CN109276543A - A kind of Xi Gelieta solid dispersions and its preparation method and application - Google Patents
A kind of Xi Gelieta solid dispersions and its preparation method and application Download PDFInfo
- Publication number
- CN109276543A CN109276543A CN201710592206.1A CN201710592206A CN109276543A CN 109276543 A CN109276543 A CN 109276543A CN 201710592206 A CN201710592206 A CN 201710592206A CN 109276543 A CN109276543 A CN 109276543A
- Authority
- CN
- China
- Prior art keywords
- compound
- solid
- gelieta
- solid dispersions
- formula
- 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.)
- Granted
Links
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 239000007787 solid Substances 0.000 claims abstract description 34
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000004090 dissolution Methods 0.000 claims abstract description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 17
- 229940069328 povidone Drugs 0.000 claims abstract description 17
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 229920003081 Povidone K 30 Polymers 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 2
- 230000000116 mitigating effect Effects 0.000 claims description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 229920003083 Kollidon® VA64 Polymers 0.000 description 22
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 9
- 238000005286 illumination Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000013112 stability test Methods 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- -1 2- (4- fluoro benzoyl) phenyl amino Chemical group 0.000 description 4
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 102000006255 nuclear receptors Human genes 0.000 description 3
- 108020004017 nuclear receptors Proteins 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 208000001145 Metabolic Syndrome Diseases 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 208000016097 disease of metabolism Diseases 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000008236 heating water Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of Xi Gelieta solid dispersions, comprising: compound and solid carrier shown in Formulas I；The solid carrier is copolyvidone or povidone.The present invention uses copolyvidone or povidone for solid carrier, allow formula (I) compound with molecular forms or amorphous state high degree of dispersion in the carrier, not only substantially improve the water solubility of formula (I) compound, its dissolution rate and bioavilability are improved, and the stability for being formed by solid dispersions also greatly improved.
Description
Technical field
The present invention relates to chemical pharmaceutical technology fields more particularly to a kind of Xi Gelieta solid dispersions and preparation method thereof
And application.
Background technique
2- (2- (4- fluoro benzoyl) phenyl amino) -3- (4- (2- (9H- carbazole -9- base) ethyoxyl) phenyl) propionic acid is
One kind, which having metabolic disease and illness, treats and prevents active phenylalanine class compound, is commonly called as Xi Gelieta, changes
It is shown in formula I to learn structural formula:
The compound is described in Chinese patent application CN03126974.5 and U.S. Patent application US7,268,157
Pharmacological activity.2- (2- (4- fluoro benzoyl) phenyl amino) -3- (4- (2- (9H- carbazole -9- base) ethyoxyl) phenyl) third
Acid has the ability of selective activation PPAR- α, PPAR- γ and PPAR- δ, can be used for treating disease relevant to metabolic syndrome
Disease, such as diabetes.It is known in the art that the member of PPAR- α, PPAR- γ and PPAR- δ as nuclear receptor superfamily.In recent years,
Nuclear receptor family is widely paid close attention in metabolic disease field, and existing research proves, the diseases such as they and diabetes, fatty liver
The occurrence and development of disease are closely related, also referred to as metabolic nuclear receptor.However, 2- (2- (4- fluoro benzoyl) phenyl amino)-
The stability of 3- (4- (2- (9H- carbazole -9- base) ethyoxyl) phenyl) propionic acid is poor, in high temperature (60 DEG C), high humidity (90%)
It is placed 10 days under strong illumination (4500Lx), content is substantially reduced, and related substance obviously increases, this shows 2- (2- (4- fluorobenzene
Formoxyl) phenyl amino) -3- (4- (2- (9H- carbazole -9- base) ethyoxyl) phenyl) propionic acid drug manufacture, storage and transport
It easily decomposes in the process, influences the Drug safety and validity, limit it in preparation for treating and metabolic syndrome phase
Application in the drug of pass.
Moreover, the solubility of Xi Gelieta in water is minimum, almost do not dissolve, bioavilability is lower, therefore, improves it
Dissolution rate and bioavilability are of great significance.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of Xi Gelieta solid dispersions and its preparation
Methods and applications, the Xi Gelieta solid dispersions stability with higher and water solubility of preparation.
The present invention provides a kind of Xi Gelieta solid dispersions, comprising:
Compound and solid carrier shown in Formulas I；
The solid carrier is copolyvidone or povidone；
Preferably, the copolyvidone is PVP-VA64；The povidone is PVP-K30.
Preferably, the weight ratio of the compound and solid carrier is 1:(2~10), preferably 1:(3~10), more preferably
For 1:(3~8).In some embodiments of the invention, the ratio be 1:2,1:3,1:4,1:5,1:6,1:7,1:8,
1:9 or 1:10.
In some embodiments of the invention, the solid dispersions further include: optional one or more pharmacy
Upper acceptable excipient and/or carrier.
The present invention also provides the preparation methods of above-mentioned Xi Gelieta solid dispersions, comprising the following steps:
In organic solvent by compound shown in Formulas I and solid carrier dissolution, it then dries.
Preferably, the organic solvent is ethyl alcohol and/or tetrahydrofuran.
Preferably, the drying is rotary evaporation or spray drying.The temperature of the spray drying is preferably 70~120
℃。
In some preferred embodiments, the preparation method is that: weigh formula (I) compound and carrier respectively, be added
Tetrahydrofuran, is heated to formula (I) compound and carrier is completely dissolved, and is then spray-dried, and collects solid to obtain the final product.
In some preferred embodiments, the weight ratio of weighed formula (I) compound and carrier be 1:(2~10)；
The weight ratio of formula (I) compound and solvent is preferably 1:(16~150).In some embodiments, the temperature of heating for dissolving
Preferably 80 DEG C~90 DEG C of degree.
The present invention also provides Xi Gelieta solids prepared by above-mentioned Xi Gelieta solid dispersions or above-mentioned preparation method
Dispersion is preparing the application in the drug for preventing, mitigating or treating diabetes or type II diabetes.
The present invention also provides a kind of pharmaceutical preparations, including above-mentioned Xi Gelieta solid dispersions or above-mentioned preparation method system
Standby Xi Gelieta solid dispersions.
Said medicine preparation can also include pharmaceutically acceptable auxiliary material.
In the pharmaceutical preparation, Xi Gelieta solid dispersions are preferably 5wt%~50wt%, remaining is auxiliary material.
The pharmaceutic adjuvant can voluntarily be adjusted according to dosage form, preferably include glidant, disintegrating agent, any in filler
It is one or more of.The present invention is to the type of above-mentioned pharmaceutic adjuvant and is not particularly limited, and can be well known to those skilled in the art
Pharmaceutic adjuvant, the glidant preferably talc powder, magnesium stearate, superfine silica gel powder etc., the preferred sodium carboxymethyl starch of the disintegrating agent,
Crospovidone, low-substituted hydroxypropyl cellulose etc., the preferred lactose of the filler, microcrystalline cellulose, starch etc..
The dosage form of the pharmaceutical preparation can be pharmaceutically acceptable dosage form, such as tablet, capsule or granule.
The present invention carries out crystal form survey to prepared formula (I) compound solid dispersion using x-ray powder diffraction
It is fixed, the results showed that, in 3~50 ° of regions, the characteristic diffraction peak of not shown formula (I) compound, but the feature of amorphous solid is presented
Disperse peak,.Show in solid dispersions provided by the invention, formula (I) compound is highly dispersed at
In solid carrier, it is dispersed therein with molecular forms or amorphous state.
Dissolution rate test the result shows that, after formula (I) compound and above-mentioned solid carrier form solid dispersions, dissolution rate by
0.05%, rise to 78%~81%.
Meanwhile above-mentioned solid dispersions place 10 under high temperature (60 DEG C), high humidity (90%) and strong illumination (4500Lx)
It, obvious degradation does not occur for formula (I) compound, shows that the solid dispersions are particularly suitable for medicament manufacture and long term storage.
Compared with prior art, the present invention provides a kind of Xi Gelieta solid dispersions, comprising: compound shown in Formulas I
And solid carrier；The solid carrier is copolyvidone or povidone.The present invention uses copolyvidone or povidone for solid load
Body allows formula (I) compound in the carrier, not only to substantially improve formula (I) with molecular forms or amorphous state high degree of dispersion
The water solubility of compound improves its dissolution rate and bioavilability, and also greatly improved and be formed by solid dispersions
Stability.
Detailed description of the invention
Fig. 1 is formula (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:2) prepared by embodiment 3
X-ray powder diffraction figure；
Fig. 2 is formula (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:5) prepared by embodiment 6
X-ray powder diffraction figure；
Fig. 3 be embodiment 8 prepare formula (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:
10) X-ray powder diffraction figure.
Specific embodiment
In order to further illustrate the present invention, below with reference to embodiment to Xi Gelieta solid dispersions provided by the invention and
Preparation method and application are described in detail.
In the present invention, X-ray powder diffraction test condition: instrument: D/MAX-1200 (Japanese Rigaku company)；Radiation
Source: Cu-K α (40kV, 40mA).
Dissolution determination condition: by Chinese Pharmacopoeia four the second method of annex XC measurements of version in 2010；Instrument: RC806 type medicine
Object dissolution test system；Dissolution medium: water 1000mL；Revolving speed: 50rpm, temperature: 37 ± 0.5 DEG C.
Stability conditions: high temperature (60 DEG C), high humidity are carried out by two annex XIX C of Chinese Pharmacopoeia version in 2010
(90%) it is tested with strong illumination (4500Lx).
HPLC test condition: instrument: peace UltiMate3000 is worn；Chromatographic column: Shim-pack VP-ODS5 μm 250L ×
4.6；Detector: VWD-3100, Detection wavelength: 256nm；Mobile phase: methanol-water-glacial acetic acid (30:70:0.4)；Flow velocity；
1.0mL/min, column temperature: 30 DEG C.
The preparation of 1 formula of embodiment (I) compound
Formula (I) compound is prepared with reference to the embodiment 15 of Chinese patent CN03126974.5: 0.082 being added in reaction flask
Gram calorie bar azoles (0.49mmol), 0.25 gram of (0.49mmol) 2- [(2- (4- fluoro benzoyl) phenyl) amino] -3- (4- (2- bromine
Ethyoxyl) phenyl)-methyl propionate, 0.084 gram of (1.08mmol) 50%NaOH, 0.08 gram of tetrabutylammonium bromide and 10 milliliters of benzene,
Back flow reaction 10 hours, 30 milliliters of benzene are added, are washed (3 × 30 milliliters), it is dry, it is concentrated in vacuo to obtain crude product, chromatography
(solvent: methanol: chloroform=4:1) obtains 0.10 gram of (36%) target compound.
HRMS(C36H29FN2O4) calculated value (%): 572.6357；Measured value (%): 572.6354.
Elemental analysis (C36H29FN2O4) calculated value (%): C, 75.51%；H, 5.11%；N, 4.89%；Measured value (%):
C, 75.83%；H, 5.10%；N, 4.90%.
The preparation of 2 formula of embodiment (I) compound-PVP K30 solid dispersions (weight ratio 1:5)
0.5g formula (I) compound and 2.5g povidone PVP-K30 are taken, 100mL tetrahydrofuran is added, adds in 90 DEG C of water-baths
Heat is completely dissolved formula (I) compound and copolyvidone PVP-VA64, spray drying, 100 DEG C of inlet air temperature, collects solid point
Granular media.The X-ray powder diffraction of obtained solid dispersion 3~50 ° of region not shown formula (I) compounds characteristic diffraction peak,
And the feature disperse peak of amorphous solid is presented.
The preparation of 3 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:2)
0.5g formula (I) compound and 1g copolyvidone PVP-VA64 are taken, 100mL tetrahydrofuran is added, adds in 90 DEG C of water-baths
Heat is completely dissolved formula (I) compound and copolyvidone PVP-VA64, spray drying, 90 DEG C of inlet air temperature, collects solid dispersion
Body.The X-ray powder diffraction figure of obtained solid dispersion is shown in Fig. 1, in the feature of 3~50 ° of region not shown formula (I) compounds
Diffraction maximum, and the feature disperse peak of amorphous solid is presented.
The preparation of 4 formula of embodiment (I) compound-povidone PVPK30 solid dispersions (weight ratio 1:3)
0.5g formula (I) compound and 1.5g povidone PVP-K30 are taken, 100mL tetrahydrofuran is added, adds in 80 DEG C of water-baths
Heat is completely dissolved formula (I) compound and povidone PVPK30, rotary evaporation, and solid dispersions are collected in 60 DEG C of drying.Gained
In the characteristic diffraction peak of 3~50 ° of region not shown formula (I) compounds and nothing is presented in the X-ray powder diffraction of solid dispersions
The feature disperse peak of white amorphous solid.
The preparation of 5 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:4)
0.5g formula (I) compound and 2g copolyvidone PVP-VA64 are taken, 100mL tetrahydrofuran is added, adds in 90 DEG C of water-baths
Heat is completely dissolved formula (I) compound and copolyvidone PVP-VA64, rotary evaporation, and solid dispersions are collected in 60 DEG C of drying.
The X-ray powder diffraction of obtained solid dispersion is 3~50oThe characteristic diffraction peak of region not shown formula (I) compound, and be in
The feature disperse peak of existing amorphous solid.
The preparation of 6 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:5)
It takes 1g formula (I) compound and 5g copolyvidone PVP-VA64,100mL tetrahydrofuran is added, in 80 DEG C of heating water baths,
It is completely dissolved formula (I) compound and copolyvidone PVP-VA64, is spray-dried, 110 DEG C of inlet air temperature, solid dispersion is collected
Body.The X-ray powder diffraction figure of obtained solid dispersion is shown in Fig. 2, in the feature of 3~50 ° of region not shown formula (I) compounds
Diffraction maximum, and the feature disperse peak of amorphous solid is presented.
The preparation of 7 formula of embodiment (I) compound-povidone PVP-K30 solid dispersions (weight ratio 1:8)
It takes 0.5g formula (I) compound and 4g povidone PVP-K30,100mL tetrahydrofuran is added, in 80 DEG C of heating water baths,
It is completely dissolved formula (I) compound and povidone PVP-K30, solid dispersions are collected in rotary evaporation, 60 DEG C of drying.Gained is solid
The X-ray powder diffraction of body dispersion and is presented without fixed in the characteristic diffraction peak of 3~50 ° of region not shown formula (I) compounds
The feature disperse peak of shape solid.
The preparation of 8 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:10)
0.5g formula (I) compound and 5g copolyvidone PVP-VA64 are taken, 100mL tetrahydrofuran is added, adds in 80 DEG C of water-baths
Heat is completely dissolved formula (I) compound and copolyvidone PVP-VA64, rotary evaporation, and solid dispersions are collected in 60 DEG C of drying.
The X-ray powder diffraction figure of obtained solid dispersion is shown in Fig. 3, in the feature diffraction of 3~50 ° of region not shown formula (I) compounds
Peak, and the feature disperse peak of amorphous solid is presented.
9 dissolution determination of embodiment
Formula (I) compound is measured respectively by Chinese Pharmacopoeia four portion's annex X the second methods of C of version in 2015, solid in embodiment
The dissolution rate of dispersion.The sampling amount of embodiment 2~8 seven kind sample be respectively 8mg, 27mg, 32mg, 40mg, 47mg, 76mg and
87mg。
Measuring method: using PH=6.8 phosphate buffer 1 000mL as dissolution medium, revolving speed 50rpm is operated according to methods,
When through 45min, takes solution 5mL to filter, take subsequent filtrate as test solution；According to UV-VIS spectrophotometry in 235nm
Wavelength at measure absorbance, calculate dissolution rate.
Measurement result: the dissolution rate of formula (I) compound is 0.05%, 2 formula of embodiment (I) compound-povidone PVP-K30
The dissolution rate of solid dispersions (weight ratio 1:5) is 78.95%, 3 formula of embodiment (I) compound-copolyvidone PVP-VA64
The dissolution rate of solid dispersions (weight ratio 1:2) is 78.14%, 4 formula of embodiment (I) compound-povidone PVP-K30 solid
The dissolution rate of dispersion (weight ratio 1:3) is 79.62%, 5 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid
The dissolution rate of dispersion (weight ratio 1:4) is 78.37%, 6 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid
The dissolution rate of dispersion (weight ratio 1:5) is 79.39%, 7 formula of embodiment (I) compound-copolyvidone PVP-K30 solid point
The dissolution rate of granular media (weight ratio 1:8) is 78.79%, 8 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid point
The dissolution rate of granular media (weight ratio 1:10) is 81.98%.The result shows that the dissolution rate of the solid dispersions of embodiment 2-8 is equal
It is significantly improved compared with formula (I) compound.
The stability test of 10 formula of embodiment (I) compound
By 1 gained formula (I) compound of embodiment under high temperature (60 DEG C), high humidity (90%) and strong illumination (4500Lx) into
Row stability test, content and related substance with HPLC method (area normalization method) measurement formula (I) compound, measurement result
As shown in table 1.
The stability test result of 1 embodiment of table 1 gained formula (I) compound
Test result shows formula (I) compound under high temperature (60 DEG C), high humidity (90%) and strong illumination (4500Lx)
It places 10 days, formula (I) compound is without obvious degradation phenomenon.
The stability of 11 formula of embodiment (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:5) is tried
It tests
By 6 obtained solid dispersion of embodiment under high temperature (60 DEG C), high humidity (90%) and strong illumination (4500Lx) into
Row stability test, content and related substance with HPLC method (area normalization method) measurement formula (I) compound, measurement result
As shown in table 2.
The stability test result of 2 embodiment of table, 6 obtained solid dispersion
Test result shows to exist formula (I) compound-copolyvidone PVP-VA64 solid dispersions (weight ratio 1:5)
It is placed 10 days under high temperature (60 DEG C), high humidity (90%) and strong illumination (4500Lx), formula (I) compound is without obvious degradation phenomenon.
The preparation of tablet of the embodiment 12 containing formula (I) compound solid dispersion
Prescription (1000):
Preparation process: weighing solid dispersions, lactose, microcrystalline cellulose and the sodium carboxymethyl starch of recipe quantity, and mixing is equal
Even, dry granulating machine granulation is crossed 20 meshes and is crushed, the talcum powder of recipe quantity is added, after mixing, stiffened fatty acid magnesium total mix,
Tabletting to obtain the final product.
The preparation of capsule of the embodiment 13 containing formula (I) compound solid dispersion
Prescription (1000):
Preparation process: weighing solid dispersions, lactose, microcrystalline cellulose and the sodium carboxymethyl starch of recipe quantity, and mixing is equal
Even, dry granulating machine granulation is crossed 20 meshes and is crushed, the talcum powder of recipe quantity is added, after mixing, stiffened fatty acid magnesium total mix,
Filling capsule to obtain the final product.
The preparation of granule of the embodiment 14 containing formula (I) compound solid dispersion
Prescription (1000 packet):
Preparation process: solid dispersions, lactose, soluble starch, microcrystalline cellulose and the carboxymethyl for weighing recipe quantity form sediment
Powder sodium is uniformly mixed, dry granulation, is crossed 20 meshes and is crushed, dispenses to obtain the final product.
As can be seen from the above embodiments, Xi Gelieta solid dispersions prepared by the present invention stability with higher and water-soluble
Property.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (10)
1. a kind of Xi Gelieta solid dispersions characterized by comprising
Compound and solid carrier shown in Formulas I；
The solid carrier is copolyvidone or povidone；
2. Xi Gelieta solid dispersions according to claim 1, which is characterized in that the copolyvidone is PVP-
VA64；The povidone is PVP-K30.
3. Xi Gelieta solid dispersions according to claim 1, which is characterized in that the compound and solid carrier
Weight ratio is 1:(2~10).
4. Xi Gelieta solid dispersions according to claim 1, which is characterized in that further include: excipient and/or load
Body.
5. the preparation method of the described in any item Xi Gelieta solid dispersions of Claims 1 to 4, which is characterized in that including with
Lower step:
In organic solvent by compound shown in Formulas I and solid carrier dissolution, it then dries.
6. preparation method according to claim 5, which is characterized in that the organic solvent is ethyl alcohol and/or tetrahydrofuran.
7. preparation method according to claim 5, which is characterized in that the drying is rotary evaporation or spray drying.
8. the described in any item Xi Gelieta solid dispersions of Claims 1 to 4 or the described in any item systems of claim 5~7
The Xi Gelieta solid dispersions of Preparation Method preparation are preparing the medicine for preventing, mitigating or treating diabetes or type II diabetes
Application in object.
9. a kind of pharmaceutical preparation, which is characterized in that including the described in any item Xi Gelieta solid dispersions of Claims 1 to 4
Or the Xi Gelieta solid dispersions of the described in any item preparation method preparations of claim 5~7.
10. pharmaceutical preparation according to claim 9, which is characterized in that the dosage form of the pharmaceutical preparation is tablet, capsule
Or granule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710592206.1A CN109276543B (en) | 2017-07-19 | 2017-07-19 | Sitaglipta solid dispersion and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710592206.1A CN109276543B (en) | 2017-07-19 | 2017-07-19 | Sitaglipta solid dispersion and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109276543A true CN109276543A (en) | 2019-01-29 |
| CN109276543B CN109276543B (en) | 2021-01-08 |
Family
ID=65184193
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710592206.1A Active CN109276543B (en) | 2017-07-19 | 2017-07-19 | Sitaglipta solid dispersion and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109276543B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111759838A (en) * | 2020-07-02 | 2020-10-13 | 深圳微芯生物科技股份有限公司 | Pharmaceutical composition of pharmaceutically acceptable salt of sitagliptin and application thereof |
| WO2021052440A1 (en) * | 2019-09-19 | 2021-03-25 | 深圳微芯生物科技股份有限公司 | Use of chiglitazar and derivatives thereof in treating type 2 diabetes accompanied by abnormal lipids metabolism |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562970A (en) * | 2003-06-17 | 2005-01-12 | 深圳微芯生物科技有限责任公司 | PPAR full activator of amino acids of aralkyl possessing excellent activity for lowering sugar and ester |
| WO2005065639A2 (en) * | 2003-11-21 | 2005-07-21 | Torrent Pharmaceuticals Limited | Novel pharmaceutical compositions |
| CN102389396A (en) * | 2011-11-08 | 2012-03-28 | 成都恒瑞制药有限公司 | Pioglitazone hydrochloride solid dispersoid and medicinal compound thereof as well as preparation methods and applications thereof |
| CN102406622A (en) * | 2011-11-16 | 2012-04-11 | 浙江华海药业股份有限公司 | Tolvaptan solid preparation |
| CN103301066A (en) * | 2012-03-15 | 2013-09-18 | 苏州泽璟生物制药有限公司 | Solid dispersion for improving absorbing property and preparation method thereof |
| CN104434805A (en) * | 2013-09-22 | 2015-03-25 | 成都盛迪医药有限公司 | Ticagrelor solid dispersion and preparation method thereof |
| CN104473862A (en) * | 2014-11-18 | 2015-04-01 | 北京科莱博医药开发有限责任公司 | Roflumilast solid dispersoid and preparation method thereof as well as roflumilast preparation |
| CN104771363A (en) * | 2014-01-14 | 2015-07-15 | 深圳微芯生物科技有限责任公司 | Chidamide solid dispersion and preparing method and application thereof |
| CN106456539A (en) * | 2013-12-31 | 2017-02-22 | 阿森迪亚制药有限责任公司 | Pharmaceutical compositions for poorly water-soluble compounds |
-
2017
- 2017-07-19 CN CN201710592206.1A patent/CN109276543B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562970A (en) * | 2003-06-17 | 2005-01-12 | 深圳微芯生物科技有限责任公司 | PPAR full activator of amino acids of aralkyl possessing excellent activity for lowering sugar and ester |
| WO2005065639A2 (en) * | 2003-11-21 | 2005-07-21 | Torrent Pharmaceuticals Limited | Novel pharmaceutical compositions |
| CN102389396A (en) * | 2011-11-08 | 2012-03-28 | 成都恒瑞制药有限公司 | Pioglitazone hydrochloride solid dispersoid and medicinal compound thereof as well as preparation methods and applications thereof |
| CN102406622A (en) * | 2011-11-16 | 2012-04-11 | 浙江华海药业股份有限公司 | Tolvaptan solid preparation |
| CN103301066A (en) * | 2012-03-15 | 2013-09-18 | 苏州泽璟生物制药有限公司 | Solid dispersion for improving absorbing property and preparation method thereof |
| CN104434805A (en) * | 2013-09-22 | 2015-03-25 | 成都盛迪医药有限公司 | Ticagrelor solid dispersion and preparation method thereof |
| CN106456539A (en) * | 2013-12-31 | 2017-02-22 | 阿森迪亚制药有限责任公司 | Pharmaceutical compositions for poorly water-soluble compounds |
| CN104771363A (en) * | 2014-01-14 | 2015-07-15 | 深圳微芯生物科技有限责任公司 | Chidamide solid dispersion and preparing method and application thereof |
| CN104473862A (en) * | 2014-11-18 | 2015-04-01 | 北京科莱博医药开发有限责任公司 | Roflumilast solid dispersoid and preparation method thereof as well as roflumilast preparation |
Non-Patent Citations (2)
| Title |
|---|
| PING-PING LI ET AL.: "The PPAR α/γ dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats", 《BRITISH JOURNAL OF PHARMACOLOGY》 * |
| 闫亮平等: "西格列他钠的体外代谢", 《中国药理学与毒理学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021052440A1 (en) * | 2019-09-19 | 2021-03-25 | 深圳微芯生物科技股份有限公司 | Use of chiglitazar and derivatives thereof in treating type 2 diabetes accompanied by abnormal lipids metabolism |
| CN111759838A (en) * | 2020-07-02 | 2020-10-13 | 深圳微芯生物科技股份有限公司 | Pharmaceutical composition of pharmaceutically acceptable salt of sitagliptin and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109276543B (en) | 2021-01-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101290626B1 (en) | Pharmaceutical formulations comprising voriconazole and processes for preparation thereof | |
| KR20140069297A (en) | Pharmaceutical compositions of n-methyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide | |
| EP3556354A1 (en) | Oral preparation of glucokinase activator and preparation method therefor | |
| BR122021018683B1 (en) | PHARMACEUTICAL FORMULATION OF 4-[3-(4-CYCLOPROPANOCARBONYL-PIPERAZINE-1-CARBONYL)-4-FLUORINE-BENZYL]-2H-PHTHALAZIN-1-ONE, USE OF A MATRIX POLYMER, DOSAGE FORM AND METHOD FOR PRODUCING A SOLID AMORPHAUS DISPERSION | |
| Lu et al. | Enhanced dissolution and stability of lansoprazole by cyclodextrin inclusion complexation: preparation, characterization, and molecular modeling | |
| EP3437646A1 (en) | Oral preparation having exceptional elutability | |
| AU2017333056B2 (en) | Non-solvated crystal, preparation method and application thereof | |
| Som et al. | Quality by design-based crystallization of curcumin using liquid antisolvent precipitation: micromeritic, biopharmaceutical, and stability aspects | |
| Hou et al. | Effect of microenvironmental pH modulation on the dissolution rate and oral absorption of the salt of a weak acid–case study of GDC-0810 | |
| Bhanushali et al. | Molecular interactions of niclosamide with hydroxyethyl cellulose in binary and ternary amorphous solid dispersions for synergistic enhancement of water solubility and oral pharmacokinetics in rats | |
| CN102633777A (en) | Dabigatran etexilate 2-ketoglutarate as well as preparation method and application thereof | |
| CN103830192A (en) | Tenofovir disoproxil fumarate tablets allowing direct powder compression and preparation method thereof | |
| Chen et al. | Co-amorphous systems of sinomenine with platensimycin or sulfasalazine: Physical stability and excipient-adjusted release behavior | |
| Nguyen et al. | Immediate-released pelletized solid dispersion containing fenofibrate: Formulation, in vitro characterization, and bioequivalence studies in experimental beagle dogs | |
| CN109276543A (en) | A kind of Xi Gelieta solid dispersions and its preparation method and application | |
| CN103200935A (en) | A composition comprising s-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate and croscarmellose sodium | |
| CN105343028A (en) | Medicine composition with norfloxacin and method for preparing medicine composition | |
| KR20200092956A (en) | Solid dispersion | |
| Lavan et al. | Development of a pediatric mini-tablet formulation for expedited preclinical studies | |
| CN107865826B (en) | Solid dispersion of E-configuration benzamide compound | |
| CN103396378B (en) | Stable febuxostat crystal | |
| KR20230131253A (en) | Solid tablet dosage form of ridinilazole | |
| CN114533691A (en) | Apremilast tablet and industrial preparation method thereof | |
| CN103655499B (en) | Stable X-crystal-shaped agomelatine tablet and preparation method thereof | |
| CN106606786A (en) | Pharmaceutical composition containing isavuconazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |