CN103070864B - Repaglinide and metformin hydrochloride medicinal composition and its preparation method - Google Patents
Repaglinide and metformin hydrochloride medicinal composition and its preparation method Download PDFInfo
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- CN103070864B CN103070864B CN201210518601.2A CN201210518601A CN103070864B CN 103070864 B CN103070864 B CN 103070864B CN 201210518601 A CN201210518601 A CN 201210518601A CN 103070864 B CN103070864 B CN 103070864B
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 42
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 40
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 title claims abstract description 39
- 229960002354 repaglinide Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000000203 mixture Substances 0.000 title claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 6
- 239000008187 granular material Substances 0.000 claims description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 239000012530 fluid Substances 0.000 claims description 16
- 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 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 239000012943 hotmelt Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 229920001983 poloxamer Polymers 0.000 claims description 9
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 9
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 229960003194 meglumine Drugs 0.000 claims description 8
- 238000007909 melt granulation Methods 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 7
- 229960000502 poloxamer Drugs 0.000 claims description 7
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 239000004744 fabric Substances 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229920003081 Povidone K 30 Polymers 0.000 claims 2
- 238000005516 engineering process Methods 0.000 abstract description 17
- 238000000034 method Methods 0.000 abstract description 11
- 238000005469 granulation Methods 0.000 abstract description 10
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- 239000002245 particle Substances 0.000 abstract description 6
- 238000002844 melting Methods 0.000 abstract 1
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- 238000005507 spraying Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 12
- 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 12
- 238000004519 manufacturing process Methods 0.000 description 11
- HPWIKAVXRHCHPE-BQAIUKQQSA-N CN(C)C(=N)N=C(N)N.C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 Chemical compound CN(C)C(=N)N=C(N)N.C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 HPWIKAVXRHCHPE-BQAIUKQQSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229940103420 prandimet Drugs 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 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
- 238000010586 diagram Methods 0.000 description 3
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- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
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- -1 fluidizer Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100036721 Insulin receptor Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 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 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
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- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 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
- 238000007908 dry granulation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 238000010237 hybrid technique Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
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- 235000012054 meals Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical group CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 210000002381 plasma Anatomy 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a medicinal composition including active components of repaglinide and metformin hydrochloride, and its preparation method. The method comprises the following steps: carrying out hot melting granulation of metformin hydrochloride to prepare particles, directly spraying a repaglinide solution on the metformin hydrochloride particles through a one-step granulation technology, and adding parts of auxiliary materials to prepare a tablet.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is more particularly a kind of pharmaceutical composition containing repaglinide and metformin hydrochloride and preparation method thereof.
Background technology
Onset diabetes rate increases year by year, and China has become the severely afflicated area of morbidity, and diabetics number occupies second place of the world.According to Pathologic Characteristics, diabetes can be divided into two classes: type Ⅰ diabetes mellitus, i.e. insulin-dependent (IDDM) diabetes, and this kind of patient must rely on exogenous insulin and sustain life, and belong to heavy more; Type Ⅱdiabetes mellitus, i.e. non-insulin-depending type (NIDDM) diabetes, this kind of patient must not rely on exogenous insulin to sustain life, majority is adult, but also shows in teenager, and patient is mostly fat, Insulin receptor INSR is insensitive, and this kind of at least accounts for more than 80% of diabetes cases.
Repaglinide (Repaglinide) metformin hydrochloride (Metformin HCl) sheet (PrandiMet) is a kind of medicine being used for the treatment of type Ⅱdiabetes mellitus that Novo Nordisk Co., Ltd (Novo Nordisk) researches and develops, gone on the market in July, 2008 official approval by U.S. FDA, dosage strengths is repaglinide/metformin hydrochloride 1 mg/500 mg and 2 mg/500 mg.
PrandiMet is the dose formulations of first and unique quick-acting short secretion medicine repaglinide and insulin sensitivity medicine metformin hydrochloride.U.S. FDA approval PrandiMet share in close bioequivalence data based on the repaglinide of repaglinide/metformin hydrochloride 1mg/500mg, 2mg/500mg and corresponding dosage and metformin hydrochloride single medicine preparation.Clinical research proves, this product can reduce glycated hemoglobin concentration safely and effectively.The compound of repaglinide and metformin hydrochloride can control blood sugar content from two different approaches and have synergism: metformin hydrochloride is treatment diabetes choice drugs, it reduces fasting glucose (FPG) by suppressing hepatogenous blood glucose amount, it obviously can improve resistance to sugar amount and the hyperinsulinemia of patient, reduce blood plasma free fatty acid and triglyceride levels, improve the natural reaction of human body to insulin; Repaglinide is non-sulfonylurea Insulin-secreting agent, stimulates post-prandial pancreatic excreting insulin, thus very fast reduction by 2 hours blood glucoses (PPG) after the meal, its effect is faster than sulfonylurea.Papillary has good cooperative effect, more effectively can control blood glucose than independent medication, for clinical application provides new selection, is subject to the extensive favor of doctor and patient, has wide market prospect.Therefore, develop compound Repaglinide metformin hydrochloride tablet and can bring good economic benefit and social benefit.
Metformin hydrochloride and repaglinide are immediate release component, the dosage of repaglinide only has 1 or 2mg, the dosage of metformin hydrochloride is then 500 mg, two kinds of principal agent component ratio great disparities, use the general equivalent hybrid technique that progressively increases that incorporation time can be made to extend, production efficiency is lower, and is difficult to the effect reaching mix homogeneously.
Because metformin hydrochloride dosage is very large, for increasing patient's compliance, the weight of tablet should be controlled as far as possible, namely will adopt the least possible adjuvant.But the crystal formation of metformin hydrochloride is obvious, its compressibility and plasticity poor, easily there is sliver during tabletting.So metformin hydrochloride is accounted for this preparation of larger proportion, ensureing that hardness and the qualified and patient of friability are easy to accept is comparatively difficulty.
Because repaglinide dosage is very little, use common mixing and method of granulating to be difficult to ensure qualified uniformity of dosage units, therefore find the preparation technology that a kind of special and applicable domestic industryization produces very necessary.
WO2007131930 discloses and repaglinide is adopted spray granulation together with special adjuvant, pulverizes rear and metformin hydrochloride wet granulation, other adjuvant tablettings additional.This preparation technology needs to use spray drying device, and in large production, yield is wayward, and production cost is higher.WO2008037807 discloses containing repaglinide pretreatment ground product, and this ground product has non-TCP friendly flow dissolution characteristic, mixes under lower than relative humidity 25% condition with metformin part.What it adopted is granulated respectively by two parts, adds a kind of alkaline matter to promote stripping in repaglinide part simultaneously.This preparation technology adopts special adjuvant and complicated process of preparation, and production cost is higher.
It is the emerging a kind of granulation technique of Abroad in Recent Years that hot melt is granulated.This technology is different from hot-melt extruded granulation technique, and the latter needs to use special and equipment such as the hot-melt extruded granulator of costliness, and hot melt is granulated and only needed fluid bed to realize, and fluid bed is the common equipment generally used in modern pharmaceutical factory.It is that material keeps fluidized state under the effect of hot-air that fluid bed heat founds grain, and when temperature of charge reaches the fusing point of fusing agent, fusing agent fusing is also bonded to granule with unclassified stores, thus changes mobility and the compressibility of unclassified stores.This technology is time saving and energy saving, quickness and high efficiency, adapts to the development in modern pharmaceutical field.
One-step palletizing, also known as fluidized bed granulation (fluidized-bed granulation): be under the effect of the hot-air passed through from bottom to top, while making material powders keep fluidized state, spray into the solution containing adhesive, make powder tie the method being polymerized to granule.The mixing of conventional wet lay granulation, granulation, dry three steps once complete by it in hermetic container.
Summary of the invention
The repaglinide that the object of the present invention is to provide a kind of good stability, production technology convenient, quality controllable and the pharmaceutical composition of metformin hydrochloride.
Pharmaceutical composition of the present invention contains repaglinide and metformin hydrochloride and pharmaceutically acceptable excipient, described compositions first metformin hydrochloride is made granule by hot melt granulation technique, by one-step palletizing technology repaglinide solution is sprayed directly on on metformin hydrochloride granule again and granulates, after adding other excipient, be prepared into tablet.
Described pharmaceutically acceptable excipient comprises: fusing agent, disintegrating agent, fluidizer, lubricant.
Wherein, fusing agent, is selected from: one or more the mixture such as Polyethylene Glycol, poloxamer.
Wherein, disintegrating agent, is selected from: one or more the mixture such as carboxymethylstach sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose.
Wherein, fluidizer, is selected from: one or more the mixture such as silicon dioxide, gel silicon dioxide.
Wherein, lubricant, is selected from: one or more the mixture such as magnesium stearate, stearic acid, calcium stearate, Pulvis Talci, sodium lauryl sulphate, hydrogenated vegetable oil, sodium stearyl fumarate, Glyceryl Behenate.
Pharmaceutical composition of the present invention, comprises following composition:
Preferably, pharmaceutical composition of the present invention, comprises following composition:
Pharmaceutical composition of the present invention is oral formulations, is preferably tablet.
Tablet of the present invention can film coating.Coating material is selected from: polyvinyl alcohol (PVA), hypromellose (HPMC), Opadry 85F32004 or Opadry 85F23452.
Another object of the present invention is the preparation method providing pharmaceutical composition.
Preparation method of the present invention first metformin hydrochloride is made granule by hot melt granulation technique, then to be sprayed directly on on metformin hydrochloride granule by repaglinide solution by one-step palletizing technology and to granulate, and is prepared into tablet after adding other excipient.
Concrete, preparation method of the present invention, comprises the following steps:
A) repaglinide, meglumine, poloxamer and polyvidone are dissolved in 50% ethanol;
B) pulverized and sieved by metformin hydrochloride, mannitol sieves for subsequent use;
C) taking recipe quantity metformin hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, mannitol and polyethylene glycol 6000 puts in fluid bed, carries out hot melt granulation;
D) repaglinide solution is sprayed in fluid bed, carry out one-step palletizing;
E) the granule granulate made is joined magnesium stearate mixing, tabletting, film coating.
Preferably, preparation method of the present invention, comprises the following steps:
A) poloxamer and meglumine are dissolved in 50% ethanol, then add repaglinide, after dissolving, add polyvidone again;
B) metformin hydrochloride was pulverized 60 mesh sieves, 30 mesh sieves crossed by mannitol, for subsequent use;
C) taking recipe quantity metformin hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, mannitol and polyethylene glycol 6000 puts in fluid bed, arranges intake volume 500 ± 200m
3/ h, inlet temperature 90 ± 5 DEG C, product temperature 70 ± 5 DEG C, carry out hot melt granulation;
D) repaglinide solution is sprayed in fluid bed, atomizing pressure 1.0 ± 0.2bar, hydrojet speed 30 ± 10Hz are set, carry out one-step palletizing;
E) granule made is crossed 1.0mm circular hole screen cloth and carry out dry granulate;
F) magnesium stearate is added, mixing;
G) with 17 × 8.5mm oval shaped punches sheet;
H) film coating.
The present invention finds unexpectedly in experimentation, hot melt is granulated and combines with one-step palletizing technology, not only can to solve in existing preparation that metformin hydrochloride specification is comparatively large, compressibility is poor, repaglinide specification is less, homogeneity is difficult to a series of difficult problems such as guarantee, but also can overcome the production in industrialized great production of existing spray drying technology, wet granulation technique and dry granulation technology loaded down with trivial details and operation inconvenience.The present invention only uses an equipment (fluid bed) can realize two kinds of preparation technologies dexterously continuously, and centre does not need handling material, has greatly saved the production time, has reduced production cost, also saved energy consumption, reaches the object of energy-saving and emission-reduction.
Formula composition of the present invention and preparation method are through screening acquisition, its feature is, preparation technology is time saving and energy saving, quickness and high efficiency, granulation process can complete fast continuously in an equipment, obtained uniform particles, good fluidity, tablet hardness is better, friability is lower, also there will not be fragment in coating process, easily controls, this tablet stability is good simultaneously, the application of this technology not only reduces the production cost of product, but also improves the dissolution of product, effectively ensure that the quality of product.
Accompanying drawing illustrates:
Fig. 1 is the stripping curve comparison diagram of embodiment 1 and commercially available medicine " PrandiMet " (1mg/500mg).
Fig. 2 is the stripping curve comparison diagram of embodiment 3 and commercially available medicine " PrandiMet " (2mg/500mg).
Detailed description of the invention:
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1-4, tablet
Pharmaceutical composition of the present invention, preferred formula is composed as follows: prescription (1000 amounts, unit: g)
Preparation method of composition of the present invention, comprises the following steps:
A) poloxamer and meglumine are dissolved in 50% ethanol, then add repaglinide, after dissolving, add polyvidone again;
B) metformin hydrochloride was pulverized 60 mesh sieves, 30 mesh sieves crossed by mannitol, for subsequent use;
C) taking recipe quantity metformin hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, mannitol and polyethylene glycol 6000 puts in fluid bed, arranges intake volume 500 ± 200m
3/ h, inlet temperature 90 ± 5 DEG C, product temperature 70 ± 5 DEG C, carry out hot melt granulation;
D) repaglinide solution is sprayed in fluid bed, atomizing pressure 1.0 ± 0.2bar, hydrojet speed 30 ± 10Hz are set, carry out one-step palletizing;
E) granule made is crossed 1.0mm circular hole screen cloth and carry out dry granulate;
F) magnesium stearate is added, mixing 5min;
G) with 17 × 8.5mm oval shaped punches sheet;
H) with Opadry 85F32004 or Opadry 85F23452 film coating.
Embodiment 5-6, tablet of the present invention
Preparation method of composition of the present invention, comprises the following steps:
A) poloxamer and meglumine are dissolved in 50% ethanol, then add repaglinide, after dissolving, add polyvidone again;
B) metformin hydrochloride was pulverized 60 mesh sieves, 30 mesh sieves crossed by mannitol, for subsequent use;
C) taking recipe quantity metformin hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, mannitol and polyethylene glycol 6000 puts in fluid bed, arranges intake volume 500 ± 200m
3/ h, inlet temperature 90 ± 5 DEG C, product temperature 70 ± 5 DEG C, carry out hot melt granulation;
D) repaglinide solution is sprayed in fluid bed, atomizing pressure 1.0 ± 0.2bar, hydrojet speed 30 ± 10Hz are set, carry out one-step palletizing;
E) granule made is crossed 1.0mm circular hole screen cloth and carry out dry granulate;
F) magnesium stearate is added, mixing 5min;
G) with 17 × 8.5mm oval shaped punches sheet;
H) with Opadry 85F32004 or Opadry 85F23452 film coating.
The determination of physical appearance of experimental example 1, granule of the present invention and tablet
Get granule and the tablet of above-described embodiment 1-6, carry out mobility of particle, tablet hardness, friability test
Mobility of particle (angle of repose), bulk density, tap density, tablet hardness, the measurement result of friability sees the following form:
From upper table result, the mobility of particle of embodiment 1-6 is more or less the same, and tablet hardness is suitable for, and friability is less.
Experimental example 2, Determination of Content Uniformity of the present invention
Get tablet and " PrandiMet " of above-described embodiment 1-6, measure the uniformity of dosage units of repaglinide, comparing result sees the following form:
From upper table result, the uniformity of dosage units of contrast medicine and embodiment 1-6 all meets the requirements, and namely A+1.8S is less than 15.But embodiment 1-6 is more even than contrast medicine.
Experimental example 3, stripping curve of the present invention measure
Condition determination: slurry processes, pH5.0 phosphate buffer 900ml, 50rpm, 37 DEG C.
Sample time: 5,10,15,20,30min.
The stripping curve comparison diagram of embodiment 1,3 and contrast medicine is shown in accompanying drawing 1 and accompanying drawing 2.
Experimental example 4, Stability Determination of the present invention
Get the steadiness that the tablet of above-described embodiment 1-4 and " PrandiMet " place 6 months under acceleration environment (40 DEG C/75%) to see the following form
Note: RPG is repaglinide, and MTF is metformin hydrochloride.Related substance is total impurities.
In sum, all can obtain by above-mentioned six kinds of embodiments and grind the suitable preparation of medicine quality with former.Compared with prior art, preparation technology of the present invention is more convenient, production cost is lower, operability is stronger.
Claims (4)
1. a preparation method for pharmaceutical composition, is characterized in that, comprises the following steps:
Metformin hydrochloride 500g
Repaglinide 1-2g
Microcrystalline Cellulose 10-60g
Mannitol 5-20g
PVPP 7.5-30g
Polyethylene glycol 6000 18-54g
Meglumine 0.5-1g
PLURONICS F87 0.3-0.6g
30 POVIDONE K 30 BP/USP 90 1.5-6g
Magnesium stearate 1-3g
A) repaglinide, meglumine, poloxamer and polyvidone are dissolved in 50% ethanol;
B) pulverized and sieved by metformin hydrochloride, mannitol sieves for subsequent use;
C) taking recipe quantity metformin hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, mannitol and polyethylene glycol 6000 puts in fluid bed, carries out hot melt granulation;
D) repaglinide solution is sprayed in fluid bed, carry out one-step palletizing;
E) the granule granulate made is joined magnesium stearate mixing, tabletting, film coating.
2. preparation method as claimed in claim 1, is characterized in that, comprise following composition:
Metformin hydrochloride 500g
Repaglinide 1-2g
Microcrystalline Cellulose 12.7-50.7g
Mannitol 10g
PVPP 15g
Polyethylene glycol 6000 18-54g
Meglumine 0.5-1g
PLURONICS F87 0.3-0.6g
30 POVIDONE K 30 BP/USP 90 3g
Magnesium stearate 1.5g.
3. the preparation method as described in as arbitrary in claim 1-2, it is characterized in that, tablet film coating, coating material is selected from: polyvinyl alcohol, hypromellose, Opadry 85F32004 or Opadry 85F23452.
4. the preparation method as described in as arbitrary in claim 1-2, is characterized in that, comprise the following steps:
A) poloxamer and meglumine are dissolved in 50% ethanol, then add repaglinide, after dissolving, add polyvidone again;
B) metformin hydrochloride was pulverized 60 mesh sieves, 30 mesh sieves crossed by mannitol, for subsequent use;
C) taking recipe quantity metformin hydrochloride, microcrystalline Cellulose, polyvinylpolypyrrolidone, mannitol and polyethylene glycol 6000 puts in fluid bed, arranges intake volume 500 ± 200m
3/ h, inlet temperature 90 ± 5 DEG C, product temperature 70 ± 5 DEG C, carry out hot melt granulation;
D) repaglinide solution is sprayed in fluid bed, atomizing pressure 1.0 ± 0.2bar, hydrojet speed 30 ± 10Hz are set, carry out one-step palletizing;
E) granule made is crossed 1.0mm circular hole screen cloth and carry out dry granulate;
F) magnesium stearate is added, mixing;
G) with 17 × 8.5mm oval shaped punches sheet;
H) film coating.
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| CN103385878B (en) * | 2013-07-24 | 2015-07-15 | 山东省医药工业研究所 | Repaglinide and dimethyldiguanide pharmaceutical composition and preparation method thereof |
| CN104337811A (en) * | 2013-08-02 | 2015-02-11 | 江苏柯菲平医药股份有限公司 | Repaglinide-metformin hydrochloride tablet and preparing method thereof |
| CN103494816B (en) * | 2013-09-29 | 2019-06-14 | 威海迪素制药有限公司 | A kind of pharmaceutical composition for treating diabetes |
| CN103705515B (en) * | 2013-12-27 | 2016-05-11 | 华润赛科药业有限责任公司 | The preparation method of the pharmaceutical composition that contains Repaglinide and Metformin hydrochloride |
| CN105582008A (en) * | 2014-11-14 | 2016-05-18 | 北京赛林泰医药技术有限公司 | Composition containing vildagliptin and metformin and preparation method of composition |
| CN105456220A (en) * | 2015-12-08 | 2016-04-06 | 青岛正大海尔制药有限公司 | Ambroxol and salbutamol enteric-coated tablet |
| CN105816435A (en) | 2016-03-17 | 2016-08-03 | 赛乐医药科技(上海)有限公司 | Metformin hydrochloride osmotic pump tablet and preparation method thereof |
| WO2018034627A1 (en) * | 2016-08-18 | 2018-02-22 | İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi | Pharmaceutical composition of antidiabetic tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN101756971A (en) * | 2008-10-09 | 2010-06-30 | 北京德众万全药物技术开发有限公司 | Oral solid drug composition of metformin hydrochloride repaglinide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN101756971A (en) * | 2008-10-09 | 2010-06-30 | 北京德众万全药物技术开发有限公司 | Oral solid drug composition of metformin hydrochloride repaglinide |
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