CN1112926C - Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione - Google Patents
Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dioneInfo
- Publication number
- CN1112926C CN1112926C CN98805686A CN98805686A CN1112926C CN 1112926 C CN1112926 C CN 1112926C CN 98805686 A CN98805686 A CN 98805686A CN 98805686 A CN98805686 A CN 98805686A CN 1112926 C CN1112926 C CN 1112926C
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- chemical compound
- compositions
- acceptable form
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 96
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims description 5
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 title description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 238000000034 method Methods 0.000 claims abstract description 39
- 239000003937 drug carrier Substances 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 12
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 206010012601 diabetes mellitus Diseases 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 11
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 9
- 239000002552 dosage form Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 abstract 1
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- 239000003795 chemical substances by application Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 4
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- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical class O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
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- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
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- 206010036049 Polycystic ovaries Diseases 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 239000008168 almond oil Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
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- 239000003240 coconut oil Substances 0.000 description 1
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- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
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- 235000010445 lecithin Nutrition 0.000 description 1
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- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a pharmaceutical composition comprising compound , characterised in that the composition comprises 2-12mg of compound in a pharmaceutically acceptable form and optionally a pharmaceutically acceptable carrier, to the use of such a composition in medicine, to a process for preparing such a composition and to intermediate compositions used in such a process.
Description
The present invention relates to compositions, relate in particular to Pharmaceutical composition, relate to the purposes of this compositions in medicine, relate to this method for compositions of preparation and relate to the compositions of using in this method.
European patent application published numbers 0,306,228 relates to the thiazolidine diketone derivative that some has blood sugar lowering and hypolipidemic activity.At EP 0,306, a disclosed concrete thiazolidinedione is 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl in 228] benzyl] thiazolidine-2,4-diketone (after this being called chemical compound (I)).Come into the open among the international application published WO 94/05659 some salt of compound (I) comprises the maleate of embodiment 1.
We find that surprisingly chemical compound (I) single, particular day dosage has useful especially effect to glycemic control at present, and therefore particularly useful to treatment diabetes (particularly type ii diabetes) and the disease relevant with diabetes.
We have found that also preparation contains new, the advantageous method of the Pharmaceutical composition (the particularly compositions of unit dose) of chemical compound (I).This new method comprises pre-administration (pre-administration) concentrate of preparation chemical compound (I), after this this concentrate is formulated as required unit dose in effective, economic mode.This new method is for the tablet advantageous particularly of preparation chemical compound (I).
Therefore,, the invention provides the Pharmaceutical composition (being suitably for unit dosage forms) that contains chemical compound (I), it is characterized in that said composition contains chemical compound of the pharmaceutically acceptable form of 2-12mg (I) and optional pharmaceutically acceptable carrier aspect first.
The chemical compound (I) of the pharmaceutically acceptable form that is fit to comprises pharmaceutically acceptable salt form and pharmaceutically acceptable solvate forms, and comprises the pharmaceutically acceptable solvate forms of pharmaceutically acceptable salt.
Suitable compositions contains 2,3,4,5,6,7,8,9,10,11 or the chemical compound (I) of the pharmaceutically acceptable form of 12mg.
Concrete compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 2-4mg.
Concrete compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 4-8mg.
Concrete compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 8-12mg.
A kind of compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 2mg.
Preferred compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 4mg.
Preferred compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 8mg.
The suitable pharmaceutically acceptable salt form of chemical compound (I) is included in those that describe among EP 0306228 and the WO 94/05659.The salt of preferred pharmaceutical compositions is maleate.
The suitable pharmaceutically acceptable solvate forms of chemical compound (I) is included in those that describe among EP0306228 and the WO 94/05659, particularly hydrate.
According to the method for knowing, for example those disclosed method in EP 0306228 and WO 94/05659 can prepare chemical compound (I) or its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate.The disclosure that is incorporated herein EP 0306228 and WO 94/05659 is for referencial use.
Chemical compound (I) can exist with one of several tautomeric forms, and term " chemical compound (I) " comprises used these independent tautomeric forms or their mixture.
Therefore chemical compound (I) contains chiral carbon atom, can exist with two kinds of stereoisomer forms of as many as, and term chemical compound (I) comprises the isomer that these are independent or the isomeric forms of mixture of isomers, comprises racemate.
When this uses, term " disease relevant with diabetes " comprises the disease relevant with prediabetes, disease and the diabetic complication relevant with diabetes itself.
When this uses, term " disease relevant with prediabetes " comprises as insulin resistance (comprising the heritability insulin resistance) disease, infringement property glucose tolerance and hyperinsulinemia.
" disease relevant with diabetes itself " comprises the insulin resistance hyperglycemia, comprises acquired insulin resistance and obesity.Other disease relevant with diabetes itself comprises hypertension; Cardiovascular disease, particularly atherosclerosis; Some eating disorder, particularly those need the disease of modulation of appetite and food intake, as with the very few relevant disease of feed as anorexia nervosa, and with the too much relevant disease of feed, as obesity and anorexia bulimia nerovsa (anorexia bulimia).Other disease relevant with diabetes itself comprises polycystic ovarian syndrome and inductive insulin resistance of steroid and gestational diabetes.
" diabetic complication " comprises nephropathy, and particularly relevant with type ii diabetes nephropathy comprises diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end-stage renal disease.
Comprise human and two kinds of purposes for animals at this used term " pharmaceutically acceptable ": comprise the acceptable chemical compound of for animals as term " pharmaceutically acceptable ".
The amount that exists in greater than administration composition in the proportional quantities of chemical compound (I) that the concentrate of the chemical compound (I) of the pharmaceutically acceptable form of this used term refers to pharmaceutically acceptable form.
For avoiding query, when the scalar of the chemical compound (I) that provides pharmaceutically acceptable form at this when (comprising mg amount and weight % amount), the amount of the scalar reference compound (I) of indication itself: the chemical compound (I) as 2mg maleate form is the amount that contains the maleate of 2mg chemical compound (I).
Diabetes are preferably type ii diabetes.
In yet another aspect, the invention provides the method that preparation contains the Pharmaceutical composition of the chemical compound (I) of the pharmaceutically acceptable form of 2-12mg and pharmaceutically acceptable carrier, this method comprises mixes the chemical compound of the pharmaceutically acceptable form of 2-12mg (I) with pharmaceutically acceptable carrier, and optional subsequently the compositions that produces is formulated as the form that can supply with medicine.
As mentioned above, the present invention also provides the other method of the Pharmaceutical composition for preparing the chemical compound (I) that contains pharmaceutically acceptable form, and this method is particularly suitable for preparing the chemical compound (I) of unit dosage forms.Therefore, the present invention also provides the method for the Pharmaceutical composition of preparation chemical compound (I) of pharmaceutically acceptable form and pharmaceutically acceptable carrier, and this method comprises: (i) prepare and contain the chemical compound (I) of pharmaceutically acceptable form and first compositions of first kind of pharmaceutically acceptable carrier; (ii) described first compositions is mixed with second kind of pharmaceutically acceptable carrier, obtain the compositions of required chemical compound (I), and optional subsequently the compositions that produces is formulated as the form that can supply with medicine.
The medicine the supplied with form of the Pharmaceutical composition of preferred compound (I) is the compositions of unit dose.
Except that specializing, the unit dose that is fit to contains as many as 12mg, as the chemical compound (I) of the pharmaceutically acceptable form of 1-12mg.
Other unit dose comprises those dosage mentioned herein.
A key component of a kind of method in above-mentioned back is first compositions.Therefore, the present invention also is provided at the compositions that is used as first compositions in the method for unit dose of chemical compound (I) of the pharmaceutically acceptable form of preparation.
The present invention also provides the compositions of chemical compound (I) that contains pharmaceutically acceptable form and the pharmaceutically acceptable carrier of choosing wantonly, it is characterized in that described compositions is pharmaceutically acceptable pre-administration composition.
The pharmaceutically acceptable pre-administration composition that is fit to is the concentrate (being preferably granular concentrate) of the chemical compound (I) of pharmaceutically acceptable form.This granular concentrate is particularly suitable for diluted to obtain the compositions of administration, is preferably tablet.
In yet another aspect, the invention provides the chemical compound (I) that contains pharmaceutically acceptable form and the compositions of pharmaceutically acceptable carrier, it is characterized in that described compositions is the concentrate of the chemical compound (I) of pharmaceutically acceptable form, be suitable for diluted to obtain the compositions of administration.
In first compositions, pre-administration composition or diluted composition (after this being called " first compositions " for simplicity) are fit to contain the chemical compound (I) of the pharmaceutically acceptable form of as many as 50% (weight), as 2-50% (weight).
Preferred first compositions contains the chemical compound (I) of the pharmaceutically acceptable form of 5-20% (weight), particularly 5%, 10% or 15% (weight) chemical compound (I) as the pharmaceutically acceptable form of 10% (weight).
Method of the present invention can provide any Pharmaceutical composition that makes things convenient for the chemical compound (I) of form of medication, comprises per os or parenteral form.They are particularly suitable for being prepared as the tablet of the chemical compound (I) of oral administration form, particularly pharmaceutically acceptable form.
First kind of pharmaceutically acceptable carrier can comprise the pharmaceutically acceptable carrier of any routine, comprises conventional pharmaceutically acceptable excipient, is included in those disclosed in the following handbook.Yet, because first kind of pharmaceutically acceptable carrier is not essential in the form that can supply with medicine, so it needn't contain only relevant with administration excipient.For example first kind of pharmaceutically acceptable carrier needn't contain lubricant.
Second kind of pharmaceutically acceptable carrier comprises the pharmaceutically acceptable carrier of any routine, comprises acceptable excipient on the conventional pharmaceutical (comprising disintegrating agent, diluent and lubricant), comprises those that mention in the following handbook.
A kind of first concrete compositions contains chemical compound (I), disintegrating agent, binding agent and the diluent of pharmaceutically acceptable form.
Suitable disintegrating agent is a sodium starch glycolate.
Suitable adhesive is a methyl cellulose binder, as hydroxypropyl methylcellulose 2910.
The suitable dilution agent comprises cellulose, as microcrystalline Cellulose and lactose monohydrate.
Suitable lubricant is a magnesium stearate.
We find that particularly advantageous first compositions contains the chemical compound of pharmaceutically acceptable form (I), sodium starch glycolate, hydroxypropyl methylcellulose 2910, microcrystalline Cellulose and lactose monohydrate, when granular.We find that this granular form is stable especially.
When first compositions contains the chemical compound (I) of pharmaceutically acceptable form of have an appointment 10% (weight), said composition is diluted easily, obtains containing the units dosage composition of the chemical compound (I) of 2-12mg, particularly 2-8mg, 2-4mg, 4-8mg and the pharmaceutically acceptable form of 8-12mg.
Use any conventional method that is suitable for the described first compositions character can suitably carry out described first preparation of compositions, obtain granulous first compositions as wet granulation.
Compositions of the present invention is formulated as the method that can supply with the medicine form is included in disclosed conventional formulation method in this handbook of quoting, comprise pressed disc method.
The compositions that preferred the present invention can supply with medicine is fit to oral administration.Yet they also are suitable for other route of administration, as parenteral, Sublingual or transdermal administration.
The compositions that can supply with medicine can be tablet, capsule, powder, granule, lozenge, suppository, reconstitutable powders or liquid preparation such as oral or aseptic parenteral solution or suspension.
For obtaining the concordance of administration, preferred compositions of the present invention is a unit dosage forms.
The unit dosage forms of oral administration can be tablet and capsule, and they can contain conventional excipients such as binding agent as syrup, arabic gum, gelatin, sorbitol, Tragacanth or polyvinylpyrrolidone; Filler such as lactose, sucrose, corn starch, calcium phosphate, sorbitol or glycine; Tabletting lubricant such as magnesium stearate; Disintegrating agent such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline Cellulose or pharmaceutically acceptable wetting agent such as sodium lauryl sulphate.
Except that specializing, preferred compositions of the present invention is the unit dosage forms as the appropriate amount of corresponding daily dose, and suitable unit dose contains 1,2,3,4,5,6,7,8,9,10,11 or the chemical compound (I) of the pharmaceutically acceptable form of 12mg.
Can mix by conventional method, filling or tabletting prepare solid composite (as Orally administered composition).If desired, can repeat the married operation step described active component is scattered in the compositions of using a large amount of filleies.This type of operating procedure is this area routine.Can carry out coating to tablet according to the method for knowing in the normal pharmacy practice, particularly carry out coating with film coating thing aqueous solution.
Fluid composition (as liquid oral compositions) can be prepared as emulsion, syrup or elixir form, perhaps they is prepared as the desciccate form, and water or other suitable solvent duplicate before use.This type of liquid preparation can contain conventional additive, as suspending agent as sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible fat; Emulsifying agent such as lecithin, Arlacel-80 or arabic gum; Water-insoluble solvent (can comprise edible oil) is as almond oil, fractionated coconut oil, oily ester such as glycerol, propylene glycol or alcoholic acid ester; Antiseptic such as right-methyl hydroxybenzoate or propyl ester or sorbic acid; And can contain conventional correctives or coloring agent if desired.
Reactive compound and aseptic solvent as described in parenteral compositions (comprising that the parenteral compositions is as units dosage composition) can contain, according to the concentration of using, described reactive compound can be suspended in or be dissolved in this solvent.When preparing the solution of parenteral, compositions of the present invention can be dissolved in the water for injection filtration sterilization, fill also sealing in suitable glass tube vial or ampoule then.As described in preferably adjuvant being dissolved in as local anesthetic, antiseptic and buffer agent in the solvent.For increasing stability, freezing after the said composition fill is in glass tube vial and vacuum can be removed moisture.Can prepare the parenteral suspension with essentially identical method, but described reactive compound is to be suspended in the solvent rather than to be dissolved in the solvent, and degerming can not be undertaken by filtration.Described chemical compound can be sterilized by being exposed in the oxirane, then it is suspended in the aseptic solvent.Preferably contain surfactant or wetting agent in the said composition to help the uniform distribution of this chemical compound.
Except that specializing, according to the method difference of administration, compositions of the present invention can contain the active substance of 0.1% to 99% (weight), preferred 10% to 60% (weight).
If desired, described compositions can be for having the packaged form of operation instruction.
According to conventional methods, as at the canonical reference book as Britain and American Pharmacopeia, Remington ' sPharmaceutical Sciences (Mack Publishing Co.), Martindale The ExtraPharmacopoeia (London, The Pharmaceutical Press) and those methods of describing among the Harry ' sCosmeticology (Leonard Hill Books), prepare and prepare compositions of the present invention.
The present invention also provides the Pharmaceutical composition that contains 2-12mg chemical compound (I) and pharmaceutically acceptable carrier as active therapeutic agent.
Specifically, the invention provides the Pharmaceutical composition of the chemical compound that contains the pharmaceutically acceptable form of 2-12mg (I) that is used for the treatment of diabetes (particularly type ii diabetes) and the disease relevant with diabetes.
Compositions of the present invention can the administration every day 1-6 time, but most preferably every day 1 or 2 times.
Therefore, on the other hand, the invention provides the method for treatment mammal (as the people) diabetes (particularly type ii diabetes) and the disease relevant with diabetes, this method comprises the chemical compound (I) of the pharmaceutically acceptable form of mammal 2-12mg that needs every day.
Specifically, this method comprises the chemical compound (I) that gives 2-4,4-8 or the pharmaceutically acceptable form of 8-12mg.
Concrete dosage is 2mg/ day, 4mg/ day (comprise every day 2 times, each 2mg) and 8mg/ day (comprising every day 2 times, at every turn 4mg).
Specifically, this method comprises the chemical compound (I) that gives the pharmaceutically acceptable form of 2-4mg.
Specifically, this method comprises the chemical compound (I) that gives the pharmaceutically acceptable form of 4-8mg.
Specifically, this method comprises the chemical compound (I) that gives the pharmaceutically acceptable form of 8-12mg.
Preferably, this method comprises the chemical compound (I) that gives the pharmaceutically acceptable form of 2mg.
Preferably, this method comprises the chemical compound (I) that gives the pharmaceutically acceptable form of 4mg.
Preferably, this method comprises the chemical compound (I) that gives the pharmaceutically acceptable form of 8mg.
Scope 2-4mg comprises 2.1-4,2.2-4,2.3-4,2.4-4,2.5-4,2.6-4,2.7-4,2.8-4,2.9-4 or 3-4mg.
Scope 4-8mg comprises 4.1-8,4.2-8,4.3-8,4.4-8,4.5-8,4.6-8,4.7-8,4.8-8,4.9-8,5-8,6-8 or 7-8mg.
Scope 8-12mg comprises 8.1-12,8.2-12,8.3-12,8.4-12,8.5-12,8.6-12,8.7-12,8.8-12,8.9-12,9-12,10-12 or 11-12mg.
When using compositions of the present invention or method, there is not bad toxic action with above-mentioned dosage range.
The following example explanation the present invention, but do not limit the present invention in any way.
Embodiment 1: concentrate formulation
Lactose monohydrate with about 2/3rds mixes by suitable sieve and with the maleate of the chemical compound (I) that grinds.Make sodium starch glycolate, hydroxypropyl emthylcellulose, microcrystalline Cellulose and remaining lactose by suitable sieve, and add in the said mixture.Continue then to mix.With pure water the mixture that produces is made wet granular subsequently.Then to this wet granular sieve, dry in fluidized bed dryer, make dried granules pass through another kind of sieve, last homogenize.
The composition % of granular concentrate
Amounts of components (%)
Chemical compound (I) maleate 13.25 (pure maleate) that grinds
Sodium starch glycolate 5.00
Hydroxypropyl methylcellulose 2910 5.00
Microcrystalline Cellulose 20.0
Lactose monohydrate, general purpose grade to 100
Pure water *
*Work in-process is removed
Embodiment 2: described concentrate is formulated as tablet
The granule that derives from embodiment 1 is placed the rotation blender.Lactose with about 2/3rds sieves and adds in the blender.Microcrystalline Cellulose, sodium starch glycolate, magnesium stearate and remaining lactose are sieved, and add in the blender, this mixture is mixed.Then the mixture that produces is pressed into the target tablet on rotary tablet machine, for contain 1,2 and the tablet weight of 4mg active component be 150mg, for the tablet weight 300mg that contains the 8mg active component.
Then described label is transferred in the tablet coating machine,, and carries out film coating to sheet and heavily increase by 2.0% to 3.5% with hot-air (about 65 ℃) preheating.
Consumption (every mg number) tablet strength 1.0mg 2.0mg 4.0mg 8.0mg active component: compound (I) maleate concentrate particle 10.00 20.00 40.00 80.00 other components: the sodium starch glycolate 6.96 6.46 5.46 10.92 microcrystalline celluloses 27.85 25.85 21.85 43.70 lactose monohydrates 104.44 96.94 81.94 163.88 dolomols 0.75 0.75 0.75 1.50 label gross weight 150.0 150.0 150.0 300.0 film dressing thing aqueous solution 4.5 4.5 4.5 9.0 film coating tablet gross weights 154.5 154.5 154.5 309.0
Claims (17)
1. one kind contains 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl] benzyl] thiazolidine-2, the Pharmaceutical composition of 4-diketone (chemical compound (I)) is characterized in that said composition contains chemical compound of the pharmaceutically acceptable form of 2-8mg (I) and optional pharmaceutically acceptable carrier.
2. the compositions of claim 1, it contains the chemical compound (I) of the pharmaceutically acceptable form of 2-4mg.
3. the compositions of claim 1, it contains the chemical compound (I) of the pharmaceutically acceptable form of 4-8mg.
4. the compositions of claim 1, it contains the chemical compound (I) of the pharmaceutically acceptable form of 2mg.
5. the compositions of claim 1, it contains the chemical compound (I) of the pharmaceutically acceptable form of 4mg.
6. the compositions of claim 1, it contains the chemical compound (I) of the pharmaceutically acceptable form of 8mg.
7. each compositions among the claim 1-6, it contains the maleate of chemical compound (I).
8. method for preparing the Pharmaceutical composition of the chemical compound (I) that contains the pharmaceutically acceptable form of 2-8mg and pharmaceutically acceptable carrier, this method comprises mixes the chemical compound of the pharmaceutically acceptable form of 2-8mg (I) with pharmaceutically acceptable carrier.
9. the method for claim 8, wherein Zhi Bei compositions is a unit dosage forms.
10. the method for claim 8, wherein Zhi Bei compositions is a tablet.
11. one kind contains 5-[4-[2-(N-methyl-N-(2-pyridine radicals) amino) ethyoxyl] benzyl] thiazolidine-2, the Pharmaceutical composition of 4-diketone (chemical compound (I)) is used for the treatment of application in the medicine of diabetes and the disease relevant with diabetes in preparation, and described compositions is characterised in that chemical compound (I) that contains the pharmaceutically acceptable form of 2-8mg and its pharmaceutically acceptable carrier of choosing wantonly.
12. the application of claim 11, wherein said compositions contain the chemical compound (I) of the pharmaceutically acceptable form of 2-4mg.
13. the application of claim 11, wherein said compositions contain the chemical compound (I) of the pharmaceutically acceptable form of 4-8mg.
14. the application of claim 11, wherein said compositions contain the chemical compound (I) of the pharmaceutically acceptable form of 2mg.
15. the application of claim 11, wherein said compositions contain the chemical compound (I) of the pharmaceutically acceptable form of 4mg.
16. the application of claim 11, wherein said compositions contain the chemical compound (I) of the pharmaceutically acceptable form of 8mg.
17. each application among the claim 11-16, wherein said compositions contains the maleate of chemical compound (I).
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9711683.4 | 1997-06-05 | ||
| GBGB9711683.4A GB9711683D0 (en) | 1997-06-05 | 1997-06-05 | Composition |
| GB9712851.6 | 1997-06-18 | ||
| GBGB9712851.6A GB9712851D0 (en) | 1997-06-18 | 1997-06-18 | Composition |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN02149972A Division CN1430959A (en) | 1997-06-05 | 2002-11-05 | Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1259050A CN1259050A (en) | 2000-07-05 |
| CN1112926C true CN1112926C (en) | 2003-07-02 |
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Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98805686A Expired - Lifetime CN1112926C (en) | 1997-06-05 | 1998-06-02 | Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione |
| CNA2003101199090A Pending CN1526391A (en) | 1997-06-05 | 1998-06-02 | Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione |
| CN02149972A Pending CN1430959A (en) | 1997-06-05 | 2002-11-05 | Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2003101199090A Pending CN1526391A (en) | 1997-06-05 | 1998-06-02 | Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione |
| CN02149972A Pending CN1430959A (en) | 1997-06-05 | 2002-11-05 | Composition containing 5- [ 4- [ 2- (N-methyl-N-2-pyridyl) amino) ethoxy ] benzyl ] thiazolidine-2, 4-dione |
Country Status (29)
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| EP (1) | EP0998284A1 (en) |
| JP (1) | JP2001521553A (en) |
| KR (1) | KR20010013410A (en) |
| CN (3) | CN1112926C (en) |
| AP (1) | AP1214A (en) |
| AR (2) | AR015120A1 (en) |
| AU (1) | AU8215098A (en) |
| BG (1) | BG104048A (en) |
| BR (1) | BR9810405A (en) |
| CA (2) | CA2292629C (en) |
| CO (1) | CO4940400A1 (en) |
| DZ (1) | DZ2510A1 (en) |
| EA (1) | EA002384B1 (en) |
| GB (1) | GB9711683D0 (en) |
| HU (1) | HUP0004070A3 (en) |
| ID (1) | ID24264A (en) |
| IL (1) | IL133074A0 (en) |
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| NO (2) | NO995938L (en) |
| NZ (2) | NZ523725A (en) |
| OA (1) | OA11306A (en) |
| PE (1) | PE78899A1 (en) |
| PL (1) | PL337201A1 (en) |
| SK (1) | SK164899A3 (en) |
| TR (2) | TR199902963T2 (en) |
| TW (1) | TW570797B (en) |
| UY (1) | UY25032A1 (en) |
| WO (1) | WO1998055122A1 (en) |
| ZA (2) | ZA984826B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040248945A1 (en) | 1999-04-23 | 2004-12-09 | Smithkline Beecham P.L.C. | Thiazolidinedione derivative and its use as antidiabetic |
| CN1167702C (en) * | 1999-04-23 | 2004-09-22 | 史密丝克莱恩比彻姆有限公司 | Polymroph of 5-[4-[2-(n-methyl-n-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt |
| MXPA01010820A (en) | 1999-04-23 | 2002-06-04 | Smithkline Beecham Plc | Novel pharmaceutical. |
| GB0021978D0 (en) | 2000-09-07 | 2000-10-25 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0127805D0 (en) * | 2001-11-20 | 2002-01-09 | Smithkline Beecham Plc | Pharmaceutical composition |
| WO2003050112A1 (en) * | 2001-12-13 | 2003-06-19 | Smithkline Beecham Plc | Toluenesulfonate hydrates of a thiazolidinedione derivative |
| GB0129876D0 (en) * | 2001-12-13 | 2002-02-06 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0129871D0 (en) * | 2001-12-13 | 2002-02-06 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0130509D0 (en) * | 2001-12-20 | 2002-02-06 | Smithkline Beecham Plc | Novel pharmaceutical |
| EP2270007A1 (en) * | 2006-05-09 | 2011-01-05 | Teva Pharmaceutical Industries Ltd. | 2-N-{5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2-4-thiazolidinedione} butanedioic acid, methods of preparation and compositions with rosiglitazone maleate |
| US7435741B2 (en) | 2006-05-09 | 2008-10-14 | Teva Pharmaceutical Industries, Ltd. | 2-N{5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl]methyl]-2,4-thiazolidinedione} butanedioic acid, methods of preparation and compositions with rosiglitazone maleate |
| WO2015008234A1 (en) * | 2013-07-17 | 2015-01-22 | Glenmark Pharmaceuticals S.A. | Bicyclic heterocyclic compounds as ror gamma modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994005659A1 (en) * | 1992-09-05 | 1994-03-17 | Smithkline Beecham Plc | Substituted thiazolidinedione derivatives |
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| ATE186724T1 (en) * | 1987-09-04 | 1999-12-15 | Beecham Group Plc | SUBSTITUTED THIAZOLIDINEDIONE DERIVATIVES |
| WO1995021608A1 (en) * | 1994-02-10 | 1995-08-17 | Smithkline Beecham Plc | Use of insulin sensitisers for treating renal diseases |
| KR19990036290A (en) * | 1995-08-10 | 1999-05-25 | 로즈 암스트롱 | Reduction of Exogenous Insulin Dosage in Non-insulin-Dependent Diabetic Patients |
| AU7604596A (en) * | 1995-11-17 | 1997-06-11 | Warner-Lambert Company | A method of treating myotonic dystrophy |
| NZ314406A (en) * | 1996-03-18 | 2000-12-22 | Sankyo Co | Treatment or prophylaxis of pancreatitis with a medicament containing an insulin sensitiser including oxazoles and thiazoles |
| JP2000514807A (en) * | 1996-07-12 | 2000-11-07 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Novel treatment for leptin resistance |
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1997
- 1997-06-05 GB GBGB9711683.4A patent/GB9711683D0/en active Pending
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1998
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- 1998-06-02 TR TR1999/02963T patent/TR199902963T2/en unknown
- 1998-06-02 HU HU0004070A patent/HUP0004070A3/en unknown
- 1998-06-02 CA CA002292629A patent/CA2292629C/en not_active Expired - Fee Related
- 1998-06-02 KR KR19997011411A patent/KR20010013410A/en not_active Application Discontinuation
- 1998-06-02 EA EA199901116A patent/EA002384B1/en not_active IP Right Cessation
- 1998-06-02 IL IL13307498A patent/IL133074A0/en unknown
- 1998-06-02 PL PL98337201A patent/PL337201A1/en unknown
- 1998-06-02 WO PCT/EP1998/003478 patent/WO1998055122A1/en not_active Application Discontinuation
- 1998-06-02 MX MXPA99011322A patent/MXPA99011322A/en unknown
- 1998-06-02 CA CA002333352A patent/CA2333352A1/en not_active Abandoned
- 1998-06-02 AP APAP/P/1999/001696A patent/AP1214A/en active
- 1998-06-02 TR TR2000/02790T patent/TR200002790T2/en unknown
- 1998-06-02 ID IDW991520A patent/ID24264A/en unknown
- 1998-06-02 CN CN98805686A patent/CN1112926C/en not_active Expired - Lifetime
- 1998-06-02 JP JP50158799A patent/JP2001521553A/en not_active Ceased
- 1998-06-02 SK SK1648-99A patent/SK164899A3/en unknown
- 1998-06-02 BR BR9810405-5A patent/BR9810405A/en not_active IP Right Cessation
- 1998-06-02 EP EP98932144A patent/EP0998284A1/en not_active Withdrawn
- 1998-06-02 NZ NZ523725A patent/NZ523725A/en unknown
- 1998-06-02 CN CNA2003101199090A patent/CN1526391A/en active Pending
- 1998-06-03 DZ DZ980120A patent/DZ2510A1/en active
- 1998-06-04 AR ARP980102650A patent/AR015120A1/en not_active Application Discontinuation
- 1998-06-04 ZA ZA9804826A patent/ZA984826B/en unknown
- 1998-06-04 UY UY25032A patent/UY25032A1/en not_active IP Right Cessation
- 1998-06-04 ZA ZA9811572A patent/ZA9811572B/en unknown
- 1998-06-04 CO CO98031614A patent/CO4940400A1/en unknown
- 1998-06-04 AR ARP980102649A patent/AR008198A1/en not_active Application Discontinuation
- 1998-06-05 PE PE1998000466A patent/PE78899A1/en not_active Application Discontinuation
- 1998-10-23 TW TW087117536A patent/TW570797B/en not_active IP Right Cessation
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1999
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- 1999-12-27 BG BG104048A patent/BG104048A/en unknown
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2001
- 2001-09-03 NZ NZ513922A patent/NZ513922A/en unknown
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2002
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2004
- 2004-02-20 NO NO20040738A patent/NO20040738L/en not_active Application Discontinuation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994005659A1 (en) * | 1992-09-05 | 1994-03-17 | Smithkline Beecham Plc | Substituted thiazolidinedione derivatives |
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