CN105326837A - Memantine hydrochloride sustained release-donepezil quick release compound capsule - Google Patents
Memantine hydrochloride sustained release-donepezil quick release compound capsule Download PDFInfo
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- CN105326837A CN105326837A CN201510647592.0A CN201510647592A CN105326837A CN 105326837 A CN105326837 A CN 105326837A CN 201510647592 A CN201510647592 A CN 201510647592A CN 105326837 A CN105326837 A CN 105326837A
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- release
- donepezil
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- 229960003530 donepezil Drugs 0.000 title claims abstract description 31
- 239000002775 capsule Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 title claims abstract description 18
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 title abstract description 32
- 229960000967 memantine hydrochloride Drugs 0.000 title abstract description 5
- 230000002459 sustained effect Effects 0.000 title abstract 3
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 24
- 238000013268 sustained release Methods 0.000 claims abstract description 18
- 239000012730 sustained-release form Substances 0.000 claims abstract description 18
- 239000008187 granular material Substances 0.000 claims abstract description 17
- 239000010410 layer Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000011247 coating layer Substances 0.000 claims abstract description 8
- 239000000945 filler Substances 0.000 claims abstract description 7
- 229960004640 memantine Drugs 0.000 claims description 42
- 239000006187 pill Substances 0.000 claims description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 16
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 229960003943 hypromellose Drugs 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 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 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 235000012239 silicon dioxide Nutrition 0.000 claims description 9
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001856 Ethyl cellulose Substances 0.000 claims description 6
- 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 6
- 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 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 229920001249 ethyl cellulose Polymers 0.000 claims description 6
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000004014 plasticizer Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 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 4
- 229960003135 donepezil hydrochloride Drugs 0.000 claims description 4
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 4
- 235000010603 pastilles Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 239000004925 Acrylic resin Substances 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 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 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 206010013786 Dry skin Diseases 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229940081735 acetylcellulose Drugs 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 238000000465 moulding Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000005507 spraying Methods 0.000 claims description 2
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims 15
- 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 1
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 6
- 239000002552 dosage form Substances 0.000 abstract description 4
- 239000008188 pellet Substances 0.000 abstract 3
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- 230000000295 complement effect Effects 0.000 abstract 1
- 230000003203 everyday effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000024827 Alzheimer disease Diseases 0.000 description 4
- 206010025482 malaise Diseases 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229920003081 Povidone K 30 Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000027382 Mental deterioration Diseases 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- SRWFBFUYENBCGF-UHFFFAOYSA-M sodium;chloride;hydrochloride Chemical compound [Na+].Cl.[Cl-] SRWFBFUYENBCGF-UHFFFAOYSA-M 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a memantine hydrochloride sustained release-donepezil quick release compound capsule and a preparation method thereof. The memantine hydrochloride sustained release-donepezil quick release compound capsule is characterized in that a preparation consists of memantine hydrochloride sustained release pellets and donepezil quick release granules; each sustained release pellet sequentially comprises an empty pellet core, a medicated layer and a sustained release coating layer from inside to outside; and the donepezil quick release granules are prepared from main drugs, other fillers, a disintegrating agent, adhesive and the like. Compared with other dosage forms, the preparation has the features that two drugs are combined so that a complementary synergy effect is achieved, the number of tablets can be reduced, everyday medicine taking load is reduced, and obedience and compliance of a patient can also be improved.
Description
Technical field
The invention discloses and a kind ofly treat the pharmaceutical composition of moderate to severe senile dementia disease.Be specifically related to a kind of memantine slow release-donepezil rapid release compound capsule and preparation method thereof, belong to technical field of medicine.
Background technology
Alzheimer (AD) be with
memorypower goes down, cognitive dysfunction, mental act are extremely
clinicala kind of chronic progressive external mental deterioration disease of feature.
researchdisplay, along with the increase at age, the sickness rate of this disease is in rising trend, and within more than 80 years old, old people's sickness rate reaches 20%.In the U.S., nearly 5,200,000 people suffer from senile dementia at present, and the dead age is substantially at over-65s.China's AD sickness rate is about about 1%, and estimate that in current China more than 60 years old old people, AD patient can up to 5,000,000 people, over-65s sickness rate 3% ~ 5%, and is cumulative year after year trend.Due to primary disease prevalence and disability rate high, to patient home and society bring huge burden, along with the acceleration of social senilization's process, this disease develops into serious public health problem gradually.
Memantine and donepezil all belong to a line kind in global Alzheimer type senile dementia treatment.The coupling of memantine and donepezil is the selection to severe senile Alzheimer type dementia disease of the treatment moderate that has been confirmed, is a set of effective therapeutic scheme.N-methyl-D-aspartate (NMDA) receptor stimulating agent and acetylcholinesteraseinhibitors inhibitors unite two into one by this treatment, two kinds of mechanism of action complementations, increase curative effect.The curative effect of two kinds of Drug combinations exceedes and is used alone acetylcholinesteraseinhibitors inhibitors, obviously can improve the cognitive function of patient, emotion and activity of daily living, more alone donepezil hydrochloride better effects if.
The dosage form that memantine goes on the market at present is mainly tablet, oral administration solution, slow releasing capsule.The dosage form of the domestic listing of donepezil is mainly tablet, capsule, oral cavity disintegration tablet.The dosage form of two kinds of drug regimens is not had to go on the market temporarily at present.Compound capsule of the present invention, it is simultaneously containing slow release and immediate release section, immediate release section makes medicine reach therapeutic plasma concentrations fast, slow-released part can pass through slow releasing, medicine is made to maintain certain blood level, reduce the blood drug level peak valley phenomenon that general formulation presents, reduce and take number of times.
Summary of the invention
The present invention is intended to openly a kind of drug release and stablizes, is suitable for memantine slow release-donepezil rapid release compound capsule that Alzheimer type patient takes.
Memantine slow release-donepezil rapid release compound capsule can reduce the peak valley phenomenon of the blood drug level that general formulation presents, and reduces and takes number of times.
The structure of memantine slow-release micro-pill of the present invention is followed successively by celphere, medicated layer, sustained-release coating layer from inside to outside, wherein each several part percentage by weight is respectively: celphere 20% ~ 60%, medicated layer 10% ~ 80%, sustained-release coating layer 1% ~ 50%.
The size controlling scope of slow-release micro-pill of the present invention and granule is 30 order ~ 100 orders, is preferably 40 order ~ 80 orders, and in described compound capsule, the part by weight of slow-release micro-pill and granule is 1:1 ~ 3:1.
Memantine slow-release micro-pill of the present invention molding celphere used be selected from microcrystalline Cellulose ball core, starch ball core, pre-paying starch ball core, dextrin ball core, sucrose ball core one or more, be preferably microcrystalline Cellulose ball core.
Memantine slow-release micro-pill of the present invention, is characterized in that the percentage by weight of described medicated layer memantine is 50% ~ 90%, preferably 40% ~ 70%.
Memantine slow-release micro-pill of the present invention, its medicated layer except effective ingredient memantine, also comprises ethanol, water, hypromellose, polyvidone, silicon dioxide, Pulvis Talci wherein one or more.
Memantine slow-release micro-pill of the present invention, the Sustained release coating materials of its sustained-release coating layer comprises ethyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxyethyl-cellulose, glyceryl monostearate, polyacrylic resin wherein one or more.Be preferably, ethyl cellulose, hypromellose, glyceryl monostearate.
Memantine slow-release micro-pill of the present invention, its plasticizer is selected from glycerol, Polyethylene Glycol, TG acid wherein one or more.Be preferably, Polyethylene Glycol or glycerol.
Donepezil granule of the present invention, except effective ingredient donepezil, also comprises filler, disintegrating agent, binding agent.Filler is selected from lactose, mannitol, microcrystalline Cellulose, corn starch, pre-paying starch wherein one or more, is preferably, lactose and microcrystalline Cellulose; Described binding agent is selected from polyvidone, hydroxypropyl cellulose, hypromellose wherein one or more, is preferably, hypromellose; Described disintegrating agent is selected from carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose wherein one or more, is preferably, low-substituted hydroxypropyl cellulose.
Memantine slow release of the present invention-donepezil hydrochloride rapid release compound capsule, also comprises lubricant, and its lubricant is selected from Pulvis Talci, magnesium stearate, silicon dioxide, castor oil hydrogenated wherein one or more, is preferably, magnesium stearate.
The invention provides the preparation method of a kind of memantine slow release-donepezil rapid release compound capsule, described method is specific as follows:
The preparation of step one memantine slow-release micro-pill
1) memantine that medicated layer preparation takes recipe quantity is dissolved in suitable solvent, is mixed with containing medicinal liquid.
2) take celphere as core, by step 1) prepare be wrapped on celphere containing medicine liquid spray, make pastille piller;
| Memantine | 3%~15% |
| PVP K30 or HPMC | 5%~15% |
| 30% ethanol or water | 10%~50% |
| Silicon dioxide or Pulvis Talci | 5%~15% |
The uniformity of medicated layer medicinal liquid and mobility can affect the drug loading of celphere, are first dissolved in by memantine in 30% ethanol or water, medicine dissolution, add HPMC or PVPK30 again, be mixed with containing medicinal liquid, add silicon dioxide or Pulvis Talci, increase the mobility of medicinal liquid.In medicine-feeding process, celphere medicine carrying is even, and coating process is smooth.
3) by Sustained release coating materials, plasticizer dissolves in water or ethanol or other solvents, be mixed with sustained release coating liquid;
4) spraying of sustained release coating liquid is wrapped in step 3) obtained by pastille piller outer, obtained Memantine hydrochloride slow-release micro-pill
Prepared by step 2 donepezil granule
Fully mixed with filler by donepezil, then mix homogeneously with disintegrating agent, in said mixture, add certain density binding agent, 20 order ~ 80 orders are granulated, and 50 DEG C ~ 60 DEG C dryings, 20 order ~ 80 order granulate, obtain donepezil granule.
specific embodiment
Step 3 by above-mentioned two parts medicament mixed, then adds lubricant, mix homogeneously, filled capsules.
In preferred embodiments, memantine slow release provided by the invention-donepezil rapid release compound capsule comprises following composition:
1) celphere sucrose ball core or microcrystalline Cellulose ball core 10% ~ 20%
2) liquid formula of medicated layer is as follows:
| Memantine | 3％～15％ |
| PVP K30 or HPMC | 5％～15％ |
| 30% ethanol or water | 10％～50％ |
| Silicon dioxide or Pulvis Talci | 5％～15％ |
The uniformity of medicated layer medicinal liquid and mobility can affect the drug loading of celphere, are first dissolved in by memantine in 30% ethanol or water, medicine dissolution, add HPMC or PVPK30 again, be mixed with containing medicinal liquid, add silicon dioxide or Pulvis Talci, increase the mobility of medicinal liquid.In medicine-feeding process, celphere medicine carrying is even, and coating process is smooth.
3) the coating solution formula of slow release layer is as follows
| Ethyl cellulose or hypromellose | 15％～22％ |
| Polyethylene Glycol or glycerol | 1％～8％ |
| Pulvis Talci or castor oil hydrogenated | 1％～10％ |
The coating amount of slow-release material is the principal agent factor determining slow-release micro-pill rate of releasing drug, and in actual coating operations, the coating amount of polymer is whether piller after determining coating can reach required release.The present invention is by screening the scope of coating amount, and adopt cellulose family coating, especially ethyl cellulose, hydroxypropyl cellulose, is conducive to the release of medicine.In addition, when parcel amount is 20%-40%, the release of prepared slow-release micro-pill is as follows: 10-30% (1.5 hours), 30-90% (3 hours), >=85% (8 hours).
4) formula of donepezil granule is as follows:
| Donepezil | 1％～5％ |
| Lactose | 10％～40％ |
| Microcrystalline Cellulose | 5％～20％ |
| PVP K30 or HPMC | 1％～10％ |
| Silicon dioxide or Pulvis Talci | 1％～5％ |
In wet-granulation process, need control granulometric range is 20 order ~ 80 orders, and prepared mobility of particle is good.
In sum, memantine slow release-donepezil rapid release compound capsule of the present invention is quality controllable, stable yield, and release meets the requirements, and makes medicine reach the object of clinical application.
Embodiment 1
Embodiment 2
Embodiment 1 and embodiment 2 release contrast
Dissolving-out method: basket method, the sodium chloride-hydrochloric acid buffer solution of rotating speed 100rpm, dissolution medium pH1.2, stripping volume 900ml
From the dissolved corrosion of the memantine slow release obtained by embodiment 1 and embodiment 2-donepezil rapid release compound capsule, the release behavior of donepezil meets the requirement of rapid release, and memantine release behavior meets the requirement of slow releasing pharmaceutical.Both synergism, in vivo while fast onset drug effect, can maintain stable curative effect of medication again, reduce medicining times, effectively can improve the Compliance of patient.
Claims (13)
1. memantine slow release-donepezil hydrochloride rapid release compound capsule, comprises memantine slow-release micro-pill and donepezil granule forms.
2. it is characterized in that the structure of memantine slow-release micro-pill is followed successively by celphere, medicated layer, sustained-release coating layer from inside to outside, wherein each several part percentage by weight is respectively: celphere 20% ~ 60%, medicated layer 10% ~ 80%, sustained-release coating layer 1% ~ 50%.
3. the size controlling scope of the slow-release micro-pill described in and granule is 30 order ~ 100 orders, be preferably 40 order ~ 80 orders, in described compound capsule, the part by weight of slow-release micro-pill and granule is 1:1 ~ 3:1.
4. memantine slow-release micro-pill as claimed in claim 1, it is characterized in that: its molding celphere used be selected from microcrystalline Cellulose ball core, starch ball core, pre-paying starch ball core, dextrin ball core, sucrose ball core one or more, be preferably microcrystalline Cellulose ball core.
5. memantine slow-release micro-pill as claimed in claim 1, is characterized in that: the percentage by weight of described medicated layer memantine is 50% ~ 90%, is preferably 40% ~ 70%.
6. as claimed in claim 1 memantine slow-release micro-pill, is characterized in that: described medicated layer, except effective ingredient memantine, also comprises ethanol, water, hypromellose, polyvidone, silicon dioxide, Pulvis Talci wherein one or more.
7. memantine slow-release micro-pill as claimed in claim 1, it is characterized in that: the Sustained release coating materials of described sustained-release coating layer comprises ethyl cellulose, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxyethyl-cellulose, glyceryl monostearate, polyacrylic resin wherein one or more, be preferably, ethyl cellulose, hypromellose, glyceryl monostearate.
8. memantine slow-release micro-pill as claimed in claim 1, it is characterized in that: described sustained-release coating layer also comprises plasticizer, described plasticizer be selected from glycerol, Polyethylene Glycol, TG acid one or more, be preferably, Polyethylene Glycol or glycerol.
9. donepezil immediate-release granules as claimed in claim 1, is characterized in that: described granule, except effective ingredient donepezil, also comprises filler, disintegrating agent, binding agent.
10. the filler described in is selected from lactose, mannitol, microcrystalline Cellulose, corn starch, pre-paying starch wherein one or more, is preferably, lactose and microcrystalline Cellulose; Described binding agent is selected from polyvidone, hydroxypropyl cellulose, hypromellose wherein one or more, is preferably, hypromellose; Described disintegrating agent is selected from carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose wherein one or more, is preferably, low-substituted hydroxypropyl cellulose.
11. memantine z slow release-donepezil hydrochloride rapid release compound capsules as claimed in claim 1, it is characterized in that: in capsule, also comprise lubricant, described lubricant is selected from Pulvis Talci, magnesium stearate, silicon dioxide, castor oil hydrogenated wherein one or more, be preferably, magnesium stearate.
12. memantine slow release as claimed in claim 1-donepezil rapid release compound capsules, its preparation method is:
The preparation of step one memantine slow-release micro-pill
1) memantine that medicated layer preparation takes recipe quantity is dissolved in suitable solvent, is mixed with containing medicinal liquid;
2) take celphere as core, that step 1) is prepared is wrapped on celphere containing medicine liquid spray, makes pastille piller;
3) by Sustained release coating materials, plasticizer dissolves in water or ethanol or other solvents, be mixed with sustained release coating liquid;
4) the pastille piller spraying of sustained release coating liquid be wrapped in obtained by step 3) is outer, obtained memantine slow-release micro-pill
Prepared by step 2 donepezil immediate-release granules
Mixed homogeneously with filler by donepezil, then mix homogeneously with disintegrating agent, in said mixture, add certain density binding agent, 20 order ~ 80 orders are granulated, and 50 DEG C ~ 60 DEG C dryings, 20 order ~ 80 order granulate, obtain donepezil granule.
13. step 3 by above-mentioned two parts medicament mixed, then add lubricant, mix homogeneously, filled capsules.
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| CN201510647592.0A CN105326837A (en) | 2015-10-09 | 2015-10-09 | Memantine hydrochloride sustained release-donepezil quick release compound capsule |
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| CN201510647592.0A CN105326837A (en) | 2015-10-09 | 2015-10-09 | Memantine hydrochloride sustained release-donepezil quick release compound capsule |
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| CN106727439A (en) * | 2016-12-21 | 2017-05-31 | 河南中帅医药科技股份有限公司 | A kind of memantine is sustained donepezil quick-release compound capsule |
| CN107412199A (en) * | 2016-05-23 | 2017-12-01 | 海南合瑞制药股份有限公司 | A kind of Memantine hydrochloride sustained-release capsule composition |
| KR20180036579A (en) * | 2016-09-30 | 2018-04-09 | 주식회사 바이오파마티스 | Composition comprising complex for prevention and treatment of dementia and cognitive impairment |
| EP3338767A1 (en) * | 2016-12-22 | 2018-06-27 | Sanovel Ilac Sanayi ve Ticaret A.S. | Capsule compositions comprising donepezil and memantine |
| CN109908097A (en) * | 2017-12-13 | 2019-06-21 | 北京万全德众医药生物技术有限公司 | Linkou County Mo Fanse collapses sustained release tablets |
| CN110613715A (en) * | 2018-06-20 | 2019-12-27 | 晟德大药厂股份有限公司 | non-pH dependent oral dosage forms for the treatment of neurodegenerative diseases |
| CN111939139A (en) * | 2020-06-30 | 2020-11-17 | 辰欣药业股份有限公司 | Memantine hydrochloride sustained-release and donepezil hydrochloride quick-release capsule and preparation method thereof |
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| CN106727439A (en) * | 2016-12-21 | 2017-05-31 | 河南中帅医药科技股份有限公司 | A kind of memantine is sustained donepezil quick-release compound capsule |
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| CN110613715A (en) * | 2018-06-20 | 2019-12-27 | 晟德大药厂股份有限公司 | non-pH dependent oral dosage forms for the treatment of neurodegenerative diseases |
| CN111939139A (en) * | 2020-06-30 | 2020-11-17 | 辰欣药业股份有限公司 | Memantine hydrochloride sustained-release and donepezil hydrochloride quick-release capsule and preparation method thereof |
| CN112587499A (en) * | 2020-12-29 | 2021-04-02 | 成都锦华药业有限责任公司 | Berberine hydrochloride pellet and preparation method thereof |
| WO2023128890A1 (en) * | 2021-12-28 | 2023-07-06 | Ilko Ilac Sanayi Ve Ticaret A.S. | Donepezil – memantine extended release capsule composition |
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