc.

Beta-amino acids for example comprises, Beta-alanine, beta-amino cyclopropionate, beta-amino ring butanoic acid, beta-amino chaulmoogric acid, beta-amino cyclohexylenedinitrilotetraacetic acid, beta-amino ring enanthic acid, beta-amino ring are sad.These beta-amino acids can have unsaturated bond in constituting amino acid whose carbochain.

Above-described α-and beta-amino acids can be any form of D-, L-and DL-type, the L-type of native form preferably.

Described amino acid residue can have 1 or 2 substituent group on the amino group of forming on aminoacid or the amino acid side chain.

Described " being substituted on the amino group " preferably includes can substituted alkyl and can substituted piperidyl.

Alkyl in " can substituted alkyl " for example comprises C _1-6Alkyl group, C _3-12Group of naphthene base, C _2-6Kiki alkenyl group, C _3-12Cycloalkenyl groups, C _2-6Kiki alkenyl group, C _4-12Cycloalkadienyl group, C _6-14Aromatic yl group (preferably, phenyl group), C _7-15Aromatic alkyl group (preferably, benzyl group, phenethyl group), adamantyl group, dicyclo [2,2,1] heptyl group, dicyclo [3,1,1] heptyl group etc.

Hydrocarbyl group can have 1 to 3 substituent group in commutable position, and such substituent group for example comprises halogen atom (preferably, fluorine, chlorine); Cyano group; The oh group that can be replaced by carboxyl groups; Methylol groups; Can be by the C of 1 to 3 halogen atom (being preferably fluorine) replacement _1-6Alkoxy base; Can be by can substituted C _6-14Aromatic yl group or can be substituted heterocyclic radical group list replace or dibasic amino group.

Herein, the carboxyl groups on " oh group that can be replaced by carboxyl groups " for example comprises, those that exemplify as the substituent group on the ring A at described Compound I-a.

" can substituted C _6-14Aromatic yl group " in C _6-14Aromatic yl group comprises for example phenyl or naphthyl.

Heterocyclic radical group in " can substituted heterocyclic radical group " for example comprises pyridine radicals group, pyrimidine radicals group, pyrazolyl (pyrazyl) group, quinolyl group, isoquinolyl group, quinoline  quinoline group etc.

C _6-14Aromatic yl group and heterocyclic radical group can have 1 to 3 substituent group and these substituent groups for example to comprise in substituted position, halogen atom (preferably, fluorine, chlorine, bromine); Cyano group; Nitryl group; C _1-6Alkyl group; Can be by the C of 1 to 3 halogen atom (being preferably fluorine) replacement _1-6Alkoxy base; Carboxylic group; The carbamoyl group; C _1-6Alkyl sulphonyl group (preferably, methane sulfonyl group); Can be by C _1-6The alkyl group list replaces or dibasic amino-sulfonyl group (preferably dimethylamino sulfonyl group).

Particularly preferred substituent group in described " can substituted hydrocarbyl group " is 5-nitro-2-pyridinylamino group, 5-cyano group-2-pyridinylamino group, 2-pyrimidinyl-amino group, 2-pyrazolyl amino group etc.

Substituent group in described " can substituted piperidyl group " for example comprises C _1-6Alkyl group; Methylol groups, described " by can substituted C _6-14Aromatic yl group or can be substituted heterocyclic radical group list replace or dibasic amino group " in can lift into illustration " can substituted C _6-14Aromatic yl group " and " can substituted heterocyclic radical group ".Substituent number is for example 1 to 3.

Described " substituent group on the amino acid side chain " for example comprise, can substituted hydrocarbyl group, oh group, the C that can be replaced by 1 to 3 halogen atom (being preferably fluorine) _1-10Alkoxy base, carboxyl groups and can substituted amino group etc.

Herein, the alkyl in described " can substituted alkyl " for example comprises C _1-10Alkyl group, C _3-12Group of naphthene base, C _2-10Kiki alkenyl group, C _3-12Cycloalkenyl groups etc.

Hydrocarbyl group can have 1 to 3 substituent group in substituted position, and these substituent groups for example comprise amino group, C _1-6Alkyl-carbonylamino group (preferably, acetylamino group), oh group, C _1-6Alkoxy base, heterocyclic radical group (preferably, pyridine radicals group) etc.

Described " carboxyl groups " is that be preferably can substituted nitrogen heterocyclic ring-carbonyl group." can substituted nitrogen heterocyclic ring " comprises having 1 to 3 substituent nitrogen heterocyclic ring (to be preferably, pyridine, pyridazine, pyrimidine, pyrazine, imidazoles, pyrazoles, thiazole, isothiazole,  azoles, different  azoles, etc.), substituent group is selected from following group, for example, halogen atom (being preferably fluorine, chlorine, bromine), cyano group, nitryl group, the C that can be replaced by 1 to 3 halogen atom (being preferably fluorine) _1-6Alkyl group (for example, trifluoromethyl group), C _1-6Alkoxy base, can be by C _1-6The alkyl group list replaces or dibasic amino group, oh group, carboxylic group and C _1-6Alkyl-oxygen base carbonyl group.

The substituent group of described " can substituted amino group " comprises the substituent C that can have 1 to 3 to be selected from following group _1-6Alkyl group etc., for example carboxylic group, carbamoyl group, C _1-6Alkyl-oxygen base carbonyl group and nitrogen heterocyclic ring group (being preferably pyridine radicals).These substituent groups can with the couplings such as amino group on oh group, carboxylic group and the amino acid side chain.

By the suitable example of the chemical compound of formula (II) expression comprise N-(N '-substituted glycyl base)-2-cyano group-pyrrolidinyl derivant such as: (2s)-1-{{{2-[5-is cyanopyridine-based-the 2-yl] amino ethyl amino acetyl group-2-cyano group-pyrrolidinyl (DPP-728) (being described among the WO98/19998), it is expressed from the next:

(2S)-and 1-{[(3-hydroxyl-1-adamantyl) amino]-acetyl group }-2-cyano group-pyrrolidine (1-[(3-hydroxyl-1-adamantyl-1-base is amino)-acetyl group]-pyrrolidine-2 (s)-nitrile (also being called LAF237 or row spit of fland, Victor) (being described in WO00/32421), it is expressed from the next:

(2s)-and 1-{{{2-[(pyrimidine-2-base piperidin-4-yl) amino]-acetyl group-2-cyano group-pyrrolidine (being described among the WO02/30890).

(2s)-and 1-{{{2-[(pyridine-2-yl) amino] ethyl } amino } acetyl group }-2-cyano group-pyrrolidine and (s)-1-{1-[5-(N, N '-dimethylamino sulfonyl)-2-pyridinylamino]-2-methyl-propyl group amino } acetyl group-2-pyrrolidine nitrile (K-361) (being described in WO02/51836); Thiazoline or pyrrolidin derivatives such as L-Soviet Union-isoleucyl-thiazoline (P32/98), L-not-the isoleucyl-thiazoline; L-Soviet Union-isoleucyl-pyrrolidine; L-not-isoleucyl-pyrrolidine and L-Val-Pyr (being described in WO01/72290), it is expressed from the next

(3) N-that is described in WO01/55105 replaces 2-cyanopyrrole and 2-Cyanopyrolidine derivatives.Preferably (S, S)-1-(2-amino-3,3-dimethyl butyrate acyl group)-2,5-dihydro-1H-pyrroles-2-nitrile.(4) be described in the heterocyclic compound of WO02/02560.Preferably, 7-benzyl-8-[6-methylol]-1,4-phenodiazine -1-yl]-1,3-dimethyl-3,7-dihydro purine-2,6-diketone.

(5) be described among the WO01/68603 and the pyrrolidin derivatives cyclopropane condensed ring.Preferably (1S, 3S, 5S)-2-[(2S)-and 2-amino-3,3-dimethyl butyrate acyl group]-3-cyano group-2-azabicyclo [3,1,0] hexane.

(6) be described in proline derivative among the WO02/14271.(2s)-1-[(2S preferably, 4S)-4-(3-chloro-4-cyano-phenyl) amino-2-pyrrolidinyl carbonyl]-the 2-Cyanopyrolidine.

(7) be described in the Cyanopyrolidine derivatives of WO02/38451.Preferred (2S; 4S)-1-[(2S; 3S)-2-amino-3-methyl-valeryl]-2-cyano-4-fluoropyrrolidine, (2S; 4S)-2-cyano group-4-fluoro-1-[(1-methylol)-ring penta amino] acetyl-pyrrolidine; (2S, 4S)-2-cyano group-4-fluoro-1-[(1-hydroxyl-3-adamantyl amino] acetyl-pyrrolidine.

(8) such as being described in WO 02/02560, WO 03/055881, WO 03/040174, WO03/037327, WO 03/035057, WO 03/035067, WO 03/024942, WO 03/024965, WO 03/004498, WO 03/004496, WO 03/000250, WO 03/002530, WO03/002531, WO 03/002553, WO 03/000180, WO 03/000181, EP 1258476, WO 02/51836, WO 02/68420, US 6, the chemical compound of the P93/01 of 432,969 grades.

(9) another preferred DPP-4 inhibitor is to be disclosed in WO2001068603 or U.S. Patent No. 6395767 (chemical compound of embodiment 60) compd B MS-477118, also be called (1S, 3S, 5S)-2-[(2S)-2-amino-2-{3-hydroxyl three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl }-the 1-oxoethyl]-2-azabicyclo [3.1.0] hexane-3-nitrile, the benzoate of describing as the formula M in the patent application WO2004/052850 page 2 (1: 1), with corresponding free alkali, (the 1S that describes as the formula M in the patent application WO2004/052850 page 3,3S, 5S)-2-[(2S)-2-amino-2-{3-hydroxyl-three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems-the 1-yl }-the 1-oxoethyl]-2-azabicyclo-[3.1.0] hexane-3-nitrile (M ') and monohydrate (M ").Compd B MS-477118 also is known as saxagliptin.

(10) another preferred inhibitors be the chemical compound GSK23A that is disclosed in WO03/002531 (embodiment 9) also be called (2S, 4S)-1-((2R)-2-amino-3-[(4-methoxy-benzyl) sulfonyl]-3-methylbutyryl base)-4-fluoropyrrolidine-2-nitrile hydrochlorate.

(11) other preferred DPP-IV inhibitor are described among the patent application WO03/004498, and particularly embodiment 1 to 33, and embodiment 7 described most preferred following formula: compound, and also are known as MK-0431 or sitagliptin (Sitagliptin) (INN).

(12) other preferred DPP-IV inhibitor are described in patent application WO2004/037169, particularly those are described in embodiment 1 to 48 and WO02/062764 particularly describe among the embodiment 1 to 293 those, chemical compound 3-(amino methyl)-2-isobutyl group-1-oxo-4-phenyl-1 more preferably, 2-dihydro-6-isoquinolin Methanamide and be described among the 7th page and the patent application WO2004/024184 the particularly 2-{[3-amino methyl in reference embodiment 1 to 4]-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl } the oxygen base acetamide.

The specific embodiment of hydroxypropyl emthylcellulose comprises beautiful how elegant SB-4 (trade name, ShinetsuChemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 4mPas), TC-5RW (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 6mPas), TC-5S (trade name, ShinetsuChemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 15mPas), beautiful how elegant 60SH-50 (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (the viscosity under 20 ℃: about 50mPas), beautiful how elegant 65SH-50 (trade name, ShinetsuChemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 50mPas), beautiful how elegant 90SH-100 (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 100mPas), beautiful how elegant 90SH-100SR (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 100mPas), beautiful how elegant 65SH-400 (trade name, ShinetsuChemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 400mPas), beautiful how elegant 65SH-1500 (trade name, Shinetsu Chemical Industry Co.Ltd produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 1500mPas), beautiful how elegant 65SH-4000 (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 1000mPas), beautiful how elegant 65SH-1000 (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 1000mPas), beautiful how elegant 90SH-1000 (trade name, Shinetsu Chemical IndustryCo.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 4000mPas), beautiful how elegant 90SH-1000SR (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 4000mPas), beautiful how elegant 90SH-30000 (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 30000mPas), beautiful how elegant 90SH-100000 (trade name, Shinetsu ChemicalIndustry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 100000mPas), beautiful how elegant 90SH-100000SR (trade name, Shinetsu Chemical Industry Co.Ltd. produces) (2% (weight) viscosity in aqueous solution under 20 ℃: about 100000mPas).

" slow releasing preparation " of this paper or " accent release formulation " mean wherein when second method (oar method) of elution test method uses the suitable testing liquid of 900mL to test in Japanese Pharmacopoeia " elution rate during 30min after medicine is beginning to test " and are lower than 85% preparation, and wherein suitable testing liquid is that medicine 100% eluting in preparation enters testing liquid and is lower than 1/3 medicine saturation solubility.Equally, use traditional testing liquid in the technical field of pharmaceuticals, for example, water, buffer solution etc." preparation " means pharmaceutical preparation or unit dosage form for example tablet, granule.

In addition, in this manual, in carrying out Japanese Pharmacopoeia second method of elution test method (oar method) to above similar condition under during 30min after beginning to test wherein medicament elution speed be not less than 85% pharmaceutical preparation and be meant quick releasing formulation.

Dosage form of this slow releasing preparation or unit dosage forms for example comprise that oral formulations is tablet, capsule (comprising microcapsule), granule or powder for example; With parenteral administration suppository (for example, rectal suppository, vaginal suppository, etc.) and those form of dosage forms for oral administration or parenteral administration safely respectively for example.In these dosage forms, oral formulations for example tablet, capsule or granule is preferred.

Slow releasing preparation of the present invention can be by mixing DPP-IV inhibitor and hydrophilic polymer and molded production.Herein, mix and moldedly carry out according to the ethnopharmacology method.Equally, when carrying out described mixing and when molded, can using pharmaceutically acceptable carrier.

Herein, pharmaceutically acceptable carrier comprises traditional organic or inorganic carrier mass of different model, for example, excipient, polishing agent, binding agent, disintegrating agent, etc. as the host material of preparation.Moreover additives such as the additive of preparation such as antiseptic, antioxidant, coloring agent and sweeting agent also can use when needed.

When the DPP-IV inhibitor that is used for slow releasing preparation of the present invention is alkalescence, can add the eluting behavior that organic acid is regulated slow releasing preparation.Usually because the dissolubility of alkalescent medicine under acid condition than big under the neutrallty condition, the medicament elution from slow releasing preparation can change with pH on every side.In this case, medicament elution character can reduce owing to organic acid uses based on the variation of pH on every side.Because the pH of human body can change because of each patient, it is considerable obtaining consistent drug influence based on reducing of changing of the medicament elution of pH on every side for different patients.

Organic acid for example comprises, citric acid, tartaric acid, ascorbic acid, malic acid, fumaric acid, malonic acid, succinic acid, maleic acid, Aspartic Acid, glutamic acid, etc.In these acid, citric acid, tartaric acid, ascorbic acid, etc. be preferred.

Slow releasing preparation of the present invention has lower toxicity and less side effect, and correspondingly it can be used as the prevention of various diseases and curative uses for mammal (for example, people, cattle, horse, Canis familiaris L., cat, monkey, mice and rat).

Slow releasing preparation of the present invention can be used as prevention and curative, for example, for (for example such as diabetes, type 1 diabetes, type 2 diabetes mellitus, gestational diabetes mellitus), hyperlipemia (for example, HTC, hypercholesterolemia, the low HDL mass formed by blood stasis, hyperlipemia after the meal), arteriosclerosis, glucose tolerance reduces (IGT), impaired fasting glucose (IFG) (IFG), fasting glucose higher (IFG), and diabetic complication (for example, neuropathy, nephropathy, retinopathy, cataract, the trunk vascular lesion, the bone amount reduces, diabetic hyperosmolar coma, infectious disease (for example, respiratory tract infection, urinary tract infection, digestive system infection, skin soft-tissue infection, lower limb infect), diabetic gangrene, xerostomia, auditory dysesthesia, cerebrovascular, the peripheral circulation obstacle), and as the medicine of blood sugar lowering etc.

Slow releasing preparation of the present invention can prevent that tolerance is unusual, impaired fasting glucose (IFG) (IFG) or fasting glucose higher (IFG) develop into diabetes.

In addition, slow releasing preparation of the present invention can be used for improving pancreas (beta cell) function, pancreas (beta cell) regeneration, pancreas (beta cell) regeneration acceleration etc.

Because the DPP-IV inhibitor is the medicine that quickens the insulin secretion of glucose dependence, present the selectivity acceleration in there being hyperglycemic patients (for example, blood glucose value is not less than the patient of 126mg/dL on an empty stomach, or the blood glucose value behind the oral 75g glucose tolerance test 2h is not less than the patient of 140mg/dL (75g OGTT)) insulin secretion.Slow releasing preparation of the present invention is as the prevention of diabetes safety and the curative adverse effect to insulin---and inducing etc. of vascular complication, hypoglycemia has lower risk.

But the dosage of slow releasing preparation of the present invention is different because of individuality, route of administration, target disease etc., for example for being applied to the maturity-onset diabetes patient, the single dose of active component DPP-IV inhibitor should be about 0.01-100mg/kg body weight usually, preferred 0.05-30mg/kg body weight, be the 0.1-10mg/kg body weight more preferably, and be desirably and use once or twice every day.Preferably, slow releasing preparation should be used to continue to obtain the DPP-IV inhibitory action during the 2h (being preferably 4h after the meal) at least extremely after the meal before the meal in live body.

The release duration of the slow releasing preparation of this DPP-IV inhibitor in live body should be preferably 1 to 24h; More preferably be 2 to 14h.

Usually, when using the DPP-IV inhibitor to be used for prevention or treatment diabetes, need take the DPP-IV inhibitor whenever before the meal, because the substrate GLP-1 of DPP-IV is excretory when food absorption.But, because slow releasing preparation of the present invention can be at the long-time DPP-IV inhibitor that discharges, itself in addition when taking one time every day, still present sufficient DPP-IV inhibitory action.

Slow releasing preparation of the present invention can be used for using (hereinafter middle finger drug combination) for example curative, antihyperlipidemic, inhibitor and appetrol, diuretic and antithrombotic of treatment of diabetes medicine, diabetic complication with drug regimen.In this case, the administration time of the medicine of slow releasing preparation of the present invention and merging use is unrestricted.Therefore, these medicines can be applied to individuality simultaneously, or are applied to individuality respectively in the different time.Moreover slow releasing preparation of the present invention and the medicine that merge to use can be used as two kinds of preparations that every kind of preparation comprises a kind of active component and use, or use with a kind of preparation that comprises two kinds of active component.

The dosage that merges medicine can suitably be selected based on the dosage of clinical use.The ratio of slow releasing preparation of the present invention and drug combination can suitably be selected based on individuality, route of administration, target disease, symptom, combination etc.For example, when individuality is a man-hour, can use the weight that merges medicine for based on weight 0.01-100 part (by weight) of the active component DPP-IV inhibitor of slow releasing preparation than 1 part (by weight).

Described medicine for treating diabetes (antidiabetic drug) for example comprises, insulin preparation (for example, the animal insulin preparation that is extracted by cattle or Pancreas Sus domestica; The synthetic human insulin preparation of genetic engineering E.coli or yeast; Zinc insulin, insulin zinc protamine; Insulin fragment or derivant are (for example, INS-1, Deng)), glucagon (is for example improved medicine, the hydrochloric acid pioglitazone, Lociglytazone (maleate), GI-262570, Reglixane (JTT-501), Netoglitazone (MCC-555), YM-440, KRP-297, CS-011, FK-614, Ragaglitazar (NN-622), Tesaglitazar (AZ-242), DMS-298585, EML-16336, the chemical compound of describing among the WO99/58510 (for example, (E)-4-[4-(5-methyl-2-phenyl-4- azoles ylmethoxy) benzyloxy imino group]-the 4-phenylbutyric acid)), the PPAR gamma agonist, PPAR γ antagonist, PPAR γ/α dual agonists, alpha-glucosidase inhibitor (for example, voglibose, acarbose, miglitol, Emiglytate), biguanides (for example, phenformin, metformin, Buformine or its salt) (for example, hydrochlorate, fumarate, succinate)), (sulfonylureas (for example for insulin secretion stimulators, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole etc.), repaglinide, senaglinide, Nateglinide, Mitiglinide or its calcium salt hydrate), GLP-1 receptor stimulating agent (GLP-1 for example, NN-2211, AC-2993 (exedin-4), BIM-51077, Alb (8,35) h GLP-1 (7,37) NH2), the amyline agonist (for example, Plamlintide, phosphotyrosine phosphatase inhibitor (for example vanadic acid), β 3 agonist (for example, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140), novel sugared inhibitor (for example, glycogen phosphorylase inhibitor, the G-6-Pase inhibitor, glucagon antagonist, somatostatin receptor agonist), white (SGLT) inhibitor (for example T-1095) of sodium glucose co-transporter 2 etc.

The diabetic complication curative comprises that aldose reductase inhibitor (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (Phydarestat), SNK-860, CT-1 12), neurotrophic factor and dose thereof (NGF for example, NT-3, BDNF, being described in WO01/14372) neurotrophic factor production/secernent is (for example, 4-(4-chlorphenyl)-2-(2-methyl isophthalic acid-imidazole radicals)-5-[3-(2-methylphenoxy) propyl group] the  azoles etc.)), be described in WO01/14372), ACE inhibitor (ALT946 for example, pimagedine, N-phenylacetyl thiazole bromide (ALT766), (EXO-226), active oxygen-the crasing agent (for example, thioctic acid), cerebral vasodilator (for example, Tai Bili, mexiletine).

The statin compound that antihyperlipidemic comprises cholesterol synthetic inhibitor (for example; cerivastatin; pravastatin; simvastatin; rosuvastatin (Rovastatin); atorvastatin; Fluevastatin; itavastatin; or its salt (for example sodium salt)); inhibitor for squalene synthetic enzyme (for example; the chemical compound of describing among the WO 97/10224; for example; N-[[(3R; 5S)-1-(3-acetoxyl group-2; the 2-dimethyl propyl)-7-chloro-5-(2; 3-Dimethoxyphenyl-2-oxo-1; 2; 3; 5-tetrahydrochysene-4; 1-benzo  azepine -3-yl) acetyl group] piperidines-4-azetic acid etc.); fibrate (for example; bezafibrate; chlorine Bei Te; simfibrate; clinofibrate); the ACAT inhibitor (for example; avasimibe; Eflucimibe); anion exchange resin (for example cholestyramine); probucol; nicotinic acid class medicine (for example, nicomol; niceritrol); ethyl icosapentoate; plant sterol (Generol 122); gamma oryzanol; Deng.

Depressor comprises that angiotensin converting enzyme inhibitor (for example, captopril, enalapril, delapril), the Angiotensin II antagonist (for example, Candesartan, ring heptan plug, losartan, eprosartan, valsartan, telmisartan, irbesartan, Tasosartan), calcium antagonist (for example, Manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channels opening medicine (for example, levcromakalim, L-27152, AL671, NIP-121), clonidine etc.

Appetrol comprise, for example, maincenter appetrol (for example, Dexphenfluramine, Phenfluramine, Phentelmine, sibutramine, Anfepramone, Dexanfetamine, mazindol, phenylpropanolamine, Kobenzorex, pancreatic lipase inhibitor (for example orlistat), (for example CL 316243 for β 3 agonist, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140), peptide class fenisorex (Leptin for example, the ciliary nerves cytotrophy factor (CNTF)), cholecystokinin agonist (for example FPL-15849)) etc.

Diuretic for example comprises, xanthine derivative (theobromine sodium salicylate for example, diucalcin), the thiazide preparation (for example, ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, many thiazines, methichlothiazide), the aldosterone antagonist preparation (for example, spylonoacetone, trimetellen), carbonic anhydrase inhibitors (for example, acetazolamide), chlorbenzenesufonamide preparation (for example, chlortalidone, meflucide, indapamide), azocernide, isosorbide, etacrynic acid, pyrcladnide, bromethanide, flocemide etc.

Antithrombotic drug comprises that for example heparin (for example, heparin sodium, calciparine, dalteparin sodium), warfarin (for example, potassium warfarin), the antifibrin-ferment medicine (for example, argatroban), thrombolytics (for example, urokinase, Tisokinase, alteplase, Nateplase, Monteplase, pamiteplase), platelet aggregation inhibitor (for example, flolopidine hydrochlorate, cilostazol, ethylicosapentoate, Beraprost Sodium, sarpogrelate hydrochloride) etc.

Preferably insulin preparation, glucagon are improved medicine, alpha-glucosidase inhibitor, biguanides, insulin secretion stimulators (being preferably sulfonylurea drugs) etc. to the medicine of merging usefulness.

Moreover, the present invention relates to " contain the combination of the DPP-IV inhibitor of the preparation of two or more DPP-IV inhibitor and different rates of release.”。

Herein, " preparation that contains the DPP-IV inhibitor " may be the preparation of any DPP-IV of containing inhibitor, no matter be slow releasing preparation or quick releasing formulation.In addition, the release control mechanism of DPP-IV inhibitor in " preparation that contains the DPP-IV inhibitor " is without particular limitation, and preparation can be the preparation of any release DPP-IV inhibitor; Follow the degraded of preparation by passive diffusion; By response to pH variation on every side; By causing the inner swollen internal pressure of preparation owing to absorb water on every side; By the disintegrate of preparation or the rapid release of stripping etc.

Herein, " preparation that discharges the DPP-IV inhibitor by passive diffusion " for example comprises, slow releasing preparation of the present invention, (preferably, the matrix tablet of use hydrophilic polymer (for example, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, and polyethyleneoxixde), the matrix tablet of use lipophilic groups material (for example, Brazil wax, castor oil hydrogenated, hydrogenated rapeseed oil, polyglyceryl fatty acid ester), with the tablet of sustained-release matrix material coating or granule (for example, cellulosic polymer is ethyl cellulose for example, acrylate copolymer is aminoalkyl methacrylate copolymer RS (acrylic resin RS (trade name for example, Rohm Pharma Co.Ltd. produces), ethyl propylene acid esters-methacrylate copolymer suspension (acrylic resin NE (trade name, Rohm Pharma Co.Ltd. produces) etc.

" from preparation, discharge the preparation of DPP-IV inhibitor by the degraded of preparation " and for example comprise, contain the capsule of polyethyleneglycol glyceride (for example, Gelucire10/13 (trade name, GATTEFOSSE Co.Ltd. produces)) etc.

" pH changes the preparation that discharges the DPP-IV inhibitor around the response " for example comprises, (acrylate copolymer is methacrylic acid copolymer (acrylic resin L (trade name for example with the tablet of enteric solubility host material coating or granule, Rohm Pharma Co.Ltd. production)), methacrylic acid copolymer LD (acrylic resin L-30D55 (trade name, Rohm Pharma Co.Ltd. produces)), methacrylic acid copolymer S (acrylic resin S (trade name, Rohm Pharma Co.Ltd. produces)) etc.

" by discharging the preparation of DPP-IV inhibitor because the water around absorbing causes the inner swollen internal pressure of preparation " comprises for example osmotic pump system, that is, and and Concerta ^TM(Alza Co.Ltd., FortWashington, PA) etc.

" preparation that disintegrate or the stripping by preparation immediately discharges the DPP-IV inhibitor " for example comprises, mixes those preparations of molded acquisition then with pharmaceutically suitable carrier by the DPP-IV inhibitor.Herein, pharmaceutically suitable carrier comprises the carrier that those are similar to slow releasing preparation of the present invention.Equally, mix with molded can be according to the conventional medicament technology implementation.

The release control mechanism of forming " preparations of two or more DPP-IV inhibitor " of medicine of the present invention can be mutually the same or different." two or more comprise the preparation of DPP-IV inhibitor " can be unitary agent or a plurality of preparation independent of each other.Single preparation comprises the single capsule that contains two or more preparations that contain the DPP-IV inhibitor; Multilayer tablet (being preferably double-layer tablet) or multiple release control section arranged nuclear sheet etc. arranged.

Of the present invention medicine should be preferably by the slow releasing preparation that contains the DPP-IV inhibitor with contain the constituting of quick releasing formulation of DPP-IV inhibitor, and by taking this combination, outstanding DPP-IV inhibitory action can obtain after using and for a long time immediately.

The content that contains DPP-IV inhibitor in the slow releasing preparation of DPP-IV inhibitor can change with the type of DPP-IV inhibitor, amount of formulation etc., and content is the weight of for example 20-30%, preferably 25-35% weight and 25% weight ideally.

The dosage form that contains the preparation of DPP-IV inhibitor is similar to those dosage forms of slow releasing preparation of the present invention.

Medicine of the present invention has lower toxicity and less side effect, correspondingly can be applied to prevention and the curative of mammal (for example, people, cattle, horse, Canis familiaris L., cat, monkey, mice and rat) as the various diseases similar to described slow releasing preparation of the present invention.

Two or more preparations that the dosage of of the present invention medicine can comprise the DPP-IV inhibitor when using merge.Such dosage form for example comprises, 1) uses with the single preparation of two or more preparations of comprising the DPP-IV inhibitor, 2) use 3 simultaneously with two or more a plurality of preparations that comprise the DPP-IV inhibitor) two or more a plurality of preparation different times that comprise the DPP-IV inhibitor use etc.

The dosage of of the present invention medicine according to individuality, route of administration, target disease, etc. and different, when oral when being administered to the maturity-onset diabetes patient, for example, the dosage of common DPP-IV inhibitor, active component should be about 0.01-100mg/kg body weight, preferably the 0.5mg/kg body weight more preferably is the 1-10mg/kg body weight, and this tittle should be ideally once-a-day or administered twice.Preferably, medicine of the present invention should use with in live body from before the meal to being preferably the effect that continued to obtain the DPP-IV inhibitor in 4 hours after the meal at least 2 hours after the meal.

Of the present invention medicine can be similar to the situation of slow releasing preparation of the present invention medicine merge together and use.

The invention further relates to " the sustained release preparation that contains the DPP-IV inhibitor; can after using 1h, reduce the DPP-IV activity 10 to 90% (preferred 10 to 85%) in the blood plasma ", " the sustained release preparation that contains the DPP-IV inhibitor; can after using 8h, reduce the DPP-IV activity 10 to 90% (preferred 10 to 85%) in the blood plasma ", " the sustained release preparation that contains the DPP-IV inhibitor; can after using 12h, reduce the DPP-IV activity 10 to 90% (preferably; 10 to 85%) in the blood plasma ", " the sustained release preparation that contains the DPP-IV inhibitor; can reduce DPP-IV activity 10 to 90% in the blood plasma (preferably; after using 1 to 8h during 10 to 85%) ", " the sustained release preparation that contains the DPP-IV inhibitor, can be after using 1 to 12h during reduce DPP-IV activity 10 to 90% (preferred 10 to 85%) in the blood plasma " etc.

Herein, the blood plasma in " the DPP-IV activity in the blood plasma " is meant peripheral vein blood plasma.Although DPP-IV activity and fall off rate thereof can (for example change with the type of blood plasma, vein, tremulous pulse or portal vein blood plasma), as long as they can reduce the active 10-90% (being preferably 10-85%) of DPP-IV in the peripheral vein blood plasma, any sustained release preparation all belongs to " the sustained release preparation that comprises the DPP-IV inhibitor " of the present invention.

The sustained release preparation of the DPP-IV of comprising inhibitor of the present invention can reduce the active 10-90% of DPP-IV in the blood plasma, is preferably 10-85%, more preferably 10-80%, most preferably 15-75%.

DPP-IV activity in the blood plasma can be measured according to for example " people's such as Raymond method, diabetes, Vol.47, p.1253-1258,1998 ".As long as the active fall off rate of the DPP-IV in the described blood plasma is within nominal error, they may different with described numerical value (10,15,75,80,85,90%).Moreover the active fall off rate of the DPP-IV in the blood plasma may be different and different according to the active method of measuring in the blood plasma of DPP-IV.For example, if condition determination for example in substrate type, concentration of substrate, response time, diluted plasma multiple and the blood plasma activity of DPP-IV etc. different with the method for above document description, then the active fall off rate of the DPP-IV in the blood plasma may be greater than those numerical value described above, for example, 90% numerical value may surpass 95%.

In the preparation that comprises DPP-IV inhibitor of the present invention, the release that " the sustained release preparation that contains the DPP-IV inhibitor " of the present invention is wherein DPP-IV inhibitor is can controlled preparation.

The slow releasing preparation that such preparation is preferably invented.Equally, in the medicine of the present invention, " by the medicine of the slow releasing preparation that comprises the DPP-IV inhibitor with the combination of the quick releasing formulation that comprises the DPP-IV inhibitor " is preferred.

The sustained release preparation of the DPP-IV of containing inhibitor of the present invention has lower toxicity and less side effect, therefore can be applied to the prevention and the curative of mammal (for example, people, cattle, horse, Canis familiaris L., cat, monkey, mice and rat) as the various diseases similar to slow releasing preparation of the present invention.

The dosage that contains the controlled release preparation of DPP-IV inhibitor of the present invention can be different with individuality, route of administration, target disease etc., when oral when being applied to the maturity-onset diabetes patient, for example, the dosage of common active component DPP-IV inhibitor should be about 0.01-100mg/kg body weight, be preferably the 0.05-30mg/kg body weight, more preferably be the 0.1-10mg/kg body weight, and once-a-day administration or twice ideally.Preferably, the sustained release preparation that contains DPP-IV inhibitor of the present invention should be used so that the effect of DPP-IV inhibitor in live body is from obtaining to 2h (being preferably 4h after the meal) is lasting at least after the meal before the meal.

The controlled release preparation that contains DPP-IV inhibitor of the present invention can merge use with the medicine that accompanies under the situation of slow releasing preparation of the present invention.

The specific embodiment of microcrystalline Cellulose for example comprise Avicel  PH102 and 101 (FMCBiopolymer, Philadelphia, PA).

The specific embodiment of magnesium stearate for example comprise Synpro  magnesium stearate NF-plant level (FerroCorp., Walton Hills, OH).

The specific embodiment of lactose comprises for example lactose DT and lactose SD.

In addition, tablet often comprise adding with the weight that increases mixed-powder to obtain operating the diluent or the filler of the size that is used for tabletting.Can select a kind of, two or more diluent and/or filler.The example of pharmaceutically acceptable filler and pharmaceutically acceptable diluent includes but not limited to sugar, compressibility sugar, dextrates, dextrin, glucose, lactose, mannitol, microcrystalline Cellulose, cellulose powder, sorbitol, sucrose and the Pulvis Talci of confection.Filler and/or diluent, for example the amount that can exist is about 15% to about 50% or about 15% to about 45% of a composition weight.Most preferably the above compositions comprises one or both and is selected from the filler of microcrystalline Cellulose such as Avicel PH 102 and lactose.

Usually adding lubricant is for preventing tabletting material sticking, minimise friction being removed from mould with the tablet that allows compacting.Such lubricant normally is included in amount common in the final tablet mixture to be about 1% or to be less than 1% weight.The lubricant composition can be hydrophobic or hydrophilic.The example of such lubricant composition comprises stearic acid, Pulvis Talci and magnesium stearate.Magnesium stearate is in the friction that has reduced during tabletting and the shell fragment between die wall and the tablet mixture.It can help prevent tablet and dash and the adhesion of mould.But magnesium stearate is the flow of powder in the auxiliaring bucket and entering in the mould also.Particle size range is 450-550 μ m, and density range is 1.00-1.80g/mL.It is stable and does not assemble in press sheet mixture inside.Preferred magnesium stearate lubricant also can be used in the preparation.Preferably, lubricant is present in the amount from about 0.25% to about 6% in the tablet formulation; Equally preferably about 0.5% to about 4% weight level; And most preferred from 0.1% to about 1% weight.Other possible lubricants comprise Pulvis Talci, Polyethylene Glycol, silica gel and hardened vegetable oils.In optional embodiments of the present invention, lubricant is not present in the preparation, but is sprayed on mould or rushes to face rather than directly be added in the preparation.

The present invention describes in detail in following test details, the invention is not restricted to these embodiment and purposes of the present invention and only can change otherwise exceed this scope.

Embodiment of the present invention

The invention provides for example every drug tablet formulation (formulation C) that comprises following composition of each unit dosage forms:

(a) the DPP-IV inhibitor is preferably row spit of fland, Victor, or its officinal salt is as active component,

(b) apparent viscosity when being present in 1% solution is the hydroxypropyl emthylcellulose of 80000cP to 120000cP (the sign value is 100000cP),

(c) reach optional filler and/or lubricant.

The invention provides for example every drug tablet formulation (preparation D) that comprises following composition of each unit dosage forms:

(a) 10-50% is preferably the weight of 15-35%, is preferably the dry weight of row spit of fland, Victor or its officinal salt based on the DPP-IV inhibitor as active component,

(b) 20-60% is preferably the weight of 30-50%, is the dry weight of the hydroxypropyl emthylcellulose of 80000cP to 120000cP (the sign value is 100000cP) based on the apparent viscosity when being present in 1% solution,

(c) and optional filler and/or lubricant.

The invention provides for example every drug tablet formulation (preparation E) that comprises following composition of each unit dosage forms:

(c) filler; With

(d) lubricant.

The invention provides for example every drug tablet formulation (preparation F) that comprises following composition of each unit dosage forms:

(c) 15-55% is preferably the weight of 25-45%, based on the dry weight of pharmaceutically acceptable filler; And it is optional

(d) 0.1-10% is preferably the weight of 0.1-3%, based on the dry weight of pharmaceutically acceptable lubricant.

The invention provides for example every drug tablet formulation (preparation G) that comprises following composition of each unit dosage forms:

(b) 20-60% is preferably the weight of 30-50%, is the dry weight of the hydroxypropyl emthylcellulose of 80000cP to 120000cP (the sign value is 100000cP) based on the apparent viscosity when being present in 1% solution;

(c) 15-55% is preferably the weight of 25-45%, to be selected from one or both pharmaceutically acceptable filler dry weights of lactose and microcrystalline Cellulose; And it is optional

(d) 0.1-10% is preferably the weight of 0.1-3%, based on the pharmaceutically acceptable lubricant dry weight of magnesium stearate for example.

The invention provides for example every drug tablet formulation (preparation H) that comprises following composition of each unit dosage forms:

(C) weight of 25-40% is based on the dry weight of one or both pharmaceutically acceptable filleies of being selected from lactose and microcrystalline Cellulose; And it is optional

Drug tablet formulation as described herein, filler wherein is selected from lactose and microcrystalline Cellulose.

Drug tablet formulation as described herein (preparation I) comprises at least two kinds of filleies, is preferably lactose and microcrystalline Cellulose.In embodiments, the amount from 1 to 8% that lactose exists is preferably 1 to 5% weight, and the amount of microcrystalline Cellulose existence is 25 to 35% weight.

Wherein based on the DPP-IV inhibitor dry weight of LAF237 particularly, the weight package of 20-30% is contained in the preparation drug tablet formulation as described herein (preparation J).

Drug tablet formulation as described herein (Formulation K) is the amount from 34% to 46% of hydroxypropyl emthylcellulose existence wherein, is preferably from 38% to 42% weight.

Preparation as herein described wherein chemical compound (DPP-IV inhibitor) is that 1-[(3-hydroxyl-adamantyl-1-base is amino)-acetyl group]-pyrrolidinyl-2 (S)-nitrile (LAF237 or row spit of fland, Victor).

Preparation as herein described (preparation L), capsule, granule or tablet wherein Victor row spit of fland (LAF237) are the crystal forms (brilliant " type A ") in row spit of fland, Victor, it is characterized in that X-ray diffraction characteristic peak 2 θ angles at about 16.6 °, 17.1 °, 17.2 ° ± 0.3 ° or X-ray diffraction characteristic peak 2 θ angles at about 12.0 °, 13.5 °, 16.6 °, 17.1 °, 17.2 °, 20.1 °, 22.5 °, 27.4 °, 28.1 ° ± 0.3 °.This crystal form is described among the international patent application No.PCT/US2006/001473.

Term " row spit of fland, Victor " has covered any crystal formation in row spit of fland, Victor, is preferably the crystal formation " A " in row spit of fland, Victor.

The invention provides for example every drug tablet formulation that comprises following composition of each unit dosage forms:

(a) chemical compound of following formula is as active component:

Wherein R is the adamantyl that replaces, and n is from 0 to 3 integer, is preferably row spit of fland, Victor; Or its officinal salt;

(c) microcrystalline Cellulose; With

(d) magnesium stearate.

In embodiments, the weight with respect to preparation is as follows:

(a) chemical compound for example the amount that exists of Victor row spit of fland be from 20% to 30% weight;

(b) amount of hydroxypropyl emthylcellulose existence is from 30% to 50% weight;

(c) amount of microcrystalline Cellulose existence is from 25% to 35% weight; With

(d) amount of magnesium stearate existence is from 0.1% to 3% weight.

In another embodiment, the weight with respect to preparation is as follows:

(a) chemical compound for example the amount that exists of Victor row spit of fland be about 25% weight;

(b) amount of hydroxypropyl emthylcellulose existence is about 40% weight;

(c) amount of microcrystalline Cellulose existence is about 30% weight; With

(d) amount of magnesium stearate existence is about 1% weight.

In another embodiment, tablet contains lactose in addition.In embodiments, the amount of lactose existence is from 1% to 8% weight.In another embodiment, the amount of lactose is about 4% weight.

In embodiments; the DPP-IV inhibitor is selected from (s)-1-[2-(5-cyano group-2-pyridinylamino) ethylamino] acetyl group-2-pyrrolidine nitrile mono-hydrochloric salts; row spit of fland, Victor; L-Soviet Union-isoleucyl-Thiazolidine; sitagliptin (Sitagliptin); Saxagliptin; 3-(amino methyl)-2-isobutyl group-1-oxo-4-phenyl-1; 2-dihydro-6-isoquinolin Methanamide and 2-{[3-(amino methyl)-2-isobutyl group-4-phenyl-1-oxo-1,2-dihydro-6-isoquinolyl] the oxygen base } acetamide and optional its officinal salt.

In embodiments, chemical compound (DPP-IV inhibitor) is 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyano group (S)-ketopyrrolidine or its officinal salt.

In preferred embodiments, the present invention relates to wherein chemical compound described herein (DPP-IV inhibitor) is the compositions or the unit dosage forms of row spit of fland, Victor or its salt.

Still in another embodiment, row spit of fland, chemical compound Victor or its officinal salt are present in the preparation.

The present invention also provides drug tablet formulation (preparation A), and every 400mg sheet comprises following composition:

(a) the about 100mg of the amount of Victor row spit of fland or its officinal salt;

(b) the about 160mg of the amount of hydroxypropyl emthylcellulose, wherein the apparent viscosity of hydroxypropyl emthylcellulose when being present in 1% solution is 80000cP-120000cP (the sign value is 100000cP);

(c) the amount 120mg of microcrystalline Cellulose;

(d) the about 16mg of the amount of lactose; With

(e) the amount 4mg of magnesium stearate.

The present invention also provides drug tablet formulation (preparation B), and every 600mg tablet comprises following composition:

(a) the about 150mg of the amount of Victor row spit of fland or its officinal salt;

(b) the about 240mg of the amount of hydroxypropyl emthylcellulose, wherein the apparent viscosity of hydroxypropyl emthylcellulose when being present in 1% solution is 80000cP-120000cP (the sign value is 100000cP);

(c) the amount 180mg of microcrystalline Cellulose;

(d) the amount 6mg of magnesium stearate.

In embodiments, drug tablet formulation comprises the combination of the composition of the above amount.

The present invention also provides the active method of DPP IV in the inhibition individuality, comprises to individuality and uses the above-mentioned drug tablet formulation that suppresses the active amount of DPP IV in the individuality effectively.

In embodiments, individuality is the people.

The present invention also provides the treatment of conditions method that can be eased by the inhibition to the DPP IV of the individuality of suffering from disease, comprise drug tablet formulation, unit dosage forms that any this paper to individual administering therapeutic effective dose mentions, for example capsule, tablet, compressed tablet, directly compressed tablet, granule.

The present invention has also covered the drug tablet formulation that this paper mentions, unit dosage forms, for example capsule, tablet, compressed tablet, directly compressed tablet, particulate any purposes, the treatment of conditions medicine that is used for producing the inhibition of the individuality DPP IV by suffering from disease and can alleviates, it comprises any above-mentioned drug tablet formulation to described individual administering therapeutic effective dose.

The present invention has also covered the drug tablet formulation that this paper mentions, unit dosage forms, for example capsule, tablet, compressed tablet, directly compressed tablet, particulate any purposes, be used for the treatment of the disease that can alleviate by the inhibition of DPP IV in the individuality of suffering from disease, it comprises any above-mentioned drug tablet formulation to described individual administering therapeutic effective dose.

The preferred disease that can be eased by the inhibitory action of DPP IV is selected from non-insulin-dependent diabetes mellitus, arthritis, obesity, the allosome organ transplantation, calcitonin-osteoporosis, heart failure, impaired glucose metabolism, IGT (glucose tolerance reduction), neurodegenerative disease such as Alzheimer and parkinson, the modulability hyperlipemia, with hyperlipemia or reduction VLDL, LDL, with the relevant modulability disease of Lp (a) level, cardiovascular diseases or nephropathy are for example, diabetic cardiomyopathy, left ventricle or right ventricular hypertrophy, film thickens in tremulous pulse and/or the trunk hypertrophy, mesentery vascular system hypertrophy, glomerular mesangium thickens, neural degeneration obstacle and cognitive disorder, to produce calmness and angst resistance effect, alleviate that postoperative catabolism changes and hormone to stress response, reduce mortality rate and sickness rate after the myocardial infarction, treatment of conditions relates to the above effect that can mediate by GLP-1 and/or GLP-2 level.

In embodiments, described disease is a non-insulin-dependent diabetes mellitus.

In another embodiment, described disease is obesity, arthritis or osteoporosis.In another embodiment, individuality is the people.

The present invention also provides the method for the treatment of the disease that can alleviate by the inhibition of the DPP IV in the individuality of suffering from disease, comprises to individuality and uses and treat the antidiabetic drug of effective dose or any above-mentioned drug tablet formulation of the co-administered treatment effective dose of Etodolac.

In embodiments, individuality is the people.

The present invention also provides for example every drug tablet formulation that comprises following composition of each unit dosage forms:

(a) following formula: compound or its officinal salt are as active component:

Wherein R is that the adamantyl that replaces and n are from 0 to 3 integers; With

(b) apparent viscosity when being present in 1% solution is the hydroxypropyl emthylcellulose of 80000cP to 120000cP (the sign value is 100000cP).

In one embodiment, drug tablet formulation as herein described also contains filler.In one embodiment, filler is a lactose.In another embodiment, filler is a microcrystalline Cellulose.Filler is microcrystalline Cellulose and lactose in another embodiment.

In another embodiment, drug tablet formulation as herein described also comprises lubricant.In one embodiment, lubricant magnesium stearate preferably.

Still in another embodiment, with respect to the weight of preparation, it is 30% to 50% weight that hydroxypropyl emthylcellulose is present in amount in the preparation as herein described.

In embodiments, hydroxypropyl emthylcellulose is present in the amount 34% to 46% in the preparation as herein described, is preferably 38% to 42% weight.

In another embodiment, the present invention also relates to drug tablet formulation as herein described, and wherein in unit dosage forms, the weight in row spit of fland, Victor and the ratio of hydroxypropyl emthylcellulose weight are 0.16 to 2.5, are preferably 0.3 to 1.16 or 0.4 to 1.

Preferably the ratio or the % that represent of this paper is basic representation with the dry weight.

In another embodiment, the present invention also relates to drug tablet formulation as herein described, and wherein in unit dosage forms, the amount that row spit of fland, Victor exists is 100mg to 200mg, is preferably its any salt of 100mg, 150mg or 200mg or respective amount.

Drug tablet formulation as herein described also can be used for the arbitrary unit dosage form, for example, and oral formulations such as tablet (comprising multilayer tablet), capsule (comprise microcapsule, contain several for example capsules of two chambers), granule or powder; Or parenteral administration such as suppository or any other drug delivery system.Drug tablet formulation preferably described herein is used for capsule, granule or tablet form.

In another embodiment, the present invention also relates to the medicine multilayer tablet, and drug tablet formulation wherein as herein described is represented the one deck in the lamella.This can make multilayer tablet (one deck at another layer above) or with the outside of one deck coating at another layer.

Preferably the present invention also relates to the medicine multilayer tablet, and drug tablet formulation wherein as herein described is one deck and to comprise other formulations of active ingredients be the second layer and/or the 3rd layer.Preferably other active component is glitazone (for example, pioglitazone or rosiglitazone) or metformin.The preferably other or second layer is a quick releasing formulation.Drug tablet formulation as herein described can be represented the intermediate layer and comprise two the outer field quick releasing formulations of representing of other active component.Drug tablet formulation as herein described can be represented central core and comprise the quick releasing formulation of active component of the coatings of the other periphery represented.

In another embodiment, the present invention also relates to the medicinal tablet that obtains by drug tablet formulation compacting as herein described.

In another embodiment, the present invention also relates to the above medicinal tablet that is obtained by drug tablet formulation compacting as herein described, and wherein said drug tablet formulation is the process roll-in before being pressed into tablet.

In another embodiment, the present invention also relates to above medicinal tablet, and wherein the hardness range of 100mg Victor row spit of fland sheet is 10 to 13Kp, and row spit of fland, 150mg Victor sheet is 11 to 25Kp.

In the exploitation of pharmaceutical composition as herein described, the applicant finds, if comprise the DPP-IV inhibitor particularly the particle size distribution of LAF237 less than 250 μ m preferably at 10 to 250 μ m, compressed tablet particularly directly compressed tablet be particularly advantageous.

Therefore in another embodiment, the present invention relates to drug tablet formulation as herein described.Wherein dispersion comprises and contains the granule that the DPP-IV inhibitor is preferably the free or acid-addition salts form of LAF237, and wherein in the preparation at least 60%, be preferably 80% and most preferably to be 90% particle size distribution be less than 250 μ m or preferably between 10 to 250 μ m.

The present invention relates to drug tablet formulation as herein described, dispersion wherein comprises and contains the granule that the DPP-IV inhibitor is preferably the free or acid-addition salts form of LAF237, and at least 60% in the preparation wherein is preferably 80% and most preferably be 90% particle size distribution greater than 10 μ m.

Term " wherein at least 60%, be preferably 80% and most preferably be 90% " meaning refers at least 60%, preferably at least 80% and most preferably at least 90%.

Term " wherein at least 25%, be preferably 35% and most preferably be 45% " meaning refers at least 25%, preferably at least 35% and most preferably at least 45%.

Especially, the present invention relates to drug tablet formulation as herein described, wherein dispersion comprises and contains the LAF237 that the DPP-IV inhibitor is preferably free form or its acid-addition salts form, and wherein at least 25% in the preparation, be preferably 35% and most preferably be 45% particle size distribution between 50 to 150 μ m.

Selected particle size distribution provides acceptable dissolution characteristic, and acceptable hardness, friability, tablet fracture strength, dust dispersion quality and anti-crushing property, and suitable disintegration time, the flowability that obtains the necessary requirement of acceptable solid dosage forms and cementing property, the production viability of improvement, required mouldability.

The grain graininess of medicine, for example the grain graininess of LAF237 is (non-limiting example is described below) that is subjected to crystallization, drying and/or pulverizes/sieve control.Grain graininess also can use roll-in and pulverizing/sieve and reduce.Produce correct grain graininess and be know and be described in such as in " pharmaceutical dosage form: the 2nd volume, the 2nd edition, Ed.:H.A.Lieberman, L.Lachman, J.B.Schwartz (chapter 3, granularity reduces) ".

Studied multiple grain graininess, and found that specified particle size scope as herein described provides unexpected good result for direct compression.

Sieve to the estimation of particle size distribution by analysis:

Particle size distribution is to use screen analysis, photon correlation spectroscopy or laser light scattering (international standard ISO13320-1) or these methods well known to those skilled in the art of electronic sensor district band method, light blockage method, sedimentation or microscope to measure.Sieve is with one of the most ancient method of powder classification by particle size distribution.These methods be know and be described in such as the analytical chemistry textbook or be described in American Pharmacopeia (USP) publication US P-NF (2004-the 786th chapter-(American Pharmacopeia committee that U.S. food Drug Administration puts teeth in standard, Rockville is MD) in) the technology.The technology of using is for example to be described in pharmaceutical dosage form: the 2nd volume, the 2nd edition: Ed.:H.A.Lieberman, L.Lachman, J.B.Schwartz are good examples.Also mention (the 187th page) another kind of method: electronic sensor district band method, light blockage method, air penetration method, gas or liquid sedimentation.

In the aerojet sieve measurement method of grain graininess, air is upwards inhaled, and passes through sieve from the slit of rotation, so that the material fluidisation on the sieve.In the identical time, negative pressure puts on removes fine grained at the bottom of the sieve of gathering-device.Granule removes from the thin end of particle size distribution, implements screen analysis and average granulometry by the one sieve of continuous use.Also see " grain graininess mensuration ", the 5th edition, the 178th page, the 1st volume, T.Allen, Chapman﹠amp; Hall, London, UK, 1997, this there is more detailed description.For those skilled in the art, granulometry is a normal attribute.

Preparation as herein described can also be the form of multilayer tablet or double-layer tablet.

Preparation as herein described can also be capsule, tablet, compressed tablet, direct compressed tablet, particle form.

Be used for DPP-IV inhibitor compound of the present invention particularly Victor row spit of fland be hygroscopic, show stability problem, and be not can be pressed into tablet natively.Therefore, but need provide and can be pressed, be preferably the free-flow of the tablet that intensity is arranged that directly is pressed into acceptable external stripping, pharmacokinetics and pharmacodynamic profiles and have close-burning compositions.

The oar method of measuring medicine dissolution rate (discharging %) is used the 0.01N HCl of 1000mL.This method is known, and is described in the present technique field, such as the analytical chemistry textbook or describe among American Pharmacopeia (USP) the publication US P-NF (2004-the 711st chapter) of the standard that puts teeth in of food and drug administration.

In another embodiment, the present invention relates to two kinds of drug tablet formulations that comprise 100mg or row spit of fland, 150mg Victor respectively, and row spit of fland, the Victor release characteristics of the pharmaco-kinetic properties that is particularly suitable for providing improvement is provided.The pharmaco-kinetic properties that obtains can cause the improvement of patient treatment quality.

Therefore, the present invention relates to:

1) comprise the drug tablet formulation of row spit of fland, 100mg Victor or its salt, preferably be pressed into slow releasing tablet, wherein:

Between-10% and 16% preferably the row spit of fland, Victor between 11% and 15% behind 0.5h, discharge,

Between-18% and 24% preferably the row spit of fland, Victor between 19% and 23% behind 1h, discharge,

Between-30% and 36% preferably the row spit of fland, Victor between 31% and 35% behind 2h, discharge,

Between-46% and 52% preferably the row spit of fland, Victor between 47% and 51% behind 4h, discharge,

Between-58% and 64% preferably the row spit of fland, Victor between 59% and 63% behind 6h, discharge,

Between-67% and 73% preferably the row spit of fland, Victor between 68% and 72% behind 8h, discharge,

Between-74% and 80% preferably the row spit of fland, Victor between 75% and 79% behind 10h, discharge,

Between-80% and 86% preferably the row spit of fland, Victor between 81% and 85% behind 12h, discharge,

Between-91% and 97% preferably the row spit of fland, Victor between 92% and 96% behind 18h, discharge,

Between-95% and 100% preferably the row spit of fland, Victor between 96% and 100% behind 24h, discharge,

2) comprise the drug tablet formulation of row spit of fland, 150mg Victor or its salt, preferably be pressed into slow releasing tablet, wherein:

Between-3.8% and 9.8% preferably the row spit of fland, Victor 4.8% and 8.8% behind 0.25h, discharge,

Between-8.1% and 14.1% preferably the row spit of fland, Victor 9.1% and 13.1% behind 0.5h, discharge,

Between-14.7% and 20.7% preferably the row spit of fland, Victor 15.7% and 19.7% behind 1h, discharge,

Between-25.3% and 31.3% preferably the row spit of fland, Victor 26.3% and 30.3% behind 2h, discharge,

Between-40.9% and 46.9% preferably the row spit of fland, Victor 41.9% and 45.9% behind 6h, discharge,

Between-62.1% and 68.1% preferably the row spit of fland, Victor 63.1% and 67.1% behind 8h, discharge,

Between-76.5% and 82.5% preferably the row spit of fland, Victor 77.5% and 81.5% behind 10h, discharge,

Between-83.5% and 89.5% preferably the row spit of fland, Victor 84.5% and 88.5% behind 12h, discharge,

Between-88.5% and 94.5% preferably the row spit of fland, Victor 89.5% and 93.5% behind 18h, discharge.

Use the oar method above two kinds of drug tablet formulations to be measured the dissolution rate (discharging %) of medicine.

Preferably the above two kinds of drug tablet formulation comprises hydroxypropyl emthylcellulose, preferably weight is between 20 and 60%, between 30 and 50%, based on the dry weight of hydroxypropyl emthylcellulose.

Preferably the above two kinds of drug tablet formulation comprises the hydroxypropyl emthylcellulose that the apparent viscosity when being present in 1% solution is 80000cP to 120000cP (the sign value is 100000cP), preferably based on apparent viscosity when being present in 1% solution be 80000cP to 120000cP (the sign value is 100000cP) hydroxypropyl emthylcellulose dry weight 20% to 60% between or the hydroxypropyl emthylcellulose of weight between 30% to 50%.

Preferably the above comprises two kinds of forms that drug tablet formulation is tablet or multilayer tablet in the row spit of fland, Victor of 150mg or 100mg.

Preferably the above two kinds of tablet formulation that comprise the row spit of fland, Victor of 150mg or 100mg comprises drug tablet formulation as herein described arbitrarily.

Preferably the above two kinds of drug tablet formulation is forms of the tablet that obtains by drug tablet formulation compacting as described herein, and wherein drug tablet formulation is through roll-in before compacting in flakes.

Preferably the above medicinal tablet comprises row spit of fland, Victor or its salt of 100mg, and wherein the hardness range of tablet is between 10 to 13Kp.

Preferably the above medicinal tablet comprise the row spit of fland, Victor of 150mg or its salt wherein the hardness range of tablet between 11 to 25Kp.

On the other hand, the present invention relates to use pharmaceutical preparation as herein described, capsule, tablet, compressed tablet, direct compressed tablet, granule is used for such as non-insulin-dependent diabetes mellitus, arthritis, obesity, the allosome organ transplantation, calcitonin-osteoporosis, heart failure, impaired glucose metabolism, IGT (glucose tolerance reduction), neurodegenerative disease such as Alzheimer and parkinson, the modulability hyperlipemia, with hyperlipemia or reduction VLDL, LDL and the relevant modulability disease of Lp (a) level, cardiovascular diseases or nephropathy are for example, diabetic cardiomyopathy, left ventricle or right ventricular hypertrophy, film thickens in tremulous pulse and/or the trunk hypertrophy, mesentery vascular system hypertrophy, glomerular mesangium thickens, neural degeneration obstacle and cognitive disorder, to produce calmness and angst resistance effect, alleviate that postoperative catabolism changes and hormone to stress response, reduce mortality rate and sickness rate after the myocardial infarction, relate to the purposes of the treatment of conditions of above effect that can be by GLP-1 and/or the mediation of GLP-2 level.

Aspect another, the present invention relates to treat the method for following disease, such as non-insulin-dependent diabetes mellitus, arthritis, obesity, the allosome organ transplantation, calcitonin-osteoporosis, heart failure, impaired glucose metabolism, IGT (glucose tolerance reduction), neurodegenerative disease such as Alzheimer and parkinson, the modulability hyperlipemia, with hyperlipemia or reduction VLDL, LDL and the relevant modulability disease of Lp (a) level, cardiovascular diseases or nephropathy are for example, diabetic cardiomyopathy, left ventricle or right ventricular hypertrophy, film thickens in tremulous pulse and/or the trunk hypertrophy, mesentery vascular system hypertrophy, glomerular mesangium thickens, neural degeneration obstacle and cognitive disorder, to produce calmness and angst resistance effect, alleviate that postoperative catabolism changes and hormone to stress response, mortality rate and sickness rate after the reduction myocardial infarction, the disease that relates to above effect that may be by the mediation of GLP-1 and/or GLP-2 level comprises to its drug tablet formulation as described herein of homoiothermic animal administering therapeutic effective dose of needs, capsule, tablet, compressed tablet, direct compressed tablet, granule.

Preferably, disease is selected from following disease: non-insulin-dependent diabetes mellitus, obesity, calcitonin-osteoporosis, heart failure, impaired glucose metabolism, IGT (glucose tolerance reduction), neurodegenerative disease such as Alzheimer and parkinson, modulability hyperlipemia, with hyperlipemia or reduce VLDL, the LDL modulability disease relevant with Lp (a) level.

Aspect another, the present invention relates to prepare the method for tablet, unit dosage forms, it comprises:

(a) hybrid medicine tablet formulation as indicated above,

(b) preparation with preparation during the step (a) is pressed into the compressed tablet of unit dosage forms.

Aspect another, the present invention relates to be used to prepare the method for the tablet of unit dosage forms, it comprises:

(a) hybrid medicine tablet formulation as indicated above,

(b) preparation of preparation during the roll-in step (a),

(c) preparation with preparation during the step (b) is pressed into the compressed tablet of unit dosage forms.

(a) hybrid medicine tablet formulation as indicated above,

(b) with the preparation of preparation during the compression force between 10 to 16KN or any above-described preferred compression force roll-in step (a),

In another embodiment, row spit of fland, the Victor slow-release solid oral Pharmaceutical dosage forms that the invention provides 100mg is:

I-1) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, the arithmetic average maximal plasma concentration scope that described dosage form about 0.5h after using described dosage form to the patient provides row spit of fland, Victor between about 16h is from about 15.8ng/mL ± 6.85ng/mL extremely between about 173ng/mL ± 52ng/mL, described patient before described the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

I-2) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form with described dosage form treatment patient after described dosage form is being used in the 1st day once a day the 9th day about 0.5h to the arithmetic average maximal plasma concentration scope that row spit of fland, Victor is provided between about 16h from about 26.3ng/mL ± 13.1ng/mL extremely between about 175ng/mL ± 62.5ng/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

I-3) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form with described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day about 0.5h to the arithmetic average maximal plasma concentration scope that row spit of fland, Victor is provided between about 16h from about 26.9ng/mL ± 14.1ng/mL extremely between about 186ng/mL ± 80.6ng/mL, wherein said patient is under the empty stomach state, and/or

Ii-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor after Orally administered described dosage form _(0-inf)From about 1073 to about 1825ngh/mL being 1449ngh/mL ± 376ngh/mL, before wherein said the using the patient not with the treatment of row spit of fland, Victor and wherein said patient under the empty stomach condition, and/or

Ii-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _(0-24)From about 1001 to about 1977ngh/mL being 1489ngh/mL ± 488ngh/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Ii-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _(0-24)From about 1103 to about 2173ngh/mL being 1638ngh/mL ± 535ngh/mL, wherein said patient is under the empty stomach state, and/or

Iii-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor after Orally administered described dosage form _MaxBe 3.61h ± 1.44h, do not handle before wherein said the using with row spit of fland, Victor and wherein said patient under the empty stomach condition, and/or

Iii-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 2.59h ± 1.4h, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iii-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 3.74h ± 1.44h, wherein said patient is under the empty stomach state, and/or

Iv-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor after Orally administered described dosage form _MaxBe 205ng/ml ± 47ng/ml, before wherein said the using the patient not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iv-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 200ng/ml ± 64ng/ml, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iv-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 245ng/ml ± 68ng/ml, wherein said patient is under the empty stomach state, and/or

V-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, it is 85.64% ± 12.76% that the 24h of described dosage form after Orally administered described dosage form provides the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

V-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form is 87.78% ± 16.37% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 9th day, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

V-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form is 90.20% ± 7.35% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day, wherein said patient is under the empty stomach state, and/or

Vi-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, the pharmaco-kinetic properties that described dosage form provides after Orally administered described dosage form is depicted among Figure 24 basically, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Vi-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form once a day the 9th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted among Figure 25 basically from the 1st day with described dosage form treatment patient, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Vi-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form once a day the 10th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted in basically among Figure 26 from the 1st day with described dosage form treatment patient, and wherein said patient is under the empty stomach state.

Preferably 100mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms comprises hydroxypropyl emthylcellulose, and preferably between 20% to 60%, 30% to 50% or between 34% to 46%, weight is based on the dry weight of hydroxypropyl emthylcellulose.

Preferably 100mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms comprises the hydroxypropyl emthylcellulose that the apparent viscosity when being present in 1% solution is 80000cP to 120000cP (the sign value is 100000cP), preferably between 20% to 60%, or 30% to 50% or between 34% to 46%, weight is to be the dry weight of the hydroxypropyl emthylcellulose of 80000cP to 120000cP (the sign value is 100000cP) based on the apparent viscosity when being present in 1% solution.

Preferably 100mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms comprises any drug tablet formulation mentioned above.

Preferably 100mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms can comprise the drug tablet formulation that is selected from preparation A as herein described, B, C, D, E, F, G, H, I, J, K or L.

In another embodiment, row spit of fland, 150mg Victor provided by the invention slow-release solid oral Pharmaceutical dosage forms is:

I-a) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, the arithmetic average maximal plasma concentration scope that described dosage form about 0.5h after using described dosage form to the patient provides row spit of fland, Victor between about 16h is from about 30.7ng/mL ± 21.9ng/mL extremely between about 223ng/mL ± 77.3ng/mL, described patient before described the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

I-b) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form with described dosage form treatment patient after described dosage form is used in the 1st day once a day the 9th day about 0.5h to the arithmetic average maximal plasma concentration scope that row spit of fland, Victor is provided between about 16h from about 48.7ng/mL ± 25.8ng/mL extremely between about 223ng/mL ± 99.7ng/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

I-c) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form with described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day about 0.5h to the arithmetic average maximal plasma concentration scope that row spit of fland, Victor is provided between about 16h from about 44.6ng/mL ± 28.5ng/mL extremely between about 263ng/mL ± 84.4ng/mL, wherein said patient is under the empty stomach state, and/or

Ii-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor after Orally administered described dosage form _(0-inf)From about 1346 to about 3196ngh/mL being 2271ngh/mL ± 925ngh/mL, before wherein said the using not with the treatment of row spit of fland, Victor and wherein said patient under the empty stomach condition, and/or

Ii-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _(0-24)From about 1277 to about 3207ngh/mL being 2242ngh/mL ± 965ngh/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Ii-c) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _(0-24)From about 1643 to about 3273ngh/mL being 2458ngh/mL ± 815ngh/mL, wherein said patient is under the empty stomach state, and/or

Iii-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor after Orally administered described dosage form _MaxBe 3.57hr ± 1.17h, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iii-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 2.87hr ± 1.59h, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iii-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 4.13hr ± 1.24h, wherein said patient is under the empty stomach state, and/or

Iv-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor after Orally administered described dosage form _MaxBe 257ng/ml ± 59ng/ml, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iv-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 272ng/ml ± 111ng/ml, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iv-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 308ng/ml ± 91ng/ml, wherein said patient is under the empty stomach state, and/or

V-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, it is 90.04% ± 11.91% that the 24h of described dosage form after Orally administered described dosage form provides the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

V-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form is 90.4% ± 17.50% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 9th day, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

V-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form is 91.64% ± 8.47% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day, wherein said patient is under the empty stomach state, and/or

Vi-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, the pharmaco-kinetic properties that described dosage form provides after Orally administered described dosage form is depicted among Figure 24 basically, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Vi-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form once a day the 9th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted among Figure 25 basically from the 1st day with described dosage form treatment patient, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Vi-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form once a day the 10th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted in basically among Figure 26 from the 1st day with described dosage form treatment patient, and wherein said patient is under the empty stomach state.

Preferably 150mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms comprises hydroxypropyl emthylcellulose, and preferably between 20% to 60%, 30% to 50% or between 34% to 46%, weight is based on the dry weight of hydroxypropyl emthylcellulose.

Preferably 150mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms comprises the hydroxypropyl emthylcellulose that the apparent viscosity when being present in 1% solution is 80000cP to 120000cP (the sign value is 100000cP), preferably between 20% to 60%, or 30% to 50% or between 34% to 46%, weight is to be the dry weight of the hydroxypropyl emthylcellulose of 80000cP to 120000cP (the sign value is 100000cP) based on the apparent viscosity when being present in 1% solution.

Preferably 150mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms comprises any drug tablet formulation mentioned above.

Preferably 150mg Victor row spit of fland slow-release solid oral Pharmaceutical dosage forms can comprise the drug tablet formulation that is selected from preparation A as herein described, B, C, D, E, F, G, H, I, J, K or L.

Any above-described 100mg or row spit of fland, 150mg Victor slow-release solid oral Pharmaceutical dosage forms, wherein:

I) preparation is the skeleton preparation that comprises the pharmaceutically acceptable hydrophilic polymer that can block the diffusion of row spit of fland, Victor,

Ii) the Peroral solid dosage form pharmaceutical dosage form is a compressed tablet and randomly

Iii) when carrying out the test of oar method, the elution rate of 30min is lower than 30% to row spit of fland, Victor beginning to test afterwards.

" but the pharmaceutically acceptable hydrophilic polymer of blocking activity composition diffusion " is for example hydroxypropyl emthylcellulose known in the art.

Test details

I. Drug development and production

A. selected preparation and method

Compositions

The dried mixing method of exploitation roll-in is used for direct compression, as shown in process chart (Fig. 1).Select the row spit of fland, Victor of two kinds of dosage specification 100mg and 150mg to be used for further exploitation, be shown in table 2-1 and 2-2.This method has used common the doing of two kinds of specifications to mix thing.

What table 2-1 contained 40%HPMC K100M is used to go on the market the composition of every 100mg dosage forms unit of preparation

Name of product: row spit of fland, Victor sheet 100mg
Name of product: row spit of fland, Victor sheet 100mg					Basis numbering/variant: 3768652.003 shape/size/color/impression: 11mm FFBE (circle)/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 151,580 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl emthylcellulose K100M magnesium stearate	100 120 16 160 4 400	?Novartis?Ph.Eur.，NF Ph.Eur.，NF Ph.Eur.，NF Ph.Eur.，NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

What table 2-2 contained 40%HPMC K100M is used to go on the market the composition of every 150mg dosage forms unit of preparation

Name of product: row spit of fland, Victor sheet 150mg
Name of product: row spit of fland, Victor sheet 150mg					Basis numbering/variant: 6001732.001 shape/size/color/impression: 17 * 6.7mm (oval)/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 151,580 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl emthylcellulose K100M magnesium stearate	150 180 24 240 6 600	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

Method

Selected production method is shown in Fig. 2-1.

B. preparation and selectivity variant

Estimated several formulation variants as potential clinical service preparation (CSF) so that required release rate properties is provided.Term clinical service preparation (CSF) means the preparation that is suitable for being applied to the patient.Studied the release rate properties of a few types; Particularly slow in fast.Characteristic speed is selected polymer type and/or the decision of tablet technology.Selected listing preparation (MF) have the slow release rate properties of specificity (seeing the I.A. part) be specially adapted to once a day medication and the production of compressed tablet.The example of quick-release formulation is shown in table 2-3 to 2-7, and the preparation with slow release characteristics is shown in table 2-8 to 2-10.

Table 2-3 comprises the composition of every 100mg dosage forms unit of the quick-releasing property of 20%HPMC K100LV

Name of product: row spit of fland, Victor sheet 100mg
Name of product: row spit of fland, Victor sheet 100mg					Basis numbering/variant: 3768652.001 shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 151,580 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl emthylcellulose K100LVP magnesium stearate	100 170 46 80 4 400	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

Table 2-4 comprises the composition of every 200mg dosage forms unit of 20%HPMC K100LV rapid release characteristic

Name of product: row spit of fland, Victor sheet 200mg
Name of product: row spit of fland, Victor sheet 200mg					Basis numbering/variant: 3768660.002 shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	?146082?103266 103282 151580	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl first	200 340 92 160	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.，	Crude drug tablet filler tablet filler controlled release polymer

Name of product: row spit of fland, Victor sheet 200mg
Name of product: row spit of fland, Victor sheet 200mg					Basis numbering/variant: 3768660.002 shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	100217 gross weights	Base cellulose K100LVP magnesium stearate	8 800	NF Ph.Eur.， NF	Tablet lubricants

Watch 2-5 comprises the composition of every 200mg dosage forms unit of the fast rapid release characteristic of 20%HPMC E10M

Name of product: row spit of fland, Victor sheet 200mg
Name of product: row spit of fland, Victor sheet 200mg					Basis numbering/variant: shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 151,580 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl emthylcellulose E10M magnesium stearate	200 242 32 120 6 600	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

The concentration of HPMC E10M is for mating the target release rate properties 20% to 35% change.Also estimated the rate of release of the combination of HPMC E10 (15%) and HPMC K100M (10%).

Table 2-6 comprises the composition of every 100mg dosage forms unit of x%polyox quick-releasing property

Name of product: row spit of fland, Victor sheet 100mg
Name of product: row spit of fland, Victor sheet 100mg					Basis numbering/variant: shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DTPolyox? magnesium stearate	100 170 46 4 400	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

Estimate the double-layer tablet technology of 50mg rapid release (IR) sheet and second layer 150mg MR in the use ground floor, be shown in table 2-7.

Table 2-7 comprises the composition of the every 200mg dosage forms unit of double-layer tablet of HPMC K100M

Name of product: row spit of fland, Victor sheet 200mg
Name of product: row spit of fland, Victor sheet 200mg					Basis numbering/variant: NA shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	Ground floor (IR) 146,082 103,266 103282	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT Explotab	50 96 48 4	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.，	Crude drug tablet filler tablet filler disintegrating agent

Name of product: row spit of fland, Victor sheet 200mg
Name of product: row spit of fland, Victor sheet 200mg					Basis numbering/variant: NA shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	The gross weight second layer (MR) 146,082 151,580 103,266 103,282 100217 gross weights	Magnesium stearate 1-[(3-hydroxyl-adamantyl-1-base is amino)-acetyl group]-pyrrolidinyl-2 (S)-nitrile hydroxypropyl emthylcellulose K100M microcrystalline Cellulose, PH102 lactose, anhydrous DT magnesium stearate	2 200 150 130 120 46 4 450	NF Ph.Eur.， NF Nova?rtis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF	Lubricant crude drug controlled release polymer tablet filler tablet filler tablet lubricants

In every layer the amount of Victor row spit of fland DS and HPMC K100M be can change so that suitable release rate properties to be provided.For example, DS changes to 50mg (release layer) with from 150mg from 25mg and changes to 175mg (layer released in accent).The amount of HPMC K100M changes to 40% (layer released in accent) from 29%.

The slow release variant of another exploration is that HPMC concentration reduces to 30%, and roll-in and no roll-in are arranged, shown in table 2-8 and 2-9.This variation does not have influence to dissolution characteristic.But when comparing with 40%HPMC K100M, 30%HPMC K100M demonstrates lower mobile quality, and non-roll-in material and roll-in material are respectively 0.21 and 0.37.During with 30%HPMC K100M compacting, also observed peplos.

Table 2-8 uses the composition of every 100mg dosage forms unit of 30%HPMC

Name of product: row spit of fland, Victor sheet 100mg
Name of product: row spit of fland, Victor sheet 100mg					Basis numbering/variant: NA shape/size/color/impression: 11mm FFBE (circle)/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 151,580 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl emthylcellulose K100M magnesium stearate	100 120 58 120 4 400	Nova?rtis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.， NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

Table 2-9 uses the composition of every 150mg dosage forms unit of 30%HPMC

Name of product: row spit of fland, Victor sheet 150mg
Name of product: row spit of fland, Victor sheet 150mg					Basis numbering/variant: NA shape/size/color/impression: 17 * 6.7mm oval/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	?146082?103266 103282 151580	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl first	150 180 24 180	Novartis Ph.Eur.， NF Ph.Eur.， NF Ph.Eur.，	Crude drug tablet filler tablet filler controlled release polymer

Name of product: row spit of fland, Victor sheet 150mg
Name of product: row spit of fland, Victor sheet 150mg					Basis numbering/variant: NA shape/size/color/impression: 17 * 6.7mm oval/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	100217	Base cellulose K100M magnesium stearate	6	NF Ph.Eur.， NF	Tablet lubricants

Table 2-10 contains the composition of the every 200mg dosage forms unit of slow release characteristics of 40%HPMC K100M

Name of product: row spit of fland, Victor sheet 200mg
Name of product: row spit of fland, Victor sheet 200mg					Basis numbering/variant: 3768660.003 shape/size/color/impression :/white is to off-white color
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function
Overall material number	Component	Per unit is formed (mg)	The method of inspection	Function	146,082 103,266 103,282 151,580 100217 gross weights	Row spit of fland, Victor microcrystalline Cellulose, PH102 lactose, anhydrous DT hydroxypropyl emthylcellulose K100M magnesium stearate	200 240 32 320 8 800	?Nova?rtis?Ph.Eur.，?NF?Ph.Eur.，?NF?Ph.Eur.，?NF Ph.Eur.，?NF	Crude drug tablet filler tablet filler controlled release polymer tablet lubricants

Be used to produce the selection of the preparation of clinical variant

4 kinds of preparations of selected further clinical evaluation are made up of two types the release rate properties (at a slow speed with quick) of two preparation specifications (100mg and 200mg).Batch size is 4000 (or 3.1kg).Require the needs precompressed for what satisfy hardness and/or friability.The preparation at a slow speed that contains 40%HPMC K100M is shown in table 2-1 and 2-10.The quick preparation that contains 20%HPMC K100 LVP is shown in table 2-3 and 2-4.

Clinical batch of summary of table 2-11

Speed characteristic	Specification	Polymer	Form	KN number/variant	Lot number
Speed characteristic	Specification	Polymer	Form	KN number/variant	Lot number	At a slow speed fast	?100mg 200mg 100mg 200mg	?40％HPMC?K100M?40％HPMC?K100M?20％HPMC?K100LVP?20％HPMC?K100LVP	Table 2-1 table 2-10 table 2-3 table 2-4	?3768652.002 3768660.003 3768652.001 3768660.002	?AEUS20020081 AEUS20020083 AEUS20020080 AEUS20020082

The preparation principle

1-[(3-hydroxyl-adamantyl-1-base is amino)-acetyl group]-pyrrolidine-2 (S)-nitrile is that row spit of fland, Victor DS (crude drug) is that highly water-soluble (up to 125mg/mL) and the polymer that therefore need be able to serve as basic diffusion obstacle are used for significantly reducing medicine stripping and diffusion.MR dosage form once a day may need the polymer carrying capacity of significant level to be used to postpone drug diffusion.Between development period, the applicant has selected the monolithic preparation that inclines and risk than low dosage, does not use packaging technique and uses skeleton preparation.In relative consistency, delay to spread pharmacokinetics and pharmacodynamics ability, and the further investigation that accept to require of rules after, the applicant with the selection constriction of polymer to hydrophilic polymer, particularly hydroxypropyl emthylcellulose (HPMC).

Main and crucial discovery the during formulation development

Crucial excipient is the polymer HPMC of sustained release, the K100M level.At CSF between development period, estimated various controlled release polymers and added separately or make up adding, so that realize required release characteristics.HPMC, the K100M level provides the optimum matching with required release characteristics.In human body, estimate the back and select " at a slow speed " preparation.

As previously mentioned, used precompressed at clinical batch of production period.Test with further evaluation CSF preparation with to the needs of precompressed.

The CSF preparation compaction characteristics that comprises 40%HPMC is shown in Fig. 3 and 4.

Data show that compaction characteristics and friability can improve with precompressed.Carried out other research to improve compaction characteristics and to avoid using precompressed.

As shown in Figure 5, estimated 30%HPMC K100M to improve compaction characteristics.Estimated simultaneously at tablet under 40 to 80rpm speed and held the pressure influence of (resident) time.

The improvement of definite compaction characteristics can use roll-in to realize.Shown in Fig. 6 and 7.The mixture of powders intermediate that does not add magnesium stearate in use is estimated Fitzpatrick (Chilsonator , IR220 type) when improving compression force.

Shown in Fig. 8 and 9, studied roll-in with 40%HPMC K100M and compared to the influence of dissolution characteristic and with clinical batch dissolution characteristic.Conclusion is that roll-in does not influence dissolution characteristic.

Use linear relationship, for 50mm Bepex roll squeezer roll-in method has been marked scale as 50mm Fitzpatrick roll squeezer (being unit with lb/, the IR520 type) and 50mmBepex roll squeezer (is unit with KN) foundation.Shown in Figure 10 and 11, studied the influence that improves compression force.But this method of reaching a conclusion is a scale for the Bepex roll squeezer, and tablet hardness is not subjected to influence significantly with the raising of roller pressure (13-31KN) and roll-in speed (4-8rpm).

In clinical research, comprise the general introduction of the compositions of CSF

See " the variant of B. preparation and selection." part

C. production method

All variants are according to the detailed description production in the process chart shown in Figure 1, except that the variable that does not have roll-in.The batch that uses is greatly to 12kg.Use is used for all product batch numbers from the crude drug of lot number 0223007,0223008,0223009.

The description of the method for inspection and evaluation

HPMC with 30% and 40% carries out the roll-in impact assessment.Use roll-in to make mixture of powders closely knit before tabletting.Fitzpatrick (Chilsonator , IR220 type) roll squeezer is shown in Figure 12 and 13 at pressure 500 to 10000lb/in to the influence of the mixture of powders that contains 40%HPMC.

Data show the increase along with roller pressure, cause the reduction of tablet hardness.As shown in figure 14, roller pressure is poorer than the CSF that does not have roll-in or precompressed greater than the tablet press characteristic of 5000lb/in (or 43.75KN) preparation.

Roll-in is shown in Figure 14 to the influence of tablet friability.

The key component standard and the principle of final method

The key criterion of final method is based on dissolution characteristic.Because the PK/ safety research is to use and carries out in 100mg, 150mg and the 200mg tablet body, need contain the preparation of 40%HPMC K100M.Roll-in joins in the method to improve compaction characteristics.Shown in Figure 17 and 18, the dissolution characteristic of roll-in material is not different with the dissolution characteristic of CSF.Be limited to 40mg/kg on Japanese health ministry requirement HPMC K100M intake every day.It is amino to expect that intake restriction every day can not become 1-[(3-hydroxyl-adamantyl-1-base)-acetyl group]-obstacle in pyrrolidine-2 (S)-nitrile MF registration.

The physical property of various mixture of powderss is shown in table 2-12 and 2-13.

The physical property (Fitzpatrick) of table 2-12 roll-in mixture of powders

Sample	Roller pressure (lb/in) [KN theoretical value]	Flow of powder quality (Sotax)	Bulk density/tap density (g/mL)
Sample	Roller pressure (lb/in) [KN theoretical value]	Flow of powder quality (Sotax)	Bulk density/tap density (g/mL)	?TRD-1926-78?40％HPMC?TRD-1971-53?40％HPMC?TRD-1971-55?40％HPMC?TRD-1?926-79?30％HPMC?TRD-1926-79?30％HPMC?TRD-1926-01?40％HPMC?TRD-1?926-78?40％HPMC?TRD-1926-01?40％HPMC	NA NA NA NA 1,000[8.75] 500[4.37] 1,000[8.75] 1,500[13.1]	?0.38 0.33 0.36 0.21 0.37 0.25 0.49 0.53	0.38/0.576 0.38/0.66 0.36/0.59 0.385/0.60 0.432/0.645 0.398/0.588 0.448/0.652 0.448/0.666

Sample	Roller pressure (lb/in) [KN theoretical value]	Flow of powder quality (Sotax)	Bulk density/tap density (g/mL)
Sample	Roller pressure (lb/in) [KN theoretical value]	Flow of powder quality (Sotax)	Bulk density/tap density (g/mL)	?TRD-1771-123B?40％HPMC?TRD-1771-123C?40％HPMC?Avicel?PH102	5,000[43.75] 10,000[87.5] NA	0.76 ND (can not in flakes) 0.64	0.526/0.714 0.566/0.732 0.29/0.35

The physical property (Bepex) of table 2-13 roll-in mixture of powders

Sample	Roller pressure (Kn) [lb/in theoretical value]	Roll speed (rpm)	Flow of powder quality (Sotax)	Bulk density/tap density (g/mL)
Sample	Roller pressure (Kn) [lb/in theoretical value]	Roll speed (rpm)	Flow of powder quality (Sotax)	Bulk density/tap density (g/mL)	?TRD-1926-78?40％HPMC?TRD-1971-53?40％HPMC?TRD-1971-55?40％HPMC?TRD-1971-53C?40％HPMC?TRD-1971-53A?40％HPMC?TRD-1971-53B?2?40％HPMC?TRD-1971-55A?40％HPMC?TRD-1971-55B?40％HPMC?TRD-1971-55C?40％HPMC?Avicel?PH102	?NA NA NA 13[1500?lb/in]?22[2500?lb/in]?31[3500?lb/in]?13 13 13 NA	?NA NA NA 4 4 4 4 6 8 NA	0.38 0.33 0.36 0.25 0.49 0.53 0.76 ND (can not in flakes) 0.64	0.38/0.576 0.38/0.66 0.36/0.59 0.398/0.588 0.448/0.652 0.448/0.666 0.526/0.714 0.566/0.732 0.29/0.35

The use of roll-in has shown the raising of flow of powder quality and the increase of bulk density.This is subjected to the restriction of roller pressure, and the tablet of 5000lb/in and 10000lb/in power demonstrates 0.6% and the friability (100mg sheet) of＞10% difference respectively.

Roll-in is shown in Figure 19 and 20 to the influence of screen analysis.All roll-in materials use 18 mesh sieves to sieve.Select the instrument of the size of sieve, and will further estimate in the laboratory FMI stage as grain graininess control.

The equipment that uses

Table 2-14 process equipment

Describe	Model
Describe	Model	Bin mixer swing type pulverizer roll squeezer roll squeezer tablet machine	LB?Bohle，10L，25L，40L Ferwitt Fitzpatrick，Chilsonator，IR220 Bepex，50mm Manesty?Beta?Press，16sta.

The scale of final method is amplified the statement of potentiality and viability

Table 2-15 sums up the IPC of row spit of fland, the Victor 100mg MR (the 400mg sheet is heavy, 11mm FFBE) that contains 40%HPMC and use roll-in

Sample	Thickness (mm) IPC:2.8-4.2mm	Hardness (Kp)	% friability (falling 100 times)
Sample	Thickness (mm) IPC:2.8-4.2mm	Hardness (Kp)	% friability (falling 100 times)	TRD-1926-78 1,000lb/in RC (FP) TRD-1771-123A 1,000lb/in RC (FP) TRD-1926-01A 500lb/in RC (FP) TRD-1926-01B 1, the non-RC of 500lb/in RC (FP) TRD-1771-31	3.95-3.72 4.07-3.68 4.0-3.81 4.02-3.66 4.13-3.94	?40rpm：11.5-13.2?60rpm：9.76-12.69?80rpm：9.76-12.84?40rpm：8-18.3 40rpm：9.3-14.8 40rpm：7.6-19.9 40rpm：5.1-7.75	40rpm:＜0.5 60rpm:＜0.5 80rpm:＜0.5 40rpm:＜0.5 40rpm:0.1 40rpm:0.1 40rpm:6.3, the top is split

Table 2-16 contains row spit of fland, Victor 150mg MR (the 600mg sheet is heavy, 17 * 6.7mm oval) the IPC summary that 40%HPMC uses roll-in

Sample	Thickness (mm) IPC:2.8-4.2mm	Hardness (Kp)	% friability (falling 100 times)
Sample	Thickness (mm) IPC:2.8-4.2mm	Hardness (Kp)	% friability (falling 100 times)	TRD-1926-78 1,000lb/in RC (FP) TRD-1771-123A 1,000lb/in RC (FP) TRD-1926-01A 500lb/in RC (FP) TRD-1926-01B 1, the non-RC of 500lb/in RC (FP) TRD-1771-33	40rpm：6.5-6.08 60rpm：6.4-6.03 80rpm：6.6-6.07 6.4-5.84 6.56-5.99 6.5-5.84 6.59-5.97	40rpm：17.5-25.9 60rpm：15.5-24.8 80rpm：11.2-24.4 40rpm：12.3-30.4 40rpm：14.6-30.3 40rpm：13.9-32 40rpm：18.3-27.2	40rpm:＜0.2 60rpm:＜0.2 80rpm:＜0.2 40rpm:＜0.25 40rpm:0.5,1 splits 40rpm:0.25 40rpm:0.6 at 20Kn tablet item, in the 20Kn slabbing

Roll-in has improved flow of powder and compaction characteristics, need not to use precompressed.For 100mg and the acceptable hardness range of 150mg sheet is respectively 10 to 13Kp and 11 to 25Kp.Observe slabbing for the 150mg sheet during greater than 18KN in compression force.Preparation does not demonstrate holding pressure (resident) time-sensitive.Laboratory stage FMI activity will beginning during the FMI of 100mg specification figure of tablet and size affirmation.

II. The analysis and research of the strain-gauge test of variant

A. the foundation of analytical method

Assay and related substances

Quantitatively carrying out of the assay in row spit of fland, Victor and catabolite with gradient HPLC method [AM54001B (AS6105)].Sample is with methanol extraction and use 10: 90 methanol/dilution in acetonitrile to target level, uses rp-hplc method to use 210nm UV to detect then and carries out chromatography.

Drug release

Measure under the experimental condition that the stripping of row spit of fland, Victor from the sheet of row spit of fland, 6 100mg Victors described in detail in table 3-1.The sample that obtains uses 210nmUV to detect with rp-hplc method such as degree such as grade [AM50161A (AS6105)] and analyzes.The 150mg sheet has also been finished identical test with the 200mg sheet.

B. analysis result

The stability test scheme

Arrange the technology of the slow and quick preparation of CSF criticize with clinical batch carry out stability experiment, and monitor stable until 12 months.The technology of the MF variant of 100mg and 150mg is criticized stable well afoot, is shown among testing program, the table 3-2.

Table 3-2 lot number TRD-1926-078A (100mg) and TRD-1926-078B (150mg); Drug products stability-the storage requirement and the intertrial interval of [packing: HDPE, CR lid, 1g desiccant].

Storage requirement	Time (moon)
Storage requirement	Time (moon)	?5℃?25℃/60％RH?30℃/65％RH?40℃/75％RH	[24] 3、6、9、12、24 [3]、[6]、[9]、[12] 1.5、3、6

[] is optional to be detected

Stability result

Table row spit of fland, 3-3 Victor 100mg sheet, the stable conclusive table of TRD-0739-0113

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture
			25℃/60％R?H 30℃/60％R?H 40℃/75％R?H	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	Up to specification up to specification	100.8 102.6 101.0 100.1 102.5 102.3 104.3 100.3 100.7 101.4 103.3 100.7	＜LOQ ＜LOQ 0.06 0.08 0.11 0.06 0.12 0.17 0.21 0.10 0.20 0.39	＜LOD ＜LOQ 0.05 0.05 0.05 ＜LOQ 0.05 0.05 0.05 0.05 0.05 0.05	ND ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ 0.07 ＜LOQ 0.07 0.12	?ND ND ND?ND?ND?ND ND?ND?ND?ND ND＜LOQ	＜LOQ＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture	＜LO?Q＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ	?- - 0.11?0.13?0.16?0.06 0.17?0.22?0.33?0.15 0.32?0.56	?3.52 2.40 2.66?2.74?3.16?2.51 2.79?3.07?3.59?2.73 2.90?3.35

NT=does not detect, ring amidine=cyclic amidine, and diketopiperazine=diketopiperazine, the LOQ=0.05% of ring amidine, diketopiperazine and amide, row spit of fland, Victor is 0.06%; LOD=0.02%; ND=does not detect

Table row spit of fland, 3-4 Victor 100mg sheet, the dissolution data conclusive table of TRD-0739-0113

Condition	Time	Discharge percent
		Discharge percent										?0.5hr	?1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	24hr
		25℃/60％R H 30℃/860％RH 40℃/75％RH	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	?23?NT NT?NT?NT?NT?NT?NT?24?NT?23?24	?36 38?-	56 57 57 57	82 84 -	95 94 98 95	102 103 -	104 103 -	104 104 -	?0.5hr	?1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	24hr	104 100 102 100	102 101 -

NT=does not detect

Attention: only under acceleration environment, detect stripping, because the poorest situation of these representatives.

Table row spit of fland, 3-5 Victor 100mg sheet, the stable conclusive table of TRD-0739-0121

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture
			25℃/60％R?H 30℃/60％R?H 40℃/75％R?H	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	Up to specification up to specification	103.1 103.3 104.3 102.2 101.4 104.7 103.9 100.8 102.4 102.1 104.8 102.9	＜LOQ ＜LOQ 0.05 0.07 0.08 0.05 0.09 0.11 0.14 0.08 0.13 0.25	＜LOD ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ	ND ＜LOQ ＜LOD ＜LOQ ＜LOQ ＜LOQ ＜LOQ ＜LOQ 0.05 ＜LOQ 0.05 0.08	ND ND ND ND ND ND ND ND ND ND ND ＜LOQ	＜LOQ＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture	0.07＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ＜LOQ＜LOQ?＜LOQ＜LOQ	?0.07?0.00 0.05?0.07?0.08?0.05 0.09?0.11?0.19?0.08 0.18?0.33	?3.19?2.53 2.70?3.03?3.31?2.61 2.88?3.33?3.65?2.81 2.97?3.52

Table row spit of fland, 3-6 Victor 100mg sheet, the dissolution data conclusive table of TRD-0739-0121

Condition	Time	Discharge percent
		Discharge percent										?0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	?12hr	18hr	24hr
		25℃/60％RH 30℃/60％RH 40℃/75％RH	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	?12?NT?NT?NT?NT?NT?NT?NT?13?NT?13?13	20 - 21 -	30 32 32 33	45 - 49 -	56 60 59 61	65 - 70 -	72 - 77 -	?78 - 83 -	?0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	?12hr	18hr	24hr	89 94 93 95	95 98 -

NT=does not detect

The list of references of table 3-7 stability data in table 3-3-table 3-6

	Assay and purity	The % moisture	Stripping
	Assay and purity	The % moisture	Stripping	Initial 63 months 6 months 9 months 12 months weeks	TRD0958/057(XG) TRD0958/057(XG) TRD0983/082(XG) TRD1514/110(XG) TRD1645/129(MZ) TRD1642/069(JT)	TRD0958/109(XG) TRD0958/109(XG) TRD0978/110(MZ) TRD1514/110(XG) TRD1645/101(MZ) TRD1642/145(JT)	WS18431 NA WS20247 WS21349 NA WS22591

Table row spit of fland, 3-8 Victor 100mg sheet, the stability data conclusive table of AEUS/2002-0080

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture
			Initial									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture
5 ℃ of 25 ℃/60%R H, 25 ℃/60%R H (using Cotton Gossypii)	03 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months	NT up to specification is up to specification	Initial	102.0104.3101.8102.3?101.1?103.0100.6101.9101.4?102.0102.2101.7	ND 0.02 0.02 0.02 0.04 0.07 0.08 0.09 0.04 0.06 0.09 0.11	ND 0.02 0.02 0.03 0.05 0.06 0.06 0.05 0.05 0.06 0.07 0.07	ND ND ND ND ND 0.02 0.02 0.02 ND ND ND 0.03	- ND ND ND ND ND ND ND ND ND ND 0.02	0.04 0.05 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04	0.03 0.03 ND 0.03 0.04 ND 0.02 0.03 0.05 ND 0.02	- 0.00 0.00 0.00 0.05 0.13 0.14 0.14 0.05 0.12 0.16 0.18	?2.62?2.17?2.32?2.39 2.06 2.34?2.43?2.72?2.22 2.67?2.69?2.85

?℃/60％RH 40℃/75％R?H	3 months 6 months 9 months 12 months 63 months 6 months weeks	Up to specification up to specification up to specification	Catabolite
			Catabolite	102.6 102.7 101.7 101.3 101.7 101.9 102.5	0.06 0.11 0.15 0.19 0.10 0.20 0.40	0.06 0.06 0.07 0.06 0.06 0.07 0.07	ND 0.03 0.03 0.05 0.03 0.05 0.11	ND ND ND ND ND ND 0.03	0.04 0.04 0.03 0.03 0.04 0.03 0.04	0.04 0.05 ND 0.02 0.06 0.05 0.06	?0.12?0.17?0.22?0.30?0.22?0.32?0.64	?2.12?2.60?2.78?2.80?2.28?2.59?3.41

Table row spit of fland, 3-9 Victor 100mg sheet, the dissolution data conclusive table of AEUS/2002-0080

Condition	Time	Discharge percent
		Discharge percent										0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	?24hr
		40 ℃/75%RH of 30 ℃/60%RH of 25 ℃/60%R H, 25 ℃/60%R H (using Cotton Gossypii)	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	24 NT NT NT NT NT NT NT NT NT 22 NT NT 23 24	37	55 53 54 56	79	92 90 92 93	99	101	101	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	?24hr	100 102 101 104	?99

NT=does not detect

Table row spit of fland, 3-10 Victor 100mg sheet, the stability data conclusive table of AEUS/2002-0081

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture
			40 ℃/75%RH of 30 ℃/60%RH of initial 5 ℃ of 25 ℃/60%R H, 25 ℃/60%R H (using Cotton Gossypii)	03 month 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	NT up to specification is up to specification up to specification up to specification up to specification	?102.5?103.4?102.7?101.4 103.1 102.9?100.8?101.7?101.8 104.1?102.9?104.9?101.0?103.4?102.3?101.0?102.8?102.6?103.1	?ND?0.02?0.02?0.02 0.03 0.05?0.06?0.07?0.03 0.05?0.06?0.08?0.05?0.08?0.10?0.13?0.07?0.13?0.25	ND 0.01 0.02 ND 0.03 0.03 0.03 0.03 0.03 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.03 0.04 0.05	?ND?ND?ND?ND ND ND?ND?0.02?ND ND?ND?0.02?0.01?0.03?0.03?0.04?0.03?0.03?0.08	?-?ND?ND?ND ND ND?ND?0.02?ND ND?ND?ND?ND?ND?ND?0.02?ND?ND?0.02	?-?0.04?0.04?0.04 0.04 0.05?0.04?0.04?0.04 0.04?0.04?0.03?0.04?0.04?0.03?0.04?0.04?0.04?0.04	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture	0.04?0.05?0.02 0.05 0.07?ND?0.04?0.04 0.06?ND?0.03?0.05?0.07?ND?0.03?0.07?0.05?0.07	?-?0.00?0.00?0.00 0.00 0.12?0.06?0.07?0.00 0.11?0.06?0.08?0.05?0.15?0.10?0.13?0.14?0.13?0.45	?2.45?2.35?2.19?2.24 2.01 2.33?2.44?2.57?2.14 2.61?2.58?2.57?2.06?2.64?2.75?2.62?2.24?2.63?3.58

Condition	Time	Outward appearance	Catabolite
			Catabolite	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture

Table row spit of fland, 3-11 Victor 100mg sheet, AEUS/2002-0081, the dissolution data conclusive table of 30HDPE90

Condition	Time	Discharge percent
		Discharge percent										0.5hr	?1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	?24hr
		40 ℃/75%RH of 30 ℃/60%RH of 25 ℃/60%RH of 25 ℃/60%RH (using Cotton Gossypii)	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	13 NT NT NT NT NT NT NT NT NT 13 NT NT 12 12	?21	33 33 31 30	49	61 62 57 56	70	77	83	0.5hr	?1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	?24hr	94 95 89 89	?98

NT=does not detect attention: only detect stripping under acceleration environment, because the poorest situation of these representatives.

Table row spit of fland, 3-12 Victor 200mg sheet, the stability data conclusive table of AEUS/2002-0082

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture
			40 ℃/75%R of initial 5 ℃ of 25 ℃/60%R H, 25 ℃/60%R H (using Cotton Gossypii) 30 ℃/60%R H H	03 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months weeks	NT up to specification is up to specification up to specification up to specification	?100.6?100.7?100.3?99.9 100.6 100.1?99.9?99.9?100.8 99.3?99.1?100.3?99.5 100.8?100.4?99.2?101.2 99.3	ND 0.02 0.02 0.02 0.04 0.06 0.08 0.09 0.04 0.06 0.08 0.10 0.06 0.11 0.16 0.19 0.11 0.20	ND 0.02 0.02 0.02 0.04 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.06 0.05 0.05 0.05	ND ND ND ND ND ND 0.02 0.03 ND ND 0.02 0.03 ND 0.03 0.03 0.05 0.03 0.05	- ND ND ND ND ND ND 0.02 ND ND ND 0.02 ND ND ND 0.02 ND ND	0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.03 0.03 0.04 0.04 0.03 0.03 0.03 0.03	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture	0.02 0.03 ND 0.02 0.04 ND 0.02 0.02 0.04 ND 0.02 0.03 0.04 ND 0.02 0.06 0.03	- 0.00 0.00 0.00 0.00 0.11 0.14 0.14 0.05 0.11 0.14 0.16 0.12 0.16 0.22 0.29 0.22 0.30	2.61 2.23 2.54 2.46 2.16 2.50 2.56 2.53 2.22 2.59 2.64 2.63 2.18 2.59 2.75 2.77 2.31 2.51

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture
				6 months	Up to specification	99.5	?0.36	0.05	0.10	?0.02	0.04	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture	?0.05	?0.51	3.16

Table 3-13 200mg sheet, the dissolution data conclusive table of AEUS/2002-0082

Condition	Time	Discharge percent
		Discharge percent										?0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	24hr
		30 ℃/60%RH of 5 ℃ of 25 ℃/60%R H, 25 ℃/60%R H (using Cotton Gossypii)	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 3 months 6 months	?24?NT?NT?NT?NT?NT NT?NT?NT?NT NT?NT?NT?NT	36	52	73	86	93	98	99	?0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	24hr	99	97

Condition	Time	Discharge percent
		Discharge percent					?0.5hr	1hr	?2hr	4hr	?6hr	8hr	10hr	12hr	18hr	?24hr
		400℃75％RH	9 months 12 months 63 months 6 months weeks	?23?NT?NT?24?25	?51 52?54	?84 87?87	?0.5hr	1hr	?2hr	4hr	?6hr	8hr	10hr	12hr	18hr	?24hr	99 99 99

NT=does not detect

Table 3-14200mg sheet, the dissolution data conclusive table of AEUS/2002-0083

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture
			40 ℃/75%RH of 30 ℃/60%RH of 25 ℃/60%RH of initial 5 ℃ of 25 ℃/60%RH (using Cotton Gossypii)	03 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 63 months weeks	NT up to specification is up to specification up to specification up to specification	100.8 100.8 100.5 101.1 99.9 100.6 99.6 100.2 100.5 100.2 100.1 100.0 100.4 100.3 100.2 100.3 101.2 100.7	ND 0.02 ND ND 0.03 0.05 0.06 0.08 0.03 0.05 0.07 0.08 0.05 0.08 0.11 0.13 0.08 0.14	ND ND ND ND 0.02 0.03 0.03 0.02 0.03 0.03 0.03 0.03 0.03 0.03 0.03 0.02 0.03 0.03	ND ND ND ND ND ND ND 0.02 ND ND ND 0.02 ND 0.02 0.03 0.05 0.03 0.03	- ND ND ND ND ND ND 0.02 ND ND ND ND ND ND ND 0.02 ND ND	0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.03 0.03	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture	0.03 0.04 0.03 0.03 0.05 0.02 0.04 0.04 0.05 ND 0.03 0.04 0.08 ND 0.03 0.08 0.04	- 0.00 0.00 0.00 0.00 0.05 0.06 0.08 0.05 0.05 0.07 0.08 0.05 0.16 0.11 0.18 0.16 0.14	2.36 2.06 2.41 2.36 2.04 2.32 2.49 2.50 2.09 2.50 2.66 2.54 2.07 2.52 2.67 2.71 2.24 2.47

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture
				6 months	Up to specification	99.8	?0.23	?0.03	?0.07	?0.02	?0.04	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	% amounts to	% moisture	?0.06	?0.36	?3.14

Table 3-15 200mg sheet, the dissolution data conclusive table of AEUS/2002-0083

Condition	Time	Discharge percent
		Discharge percent										?0.5hr	?1hr	?2hr	?4hr	?6hr	8hr	10hr	12hr	18hr	24hr
		40 ℃/75%RH of 30 ℃/60%RH of 25 ℃ ℃/60%RH of 5 ℃ of 25 ℃/60%RH (using Cotton Gossypii)	Initial 3 months 6 months 9 months 12 months 3 months 6 months 9 months 12 months 3 months 6 months 9 months 3 months 6 months 9 months 12 months 63 months 6 months weeks	?11?NT?NT?NT?NT?NT?NT?NT?NT?NT?NT?NT?NT?NT?11?10?NT?10?10	?18	?27 27?25 25?25	?40	?50 51?48 49?48	59	66	71	?0.5hr	?1hr	?2hr	?4hr	?6hr	8hr	10hr	12hr	18hr	24hr	84 84 81 81 81	91

NT=does not detect

The list of references of stability data among the table 3-16 table 3-8-table 3-15

List of references	Assay and purity	Moisture	Dissolution
List of references	Assay and purity	Moisture	Dissolution	Initially	WS17548	TRD0958/109X G	WS19437、19427、19449、19455
6 weeks	WS20721	TRD0983/99XG	NA	Initially	WS17548	TRD0958/109X G	WS19437、19427、19449、19455
6 weeks	WS20721	TRD0983/99XG	NA	3 months	WS20768	WS20768	WS21307、20772、21321
6 months	WS21855	WS21855	WS22761、22771、22775	3 months	WS20768	WS20768	WS21307、20772、21321
6 months	WS21855	WS21855	WS22761、22771、22775	9 months	WS23831	WS23831	WS22591、22599
12 months	WS25593	WS25593	WS25471、25507	9 months	WS23831	WS23831	WS22591、22599

Table 3-17 100mg sheet, the stability data conclusive table of TRD-1926-078A (packing: HDPE, 1g desiccant and CR lid)

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture
			40℃/75％RH	Initial 6 weeks	Up to specification	102.0 98.3	?＜LOQ 0.10	?＜LOQ 0.06	?ND ＜LOQ	?ND ＜LOQ	?＜LO?Q?＜LOQ	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture	?＜LO?Q?0.06	?＜LOQ 0.22	?2.39

NT=does not detect, ring amidine=cyclic amidine, and diketopiperazine=diketopiperazine, the LOQ=0.05% of ring amidine, diketopiperazine and amide, row spit of fland, Victor is 0.06%; LOD=0.02%; ND=does not detect.

Ref: initial-TRD 1928/127 JT:6 week-TRD 1980/

Table 3-18 100mg sheet, the dissolution data conclusive table of TRD-1926-078A (packing: HDPE, 1g desiccant and CR lid)

Condition	Time	Discharge percent
		Discharge percent										0.25hr	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr
		40℃/75％R H	Initial 6 weeks are not checked	7.6	12.3	19.5	30.5	46.5	-	68.4	82.3	0.25hr	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	89.1	93.8

Ref：WS35331?KE

Table 3-19 150mg sheet, the stability data conclusive table of TRD-1926-078B (packing: HDPE, 1g desiccant and CR lid)

Condition	Time	Outward appearance	Catabolite
			Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The % husband knows the peak. (RRT=1.10)	The % total degradation	% moisture
			40℃/75％RH	Initial 6 weeks	Up to specification	101.7 99.1	＜LOQ 0.10	＜LOQ 0.07	ND ＜LOQ	ND?ND	＜LO?Q＜LOQ	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak of %. (RRT=0.77)	The % husband knows the peak. (RRT=1.10)	The % total degradation	% moisture	＜LOQ0.06	＜LOQ?0.23	?2.31

Ref: initial-TRD1928/127 JT:6 week-TRD

Table 3-20 150mg sheet, the dissolution data conclusive table of TRD-1926-078B (packing: HDPE, 1g desiccant and CR lid)

Condition	Time	Discharge percent
		Discharge percent										0.25h r	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr
		40℃/75％RH	Initial 6 weeks are not checked	6.8	11.1	17.7	28.3	-	43.9	65.1	79.5	0.25h r	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	18hr	86.5	91.5

Ref：WS35331?KE

Table 3-21 1-[(3-hydroxyl-adamantyl-1-base is amino)-acetyl group]-assay and related substances data conclusive table that the initial time of pyrrolidine-2 (S)-nitrile MR sheet (technology is criticized) is analyzed

Lot number	Outward appearance	Catabolite
		Catabolite									% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak .fRRT=0.77 of %)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture
		TRD-1971-053C 100mg	Up to specification	100.9	?ND	ND	ND	ND	＜LO Q	ND	% content	The % amide	% encircles amidine	The % diketopiperazine	The unknown peak of %. (RRT=0.26)	The unknown peak .fRRT=0.77 of %)	The unknown peak of %. (RRT=1.10)	The % total degradation	% moisture	＜LOQ	2.44
TRD-1971-055A 150mg	Up to specification	TRD-1971-053C 100mg	Up to specification	100.9	?ND	ND	ND	ND	＜LO Q	ND	120.4	?ND	ND	ND	ND	＜Lo Q	ND	＜LOQ	2.31	＜LOQ	2.44
TRD-1971-055A 150mg	Up to specification	NT=does not detect, ring amidine=cyclic amidine, and diketopiperazine=diketopiperazine, the LOQ=0.05% of ring amidine, diketopiperazine and amide, row spit of fland, Victor is 0.06%; LOD=0.02%; ND=does not detect Ref:TRD 1980/096 JT											ND	ND	ND	＜Lo Q	ND	＜LOQ	2.31

The dissolution data conclusive table that the initial time of table 3-22 Victor row spit of fland MR sheet (technology is criticized) is analyzed

Lot number	Discharge percent
	Discharge percent	0.25hr	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	?18hr
	?TRD-1971-05?3C?100mg?TRD-1971-05?5A?150mg	0.25hr	0.5hr	1hr	2hr	4hr	6hr	8hr	10hr	12hr	?18hr
?Ref：

Quality standard

During the early development of row spit of fland, Victor 25mg, 50mg and 100mg sheet, worked out temporary analytical standard [AS6105B].

III. Conclusion

Set up clinical service preparation (CSF) and contained 40%HPMC K100M " at a slow speed " release characteristics as controlled release polymer to provide.Exploitation direct compression mixture of powders is used for 100mg and 150mg specification.Determined to use roll-in can improve compaction characteristics and the powder flowbility of CSF.Roll-in shows and the similar dissolution characteristic of CSF (carrying out the human body in vivo test).Preparation do not present be subjected to roll-in speed or tabletting hold pressure (resident) time effects.

To CSF 100mg, 150mg and 200mg specification, obtained the stability data until 12 months at 25 ℃/60%RH and 30 ℃ of 60%RH.30 ℃ of 60%RH outward appearance, content, purity and stripping results after 12 months are all in the standard limit.These data are supported 100mg, 150mg and 200mg to transfer and are released 24 months the probative term again of sheet standard " store and be not higher than 25 ℃ ".Row spit of fland, Victor 150mg transfers the composition of releasing sheet to be included in the scope of 100mg and 200mg specification.Therefore, the stability of 150mg is can expection identical with the 200mg specification with 100mg.Therefore, to the 100mg again round of visits similar with the 200mg specification applicable to the 150mg sheet.Find suitable by 100mg and 150mg sheet that roll-in is produced at the stability characteristic of 6 weeks, 40 ℃/75%RH with the CSF preparation.Therefore, stability does not present the influence that comprises the roll-in step that is subjected in the production method.

Selected to comprise 40% or the roll-in preparation of 30%HPMC K100M.

Preferred formulation is described in the following table:

	100		?150
	100		?150		Composition	Mg/ unit	?％	Mg/ unit	?％
Row spit of fland, Victor	100	?25.0	?150	?25.0	Composition	Mg/ unit	?％	Mg/ unit	?％
Row spit of fland, Victor	100	?25.0	?150	?25.0	Microcrystalline Cellulose, PH102	120	?30.0	?180	?30.0
Lactose, anhydrous DT	16	?4.0	?24	?4.0	Microcrystalline Cellulose, PH102	120	?30.0	?180	?30.0
Lactose, anhydrous DT	16	?4.0	?24	?4.0	Hydroxypropyl emthylcellulose K100M	160	?40.0	?240	?40.0
Magnesium stearate	4	?1.0	?6	?1.0	Hydroxypropyl emthylcellulose K100M	160	?40.0	?240	?40.0
Magnesium stearate	4	?1.0	?6	?1.0	Total sheet heavy (mg)	400		?600

The KN number	3768652	?6001732
The KN number	3768652	?6001732	Sheet diameter, shape	11mm，FFBE	17 * 6.7mm, oval

Mode with explaination has been described the present invention, and is appreciated that the term of use is unrestricted for the attribute of text description.

Apparently, the present invention has many variations and variant according to above instruction.It is therefore to be understood that in the appended claims scope the present invention can not be by specifically describing practice.

Embodiment A: mechanical stress (particle size distribution)

Material in required grain graininess scope can be with any form of LAF237 for example amorphous or crystal form by mechanical stress production.This stress can be regulated by bump, shearing or compacting.In the available milling apparatus of most of commercializations, be the combination of these principles.Preferably use mechanical impact or jet mill for LAF237.Most preferred mechanical impact pulverizer can be installed different types of hammer (beater), sieve, liner or pin plates.Preferably use the bump grinder and the slit sieve aperture 5*2.5cm of board-like hammer (platebeater) for our method.Stroke speed should 20 and 100m/s between change with adapt to any batch with criticize between difference.The outer circular velocity of the hammer that uses under our situation is about 40-50m/s.

Pharmacokinetics and pharmacodynamic study:

Area under the AUC Cot curve

AUC _0-tBut the concentration from 0 time to a last quantitative data time point t-time song

Area under the line [ng*hr/mL]

AUC _0-infOr from 0 time to infinitely-great area under the concentration-time curve [ng*hr/mL]

AUC _(0-∞)

BAPK bioanalysis and pharmacokinetics part

C _MaxMaximal plasma concentration

CRF case report/log

CRO clinical research tissue

The CV coefficient of variation

The ECG electrocardiogram

DPP-4 peptidyl peptidase 4; DPP IV

FMI final market image

The GLP-1 glucagon-like peptide 1

ICH International Coordinating Committee

IRB Ethics Committee

Row spit of fland, LAF237 Victor

LC-MS/MS liquid chromatography-mass spectrography/mass spectrum

The LOQ quantitative limit

O.d. once a day

The PD pharmacodynamics

The PK pharmacokinetics

The p.o per os/by mouth/oral

The QC quality control

The SOP standard operating procedure

The SD standard deviation

t _MaxReach C _MaxTime

t _1/2Eliminate the half-life

The Vd/f volume of distribution, be used for the correction of absolute bioavailability

Report Summary and evaluation catalog

Research topic: at random, two kinds of new LAF237 100mg are estimated in opening, three stages, crossing research and 150mg transfers pharmacokinetics, pharmacodynamics, safety and the toleration of release formulation in the type 2 diabetes mellitus patient.

Purpose:

Main purpose

● transfer release formulation pharmaco-kinetic properties (single dose and multiple dose) after Orally administered in the type 2 diabetes mellitus patient in order to estimate two kinds of dosage specifications of LAF237 (100mg and 150mg).

● transfer two kinds of dosage specifications (100mg and 150mg) (single dose and multiple dose) of release formulation to the active influence of DPP-IV in order to estimate LAF237.

● transfer release formulation safety and toleration after Orally administered 7 days in the type 2 diabetes mellitus patient in order to estimate.

Secondary objective

● for the accent release formulation of estimating two kinds of dosage specifications of LAF237 (100mg and 150mg) to treating the influence of glucose characteristic after 7 days.

● for the pharmaco-kinetic properties of accent release formulation when giving and do not give ADA breakfast that compares two kinds of dosage specifications of LAF237.

Design: this research be single center, at random, opening, three stages, cross-over design research.Amount to 27 type 2 diabetes mellitus patients of typing (masculinity and femininity).The evaluation that three 11 days treatment stages that each experimenter participates in 28 days screening stages, three baseline period, separated by 7 days cleaning phases and research finish.

The experimenter enters following 3 treatment der group at random under William ' s design.

In proper order	Stage	1	Stage 2	Stage 3
In proper order	Stage	1	Stage 2	Stage 3	I	A	B	C
II	B	C	A		I	A	B	C
II	B	C	A	III	C	A	B

● treatment A:

● the 1st day: 100mg LAF237 MR OD, single dose

● 3-10 days: 100mg LAF237 MR OD, totally 8 days

● 11-17 days: clean

● treatment B:

● the 1st day: 150mg LAF237 MR OD, single dose

● 3-10 days: 150mg LAF237 MR OD, totally 8 days

● 11-17 days: clean

● treatment C:

● the 1st day: 50mg LAF237 BID, two dosage

● 3-10 days: 50mg LAF237 BID, totally 8 days

● 11-17 days: clean

The patient who accepts the metformin treatment needed inactive metformin at least 21 days in administration before the 1st day.In the-1 day the evening, satisfy all in when screening (the-28 days to-2 days) to be selected in/patient of exclusion standards enters the research center and be selected in/checking of exclusion standard, the baseline evaluation and continue after three der group in one randomization.The patient stays the residence until the 3rd day morning (LAF237 of the 1st dosage gives back 48h).

The 1st day of each treatment stage, the patient accepts the LAF237 of the 1st dosage behind the 10-12h that spends the night on an empty stomach.They 5h after administration continues on an empty stomach.The patient early dosage after left research place on the 3rd day with research medicine, how (the 3rd day to the 7th day) is in and is taken medicine in the time of out-patient treatment guidance and administration calendar at LAF237.

The accent release formulation of LAF237 (100mg and 150mg) is early being used once a day before the meal, and 50mgLAF237 uses twice every day, once before the meal early, once before dinner.Preserve the administration calendar that comprises all dosage of not living in the research place by the patient.

The patient got back to the research place in the 5th day morning and carries out moving this collection that imitates of administration prodrug.They before the morning of the 8th day LAF237 dosage at least 10h move in the research place up to the 12nd day morning (the 10th day dosage gives back 48h).At the 9th day, the patient gave ADA breakfast in the 30min of LAF237 dosage in morning.

Strictly carry out all and live in the research meal time on ground date.Within the 30min of dosage morning, eat the breakfast, except the 1st day and the 10th day patient empty stomach 5h after administration.Lunch and dinner during 5h after administration, 10h and 12h give respectively.

Screening	First, second and phase III
Screening	First, second and phase III						The-28～2 days	The-1 day	1-2 days	3-8 days	The 9th day	10-11 days	12-17 days
The needs of patients of accepting the metformin treatment stopped treatment at the-21 days	B/L	48h takes a sample under the empty stomach condition	The 3rd day: multiple dose administration began	The 24hr sampling gives ADA earlyMeal	The 48hr sampling exists On an empty stomachUnder the condition	W/o (after the 3rd stage, not needing)	The-28～2 days	The-1 day	1-2 days	3-8 days	The 9th day	10-11 days	12-17 days
		48h takes a sample under the empty stomach condition	The 3rd day: multiple dose administration began	The 24hr sampling gives ADA earlyMeal			The PK characteristic	The the 5th and 8 day: PK sampling before the administration	The PK characteristic	The PK characteristic
		The DPP-IV characteristic	3-7 days: the out-patient got back to the residence on the 8th day:	The DPP-IV characteristic measurement	The DPP-IV characteristic		The PK characteristic		The PK characteristic	The PK characteristic
				The DPP-IV characteristic measurement			The glucose characteristic measurement

Experimenter's quantity: 27 type 2 diabetes mellitus patients (masculinity and femininity)

Inclusion criteria:

● the age between 20 years old to 65 years old, the type 2 diabetes mellitus patient of masculinity and femininity (after menopause, operation can not give birth to or use two kinds of contraceptive devices).

● between the Hb1Ac scope 6.5 to 9%.

● Body Mass Index 22-40 kg/m ²Between.

● the patient must not take diabetes medicament or treats with metformin.

● the patient must be able to finish the cleaning in 3 weeks of current metformin treatment.Monitoring FPG and numerical value are phoned PI above 250mg/dL if the patient will be in.

● the patient must not take prescription drugs or nonprescription drugs.

● the patient is when screening and fasting glucose must be at 7.0-12.2mmo/dL (100-240mg/dL) before the 1st day administration.

● use the patient of diuretic or periodically hormone therapy must be in consistent dose (before the screening at least 3 months) and during studying maintenance dose cannot adjust.

● all experimenters must participate in the research prerequisite for written Informed Consent Form.

Exclusion standard:

● the secondary form of type i diabetes history, the diabetes that cause the pancreatic injury or diabetes, for example cushing's syndrome and acromegaly.

● pro-used the Thiazolidine ketone in 3 months.

● ketoacidosis disease history is arranged.

● pro-needs to use insulin in 3 months.

● significant disease or diabetic complication are together arranged.

● empty stomach triglyceride＞5.1mmol/L in 4 weeks in the past (＞450mg/dL).

● the treatment of whole body steroidal.

● any gastrointestinal procedures historical example is arranged such as intestinal partly excises, stomach divides excision etc. patient.

The research medicine:

LAF237 100mg MR (the MR preparation released in preferred accent as herein described)

LAF237 150mg MR (the MR preparation released in preferred accent as herein described)

LAF237 50mg (as described in U.S. Provisional Patent Application No.60/604274)

The treatment persistent period: 46 days total research length comprises wash phase.

Treatment A (LAF237 100mgMR OD):8 days multiple dose treatment of the 1st day single-dose treatment and beginning in the 3rd day.

Treatment B (LAF237 150mg MR OD):8 days multiple dose treatment of the 1st day single-dose treatment and beginning in the 3rd day.

Treatment C (50mg BID):8 days multiple dose treatment of the 1st day BID treatment and beginning in the 3rd day.

Two wash phases of 7 days between above treatment.

Estimate and assessment:

Background, demography and use evaluation

● selected/exclusion standard; Relevant administration history/current medication situation: screening, baseline are investigated

● population: screening

● physical examination: when screening, baseline, research end

● hepatitis examination, HIV examination: screening

● alcohol testing, medicine examination, urine cotinine: screening, baseline

● pregnancy tests: screening, baseline, research finish

● medication administration record: each study drug-administration

● the record of having a dinner: 1st, 2,8,9,10 and 11 days.

● information is finished in research: research finishes

● comment: when needing

Safety and toleration evaluation

● vital sign and body measurement

● height: screening

● body weight: screening, baseline, research finish

● body temperature: screening, baseline, research finish

● blood pressure, pulse rate: before screening *, baseline *, the administration and 1,6,12 and 24h after the administration in the 1st, 2,8,9 and 10 day, research finish (note: if measurement be dorsal position or labelling * dorsal position and behind the 3min that stands)

● ECG estimates: screening, baseline, research finish

● the hematology; Hematochemistry; Urinalysis: screening, baseline, research finish

● adverse events; Medication/significant non-drug therapy simultaneously: from the extremely research end of the study drug-administration first time

Pharmacokinetics is estimated

● blood collection (every this 2mL of increment blood, calparine pipe (blood plasma)):

1st, 9 ^*, 10 days: before the administration, after the administration 0.5,1,1.5,2,2.5,3,4,6,8,10,12,14,16,24,36 and 48h

The the 5th and 8 day: before the administration.

^*At sample collection in the 9th day 24h after the administration.Sample is also as the 9th day 24h sample before the administration in the 10th day.

● Analyte, medium and method: the LAF237 in the blood plasma measures with LC-MS-MS, and LOQ is 2ng/mL.

● The PK parameter: each treatment stage will be estimated AUC _0-t, AUC _(0-∞), C _Max, t _Max, t _1/2And C _Max/ AUC _(0-t)

Pharmacodynamics is estimated

The DPP-IV activity will be measured at the 1st, 9 and 10 day.

● Blood collection(every this 1mL of increment blood, EDTA manages (blood plasma)):

1st, 9 ^*With 10 days: before the administration, after the administration 0.25,0.5,0.75,1,2,4,6,8,10,12,14,16,24,36 and 48h

The 9th day glucose sample.

● blood collection (every this 2mL of increment blood, sodium fluoride pipe (blood plasma))

Behind the morning dosage 0.75,1,1.25,1.5,2., 2.5,3,4,5 (ante prandiums), 5.5,5.75,6,6.5,7,8,9.75 (before evening dosage and the dinner), 10.25,10.75,11,11.25,11.5,12,12.5,13,14,16 and 24h.

Statistical method

Sample size: sample size is based on that sided t-check 5% significance level people such as (, 1997) Chen of PK parameter determines.When test group-when reference group ratio equals 0.95, if CV is not more than 0.20 in the experimenter, the power of a test (power) of 24 experimenters' sample size permission at least 88% satisfies the bioequivalence standard, promptly, the test group of bioavailability measured value-reference group ratio has 90% CI to be included in the bioequivalence scope of (0.8,1.25); If or CV equals 0.25 in the experimenter, and 72% power of a test (power) is then arranged.Be used for determining that CV is deduced out in health volunteer's research by the similar preparation (LAF237A2214) of front in the experimenter of sample size, wherein to CV in the observed maximum experimenter of Cmax about 0.20.

Statistical analysis: use PROC MIXED SAS program that AUC and Cmax data to number conversion are carried out variance analysis (ANOVA).The source of variation that is included in the ANOVA model is order, experimenter (in proper order), stage and treatment, and experimenter (in proper order) is as stochastic effect.Use the ESTIMATE statement of PROC MIXED SAS program, between test group and reference therapy group, make up contrast to obtain p-value, the average difference of estimating, test group-reference group difference 90% confidence interval (CI) of logarithm value (log-scale).The antilogarithm of the average difference of estimating and the ratio that 90%CI has constituted geometric mean and the 90%CI of real test group-reference group ratio.With output the results list relatively.

In order to compare between the bioavailability to MR OD and IR BID, test group is MROD, and the reference group is IR BID.In ANOVA, between two treatment groups, compare AUC and the Cmax of LAF237.

Use aforesaid identical ANOVA model analysis PD terminal point.

Medicament administration

1st, 3,5,8,9 and 10 days research medicine is being used behind the 10h between 7:00～8:00 with 240mL water at least on an empty stomach by the research center personnel.All experimenter's dosing intervals are to the maximum in the 1h.Must teach the experimenter and not chew medicine, but full wafer is swallowed.Researcher must check that each experimenter's oral cavity is to guarantee that medicine is swallowed.If do not carry out research evaluation, the experimenter must be in ensuing 4h erect position rest quietly.Except the 1st day and the 10th day be that 5h gives first meal after administration, ADA gives in the 30min after administration.

During treatment C, the patient bowl before the meal 30min accept the dosage in evening of 50mg LAF237.General Study condition and restriction

The definition of conceptual phase

Screening

" screening " be defined as preceding 2 days of research beginning (that is, giving promptly the 1st day that day of first dosage) to the preceding evaluation of carrying out in 28 days to determine to enter the qualification of research.Screening inspection shows the unusual potential suitable experimenter that any discomfort is closed, if rechecking once but researcher is wished this experimenter of typing.

Baseline

If firmly do not study the place, the experimenter should be before each treatment phase administration at least 10h move in the research place." baseline " is defined as the lasting existence (the-1 day) of 30min experimenter on research equipment before the research medicament administration.Baseline activity comprises the safety evaluatio of listing as in research summary and the evaluation table.

The treatment phase

That each treatment phase comprises is movable before the administration (before administration in the 30min), medicament administration, administration post-evaluation 24h after administration, if possible also comprises the cleaning phase before treating the phase administration next time.Research finishes

Treat the last day of phase the last time, before the experimenter disbands from the research place, study the evaluation of end.

Inhabitation and doctor's coverage

Before the 1st day research medicament administration at least 10h until the 3rd day research medicament administration after 1h, the patient should be limited in the research center.The patient got back to blood specimen collection before administration is carried out in the research center in the 5th day morning.The patient before the 8th day research medicament administration at least 10h should live into, until 48h behind the dosage in the morning of accepting LAF237 on the 10th day.

The expectation doctor during the administration in each stage at least the 2h after administration research the place.The doctor should can find in the every other time of whole research by pager.Diet, liquid and other restrictions

During recruiting, informed consent inspection and baseline period, the experimenter is apprised of and reminds following restriction:

● can not carry out nervous physical exercise (for example, body weight training, aerobic training, football) in 7 days that before administration, finish until research evaluation.

● 72h finishes the diet red meat that do not have until research at least before entering research.

● 72h finishes and can not drink until research evaluation before administration.

● the xanthic absorption (for example, caffeine) that is included in the F﹠B must be interrupted 49h before administration.Any time after being consumed in the experimenter and moving in of such F﹠B (that is, coffee, tea, soda, chocolate) does not all allow, and must be labeled on the CRF page or leaf.

All live into date, removed the 1st day and the 10th day, the patient ADA early before the meal 30min accept the research medicine, and the empty stomach 10h that spends the night.The 1st day and the 10th day, do not have breakfast.

During treatment C, the patient also accepts the late dosage of research medicine before dinner.Trial drug should use 240mL (8fl oz) water to use.Except giving liquid when the administration, 2h 2h after administration does not allow intake liquid before the administration.In addition, the experimenter in the recovery time except have a dinner and the liquid of medicine, every 4h should take in 200mL liquid at least.

During the date of living, should be respectively after administration 5h and 10h have lunch and dinner, and 12h should advance a fast food after administration.

The experimenter should observe the diet of the body weight that maintains the standard in the date of the non-administration of living.Any time during conditioning should not consumed other foods.The experimenter should consume all foods of every meal.Should be similar for the calorie content that all experimenters had a dinner on the same day of administration with distribution.

When meal time and blood drawing time-interleaving, blood is being used extraction before the meal.Comprise the food of xanthine (for example, caffeine) or the absorption of beverage and must before administration, interrupt 48h.Such F﹠B (that is, coffee, tea and soda, chocolate) is consumed in any time that the experimenter moves in and is not allowed to.If deviation takes place during moving in, must be labeled in the CRF page or leaf of comment.Background, demography and use evaluation

Inclusion criteria/exclusion standard

The selection that has checked the experimenter by all inclusion criteria/exclusion standards.Relative recording (for example, checklist) must be stored in the research place to file.Any violation that enters standard will be got rid of the experimenter and enter research, unless the specific permission of bidding person.

Medication administration record

The date and time that dosage is used is recorded in the dosage administration records part of CRF, and if feasible, also be recorded in the blood collection CRF page or leaf of pharmacokinetics and pharmacodynamics evaluation.

The dining record

In the suitable part that date of having meal and time started are recorded in all CRF that live the date.

The research ending message

Take medicine at last information that date, experimenter research finished or studied the date of interruption and the reason that research is interrupted of experimenter is recorded in research and finishes in the CRF page or leaf.

Pharmacokinetics is estimated

Blood collection: the whole blood sample is directly got by venipuncture or is taken a sample by the indwelling intubate of inserting forearm vein.

LAF237: for the LAF237 sample of each time that is ranked, specified time point is gathered the 2mL blood sample to heparin sodium or Lithium acid heparin pipe in the evaluation time table.

The processing of blood sample

After every pipe blood sample extracts immediately, the jolting mixing of in vitro tolerant to guarantee (for example, anticoagulant) for several times gently.Avoid sample to contact with rubber stopper for a long time.Test tube vertically is placed in the test tube rack (for example, on every side with ice, or at room temperature) until centrifugal.In 15min, the centrifugal sample 15min of about 2500rpm between 3 to 5 ℃.Get in the blood 60min at vein, shift all acquired blood plasma to polypropylene tool plug test tube and be frozen in-70 ℃ or following.

Analytical method

Analyte, medium and method: the LAF237 in the blood plasma analyzes with LC-MS-MS; LLOQ is 2ng/mL.

Pharmacodynamics is estimated: every patient's whole blood sample is by the venipuncture direct sample or by inserting the indwelling intubate sampling of forearm vein.

Glucose: to the glucose sample of each time that is ranked, the fixed time point in the evaluation time table is gathered the 2mL blood sample to sodium fluoride (Lycoperdon polymorphum Vitt top) pipe.The central laboratory that is used for analysed for plasma glucose sample does not measure at this point.In case measure, sample process and data transfering method summarized in the testing program appendix.

DPP-IV:DPP-IV measures and is undertaken by Novartis's laboratory.For the DPP-4 enzyme analyzing samples collection of the time of being ranked, gather 1ml blood to the test tube that contains EDTA potassium.Upset is for several times to mix the content of test tube gently.Avoid sample Long contact time rubber stopper.Vertically place test tube and in frame, put ice until centrifugal on every side.After collection in the 15min, the centrifugal sample 15min of about 2500rpm between 3 to 5 ℃.In the 60min of vein sampling, shift all blood plasma that obtain to polypropylene tool plug micro test tube and be chilled in-70 ℃ or following.

Labelling and transport instruction are seen the 9th joint, the B part.

Data analysis

Data analysis will carry out under the personnel's of Novartis guidance.

General statistics is considered

Sample size is determined

(people such as Chen, 1997-Chen KW, Chow SC, Li G (1997) that sample size is based on that sided t-check 5% significance level determines.One piece of paper that the sample size of the bioequivalence Journal of Sex Research of more senior cross-over design is determined.J?Parmarcokin，Biopharm.25：753-765.)。When test group-when reference group ratio equals 0.95, if CV is not more than 0.20 in the experimenter, the power of a test (power) of 24 experimenters' sample size permission at least 88% satisfies the bioequivalence standard, promptly, the test group of bioavailability measured value-reference group ratio has 90% CI to be included in the bioequivalence scope of (0.8,1.25); If or CV equals 0.25 in the experimenter, and 72% power of a test (power) is then arranged.Be used for determining that CV is deduced out in health volunteer's research by the similar preparation (LAF237A2214) of front in the experimenter of sample size, wherein to CV in the observed maximum experimenter of Cmax about 0.17.

Background, demography and use data analysis

Background and population variable such as age, body weight, height, sex and race's descriptive statistics is provided.

List relevant administration history, current medication situation, laboratory screening result, drug test and any other relevant information.

Safety and tolerance data analysis

Accepting at least, all experimenters of seance are included in safety and the toleration evaluation.

Pharmacokinetic data available is analyzed

All experimenters that finish are included in the pharmacokinetic data available analysis.

The pharmacokinetics variable

Each treatment stage is estimated following pharmacokinetic parameters: AUC _0-t, AUC _(0-∞), C _Max, t _Max, t _1/2, and C _Max/ AUC _(0-t)

Biological fluid concentration is with the quality representation of every volume unit.All concentration or missing datas below quantitative limit are marked in the concentration data tabulation.In conduct zero processing in summary statistics and pharmacokinetic parameters calculating of the concentration below the quantitative limit.

Descriptive statistic in the pharmacokinetic parameters comprises average, SD and CV, minima and maximum.When present be geometric mean the time should indicate.Present for the scope of selected variable with numerical value.Because t _MaxGeneral use nonparametric technique evaluation provides intermediate value and scope to this parameter.

Pharmacokinetic parameters uses WinNonlin Pro to calculate based on non-compartment method.

The statistical method of pharmacokinetic analysis

Use PROC MIXED SAS program to carry out variance analysis (ANOVA) to AUC and Cmax data to number conversion.The source of variation that is included in the ANOVA model is order, experimenter (in proper order), cycle and treatment, and experimenter (in proper order) is as stochastic effect.Use the ESTIMATE statement of PROC MIXED SAS program, between test group and reference group, make up average difference, 90% confidence interval (CI) of contrast with the estimation of the test group-reference group difference of acquisition p-value, log scale.The average difference of estimating and the antilogarithm of 90% confidence interval constitute the ratio and 90% confidence interval of the geometric mean of real test group-reference group.Correlated output the results list.

In order to compare the bioavailability between MR OD and the IR BID, the test of cure group is MROD, and the reference group is IR BID.The AUC and the Cmax that in ANOVA, compare the LAF237 between two treatment groups.

The pharmacodynamics data analysis

All experimenters that finish valuable pharmacodynamics (PD) mensuration are included in the data analysis.

The pharmacodynamics variable

Following glucose parameter can be used for deriving the contrast of treatment:

0 time of AUE area to the drug effect-time graph of can be observed by linear trapezoid method last time point

E _MaxCeiling effect (minima)

t _MaxThe time that ceiling effect occurs for the first time.

In order not lose experimenter's data, use following algorithm to replace the numerical value of disappearance owing to disappearance numerical value:

If ● the observed result disappearance of first or last experimenter record, then with the observed result replacement of second or front they.

If ● in non-disappearance observed result series, lack observed result, then lack numerical value and replace by the linear regression result based near the numerical value it.

If ● two successive observed result disappearances, then ignore this record fully.

The statistical method of pharmacodynamic analysis

The glucose parameter uses the identical ANOVA model of statistics of the PK of being used for parameter as indicated above to analyze.

In addition, use above-described identical ANOVA model to carry out the contrast of the time point direction of concentration of glucose.

The result:

Pharmacokinetics result (being described in Figure 24,25,26)

Treatment	Tmax (h) intermediate value (min, max)	Cmax (ng/mL) mean value SD (CV%)	AUC a (hng/mL) mean value SD (CV%)	CL/F (L/h) mean value SD (CV%)	T1/2 (h) mean value SD (CV%)
Treatment	Tmax (h) intermediate value (min, max)	Cmax (ng/mL) mean value SD (CV%)	AUC a (hng/mL) mean value SD (CV%)	CL/F (L/h) mean value SD (CV%)	T1/2 (h) mean value SD (CV%)	The 1st day (single dose on an empty stomach) (N=27)
LAF237100mg?MROD	4.00(1.50，6.00)	205±47(23)	1449±376(26)	73.60±19.60(27)	11.69±5.68(49)	The 1st day (single dose on an empty stomach) (N=27)
LAF237100mg?MROD	4.00(1.50，6.00)	205±47(23)	1449±376(26)	73.60±19.60(27)	11.69±5.68(49)	LAF237150mg?MROD	4.00(1.50，6.00)	257±59(23)	2271±925(41)	75.63±28.54(38)	10.75±5.01(47)
LAF23750mg MRBID	1.00(0.50，4.00)	278±75(27)	2159±425(20)	?45.14±7.91(18)	2.43±1.12(46)	LAF237150mg?MROD	4.00(1.50，6.00)	257±59(23)	2271±925(41)	75.63±28.54(38)	10.75±5.01(47)
LAF23750mg MRBID	1.00(0.50，4.00)	278±75(27)	2159±425(20)	?45.14±7.91(18)	2.43±1.12(46)	The 9th day (multiple dose is had a dinner) (N=27)
LAF237100mg?MROD	2.00(1.00，6.00)	200±64(32)	1489±488(33)	75.45±29.07(39)	8.70±3.75(43)	The 9th day (multiple dose is had a dinner) (N=27)
LAF237100mg?MROD	2.00(1.00，6.00)	200±64(32)	1489±488(33)	75.45±29.07(39)	8.70±3.75(43)	LAF237150mg?MROD	2.50(1.00，6.00)	272±111(41)	2242±965(43)	78.84±31.30(40)	10.34±5.06(49)
LAF23750mg?BID	1.00(1.00，4.00)	285±91(32)	1992±461(23)	50.92±16.51(32)	2.83±0.62(22)	LAF237150mg?MROD	2.50(1.00，6.00)	272±111(41)	2242±965(43)	78.84±31.30(40)	10.34±5.06(49)
LAF23750mg?BID	1.00(1.00，4.00)	285±91(32)	1992±461(23)	50.92±16.51(32)	2.83±0.62(22)	The 10th day (multiple dose on an empty stomach) (N=27)
LAF237100mg?MROD	3.00(1.00，6.00)	215±68(31)	1638±535(33)	66.77±20.87(31)	11.80±5.69(48)	The 10th day (multiple dose on an empty stomach) (N=27)
LAF237100mg?MROD	3.00(1.00，6.00)	215±68(31)	1638±535(33)	66.77±20.87(31)	11.80±5.69(48)	LAF237150mg?MROD	4.00(2.50，6.00)	309±91(29)	2458±815(33)	67.19±21.27(32)	10.54±5.39(51)

LAF23750mg?MRBID	2.00(0.50，9.97)	257±60(23)	2198±492(22)	44.92±10.97(24)	3.38±2.62(77)
LAF23750mg?MRBID	2.00(0.50，9.97)	257±60(23)	2198±492(22)	44.92±10.97(24)	3.38±2.62(77)	A: AUC at the 1st day _0-inf, AUC at the 9th and the 10th day _0-24，LAF237 50mg BID was at the 1st day AUC _0-24

The result:

Pharmacodynamic result (being described in Figure 21,22,23)

Treatment	DPP-4-AUC24 (%.h) mean value SD (CV%)	DPP-4-MRT (h) mean value SD (CV%)	DPP-4-Avg (%) mean value SD (CV%)	DPP-4-24h (%) mean value SD (CV%)
Treatment	DPP-4-AUC24 (%.h) mean value SD (CV%)	DPP-4-MRT (h) mean value SD (CV%)	DPP-4-Avg (%) mean value SD (CV%)	DPP-4-24h (%) mean value SD (CV%)	The 1st day (single dose on an empty stomach) (N=27)
LAF237100mg?MR?OD	2208±73(3)	11.8±0.3(3)	92.01±3.03(3)	85.64±12.76(15)	The 1st day (single dose on an empty stomach) (N=27)
LAF237100mg?MR?OD	2208±73(3)	11.8±0.3(3)	92.01±3.03(3)	85.64±12.76(15)	LAF237150mg?MR?OD	2242±70(3)	11.9±0.3(3)	93.43±2.93(3)	90.04±11.91(13)
LAF23750mg?MR?BID	2225±48(2)	11.7±0.2(2)	92.69±2.01(2)	80.92±9.03(11)	LAF237150mg?MR?OD	2242±70(3)	11.9±0.3(3)	93.43±2.93(3)	90.04±11.91(13)
LAF23750mg?MR?BID	2225±48(2)	11.7±0.2(2)	92.69±2.01(2)	80.92±9.03(11)	The 9th day (multiple dose is had a dinner) (N=27)
LAF237100mg?MR?OD	2240±98(4)	11.8±0.5(4)	93.35±4.09(4)	87.78±16.37(19)	The 9th day (multiple dose is had a dinner) (N=27)
LAF237100mg?MR?OD	2240±98(4)	11.8±0.5(4)	93.35±4.09(4)	87.78±16.37(19)	LAF237150mg?MR?OD	2270±86(4)	11.8±0.5(4)	94.59±3.57(4)	90.40±17.50(19)
LAF23750mg?BID	2252±33(1)	11.8±0.1(1)	93.85±1.36(1)	86.15±4.78(6)	LAF237150mg?MR?OD	2270±86(4)	11.8±0.5(4)	94.59±3.57(4)	90.40±17.50(19)
LAF23750mg?BID	2252±33(1)	11.8±0.1(1)	93.85±1.36(1)	86.15±4.78(6)	The 10th day (multiple dose on an empty stomach) (N=27)
LAF237100mg?MR?OD	2261±40(2)	11.9±0.2(1)	94.21±1.66(2)	90.20±7.35(8)	The 10th day (multiple dose on an empty stomach) (N=27)
LAF237100mg?MR?OD	2261±40(2)	11.9±0.2(1)	94.21±1.66(2)	90.20±7.35(8)	LAF237150mg?MR?OD	2281±49(2)	11.9±0.2(2)	95.06±2.03(2)	91.64±8.47(9)
LAF23750mg?MR?BID	2243±46(2)	11.7±0.2(1)	93.44±1.94(2)	82.80±7.39(9)	LAF237150mg?MR?OD	2281±49(2)	11.9±0.2(2)	95.06±2.03(2)	91.64±8.47(9)

Claims

The per unit dosage form for example every drug tablet formulation comprise following composition:

(a) as the compound or pharmaceutically acceptable salt thereof of active component, wherein said chemical compound has the structure of following formula:

Wherein R is the adamantyl that replaces, and n is from 0 to 3 integer;

(b) apparent viscosity in the time of in being present in 1% solution is 80,000cP to 120,000cP (sign value 100, hydroxypropyl emthylcellulose 000cP);

(C) microcrystalline Cellulose; With

(d) magnesium stearate.
2. the drug tablet formulation of claim 1, wherein with respect to the weight of preparation:

(a) chemical compound exists with 20% to 30% weight;

(b) hydroxypropyl emthylcellulose exists with 30% to 50% weight;

(c) microcrystalline Cellulose exists with 25% to 35% weight; With

(d) magnesium stearate exists with 0.1% to 3% weight.
3. claim 1 or 2 drug tablet formulation, wherein with respect to the weight of preparation:

(a) chemical compound exists with about 25% weight;

(b) hydroxypropyl emthylcellulose exists with about 40% weight;

(c) microcrystalline Cellulose exists with about 30% weight; With

(d) magnesium stearate exists with about 1% weight.
4. any the drug tablet formulation of claim 1-3 also comprises lactose.
5. the drug tablet formulation of claim 4, wherein lactose exists with 1% to 8% weight.
6. the drug tablet formulation of claim 3 also comprises the lactose of about 4% weight.
7. any drug tablet formulation of claim 1-6, wherein said chemical compound is 1-[2-[(5-cyanopyridine-2-yl) amino] ethylamino] acetyl group-2-cyano group (s)-ketopyrrolidine or its officinal salt.
8. any drug tablet formulation of claim 1-6, wherein said chemical compound is row spit of fland, Victor or its officinal salt.
9. the drug tablet formulation of claim 8, wherein said chemical compound is that the crystal form in row spit of fland, Victor is preferably crystal formation " A " or its officinal salt.
10. drug tablet formulation, its every 400mg sheet comprises following composition:

(a) Victor row spit of fland or its officinal salt;

(b) hydroxypropyl emthylcellulose of about 160mg amount has 80 when wherein hydroxypropyl emthylcellulose is in being present in 1% solution, 000cP to 120, the apparent viscosity of 000cP (sign value 100,000cP);

(c) microcrystalline Cellulose of 120mg amount;

(d) lactose of about 16mg amount; With

(e) magnesium stearate of 4mg amount.
11. the method for any the drug tablet formulation of preparation claim 1-10, it comprises the composition of measuring described in this claim of combination.
12. the active method of DPP IV in the inhibition individuality, it comprises the amount of using the active drug tablet formulation of DPP IV in any effective inhibition individuality of claim 1-10 to individuality.
13. the method for claim 12, wherein said individuality is the people.
14. the treatment of conditions method by dipeptidyl peptidase in the individuality that suppresses to suffer this disease can be eased comprises any drug tablet formulation to the claim 1-10 of described individual administering therapeutic effective dose.
15. the method for claim 14, wherein said disease is a non-insulin-dependent diabetes mellitus.
16. the method for claim 14, wherein said disease are obesity, arthritis or osteoporosis.
17. any the method for claim 14-16, wherein said individuality is the people.
18. by the treatment of conditions method that dipeptidyl peptidase in the individuality that suppresses to suffer this disease can be eased, it comprises any the drug tablet formulation of claim 1-10 of using and treating the treatment effective dose of the anti-diabetic of effective dose or the combination of arthritis medicine to individuality.
19. the method for claim 18, wherein said individuality is the people.
20. per unit dosage form for example every drug tablet formulation comprises following composition:

(a) as the compound or pharmaceutically acceptable salt thereof of active component, wherein said chemical compound has the structure of following formula:

Wherein R is that the adamantyl that replaces and n are from 0 to 3 integers; With

(b) have 80 in the time of in being present in 1% solution, 000cP to 120,000cP (sign value 100, the hydroxypropyl emthylcellulose of apparent viscosity 000cP).
21. the drug tablet formulation of claim 20 wherein also comprises filler.
22. the drug tablet formulation of claim 21, wherein said filler is a lactose.
23. the drug tablet formulation of claim 21, wherein said filler is a microcrystalline Cellulose.
24. the drug tablet formulation of claim 20 wherein also comprises lubricant.
25. the drug tablet formulation of claim 24, wherein said lubricant is a magnesium stearate.
26. the drug tablet formulation of claim 20, wherein in weight with respect to preparation, the amount from 30% to 50% that hydroxypropyl emthylcellulose exists.
27. the drug tablet formulation of claim 20, the weight from 34% to 46% that hydroxypropyl emthylcellulose wherein exists is preferably 38% to 42%.
28. per unit dosage form for example every drug tablet formulation comprises following composition:

(d) as row spit of fland, Victor or its officinal salt of active component,

(e) have 80 in the time of in being present in 1% solution, 000cP to 120,000cP (sign value 100, the hydroxypropyl emthylcellulose of apparent viscosity 000cP),

(f) also optional filler and/or lubricant.
29. according to the drug tablet formulation of claim 28, wherein in unit dosage forms, the weight ratio of row spit of fland, Victor and hydroxypropyl emthylcellulose is 0.16 to 2.5, is preferably 0.3 to 1.16 or 0.4 to 1.
30. according to the drug tablet formulation of claim 28 or claim 29, it comprises:

(a) the 15-55% pharmaceutically acceptable filler based on dry weight of 25-45% weight preferably; And it is optional

(b) the pharmaceutically acceptable lubricant based on dry weight of the preferred 0.1-3% weight of 0.1-10%.
31. according to the drug tablet formulation of claim 28 or 29, it comprises:

(a) the preferred 25-45% weight of 15-55% is selected from the pharmaceutically acceptable filler of lactose and microcrystalline Cellulose based on one or both of dry weight; And it is optional

(b) the pharmaceutically acceptable lubricant based on dry weight of the preferred 0.1-3% weight of 0.1-10%.
32. according to the drug tablet formulation of claim 28, the per unit dosage form comprises:

(a) row spit of fland, Victor or its officinal salt based on dry weight of the preferred 15-35% weight of 10-50% as active component,

(b) the preferred 30-50% weight of 20-60% based on dry weight in being present in 1% solution the time have 80,000cP to 120, the apparent viscosity of 000cP (sign value 100, hydroxypropyl emthylcellulose 000cP),

And optional filler and/or lubricant.
33. according to the drug tablet formulation of claim 28, the per unit dosage form comprises:

(a) row spit of fland, Victor or its officinal salt based on dry weight of the preferred 15-35% weight of 10-50% as active component,

(b) the preferred 30-50% weight of 20-60% based on dry weight in being present in 1% solution the time have 80,000cP to 120, the apparent viscosity of 000cP (sign value 100, hydroxypropyl emthylcellulose 000cP);

(c) filler; With

(d) lubricant.
34. according to the drug tablet formulation of claim 28, the per unit dosage form comprises:

(c) row spit of fland, Victor or its officinal salt based on dry weight of the preferred 15-35% weight of 10-50% as active component,

(d) the preferred 30-50% weight of 20-60% based on dry weight in being present in 1% solution the time have 80,000cP to 120, the apparent viscosity of 000cP (sign value 100, hydroxypropyl emthylcellulose 000cP);

(e) the pharmaceutically acceptable filler based on dry weight of the preferred 25-45% weight of 15-55%; And it is optional

(f) the pharmaceutically acceptable lubricant based on dry weight of the preferred 0.1-3% weight of 0.1-10%.
35. according to the drug tablet formulation of claim 28, the per unit dosage form comprises:

(c) row spit of fland, Victor or its officinal salt based on dry weight of the preferred 15-35% weight of 10-50% as active component,

(d) the preferred 30-50% weight of 20-60% based on dry weight in being present in 1% solution the time have 80,000cP to 120, the apparent viscosity of 000cP (sign value 100, hydroxypropyl emthylcellulose 000cP);

(e) the preferred 25-45% weight of 15-55% is selected from the pharmaceutically acceptable filler of lactose and microcrystalline Cellulose based on one or both of dry weight; And it is optional

(f) the pharmaceutically acceptable lubricant based on dry weight of the preferred 0.1-3% weight of 0.1-10%.
36. according to the drug tablet formulation of claim 28, the per unit dosage form comprises:

(a) row spit of fland, Victor or its officinal salt based on dry weight of the preferred 15-35% weight of 10-50% as active component,

(b) the preferred 30-50% weight of 20-60% based on dry weight in being present in 1% solution the time have 80,000cP to 120, the apparent viscosity of 000cP (sign value 100, hydroxypropyl emthylcellulose 000cP);

(c) 25-40% weight is selected from the pharmaceutically acceptable filler of lactose and microcrystalline Cellulose based on one or both of dry weight; And it is optional

(d) the pharmaceutically acceptable lubricant based on dry weight of the preferred 0.1-3% weight of 0.1-10%.
37. according to any the drug tablet formulation of claim 28-36, wherein said filler is selected from lactose and microcrystalline Cellulose.
38. according to any the drug tablet formulation of claim 28-37, it comprises at least two kinds of filleies.
39. according to the drug tablet formulation of claim 38, wherein said filler is lactose and microcrystalline Cellulose.
40. according to the drug tablet formulation of claim 39, the amount that wherein said lactose exists is from 1 to 8% preferred 1 to 5% by weight, and the amount that exists of microcrystalline Cellulose by weight from 25 to 35%.
41. according to any the drug tablet formulation of claim 28-40, wherein the row spit of fland, Victor based on dry weight of 20-30% weight is comprised in the preparation.
42. according to any drug tablet formulation of claim 28-41, the amount that wherein said hydroxypropyl emthylcellulose exists by weight from 34% to 46% preferably from 38% to 42%.
43. according to any the drug tablet formulation of claim 28-42, wherein said lubricant is a magnesium stearate.
44. according to the drug tablet formulation of any of aforementioned claim, in the unit dosage forms therein, the amount that row spit of fland, Victor exists is 100mg to 200mg, or the respective amount of its any salt.
45. according to the drug tablet formulation of any of aforementioned claim, in the unit dosage forms therein, the amount that row spit of fland, Victor exists is 100mg, 150mg or 200mg, or the respective amount of its any salt.
46. the drug tablet formulation of every 600mg sheet comprises following composition:

(a) the 1-[(3-hydroxyl-adamantyl of about 150mg amount-1-base is amino)-acetyl group]-pyrrolidine-2 (S)-nitrile or its officinal salt;

(b) hydroxypropyl emthylcellulose of about 240mg amount has 80 when wherein hydroxypropyl emthylcellulose is in being present in 1% solution, 000cP to 120, and (the sign value is 100 to the apparent viscosity of 000cP, 000cP);

(c) microcrystalline Cellulose of 180mg amount;

(d) lactose of about 24 mg amount; With

(e) magnesium stearate of 6mg amount.
47. drug tablet formulation, its every 400mg sheet comprises following composition:

(a) the 1-[(3-hydroxyl-adamantyl of about 100mg amount-1-base is amino)-acetyl group]-pyrrolidine-2 (S)-nitrile or its officinal salt;

(b) hydroxypropyl emthylcellulose of about 160mg amount has 80 when wherein hydroxypropyl emthylcellulose is in being present in 1% solution, 000cP to 120, and (the sign value is 100 to the apparent viscosity of 000cP, 000cP);

(c) microcrystalline Cellulose of 120mg amount;

(d) be about the lactose that 16mg measures; With

(e) magnesium stearate of 4mg amount.
48. the medicine multilayer tablet, wherein any the drug tablet formulation of claim 28-47 is represented the one deck in the lamella.
49. according to the medicine multilayer tablet of claim 48, wherein other layer comprises lattice row ketone (for example, pioglitazone or rosiglitazone) or metformin.
50. according to the medicine multilayer tablet of claim 48, wherein other layer is the quick releasing formulation that comprises lattice row ketone (for example, pioglitazone or rosiglitazone) or metformin.
51. medicinal tablet, its drug tablet formulation by any of compacting claim 1 to 47 obtains.
52. by the medicinal tablet that any drug tablet formulation suppressing claim 1 to 47 obtains, wherein said drug tablet formulation is the process roll-in before tablet forming.
53. according to the medicinal tablet of claim 52, it comprises row spit of fland, Victor or its salt of 100mg, wherein said tablet hardness scope is between 10 to 13Kp.
54. according to the medicinal tablet of claim 52, it comprises row spit of fland, Victor or its salt of 150mg, wherein said tablet hardness scope is between 11 to 25Kp.
55. comprise the row spit of fland, Victor of 100mg or the drug tablet formulation of its salt, preferably be pressed into the form of slow releasing tablet, wherein:

Between-10% and 16% preferably the row spit of fland, Victor between 11% and 15% behind 0.5h, discharge,

Between-18% and 24% preferably the row spit of fland, Victor between 19% and 23% behind 1h, discharge,

Between-30% and 36% preferably the row spit of fland, Victor between 31% and 35% behind 2h, discharge,

Between-46% and 52% preferably the row spit of fland, Victor between 47% and 51% behind 4h, discharge,

Between-58% and 64% preferably the row spit of fland, Victor between 59% and 63% behind 6h, discharge,

Between-67% and 73% preferably the row spit of fland, Victor between 68% and 72% behind 8h, discharge,

Between-74% and 80% preferably the row spit of fland, Victor between 75% and 79% behind 10h, discharge,

Between-80% and 86% preferably the row spit of fland, Victor between 81% and 85% behind 12h, discharge,

Between-91% and 97% preferably the row spit of fland, Victor between 92% and 96% behind 18h, discharge,

Between-95% and 100% preferably the row spit of fland, Victor between 96% and 100% behind 24h, discharge.
56. comprise the row spit of fland, Victor of 150mg or the drug tablet formulation of its salt, preferably be pressed into the form of slow releasing tablet, wherein:

Between-3.8% and 9.8% preferably the row spit of fland, Victor between 4.8% and 8.8% behind 0.25h, discharge,

Between-8.1% and 14.1% preferably the row spit of fland, Victor between 9.1% and 13.1% behind 0.5h, discharge,

Between-14.7% and 20.7% preferably the row spit of fland, Victor between 15.7% and 19.7% behind 1h, discharge,

Between-25.3% and 31.3% preferably the row spit of fland, Victor between 26.3% and 30.3% behind 2h, discharge,

Between-40.9% and 46.9% preferably the row spit of fland, Victor between 41.9% and 45.9% behind 6h, discharge,

Between-62.1% and 68.1% preferably the row spit of fland, Victor between 63.1% and 67.1% behind 8h, discharge,

Between-76.5% and 82.5% preferably the row spit of fland, Victor between 77.5% and 81.5% behind 10h, discharge,

Between-83.5% and 89.5% preferably the row spit of fland, Victor between 84.5% and 88.5% behind 12h, discharge,

Between-88.5% and 94.5% preferably the row spit of fland, Victor between 89.5% and 93.5% behind 18h, discharge.
57. according to the drug tablet formulation of claim 55 or 56, it comprises hydroxypropyl emthylcellulose, based on the weight of the dry weight of hydroxypropyl emthylcellulose preferably between 20% and 60%, between 30% and 50%.
58. drug tablet formulation according to claim 55 or 56, apparent viscosity when it comprises in being present in 1% solution is 80,000cP to 120, (the sign value is 100 to 000cP, hydroxypropyl emthylcellulose 000cP), the apparent viscosity with in being present in 1% solution the time is 80,000cP to 120,000cP (the sign value is 100, the dry weight of hydroxypropyl emthylcellulose 000cP) be the basis weight preferably between 20% and 60% or between 30% and 50%.
59. according to any drug tablet formulation of claim 55 to 56 are drug tablet formulations of any according to claim 1 to 47.
60. medicinal tablet, its drug tablet formulation of any by compacting claim 55 to 59 obtains.
61. by the medicinal tablet according to claim 60 that any drug tablet formulation suppressing claim 1 to 47 or 55 to 59 obtains, wherein said drug tablet formulation is the process roll-in before being pressed into tablet.
62. comprise the row spit of fland, Victor of 100mg or the medicinal tablet of its salt according to claim 60 or claim 61, the hardness range of wherein said tablet is between 10 to 13Kp.
63. comprise the row spit of fland, Victor of 150mg or the drug tablet formulation of its salt according to claim 60 or claim 61, wherein the hardness range of tablet is between 11 to 25Kp.
64. medicament capsule, tablet, compressed tablet, direct compressed tablet, granule, it comprises any drug tablet formulation of claim 1 to 47 or 55 to 59.
65. any drug tablet formulation or medicinal tablet according to claim 1 to 64, wherein said dispersion comprises and contains the particle that the DPP-IV inhibitor is preferably the row spit of fland, Victor of free form or acid-addition salts form, and wherein the particle size distribution in the preparation at least 60%, be preferably 80% and most preferably to be 90% be less than 250 μ m or preferably between 10 to 250 μ m.
66. drug tablet formulation or medicinal tablet according to claim 1 to 64, wherein said dispersion comprises and contains the particle that the DPP-IV inhibitor is preferably the row spit of fland, Victor of free form or acid-addition salts form, and wherein the particle size distribution in the tablet at least 60%, be preferably 80% and most preferably be 90% greater than 10 μ m.
67. drug tablet formulation or medicinal tablet according to claim 1 to 66, wherein said dispersion comprises and contains the LAF237 that the DPP-IV inhibitor is preferably free form or acid-addition salts form, and wherein in the preparation at least 25% of particle size distribution, be preferably 35% and the particle size distribution that most preferably is in 45% the preparation be between 50 to 150 μ m.
68., comprise another therapeutic agent at least according to the drug tablet formulation or the medicinal tablet of claim 1 to 67.
69. according to the drug tablet formulation or the medicinal tablet of claim 68, comprising at least, another is selected from the therapeutic agent of antidiabetic drug, Angiotensin II antagonist or statins.
70. according to any drug tablet formulation or medicinal tablet of claim 68 and 69, wherein said antidiabetic drug is selected from pioglitazone, rosiglitazone or metformin.
71. according to any the drug tablet formulation or the medicinal tablet of claim 1 to 70, wherein said drug tablet formulation is that the form with one deck of multilamellar or double-layer tablet exists.
72. any pharmaceutical preparation according to aforesaid claim, capsule, tablet, compressed tablet, direct compressed tablet, granule be used for the following disease of production for treating with the purposes of medicine that can be by the relevant disease of the above effect of GLP-1 and/or GLP-2 level mediation, described disease comprises such as non-insulin-dependent diabetes mellitus, arthritis, fat, the allosome organ transplantation, calcitonin-osteoporosis, heart failure, impaired glucose metabolism, IGT (glucose tolerance reduction), neurodegenerative disease such as Alzheimer and parkinson, the modulability hyperlipemia, with hyperlipemia or reduction VLDL, LDL, with the relevant modulability disease of Lp (a) level, cardiovascular diseases or nephropathy be diabetic cardiomyopathy for example, left ventricle or right ventricular hypertrophy, film thickens in tremulous pulse and/or the trunk hypertrophy, mesentery vascular system hypertrophy, glomerular mesangium thickens, neural degeneration obstacle and cognitive disorder, to produce calmness and angst resistance effect, alleviate that postoperative catabolism changes and hormone to stress response, mortality rate and sickness rate after the reduction myocardial infarction.
73. treat following disease with can be by the method for the relevant disease of the above effect of GLP-1 and/or GLP-2 level mediation, such as non-insulin-dependent diabetes mellitus, arthritis, fat, the allosome organ transplantation, calcitonin-osteoporosis, heart failure, impaired glucose metabolism, IGT (glucose tolerance reduction), neurodegenerative disease such as Alzheimer and parkinson, the modulability hyperlipemia, with hyperlipemia or reduction VLDL, LDL, with the relevant modulability disease of Lp (a) level, cardiovascular diseases or nephropathy be diabetic cardiomyopathy for example, left ventricle or right ventricular hypertrophy, film thickens in tremulous pulse and/or the trunk hypertrophy, mesentery vascular system hypertrophy, glomerular mesangium thickens, neural degeneration obstacle and cognitive disorder, to produce calmness and angst resistance effect, alleviate that postoperative catabolism changes and hormone to stress response, reduce mortality rate and sickness rate after the myocardial infarction, Therapeutic Method comprises to its any the pharmaceutical preparation according to aforementioned claim of homoiothermic animal administering therapeutic effective dose of needs, capsule, tablet, compressed tablet, direct compressed tablet, granule.
74. the method for the tablet of preparation unit dosage forms, it comprises:

(a) mix any drug tablet formulation according to aforementioned claim,

(b) preparation for preparing during compacting (a) step, the compressed tablet of formation unit dosage forms.
75. the method for the tablet of preparation unit dosage forms comprises

(a) mix according to aforementioned claim drug tablet formulation arbitrarily,

(b) preparation of preparation during the roll-in step (a),

(C) preparation for preparing during the pressing step (b) is to form the compressed tablet of unit dosage forms.
76. the method for the tablet of preparation unit dosage forms, it comprises:

(a) mix any drug tablet formulation according to aforementioned claim,

(b) with the preparation for preparing during the compression force roll-in step (a) that comprises between 10 to 16KN,

(c) preparation for preparing during step (b) of roll-in is to form the compressed tablet of unit dosage forms.
77. the slow-release solid oral Pharmaceutical dosage forms, it is:

I-1) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, the arithmetic average maximal plasma concentration scope that described dosage form about 0.5h after using described dosage form to the patient provides row spit of fland, Victor between about 16h is from about 15.8ng/mL ± 6.85ng/mL extremely between about 173ng/mL ± 52ng/mL, described patient before described the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

I-2) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form with described dosage form treatment patient after described dosage form is being used in the 1st day once a day the 9th day about 0.5h to the arithmetic average maximal plasma concentration scope that row spit of fland, Victor is provided between about 16h from about 26.3ng/mL ± 13.1ng/mL extremely between about 175ng/mL ± 62.5ng/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

I-3) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form with described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day about 0.5h to the arithmetic average maximal plasma concentration scope that row spit of fland, Victor is provided between about 16h from about 26.9ng/mL ± 14.1ng/mL extremely between about 186ng/mL ± 80.6ng/mL, wherein said patient is under the empty stomach state, and/or

Ii-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor after Orally administered described dosage form _(0-inf)From about 1073 to about 1825ngh/mL being 1449ngh/mL ± 376ngh/mL, before wherein said the using not with the treatment of row spit of fland, Victor and wherein said patient under the empty stomach condition, and/or

Ii-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _(0-24)From about 1001 to about 1977ngh/mL being 1489ngh/mL ± 488ngh/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Ii-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _(0-24)From about 1103 to about 2173ngh/mL being 1638ngh/mL ± 535ngh/mL, wherein said patient is under the empty stomach state, and/or

Iii-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor after Orally administered described dosage form _MaxBe 3.61h ± 1.44h, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iii-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form is being treated the patient provided row spit of fland, Victor after the 9th day Orally administered described dosage form once a day from the 1st day arithmetic average t with described dosage form _MaxBe 2.59h ± 1.4h, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iii-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 3.74h ± 1.44h, wherein said patient is under the empty stomach state, and/or

Iv-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor after Orally administered described dosage form _MaxBe 205ng/ml ± 47ng/ml, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iv-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 200ng/ml ± 64ng/ml, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iv-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 245ng/ml ± 68ng/ml, wherein said patient is following in the empty stomach state, and/or

V-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, it is 85.64% ± 12.76% that the 24h of described dosage form after Orally administered described dosage form provides the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

V-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form is 87.78% ± 16.37% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 9th day, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

V-3) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form is 90.20% ± 7.35% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day, wherein said patient is following in the empty stomach state, and/or

Vi-1) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, the pharmaco-kinetic properties that described dosage form provides after Orally administered described dosage form is depicted among Figure 24 basically, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Vi-2) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form once a day the 9th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted among Figure 25 basically from the 1st day with described dosage form treatment patient, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Vi-3) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 100mg or its respective amount, described dosage form once a day the 10th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted in basically among Figure 26 from the 1st day with described dosage form treatment patient, and wherein said patient is under the empty stomach state.
78. according to the slow-release solid oral drug preparation of claim 77, it comprises the drug tablet formulation according to any of aforementioned claim.
79. the slow-release solid oral drug preparation, it is:

I-a) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form about 0.5h after using described dosage form to the patient provides the arithmetic average maximal plasma concentration scope in row spit of fland, Victor between about 30.7ng/mL ± 21.9ng/mL to 223ng/mL ± 77.3ng/mL between about 16h, described patient before described the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

I-b) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form is extremely providing the arithmetic average maximal plasma concentration scope in row spit of fland, Victor between about 48.7ng/mL ± 25.8ng/mL to 223ng/mL ± 99.7ng/mL between about 16h with described dosage form treatment patient about 0.5h after described dosage form is used in the 1st day once a day the 9th day, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

I-c) comprise officinal salt, and the Peroral solid dosage form pharmaceutical dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form is extremely providing the arithmetic average maximal plasma concentration scope in row spit of fland, Victor between about 44.6ng/mL ± 28.5ng/mL to 263ng/mL ± 84.4ng/mL between about 16h with described dosage form treatment patient about 0.5h after described dosage form is used in the 1st day once a day the 10th day, wherein said patient is under the empty stomach state, and/or

Ii-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor after Orally administered described dosage form _(0-inf)From about 1346 to about 3196ngh/mL being 2271ngh/mL ± 925ngh/mL, before wherein said the using not with the treatment of row spit of fland, Victor and wherein said patient under the empty stomach condition, and/or

Ii-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _(0-24)From about 1277 to 3207ngh/mL being 2242ngh/mL ± 965ngh/mL, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Ii-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average AUC in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _(0-24)From about 1643 to 3273ngh/mL being 2458ngh/mL ± 815ngh/mL, wherein said patient is under the empty stomach state, and/or

Iii-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor after Orally administered described dosage form _MaxBe 3.57hr ± 1.17h, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iii-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 2.87hr ± 1.59h, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iii-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average t in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 4.13hr ± 1.24h, wherein said patient is under the empty stomach state, and/or

Iv-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor after Orally administered described dosage form _MaxBe 257ng/ml ± 59ng/ml, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Iv-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 9th day _MaxBe 272ng/ml ± 111ng/ml, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Iv-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form provides the arithmetic average C in row spit of fland, Victor treating the patient with described dosage form after described dosage form is used in the 1st day once a day the 10th day _MaxBe 308ng/ml ± 91ng/ml, wherein said patient is under the empty stomach state, and/or

V-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, it is 90.04% ± 11.91% that the 24h of described dosage form after Orally administered described dosage form provides the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV, do not handle before wherein said the using with row spit of fland, Victor and wherein said patient under the empty stomach condition, and/or

V-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form is 90.4% ± 17.50% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 9th day, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

V-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form is 91.64% ± 8.47% providing the arithmetic mean of instantaneous value of the active inhibitory action % of DPP-IV with the 24h of described dosage form treatment patient after described dosage form is used in the 1st day once a day the 10th day, wherein said patient is under the empty stomach state, and/or

Vi-a) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, the pharmaco-kinetic properties that described dosage form provides after Orally administered described dosage form is depicted among Figure 24 basically, before wherein said the using not with row spit of fland, Victor treatment and wherein said patient under the empty stomach condition, and/or

Vi-b) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form once a day the 9th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted among Figure 25 basically from the 1st day with described dosage form treatment patient, wherein said patient uses in the morning in the 30min of described dosage form breakfast with ADA is provided, and/or

Vi-c) comprise officinal salt, and the solid oral dosage form of carrier matrix of the Victor row spit of fland free alkali of about 150mg or its respective amount, described dosage form once a day the 10th day the pharmaco-kinetic properties that provides after the described dosage form is being provided is being depicted in basically among Figure 26 from the 1st day with described dosage form treatment patient, wherein said patient be in the empty stomach state down.
80. according to the slow-release solid oral drug preparation of claim 79, it comprises any drug tablet formulation according to aforementioned claim.
81. according to the slow-release solid oral drug preparation of claim 79 or claim 77, it comprises hydroxypropyl emthylcellulose, based on the weight of the dry weight of hydroxypropyl emthylcellulose preferably between 20% and 60%, between 30% and 50%.
82. slow-release solid oral drug preparation according to claim 79 or claim 77, apparent viscosity when it comprises in being present in 1% solution is 80,000cP to 120, (apparent viscosity with in being present in 1% solution the time is 80 to 000cP for sign value 100, hydroxypropyl emthylcellulose 000cP), 000cP to 120, (sign value 100, the dry weight of hydroxypropyl emthylcellulose 000cP) be that basic weight is preferably between 20% and 60%, or between 30% and 50% to 000cP.
83. according to the slow-release solid oral Pharmaceutical dosage forms of claim 79 or claim 77, wherein:

I) preparation is the skeleton preparation that comprises the pharmaceutically acceptable hydrophilic polymer that can block the diffusion of row spit of fland, Victor,

Ii) described Peroral solid dosage form pharmaceutical dosage form is a compressed tablet, and optional

Iii) when using the oar method, the elution rate of 30min is lower than 30% to row spit of fland, Victor beginning to test afterwards.