CN116421573B - Topiroxostat sustained release preparation and preparation method thereof - Google Patents
Topiroxostat sustained release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN116421573B CN116421573B CN202310498153.2A CN202310498153A CN116421573B CN 116421573 B CN116421573 B CN 116421573B CN 202310498153 A CN202310498153 A CN 202310498153A CN 116421573 B CN116421573 B CN 116421573B
- Authority
- CN
- China
- Prior art keywords
- topiroxostat
- sustained release
- release preparation
- preparation
- active ingredient
- 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.)
- Active
Links
- UBVZQGOVTLIHLH-UHFFFAOYSA-N 4-[5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl]-pyridine-2-carbonitrile Chemical compound C1=NC(C#N)=CC(C=2N=C(NN=2)C=2C=CN=CC=2)=C1 UBVZQGOVTLIHLH-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 229950004176 topiroxostat Drugs 0.000 title claims abstract description 84
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title abstract description 17
- 239000013078 crystal Substances 0.000 claims abstract description 33
- 239000004480 active ingredient Substances 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims description 23
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 17
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 17
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 10
- -1 polyoxyethylene Polymers 0.000 claims description 10
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 9
- 239000011118 polyvinyl acetate Substances 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 7
- 229920002125 Sokalan® Polymers 0.000 claims description 7
- 229960001631 carbomer Drugs 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000013268 sustained release Methods 0.000 claims description 7
- 239000012730 sustained-release form Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000004080 punching Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 30
- 210000002784 stomach Anatomy 0.000 abstract description 19
- 230000008961 swelling Effects 0.000 abstract description 16
- 239000000463 material Substances 0.000 abstract description 15
- 239000011159 matrix material Substances 0.000 abstract description 15
- 239000000314 lubricant Substances 0.000 abstract description 9
- 210000000813 small intestine Anatomy 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- 230000000717 retained effect Effects 0.000 abstract description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 description 41
- 229940079593 drug Drugs 0.000 description 27
- 230000000694 effects Effects 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 201000005569 Gout Diseases 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 210000001187 pylorus Anatomy 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 201000001431 Hyperuricemia Diseases 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229960005101 febuxostat Drugs 0.000 description 3
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- 229960003459 allopurinol Drugs 0.000 description 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000008855 peristalsis Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- FYGHPRWSAALUHI-UHFFFAOYSA-N 3,7-dihydropurine-2,6-dione;7h-purine Chemical compound C1=NC=C2NC=NC2=N1.O=C1NC(=O)NC2=C1NC=N2 FYGHPRWSAALUHI-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- VGGGPCQERPFHOB-UHFFFAOYSA-N Bestatin Natural products CC(C)CC(C(O)=O)NC(=O)C(O)C(N)CC1=CC=CC=C1 VGGGPCQERPFHOB-UHFFFAOYSA-N 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102000005773 Xanthine dehydrogenase Human genes 0.000 description 1
- 108010091383 Xanthine dehydrogenase Proteins 0.000 description 1
- 108010093894 Xanthine oxidase Proteins 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 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 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000003010 ionic group Chemical group 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910021487 silica fume Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a topiroxostat sustained release preparation and a preparation method thereof, wherein the topiroxostat sustained release preparation comprises the following components in percentage by mass: 2.5-20% of topiroxostat active ingredient, 5-50% of matrix forming agent, 5-50% of swelling agent, 5-50% of slow release material and 0.1-3% of lubricant, wherein the topiroxostat active ingredient is topiroxostat crystal form I. The topiroxostat sustained release preparation provided by the invention can be retained in the stomach, the topiroxostat is released continuously, and finally, the pharmaceutical composition leaves the stomach to enter the small intestine, and is absorbed continuously in the small intestine. The present invention allows QD administration by extending the release time of topiroxostat in the stomach effectively widens the absorption window associated with immediate release formulation administration. The topiroxostat sustained release preparation provided by the invention can greatly slow down the release rate and can maintain better crystal form stability.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a topiroxostat sustained-release preparation and a preparation method thereof.
Background
The prevalence of Chinese hyperuricemia and gout increases year by year, according to the research results disclosed in the diagnosis and treatment guide 2019 for gout and hyperuricemia base course: hyperuricemia patients already account for 13.3% of the general population, and gout prevalence is 1% -3%. In the past few decades, the research and development of gout drugs have been seriously neglected, only a small amount of drugs are marketed in batches, and the drugs for inhibiting uric acid generation mainly comprise allopurinol and non-bestatin tablets, but both have certain defects. Allopurinol is used in large dosage and has serious side effects; febuxostat tablets present a hidden danger to the cardiovascular system.
Topiroxostat (4- [5- (pyridin-4-yl) -1H-1,2, 4-triazol-3-yl ] pyridine-2-carbonitrile) is a non-purine xanthine oxidoreductase selective inhibitor synthesized by japan Fuji pharmaceutical co. Topiroxostat tablet is a xanthine oxidase inhibitor of yet another non-purine class following febuxostat, which reaches the peak of blood concentration faster than febuxostat, thus having a faster onset of action; no accumulation phenomenon in the body; is not affected by diet, has low adverse side effects on cardiovascular system, and improves safety and compliance of patient administration.
According to the instructions of topiroxostat tablets on the market in Japan, the dosage of the drug is 20mg each time at the beginning of adults, and the drug is orally taken in the morning and evening (BID). Thereafter, uric acid levels in the blood are examined, and the dosage is gradually increased as needed. The maintenance dose is usually 60mg each time, 2 times a day, and can be appropriately increased or decreased according to the state of the patient, and the maximum administration dose is 80mg each time, 2 times a day. It can be seen that either 20mg, 40mg or 60mg is 2 times daily. However, the majority of gout patients are elderly patients, and the convenience of QD dosing (dosing 1 time a day) can generally improve patient compliance for elderly patients and patients taking multiple medications. QD dosing can not only reduce or avoid potential, undesired dose-related side effects by reducing the highest concentration (Cmax) in the blood, but can also increase drug efficacy by increasing the lowest concentration (Cmin) in the plasma.
The half life of topiroxostat tablet is 4.56-7.49 hours, the drug concentration reaches the peak within 1 hour, and topiroxostat is mainly absorbed at the upper end of small intestine, so that the drug needs to be prepared into a QD (Quaternary drug) taking mode, namely, the variety reaching the peak within 1 hour per se needs to be prepared into a sustained release preparation which is taken once within 24 hours, and great difficulty exists.
Disclosure of Invention
The invention provides a topiroxostat sustained-release preparation composition and a preparation method thereof, which aim to solve the technical problem that the conventional topiroxostat cannot realize QD medicine taking.
According to one aspect of the invention, there is provided a topiroxostat sustained release preparation comprising the following components in percentage by mass: 2.5-20% of topiroxostat active ingredient, 5-50% of matrix forming agent, 5-50% of swelling agent, 5-50% of slow release material and 0.1-3% of lubricant, wherein the topiroxostat active ingredient is topiroxostat crystal form I.
Further, the composition comprises the following components in percentage by mass: topiroxostat active ingredient 2.5-15%, matrix forming agent 20-50%, swelling agent 20-40%, slow release material 5-20% and lubricant 0.5-2%.
Further, the matrix forming agent is a mixture of polyvinyl acetate and polyvinylpyrrolidone, wherein the mass ratio of the polyvinyl acetate to the polyvinylpyrrolidone is (6:4) - (9:1).
Further, the swelling agent comprises at least one of crosslinked polyvinylpyrrolidone, sodium carboxymethyl cellulose, a crosslinked product of sodium carboxymethyl cellulose, sodium carboxymethyl starch, a crosslinked product of sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.
Further, the slow release material comprises one or more of polyoxyethylene, carbomer, hypromellose and sodium alginate.
Further, the polyoxyethylene is used as an aqueous solution having a viscosity exceeding 100 mpa.s.
Further, the lubricant comprises magnesium stearate, talcum powder or micro silica gel.
Further, the topiroxostat sustained release preparation has an average hardness of 10-20 kg.
Further, the topiroxostat sustained release preparation has a size of 19mm×10mm, is suitable for once daily oral administration, and expands to a minimum size of 12mm or more after administration.
According to another aspect of the present invention, there is also provided a method for preparing the topiroxostat sustained release preparation described above, comprising the steps of: blending topiroxostat active ingredient, matrix forming agent, swelling agent and sustained-release material for 15-25 min; adding a lubricant and mixing for 1-3 min to obtain a blend; and (5) punching and tabletting to obtain the topiroxostat sustained-release preparation.
The invention has the following beneficial effects:
the invention provides a topiroxostat sustained release preparation which is suitable for oral administration once a day. When administered in a solid dosage form (e.g., a tablet), the pharmaceutical composition remains in the stomach for a longer period of time than an immediate release dosage form. While retained in the stomach, the pharmaceutical composition may release topiroxostat continuously, eventually leaving the stomach into the small intestine where it is absorbed continuously. The present invention allows QD administration by extending the release time of topiroxostat in the stomach effectively widens the absorption window associated with immediate release formulation administration.
The topiroxostat sustained release preparation provided by the invention can greatly slow down the release rate and can keep better crystal form stability (the bare chip is placed with 75% RH for 15 days at 25 ℃ and the crystal form is not changed).
Detailed Description
In order to make the objects, technical solutions and advantageous technical effects of the present invention clearer, the present invention will be further described in detail with reference to examples. It should be understood that the examples described in this specification are for the purpose of illustrating the invention only and are not intended to limit the invention.
For simplicity, only a few numerical ranges are explicitly disclosed herein. However, any lower limit may be combined with any upper limit to form a range not explicitly recited; and any lower limit may be combined with any other lower limit to form a range not explicitly recited, and any upper limit may be combined with any other upper limit to form a range not explicitly recited. Furthermore, each point or individual value between the endpoints of the range is included within the range, although not explicitly recited. Thus, each point or individual value may be combined as a lower or upper limit on itself with any other point or individual value or with other lower or upper limit to form a range that is not explicitly recited.
In the description herein, unless otherwise indicated, "above" and "below" are intended to include the present number, "one or more" means two or more, and "one or more" means two or more.
The embodiment of the first aspect of the invention provides a topiroxostat sustained release preparation, which comprises the following components in percentage by mass: 2.5-20% of topiroxostat active ingredient, 5-50% of matrix forming agent, 5-50% of swelling agent, 5-50% of slow release material and 0.1-3% of lubricant, wherein the topiroxostat active ingredient is topiroxostat crystal form I.
The gastric retention drug delivery system is a novel drug delivery system which can be retained in gastric juice, prolong the release time of drugs in gastrointestinal tracts, improve the drug absorption, or enhance the therapeutic effect of the drugs in the local stomach, reduce adverse reactions and drug administration times and improve the clinical curative effect. The system can promote the absorption of weak acid medicine, medicine absorbed at specific part of gastrointestinal tract, medicine actively transported in duodenal segment, medicine unstable in intestinal environment and medicine with narrow therapeutic window, and make up for the defect of short biological half-life of medicine. However, there are few drugs currently marketed using the gastric retention mechanism, mainly because of the characteristics of the active ingredient and the problems of the gastric retention material, and the stability of the product.
The gastric retention preparation is developed by considering the influence of various factors, which are mainly physiological factors, pathological factors and preparation factors. Physiological factors such as the age, sex, posture, physical condition, emotional state, and feeding of the patient can have an effect on the residence time of the drug in the stomach. Pathological factors such as the patient's disease state (e.g., crohn's disease, diabetes, etc.) and ingestion of drugs affecting gastrointestinal motility (e.g., anticholinergic agent atropine, opioid codeine, and the gastrointestinal motility agent cisapride, etc.) all have a certain effect on the gastric emptying rate. Formulation factors such as size and shape of the formulation, and density can affect the therapeutic efficacy of the drug. The preparation is not easy to swallow when the size is too large, and the pylorus is easily discharged by the peristalsis of the stomach when the size is too small, so that the time for staying in the stomach is greatly shortened; annular and tetrahedral formulations have longer gastric residence times than other shapes; the density of the formulation may determine whether it is in a floating or settled state in the stomach.
Taking topiroxostat as an example, since topiroxostat belongs to BCS II medicines and has poor solubility, the raw medicines are crushed to D90 smaller than 50 microns to be effectively absorbed in a human body and exert the medicine effect. However, the particle size of the raw materials is small, and the defect of sticking and flushing can be easily caused in the preparation process. And many slow release materials are also easily hygroscopic and water-absorbing, resulting in easier sticking. The problems are overcome when topiroxostat sustained-release preparation is prepared.
Topiroxostat exists in three crystalline forms, either form I, form ii or as a hydrate. The three crystal forms can be mutually converted under a certain condition, and the solubility of the different crystal forms is different, so that the bioavailability of the medicine is affected. Thus, there is a need to select a crystalline form of topiroxostat suitable for use in gastroretentive sustained release formulations which has a relatively high solubility in the stomach but a low solubility in the intestinal system and which meets the commercial production of pharmaceuticals and good stability. Polymorphism is widely existed in medicines, and the crystal forms of the medicines are different, so that the crystal lattice energy is different, and the melting point, the dissolution speed, the solubility and the like are also different. The crystal form with the smallest lattice energy is the most stable, called stable form, which has less solubility and dissolution rate; the lattices of other crystal forms can be larger than those of stable forms, are called metastable forms, have lower melting points and densities, and have higher solubility and dissolution speed than those of stable forms. And according to the solubility data, the crystal form I is more than the crystal form II is more than the hydrate, and then the stability result is that the crystal form I is less than the crystal form II and less than the hydrate, namely the hydrate crystal form is the most stable. The invention selects the crystal form I as a medicine crystal form by comprehensively considering two kinds of solubility and stability.
According to the embodiment of the application, since topiroxostat belongs to BCS II medicines, the topiroxostat has poor solubility, and raw medicines are crushed to D90 smaller than 50 microns to be effectively absorbed and exert the medicine effect in a human body. However, the particle size of the raw materials is small, and the defect of sticking and flushing can be easily caused in the preparation process. The composition can maintain a tablet-shaped state for a long time when dissolved out by screening a proper prescription and prescription proportion, can achieve gastric retention effect, and has good slow release effect, proper expansion volume, long expansion duration, quick floating time and long duration floating time.
The pharmaceutical composition of the present invention is taken in its entirety and begins to swell or swell when contacted with gastric fluid (water) in the stomach of a patient. The dosage form may have any shape including circular or oval, defined by a pair of circular or oval convex or planar surfaces.
In the embodiment of the application, in order to further optimize the effect of the topiroxostat sustained-release preparation, the components with the following mass percentages are mixed: topiroxostat active ingredient 2.5-15%, matrix forming agent 20-50%, swelling agent 20-40%, slow release material 5-20% and lubricant 0.5-2%.
In the embodiment of the application, the matrix forming agent is a mixture of polyvinyl acetate and polyvinylpyrrolidone, wherein the mass ratio of the polyvinyl acetate to the polyvinylpyrrolidone is (6:4) - (9:1). The matrix forming agent is also called a framework material, wherein polyvinylpyrrolidone forms a pore canal when meeting water and is taken as a channel for the active ingredient to diffuse outwards; the polyvinyl acetate has no ionic group and no influence on drug release, and is used as a framework tablet material of a direct tabletting process, which is not influenced by pH value change. The material has viscoelasticity after meeting water, can keep a complete sheet shape, and can not collapse or break. The cross-linked polyvinylpyrrolidone is used as a volume-expanding swelling agent, is applied to a slow-release preparation, has a large prescription proportion, is a swelling material, and can expand a tablet body to be large, is blocked in the stomach and is not emptied. The matrix forming agent and the swelling agent are effectively matched, and the sustained-release preparation is effectively applicable to topiroxostat.
In an embodiment of the present application, the swelling agent includes at least one of crosslinked polyvinylpyrrolidone, sodium carboxymethyl cellulose, a crosslinked product of sodium carboxymethyl cellulose, sodium carboxymethyl starch, a crosslinked product of sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose. Among them, the crosslinked polyvinylpyrrolidone has high capillary activity, and thus can rapidly absorb water into a tablet. Since the internal pressure (swelling pressure) exceeds the strength of the tablet, the tablet disintegrates instantaneously. Also, because of the folded molecular chains between crosslinks, when water or aqueous solution infiltrates, it is stretched by sudden impact, and is forced to separate immediately. The net volume increases (approximately a factor of two in 5 minutes) as a result of the expansion.
In an embodiment of the present application, the slow release material comprises one or more of polyoxyethylene, carbomer, hypromellose, and sodium alginate.
The polyoxyethylene plays a slow release role in gastric acid environment; the carbomer has pH dependency, does not play a slow release role in gastric acid environment with pH less than 4.0, partial broken fragments are emptied into small intestine under long-time mechanical peristalsis of stomach, gel state is formed under small intestine environment with pH more than 4.0, partial medicine is wrapped, the second layer slow release role is played, meanwhile, viscosity is enhanced, and the residence time of intestinal tracts is prolonged.
In the examples of the present application, the polyoxyethylene is used as an aqueous solution having a viscosity exceeding 100mpa.s, and a good friability can be ensured.
In embodiments of the present application, the lubricant comprises magnesium stearate, talc or fumed silica.
In the examples of the present application, the topiroxostat sustained release preparation has an average hardness of 10 to 20kg, and below this hardness range, it is easily broken during transportation, and above this hardness range, it is difficult to disintegrate in vivo, and the drug effect cannot be exerted.
In the examples of the present application, the topiroxostat sustained release preparation has a size of 19mm×10mm, and is suitable for once daily oral administration, and the minimum size direction of the topirst sustained release preparation expands to 12mm or more after administration.
QD dosage forms are retained in the stomach by size exclusion, meal dosing, pre-sleep dosing, and some combination of these methods. For retention by size exclusion alone, the dosage form swells to a certain size. Thereby preventing it from exiting the stomach via the pylorus. Since the adult pyloric sphincter has a diameter of 12mm or more, the expanded dosage form has a size in the range of about 12mm to about 20 mm or more. Herein, the "size" of the dosage form corresponds to the longest linear dimension of the cross-section of the dosage form having the smallest area. For example, a circular tablet has a size corresponding to its diameter, while a shaped tablet has a size corresponding to the minor axis of the elliptical cross-section of the minor diameter side.
Topiroxostat sustained release formulations swell or expand to about 12mm to 22 mm in the short axis of the cross section of the dosage form (e.g., using a 19mm x 10mm capsule punch) upon contact with water in human gastric juice, and have some rigidity; the pylorus and the place where the stomach contents are necessary have the diameter of more than 12mm, so that the preparation provided by the invention can be effectively retained in the stomach, the aim of continuously and slowly releasing the main ingredients of the medicine is achieved, and finally, the long-time absorption of topirst in the small intestine is effectively promoted.
Another aspect of the embodiments of the present application provides a method for preparing the topiroxostat sustained release preparation, which includes the following steps: blending topiroxostat active ingredient, matrix forming agent, swelling agent and sustained-release material for 15-25 min; adding a lubricant and mixing for 1-3 min to obtain a blend; and (5) punching and tabletting to obtain the topiroxostat sustained-release preparation. The powder direct-pressing process is simple to operate and high in production efficiency.
Examples
The following examples more particularly describe the disclosure of the present application, which are intended as illustrative only, since numerous modifications and variations within the scope of the disclosure will be apparent to those skilled in the art. Unless otherwise indicated, all parts, percentages, and ratios reported in the examples below are by weight, and all reagents used in the examples are commercially available or were obtained synthetically according to conventional methods and can be used directly without further treatment, as well as the instruments used in the examples.
Table 1 shows the component distribution in mass percent of examples 1 to 3 and comparative examples 1 to 3, and topiroxostat sustained-release preparations were prepared respectively as follows:
all tablet components except the magnesium stearate were blended in a mixer for 15-25 minutes and then mixed with magnesium stearate for 1-3 minutes to obtain the final blend. With proper die tabletting, tablets with an average hardness of 10-20kg can be obtained with a weight loss of 0.1% in friability check at a proper set main pressure.
TABLE 1 distribution of Components by mass for examples 1 to 3 and comparative examples 1 to 3
Topiroxostat tablet (lot number F033H, manufactured by Fuji pharmaceutical Co., ltd.) commercially available for oral administration 2 times daily was used as comparative example 4.
The topiroxostat sustained release preparation prepared in example 1 was measured at 37℃in a paddle apparatus of the Chinese pharmacopoeia 2020 edition containing 0.1N HCl solution, and Table 2 shows the size (length, width, thickness in mm) and volume (in mm 3) versus time (hours) of the topiroxostat sustained release preparation prepared in example 1.
Table 2 relationship between topiroxostat sustained release preparation (tablet) size and time of example 1
| Time | Long length | Wide width of | Thickness of thick | Volume of |
| 0h | 19.10 | 10.10 | 7.70 | 1485.41 |
| 0.5h | 20.89 | 12.23 | 12.12 | 3096.47 |
| 2h | 22.04 | 12.33 | 12.22 | 3320.82 |
| 4h | 22.98 | 13.43 | 12.29 | 3792.96 |
| 6h | 23.23 | 13.98 | 12.99 | 4218.57 |
| 8h | 23.99 | 14.21 | 13.41 | 4571.44 |
As can be seen from table 2, the topiroxostat sustained release preparation of example 1 was volume-expanded to a minimum size of more than 12mm within 0.5 hour.
1. Investigation of dissolution results
To examine the dissolution results of topiroxostat, the applicant carried out measurement of the release amount of topiroxostat with respect to time at 37 ℃ in a paddle method apparatus of chinese pharmacopoeia 2020 edition containing 0.1N HCl solution, as shown in table 3.
Table 3 topiroxostat release (%) versus time (hours)
From the data in Table 3, it is shown that topiroxostat sustained release effect can be effectively achieved by adopting the combination of matrix forming agent and swelling agent in the range of the invention. The preparation prepared by the topiroxostat crystal form I can reach the complete (nearly 100%) dissolution expectation of 24h slow release, but the preparation prepared by the topiroxostat hydrate crystal does not reach 50% of 24h release, and the preparation prepared by the topiroxostat crystal form II does not reach 70% of 24h release, so the slow release preparation prepared by matching the matrix forming agent and the swelling agent of the topiroxostat crystal form I in the range of the invention has good slow release effect.
2. Investigation of the crystal transformation phenomenon
To examine the crystal transition phenomenon of topiroxostat sustained-release formulations prepared in examples 1 to 3 and comparative example 1, bare chips of samples (prepared from the same bulk drug) were placed at 75% RH for 15 days at 25℃to examine XRD, and at the same time, compared with samples of bulk drug for 0 day, whether the crystal forms were changed after 15 days was examined, and the results are shown in Table 4.
Table 4 data on the stability of crystal forms of topiroxostat preparations prepared in examples 1 to 3 and comparative example 1
As can be seen from the data in Table 4, the formulations prepared using the ranges of the pharmaceutical compositions of the present invention maintain the crystalline form (form I crystals) unchanged. In comparative example 1, since the matrix forming agent and the swelling agent are not within the scope of the present invention, a seeding phenomenon occurs.
3. Solubility test of different crystalline forms
For the form I crystals, the form II crystals, and the solubility of the hydrate in water, the saturated solution concentration of each sample was calculated by absorbance measurement. The solubility of form I crystals in water was 6.5. Mu.g/mL, while the solubility of form II crystals was 4.0. Mu.g/mL, and the hydrate was 1.6. Mu.g/mL.
4. Investigation of sticking and flushing phenomena
At the time of tabletting of each of examples and comparative examples, it was observed whether or not the sticking phenomenon occurred, and the results are as follows:
table 5 sticking during tabletting of examples 1 to 3 and comparative examples 1 to 2
| Sample of | Whether or not to generate sticking and flushing phenomena |
| Example 1 | Whether or not |
| Example 2 | Whether or not |
| Example 3 | Whether or not |
| Comparative example 1 | Is that |
| Comparative example 2 | Whether or not |
From the above table data, it is seen that the matrix forming agent formulation ratio is in the range of 5 wt% to about 50 wt% and is effective in avoiding topirst sticking.
While the present application has been described with reference to a preferred embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the present application, and in particular, the technical features mentioned in the various embodiments may be combined in any manner as long as there is no structural conflict. The present application is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions falling within the scope of the claims.
Claims (5)
1. The topiroxostat sustained release preparation is characterized by comprising the following components in percentage by mass:
topiroxostat active ingredient 2.5%, polyvinyl acetate and polyvinylpyrrolidone mixture 50.0%, crosslinked polyvinylpyrrolidone 25.0%, polyoxyethylene 12.5%, carbomer 9.0% and magnesium stearate 1.0%;
or comprises: topiroxostat active ingredient 5.0%, polyvinyl acetate and polyvinylpyrrolidone mixture 47.5%, crosslinked polyvinylpyrrolidone 30.0%, polyoxyethylene 9.5%, carbomer 7.0% and magnesium stearate 1.0%;
or comprises: topiroxostat active ingredient 7.5%; 42.5% of a mixture of polyvinyl acetate and polyvinylpyrrolidone; 35.0% of crosslinked polyvinylpyrrolidone; 10% of polyoxyethylene; carbomer 4%; 1.0 percent of magnesium stearate,
the topiroxostat active ingredient is topiroxostat crystal form I.
2. Topiroxostat sustained release formulation according to claim 1, characterized in that the polyoxyethylene is formulated in aqueous solution with a viscosity exceeding 100mpa.s at the time of use.
3. The topiroxostat sustained release preparation according to claim 1, characterized in that the average hardness of the topiroxostat sustained release preparation is 10-20 kg.
4. A topiroxostat sustained release preparation according to any one of claims 1 to 3, characterized in that the topiroxostat sustained release preparation has a size of 19mm x 10mm and is suitable for once daily oral administration, and the minimum size direction of the topiroxostat sustained release preparation expands to 12mm or more after administration.
5. A method for preparing a topiroxostat sustained release preparation according to any one of claims 1 to 4, comprising the steps of:
mixing topiroxostat active ingredient, a mixture of polyvinyl acetate and polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyoxyethylene and carbomer for 15-25 min;
adding magnesium stearate, and mixing for 1-3 min to obtain a blend;
and (5) punching and tabletting to obtain the topiroxostat sustained-release preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310498153.2A CN116421573B (en) | 2023-05-06 | 2023-05-06 | Topiroxostat sustained release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310498153.2A CN116421573B (en) | 2023-05-06 | 2023-05-06 | Topiroxostat sustained release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116421573A CN116421573A (en) | 2023-07-14 |
| CN116421573B true CN116421573B (en) | 2024-02-23 |
Family
ID=87094428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310498153.2A Active CN116421573B (en) | 2023-05-06 | 2023-05-06 | Topiroxostat sustained release preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116421573B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1319391A (en) * | 2000-03-27 | 2001-10-31 | Basf公司 | Active content contained floating form having polyacetic vinylester and polyvinyl pyrrolidone, its preparation and use |
| CN104411700A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
| JP2019019112A (en) * | 2017-07-12 | 2019-02-07 | 株式会社富士薬品 | Sustained release formulation comprising 4-[5-(pyridin-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile or salt thereof |
| WO2022193723A1 (en) * | 2021-03-17 | 2022-09-22 | 长沙晶易医药科技有限公司 | Composition, preparation method therefor, and use thereof |
-
2023
- 2023-05-06 CN CN202310498153.2A patent/CN116421573B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1319391A (en) * | 2000-03-27 | 2001-10-31 | Basf公司 | Active content contained floating form having polyacetic vinylester and polyvinyl pyrrolidone, its preparation and use |
| CN104411700A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
| JP2019019112A (en) * | 2017-07-12 | 2019-02-07 | 株式会社富士薬品 | Sustained release formulation comprising 4-[5-(pyridin-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile or salt thereof |
| WO2022193723A1 (en) * | 2021-03-17 | 2022-09-22 | 长沙晶易医药科技有限公司 | Composition, preparation method therefor, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116421573A (en) | 2023-07-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7985421B2 (en) | Sustained release formulations of guaifenesin and additional drug ingredients | |
| ES2301537T3 (en) | TABLETS AND FORMULATION OF GUAIFENESINE OF SUSTAINED LIBERATION. | |
| JP6151727B2 (en) | Ulipristal acetate ester tablets | |
| TWI324075B (en) | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract | |
| CN111840239B (en) | Pregabalin sustained release preparation | |
| CN104902928B (en) | Include the total micronizing product of uliprista acetate | |
| US20060240101A1 (en) | Orally disintegrating pharmaceutical tablet formulations of olanzapine | |
| CN111053749B (en) | Pregabalin sustained-release composition and preparation method thereof | |
| EP1931314A2 (en) | Ramipril formulation | |
| CN113274364B (en) | Ramelteon sustained-release preparation and preparation method thereof | |
| CN114146062A (en) | Composition and preparation method and application thereof | |
| CN116421573B (en) | Topiroxostat sustained release preparation and preparation method thereof | |
| JP6990470B2 (en) | Lenalidomide gastric retention type sustained release tablet and its preparation method | |
| Kumar et al. | A recent update on gastro retentive drug delivery systems | |
| EP4313014A1 (en) | A method for the production of gastroretentive compact matrices for the controlled release of active substances and compact matrices thus obtained | |
| US10688072B2 (en) | Misoprostol dispersible tablet | |
| WO2021197376A1 (en) | A febuxostat tablet | |
| EP2181705A1 (en) | Sustained-release formulation of gliclazide | |
| ES2273271T3 (en) | COMPOSITION OF CONTROLLED RELEASE OF FARMACO RESISTANT TO IN VIVO MECHANICAL VOLTAGE. | |
| CN100500151C (en) | Water-soluble medicine sublingual-medicating formulation | |
| JP6532529B2 (en) | Misoprostol dispersible tablets | |
| CN117679385B (en) | Pirfenidone sustained release preparation and preparation method and application thereof | |
| Mondal | Design, development and in-vitro evaluation of prazosin hydrochloride donut shaped floating tablets | |
| EP2965750B1 (en) | Misoprostol dispersible tablet | |
| CN114681415A (en) | Trimetazidine hydrochloride sublingual tablet pharmaceutical preparation |
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 |