CN116370430A - Dapagliflozin and metformin sustained release tablet and preparation method thereof - Google Patents
Dapagliflozin and metformin sustained release tablet and preparation method thereof Download PDFInfo
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- CN116370430A CN116370430A CN202310529276.8A CN202310529276A CN116370430A CN 116370430 A CN116370430 A CN 116370430A CN 202310529276 A CN202310529276 A CN 202310529276A CN 116370430 A CN116370430 A CN 116370430A
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- dapagliflozin
- metformin
- lubricant
- sustained
- release
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 79
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 51
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 51
- 229960003105 metformin Drugs 0.000 title claims abstract description 27
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 50
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000010410 layer Substances 0.000 claims abstract description 49
- 239000008188 pellet Substances 0.000 claims abstract description 44
- 239000000314 lubricant Substances 0.000 claims abstract description 42
- 238000013268 sustained release Methods 0.000 claims abstract description 40
- 239000012730 sustained-release form Substances 0.000 claims abstract description 40
- 239000000853 adhesive Substances 0.000 claims abstract description 30
- 230000001070 adhesive effect Effects 0.000 claims abstract description 30
- 239000000945 filler Substances 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 21
- 239000007888 film coating Substances 0.000 claims abstract description 17
- 238000009501 film coating Methods 0.000 claims abstract description 17
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- GOADIQFWSVMMRJ-UPGAGZFNSA-N dapagliflozin propanediol monohydrate Chemical compound O.C[C@H](O)CO.C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl GOADIQFWSVMMRJ-UPGAGZFNSA-N 0.000 claims abstract description 10
- 238000002955 isolation Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 27
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 27
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 27
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 25
- 239000011248 coating agent Substances 0.000 claims description 19
- 238000000576 coating method Methods 0.000 claims description 19
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 15
- 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 claims description 15
- 239000008101 lactose Substances 0.000 claims description 15
- 229960001375 lactose Drugs 0.000 claims description 15
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 13
- 239000008116 calcium stearate Substances 0.000 claims description 13
- 235000013539 calcium stearate Nutrition 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 229960001855 mannitol Drugs 0.000 claims description 10
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 10
- 239000000811 xylitol Substances 0.000 claims description 10
- 229960002675 xylitol Drugs 0.000 claims description 10
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 10
- 235000010447 xylitol Nutrition 0.000 claims description 10
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 7
- 239000003826 tablet Substances 0.000 claims description 7
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 6
- 229960000346 gliclazide Drugs 0.000 claims description 6
- QMYDVDBERNLWKB-UHFFFAOYSA-N propane-1,2-diol;hydrate Chemical compound O.CC(O)CO QMYDVDBERNLWKB-UHFFFAOYSA-N 0.000 claims description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims 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 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000001125 extrusion Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 239000007779 soft material Substances 0.000 claims description 3
- 238000005563 spheronization Methods 0.000 claims 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 claims description 2
- 229920000178 Acrylic resin Polymers 0.000 claims description 2
- 239000004925 Acrylic resin Substances 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 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 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 238000013265 extended release Methods 0.000 claims 1
- 238000013270 controlled release Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 description 14
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
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- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000000738 kidney tubule Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- 230000002195 synergetic effect Effects 0.000 description 2
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- XOBOCRSRGDBOGH-UHFFFAOYSA-N 5-phenylnonan-5-ol Chemical compound CCCCC(O)(CCCC)C1=CC=CC=C1 XOBOCRSRGDBOGH-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000001280 Prediabetic State Diseases 0.000 description 1
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- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000002700 urine Anatomy 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a dapagliflozin and metformin sustained release tablet which sequentially comprises a metformin hydrochloride sustained release pellet core, an isolation layer, a dapagliflozin layer and a film coating layer from inside to outside; the metformin hydrochloride sustained-release pellet core comprises metformin hydrochloride, an adhesive I, a sustained-release material, a lubricant I and a filler; the dapagliflozin layer comprises dapagliflozin propylene glycol monohydrate, a binder II and a lubricant II. The invention provides a dapagliflozin and metformin sustained release tablet, which is prepared by combining dapagliflozin and metformin and a controlled release pellet technology. The preparation process is simple, the product stability is good, and the method is easy to popularize and use.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to dapagliflozin and metformin sustained-release tablets and a preparation method thereof.
Background
The epidemiological investigation result of diabetes in Chinese population shows that the prevalence rate of adult diabetes is 12.8%, and the pre-diabetes population is as high as 35.2%, the diabetes can be divided into type I and type II according to the pathogenesis, and the type II accounts for more than 80% of the total number of diabetics. Dapagliflozin is a column-like medicament acting on SGLT-2 target sites. Through the combination with the SGLT-2 of the kidney tubule, the glucose is inhibited from exerting glucose steady-state regulation effect, so that glucose cannot be reabsorbed back into blood by the kidney tubule, and finally, along with the urine discharged out of the body, the blood sugar of a human body is also reduced. Metformin can increase insulin sensitivity, so that the human body can use less insulin to achieve the effect of reducing blood sugar. The traditional effective treatment scheme is dapagliflozin combined with metformin, has a synergistic effect, can effectively regulate blood sugar of patients, and can also reduce adverse reactions.
Patent CN 106924208A discloses and a compound dapagliflozin metformin sustained release tablet, comprising: a tablet core containing metformin hydrochloride, a dapagliflozin quick-release layer and a film coating layer. The invention also provides a preparation method of the compound dapagliflozin and metformin sustained-release tablet, which comprises 1) preparing a tablet core containing metformin; 2) Packaging the dapagliflozin quick release layer and 3) packaging the film coating layer. The preparation process flow of the method is complex, the dapagliflozin quick-release layer is directly coated on the tablet core containing the metformin hydrochloride, and 2 components are in close contact, so that the product is easy to be unstable, and meanwhile, the method has high requirements on the production process, and the quality of the product is difficult to ensure under the advance of high production cost.
The controlled release pellet is a pellet prepared by mixing the drug and the retarder or a small pellet coated with a controlled release coating film on the basis of a common pellet core, and has the characteristics of attractive appearance, good fluidity, wide drug carrying range, stable drug release, small local irritation and the like. The invention combines the controlled release pellet technology with dapagliflozin and metformin, and develops a novel dapagliflozin-metformin sustained-release tablet.
Disclosure of Invention
The invention aims to provide a dapagliflozin metformin sustained-release tablet which is simple in preparation process, high in uniformity and slow in release.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a dapagliflozin and metformin sustained release tablet which sequentially comprises a metformin hydrochloride sustained release pellet core, an isolation layer, a dapagliflozin layer and a film coating layer from inside to outside; wherein, the raw materials for preparing the metformin hydrochloride sustained-release pellet core comprise metformin hydrochloride, an adhesive I, a sustained-release material, a lubricant I and a filler; the dapagliflozin layer is prepared from dapagliflozin propylene glycol monohydrate, an adhesive II and a lubricant II.
In a preferred embodiment, the raw materials for preparing the metformin hydrochloride sustained-release pellet core comprise 50-75% of metformin hydrochloride, 4-26% of a binder I, 12-30% of a sustained-release material, 1-10% of a lubricant I and 1-15% of a filler in percentage by mass; the dapagliflozin layer comprises 2-15% of dapagliflozin propylene glycol monohydrate, 70-95% of adhesive II and 1-15% of lubricant II.
Preferably, the raw materials for preparing the metformin hydrochloride sustained-release pellet core comprise 55-60% of metformin hydrochloride, 7-21% of adhesive I, 20-26% of sustained-release material, 1-5% of lubricant I and 5-10% of filler in percentage by mass; the dapagliflozin layer is prepared from 2-10% of dapagliflozin propylene glycol monohydrate, 85-90% of adhesive II and 5-10% of lubricant II.
In order to improve the slow release performance, uniformity and stability of the dapagliflozin and metformin hydrochloride slow release tablet, it is further preferable that the raw materials for preparing the metformin hydrochloride slow release pellet core comprise, by mass, 51% of metformin hydrochloride, 15% of an adhesive, 23% of a slow release material, 3% of a lubricant and 8% of a filler; the dapagliflozin layer is prepared from 6% of dapagliflozin propylene glycol monohydrate, 86% of an adhesive and 8% of a lubricant. The metformin hydrochloride is purchased from Albumin PHR1084.
In a preferred embodiment, the binder i is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, crospovidone, sodium carboxymethylcellulose, ethylcellulose, polyethylene oxide, acrylic resins; the lubricant I is one or more selected from magnesium stearate, calcium stearate, sodium stearate fumarate, stearic acid and talcum powder; the filler is selected from one or more of xylitol, mannitol, lactose, microcrystalline cellulose and pregelatinized starch; the slow release material is one or more selected from hydroxypropyl cellulose, hypromellose, ethyl cellulose and sodium alginate.
Preferably, the binder i is selected from polyethylene oxides; the lubricant I is selected from magnesium stearate and calcium stearate, and the weight ratio is 1:3 to 12. Further preferably, the lubricant I is selected from magnesium stearate and calcium stearate, and the weight ratio is 1:6. further, in order to improve the slow release effect, the polyethylene oxide has a viscosity average molecular weight of 1x10 5 200-500ppm of dibutyl hydroxyl toluene stabilizer, the melting point is 87-140 ℃, the density is 0.93g/mL at 25 ℃, the softening point is 65-67 ℃, and the embrittlement point is-50 ℃. Purchased from siella chemical technology (shandong) limited C21595-25g.
The adhesive I of the metformin hydrochloride sustained-release pellet core is selected from polyethylene oxide, the inventor discovers that the sustained-release performance can be obviously improved by using polyethylene oxide as the adhesive, and simultaneously discovers that the molecular weight of the polyethylene oxide has important significance on the release rate and biocompatibility of the drug, and the different molecular weights of the polyethylene oxide have different effects in the metformin hydrochloride sustained-release pellet core. It has been found that when the system according to the invention uses a viscosity average molecular weight of 1X10 5 The polyethylene oxide slow release effect is optimal. Because the molecular weight is too high, the solubility is too low, the uniformity of the sustained-release tablet is poor, and the sustained-release effect is poor because the molecular weight is too low. The dibutyl hydroxy toluene (BHT) stabilizer in the polyethylene oxide selected in the embodiment of the invention inhibits corrosionThe stability of the agent is improved.
For improved sustained release effect and uniformity of the corrosion inhibitor, preferably, the filler is selected from xylitol, mannitol and lactose. Further preferably, the lactose content of the filler is not more than 55wt% of the filler. Further preferably, the xylitol is 1,2,3,4, 5-pentitol available from Zhejiang Huakang pharmaceutical industry Co., ltd. The mannitol is purchased from zemoeizemoeizemoeizemoeizemoeizemoeizemoeizemoeizemoeizemoeizeh 14030 and the lactose is purchased from zemoeizemoeizemoeizemoeizemoeizemoeizemoeizemoeizemoeizeh 11074. Further preferred is a weight ratio of xylitol, mannitol and lactose of 4:2:1.
The inventors found that the overall effect of the filler being all lactose corrosion inhibitor is not ideal. After three kinds of xylitol, mannitol and lactose are compounded, the performance of the corrosion inhibitor can be improved by synergistic effect, and the effect of the lactose in the filler is optimal, wherein the weight percentage of the lactose in the filler is not more than 55%. The inventors hypothesize that the pore-forming effect of the different types of fillers is different, and after the filler is combined with the rest of components, the slow release property of the pellet core can be influenced, and meanwhile, the uniformity of the corrosion inhibitor can be influenced.
The slow release material is one or more selected from hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M and hydroxypropyl methylcellulose K100 LV. In order to improve the slow release effect of the metformin hydrochloride, the slow release material is further preferably selected from hydroxypropyl methylcellulose K15M, methoxy value of 19-30%, hydroxypropyl value of 4-12%, viscosity (22 ℃, 2%) of 5-200000 Pa.s, and gel temperature (0.2%) of 50-90 ℃ from the pharmaceutical auxiliary material company of An Jin Hunan, inc.
The inventor discovers that the performance parameters of the hydroxypropyl methylcellulose K15M have great influence on the slow release effect, and the slow release effect is greatly improved by selecting and compounding the proper hydroxypropyl methylcellulose K15M with the rest components. The hydroxypropyl methylcellulose K15M has performance parameters and structural characteristics, is reasonably matched with the dosage, increases the strength of gel formed after meeting water, slows down the corrosion rate and realizes excellent slow release effect.
In a preferred embodiment, the isolating layer is 'Opadry' series gastric-soluble coating powder, accounting for 8-15% of the weight of the metformin hydrochloride sustained-release pellets. Preferably, the isolating layer is 'Opadry' series gastric-soluble coating powder, and accounts for 13% of the weight of the metformin hydrochloride sustained-release pellets. The "Opadry" series of gastric-soluble coating powders were purchased from Shanghai Carlekang.
In a preferred embodiment, the binder ii is selected from one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, and hydroxypropyl methylcellulose K100 LV; the lubricant II is selected from magnesium stearate and/or calcium stearate.
In order to improve the uniformity and dissolution rate of dapagliflozin, preferably, the binder II is selected from hydroxypropyl methylcellulose K100M, which is purchased from the pharmaceutical excipients company of West An Jin Hunan; the lubricant is selected from magnesium stearate and calcium stearate, and the weight ratio is 1-5:1. Further preferred, the lubricant is selected from magnesium stearate and calcium stearate in a weight ratio of 3:1.
The invention also provides a preparation method of the dapagliflozin metformin sustained-release tablet, which comprises the following steps:
(1) Preparing a metformin hydrochloride sustained-release pellet core: uniformly mixing metformin hydrochloride, an adhesive I, a slow-release material, a lubricant I and a filler, adding water to prepare a soft material, using an extrusion spheronization machine to prepare pellets, and drying to obtain a metformin hydrochloride slow-release pellet core;
(2) And (3) a package isolation layer: preparing coating powder into coating liquid, and coating the metformin hydrochloride sustained-release pellet cores;
(3) Bao Dage column clean layer: dissolving gliclazide propylene glycol monohydrate, an adhesive II and a lubricant II with water, and then wrapping the dissolved gliclazide propylene glycol monohydrate, the adhesive II and the lubricant II on an isolating layer;
(4) Coating a film coating layer: preparing gastric-soluble film coating and coating the film coating.
In a preferred embodiment, the dapagliflozin layer weight gain is 1-10wt% of the total weight of the sustained release tablet, and the film coating layer weight gain is 0.5-7wt% of the total weight of the sustained release tablet.
Compared with the prior art, the invention has the advantages that: the invention provides a dapagliflozin and metformin sustained release tablet, which is prepared by combining dapagliflozin and metformin and combining a controlled release pellet technology. The preparation process is simple, the product stability is good, and the method is easy to popularize and use.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The embodiment provides a dapagliflozin metformin sustained release tablet, which sequentially comprises from inside to outside: the metformin hydrochloride sustained-release pellet comprises a pellet core, an isolation layer, a dapagliflozin layer and a film coating layer; the metformin hydrochloride sustained-release pellet core comprises metformin hydrochloride, an adhesive I, a sustained-release material, a lubricant I and a filler; the dapagliflozin layer comprises dapagliflozin propylene glycol monohydrate, a binder II and a lubricant II.
The metformin hydrochloride sustained-release pellet core comprises 51% of metformin hydrochloride, 15% of an adhesive I, 23% of a sustained-release material, 3% of a lubricant and 8% of a filler; the dapagliflozin layer comprises 6% of dapagliflozin propylene glycol monohydrate, 86% of a binder II and 8% of a lubricant II. The adhesive I is selected from polyethylene oxide; the lubricant I is selected from magnesium stearate and calcium stearate, and the weight ratio is 1:6. the filler is selected from xylitol, mannitol and lactose. The weight ratio of xylitol, mannitol and lactose was 4:2:1. The slow release material is selected from hydroxypropyl methylcellulose K15M.
The isolation layer is opadry II type gastric-soluble coating powder, and accounts for 13% of the weight of the metformin hydrochloride sustained-release pellets.
The adhesive II is selected from hydroxypropyl methylcellulose K100M; the lubricant is selected from magnesium stearate and calcium stearate, and the weight ratio is 3:1.
The invention also provides a preparation method of the dapagliflozin metformin sustained-release tablet, which comprises the following steps:
(1) Preparing a metformin hydrochloride sustained-release pellet core: uniformly mixing metformin hydrochloride, an adhesive I, a slow-release material, a lubricant I and a filler, adding a proper amount of water to prepare a soft material, using an extrusion spheronization machine to prepare pellets, and drying at 65 ℃ to obtain a metformin hydrochloride slow-release pellet core;
(2) And (3) a package isolation layer: adding water into the coating powder to prepare coating liquid, and coating the metformin hydrochloride sustained-release pellet cores; the isolating layer accounts for 13% of the metformin hydrochloride sustained-release pellets in weight percent;
(3) Bao Dage column clean layer: dissolving gliclazide propylene glycol monohydrate, an adhesive II and a lubricant II with water, and then wrapping the dissolved gliclazide propylene glycol monohydrate, the adhesive II and the lubricant II on an isolating layer; the weight gain of the dapagliflozin layer is 5 percent of the total weight of the sustained release tablet,
(4) Coating a film coating layer: preparing gastric-soluble film coating and coating the film coating. The weight of the film coating layer is 2wt% of the total weight of the sustained release tablet.
Example 2
This embodiment differs from embodiment 1 in that: the binder I is selected from the group consisting of crospovidone available from Merck 21902.
Example 3
This embodiment differs from embodiment 1 in that: the slow release material is selected from ethylcellulose, available from merck 200689.
Example 4
This embodiment differs from embodiment 1 in that: the lubricant I is selected from magnesium stearate and calcium stearate, and the weight ratio is 1:1.
example 5
This embodiment differs from embodiment 1 in that: the filler is selected from xylitol, mannitol and lactose, and the weight ratio is 1:1:8.
Example 6
This embodiment differs from embodiment 1 in that: the adhesive II is selected from crosslinked povidone, and the lubricant II is selected from talcum powder.
Performance testing
(1) The release degree measuring method of the metformin hydrochloride sustained-release pellets prepared in examples 1 to 5 in 1000mL of phosphate buffer solution with pH of 6.8 and carried in Chinese pharmacopoeia comprises the steps of basket method, rotating at 100rpm, and measuring release amounts in 1h, 6h and 12h respectively. See table 1.
TABLE 1 metformin hydrochloride sustained release pellet core Performance test results
| Project | 1h | 6h | 12h |
| Example 1 | 23.1％ | 63.8％ | 90.6％ |
| Example 2 | 24.4％ | 71.2％ | 92.5％ |
| Example 3 | 24.7％ | 72.3％ | 91.1％ |
| Example 4 | 25.7％ | 76.8％ | 96.3％ |
| Example 5 | 27.5％ | 77.1％ | 95.3％ |
(2) The release rate of dapagliflozin layers prepared in example 1 and example 6 in 1000mL of phosphate buffer solution with pH of 6.8 was measured by basket method at 100rpm in Chinese pharmacopoeia, and release rates at 5min and 30min were measured respectively. See Table 2
TABLE 2 dapagliflozin layer Performance test results
| Project | 5min | 30min |
| Example 1 | 44％ | 95％ |
| Example 6 | 29％ | 84％ |
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The dapagliflozin and metformin sustained release tablet is characterized by sequentially comprising a metformin hydrochloride sustained release pellet core, an isolation layer, a dapagliflozin layer and a film coating layer from inside to outside; wherein, the raw materials for preparing the metformin hydrochloride sustained-release pellet core comprise metformin hydrochloride, an adhesive I, a sustained-release material, a lubricant I and a filler; the dapagliflozin layer is prepared from dapagliflozin propylene glycol monohydrate, an adhesive II and a lubricant II.
2. The dapagliflozin and metformin sustained release tablet according to claim 1, wherein the raw materials for preparing the metformin hydrochloride sustained release pellet core comprise 50-75% of metformin hydrochloride, 4-26% of adhesive I, 12-30% of sustained release material, 1-10% of lubricant I and 1-15% of filling agent according to mass percent; the dapagliflozin layer is prepared from 2-15% of dapagliflozin propylene glycol monohydrate, 70-95% of adhesive II and 1-15% of lubricant II.
3. The dapagliflozin and metformin sustained release tablet according to claim 2, wherein the raw materials for preparing the metformin hydrochloride sustained release pellet core comprise, by mass, 55-60% of metformin hydrochloride, 7-21% of an adhesive, 20-26% of a sustained release material, 1-5% of a lubricant I and 5-10% of a filler; the dapagliflozin layer is prepared from 2-10% of dapagliflozin propylene glycol monohydrate, 85-90% of adhesive II and 5-10% of lubricant II.
4. The dapagliflozin and metformin sustained release tablet according to claim 1, wherein the binder I is one or more selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, crospovidone, sodium carboxymethyl cellulose, ethyl cellulose, polyethylene oxide and acrylic resin; the lubricant I is one or more selected from magnesium stearate, calcium stearate, sodium stearate fumarate, stearic acid and talcum powder; the filler is selected from one or more of xylitol, mannitol, lactose, microcrystalline cellulose and pregelatinized starch; the slow release material is one or more selected from hydroxypropyl cellulose, hypromellose, ethyl cellulose and sodium alginate.
5. A dapagliflozin metformin extended release tablet in accordance with claim 4 wherein said binder i is selected from polyethylene oxide; the lubricant I is selected from magnesium stearate and calcium stearate, and the weight ratio of the magnesium stearate to the calcium stearate is 1:3 to 12.
6. A dapagliflozin metformin extended release tablet according to claim 4 wherein said filler is selected from xylitol, mannitol and lactose and said extended release material is selected from one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, and hydroxypropyl methylcellulose K100 LV.
7. A dapagliflozin metformin extended release tablet according to claim 6 wherein the lactose content of said filler is no more than 55% by weight of the filler.
8. The dapagliflozin and metformin sustained-release tablet according to claim 1, wherein the isolation layer is 'Opadry' series gastric-soluble coating powder, and accounts for 8-15% of the weight of the metformin hydrochloride sustained-release pellet.
9. A dapagliflozin metformin sustained release tablet according to claim 1, wherein said binder ii is selected from one or more of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, and hydroxypropyl methylcellulose K100 LV; the lubricant II is selected from magnesium stearate and/or calcium stearate.
10. A method for preparing a dapagliflozin metformin sustained-release tablet according to any one of claims 1 to 9, which is characterized by comprising the following steps:
(1) Preparing a metformin hydrochloride sustained-release pellet core: uniformly mixing metformin hydrochloride, an adhesive I, a slow-release material, a lubricant I and a filler, adding water to prepare a soft material, using an extrusion spheronization machine to prepare pellets, and drying to obtain a metformin hydrochloride slow-release pellet core;
(2) And (3) a package isolation layer: preparing coating powder into coating liquid, and coating the metformin hydrochloride sustained-release pellet cores;
(3) Bao Dage column clean layer: dissolving gliclazide propylene glycol monohydrate, an adhesive II and a lubricant II with water, and then wrapping the dissolved gliclazide propylene glycol monohydrate, the adhesive II and the lubricant II on an isolating layer;
(4) Film coating: preparing gastric-soluble film coating and wrapping the film coating.
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| CN117442580A (en) * | 2023-12-21 | 2024-01-26 | 泊诺(天津)创新医药研究有限公司 | High-bioavailability sodium mycophenolate enteric-coated tablet and preparation method thereof |
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| CN106924208A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof |
| CN113398097A (en) * | 2021-07-14 | 2021-09-17 | 南京康川济医药科技有限公司 | Dapagliflozin metformin sustained release preparation and preparation method thereof |
| CN116473934A (en) * | 2023-05-15 | 2023-07-25 | 山东诺明康药物研究院有限公司 | Dapagliflozin and metformin sustained release tablet as well as preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106924208A (en) * | 2015-12-30 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof |
| CN113398097A (en) * | 2021-07-14 | 2021-09-17 | 南京康川济医药科技有限公司 | Dapagliflozin metformin sustained release preparation and preparation method thereof |
| CN116473934A (en) * | 2023-05-15 | 2023-07-25 | 山东诺明康药物研究院有限公司 | Dapagliflozin and metformin sustained release tablet as well as preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117442580A (en) * | 2023-12-21 | 2024-01-26 | 泊诺(天津)创新医药研究有限公司 | High-bioavailability sodium mycophenolate enteric-coated tablet and preparation method thereof |
| CN117442580B (en) * | 2023-12-21 | 2024-04-05 | 泊诺(天津)创新医药研究有限公司 | High-bioavailability sodium mycophenolate enteric-coated tablet and preparation method thereof |
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