CN106727371B - Donepezil hydrochloride pharmaceutical composition and preparation method thereof - Google Patents
Donepezil hydrochloride pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN106727371B CN106727371B CN201611122869.9A CN201611122869A CN106727371B CN 106727371 B CN106727371 B CN 106727371B CN 201611122869 A CN201611122869 A CN 201611122869A CN 106727371 B CN106727371 B CN 106727371B
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- donepezil hydrochloride
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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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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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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Abstract
The invention relates to a donepezil hydrochloride pharmaceutical composition and a preparation method thereof, in particular to a donepezil hydrochloride tablet which contains donepezil hydrochloride, a disintegrating agent, a filling agent, a bonding agent, a lubricating agent and a glidant. The donepezil hydrochloride tablet provided by the invention has the advantages of good stability and dissolution rate, simple preparation process and low requirement on storage conditions, and is very suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a donepezil hydrochloride pharmaceutical composition and a preparation method thereof.
Background
The aging trend increases the number of patients with senile dementia, China enters the aging society, and the incidence of AD (AD) is increased year by year along with a not negligible problem. The investigation shows that: the average age of AD in northern China is 75 and 76 years old, and the ratio of AD in people over 65 years old reaches more than 15 percent. The daily life capacity of AD patients is reduced, and the AD patients can not take care of themselves without knowing spouses and children, dressing, eating and relieving bowels, and are particularly inconvenient to take medicine; some of them have the illusion of auditory sensation, which brings endless pain and annoyance to themselves and people around them. The average survival time of AD patients is 5.5 years, and AD diseases become the fourth killer of the health of the old people after cardiovascular diseases, cerebrovascular diseases and cancers.
Donepezil Hydrochloride (Donepezil Hydrochloride) is the second generation cholinesterase inhibitor (AChEI) for treating Alzheimer's disease, has strong selectivity to neuronal acetylcholinesterase, and increases the acetylcholine content in animal brain by inhibiting acetylcholinesterase, so that the acetylcholine content in synapses directly participating in neurotransmission is increased, thereby generating a therapeutic effect, and improving learning disorder, and almost no inhibition effect is exerted on the acetylcholinesterase of heart and intestine, therefore, the Donepezil Hydrochloride (Donepezil Hydrochloride) has the characteristics of strong selectivity, long action time, small side effect, no liver toxicity and the like, and is a relatively ideal medicament for treating presenile dementia.
Chinese patent 201410109709.5 discloses a donepezil hydrochloride dispersible tablet, which comprises the following components by weight percent: 1-5% of donepezil hydrochloride, 40-90% of disintegrant, 1-15% of lubricant and glidant and 1-15% of adhesive, wherein the adhesive is povidone, and the disintegrant is low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Chinese patent 200810225017.1 discloses an orally disintegrating tablet of donepezil hydrochloride, the formulation of which is as follows: 2-50% of donepezil hydrochloride, 10-80% of filler, 2-35% of disintegrant, 1-40% of flavoring agent, 0-10% of adhesive, 0-30% of effervescent agent, 0.01-5% of glidant, 0.3-3% of lubricant and 0-40% of coating material, wherein the filler is lactose or microcrystalline cellulose, the adhesive is povidone and the disintegrant is low-substituted hydroxypropyl cellulose. Chinese patent 200810032435.9 discloses a solid donepezil hydrochloride preparation and its preparation process, wherein the preparation comprises the following components by weight: 1-40% of donepezil hydrochloride, 1-90% of diluent, 1-90% of adhesive, 1-40% of disintegrating agent, 0.1-10% of lubricant and 0.1-10% of lubricant, wherein the adhesive is povidone, the disintegrating agent is low-substituted hydroxypropyl cellulose, and the diluent is lactose or microcrystalline cellulose. Chinese patent 201210157499.8 discloses a granule containing donepezil hydrochloride, which comprises 0.1-2% donepezil hydrochloride, 82-95% filler, 2-10% binder, 0.1-10% sweetener, 1-10% sour agent, wherein the filler is lactose, and the binder is hydroxypropyl cellulose.
Clinical verification for many years shows that the donepezil hydrochloride is mainly used for treating senile dementia and has obvious effect. The capsule and the tablet as oral preparations are more popular with consumers because of more convenient taking and carrying. However, the oral preparation on the market is the donepezil hydrochloride common tablet which can be completely disintegrated within 40 minutes, and the oral preparation is not beneficial to the dissolution and absorption of the medicine.
Compared with common solid preparations such as tablets, capsules and the like, the dispersible tablet has the characteristics of convenient administration, rapid disintegration, rapid absorption, high bioavailability and the like. The donepezil hydrochloride is prepared into fast disintegrating and quick acting preparation, such as dispersible tablet, orally disintegrating tablet, etc. although the problem of medicine dissolving and absorption can be solved, the dispersible tablet type also has its limitation. In the production process of the dispersible tablet, the raw material medicines are generally required to be micronized, so that the production procedures are increased; the cost is high because a good disintegrating agent needs to be selected; the quality requirement is relatively high, the control difficulty of the quality standard is high, and the like. The dispersible tablet has larger disintegrating dosage, stronger hygroscopicity, higher requirement on the moisture-resistant effect of a packaging material and higher storage condition than that of a common tablet, so the packaging and storage cost is higher.
Disclosure of Invention
The invention aims to provide a donepezil hydrochloride common tablet, which consists of donepezil hydrochloride and pharmaceutic adjuvant, wherein the pharmaceutic adjuvant contains a disintegrant, a filler, an adhesive, a lubricant and a glidant, the disintegrant consists of carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose together, and the mass ratio of the carboxymethyl starch sodium to the low-substituted hydroxypropyl cellulose is selected from 1: 0.4-0.8, also can be 1: 0.5-0.7, and also can be 1: 0.6; and the content of the disintegrant is less than 30% by weight.
The donepezil hydrochloride tablet provided by the invention comprises the following components in percentage by weight: 1-10% of donepezil hydrochloride, 60-85% of filler, 10-30% of disintegrant, 1-10% of adhesive, 0.1-10% of lubricant and 0.1-10% of glidant.
The donepezil hydrochloride tablet provided by the invention comprises the following components in percentage by weight: 2-4% of donepezil hydrochloride, 70-80% of filler, 10-20% of disintegrant, 1-5% of adhesive, 0.1-2% of lubricant and 0.1-3% of glidant.
The donepezil hydrochloride tablet provided by the invention has the filler selected from one or two of lactose or microcrystalline cellulose, the binder selected from povidone, the lubricant selected from magnesium stearate or sodium hard fumarate, and the glidant selected from silicon dioxide.
When the filler is selected from a mixture of lactose and microcrystalline cellulose, the mass ratio of the lactose to the microcrystalline cellulose is selected from 1: 0.5-1, can be 1: 0.7-0.8, and can also be 1: 0.75.
The donepezil hydrochloride tablet provided by the invention can be prepared by the following formula:
the main prescription is as follows: (tablet core prescription)
And (3) secondary prescription: (coating solution prescription)
| Name/specification of raw and auxiliary materials | 35 ten thousand tablets |
| Film coating premix (gastric soluble type)/Y-1-7000 | 1.05kg |
| Ethanol/pharmaceutic adjuvant | 12.08kg |
| Purified water | 4.32kg |
The preparation process of the donepezil hydrochloride tablet provided by the invention comprises the following steps:
(1) premixing: uniformly mixing donepezil hydrochloride, a disintegrating agent and a filling agent;
(2) and (3) wet granulation: adding a binding agent for wet granulation, and performing wet granulation after the granulation is finished;
(3) drying and granulating: drying and finishing wet granules;
(4) total mixing: adding a lubricant and a glidant for total mixing;
(5) tabletting;
(6) and (4) coating.
Compared with the prior art, the invention has the following excellent effects:
(1) the donepezil hydrochloride tablet provided by the invention improves the in vitro dissolution rate of the medicine, approaches to or even reaches the in vitro dissolution rate level of the donepezil hydrochloride dispersible tablet, and is very favorable for the dissolution and absorption of the medicine.
(2) The donepezil hydrochloride tablet provided by the invention improves the stability of the medicine, ensures the quality of the medicine and prolongs the storage period of the medicine. Through stability inspection, the quality standards such as properties, content and the like of the sample are not obviously changed and meet the quality standard specification.
(3) The donepezil hydrochloride tablet provided by the invention reduces the storage condition of the medicine, simplifies the production process and is very suitable for industrial production.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention.
Example 1
Prescription:
the particle diameters (Malvern 2000 laser particle size Analyzer, dry method determination) of donepezil hydrochloride raw material medicines used in different prescriptions are as follows:
wherein, the donepezil hydrochloride raw material medicines used in the prescriptions 1 and 2 are not micronized, and the donepezil hydrochloride raw material medicines used in the prescriptions 3 to 6 are micronized.
The prescription of the coating liquid is as follows:
| name/specification of raw and auxiliary materials | Dosage of |
| Film coating premix (gastric soluble type)/Y-1-7000 | 3.00g |
| Ethanol | 34.5g |
| Purified water | 12.3g |
The preparation process comprises the following steps:
(1) premixing: adding the prescribed amount of low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, donepezil hydrochloride, lactose and microcrystalline cellulose into a wet-process granulator, and preliminarily mixing uniformly;
(2) preparation of adhesive solution: adding purified water and ethanol in a formula amount into a pneumatic stirring barrel, adding povidone K30 while stirring to completely dissolve the purified water and ethanol, and standing until the mixture is clear and transparent to obtain an adhesive solution;
(3) and (3) wet granulation: starting a wet granulation machine to wet granules, and carrying out wet granulation after granulation is finished;
(4) drying and granulating: drying and granulating by a multifunctional boiling granulator;
(5) total mixing: adding a lubricant and a glidant in a prescribed amount for total mixing;
(6) tabletting;
(7) and (4) coating.
Dissolution test
The dissolution (%) of each donepezil hydrochloride tablet and the commercially available donepezil hydrochloride general tablet (5 mg/tablet) is determined by referring to a dissolution determination method (XC second method in the second appendix of 2010 edition of Chinese pharmacopoeia):
| prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | Common tablet | |
| 10min | 68.24 | 68.25 | 68.45 | 68.52 | 68.21 | 68.38 | 55.58 |
| 15min | 100.97 | 100.75 | 100.54 | 100.76 | 100.52 | 100.48 | 82.37 |
| 30min | 101.33 | 100.97 | 101.12 | 101.05 | 100.84 | 100.87 | 95.64 |
| 45min | / | / | / | / | / | / | 100.38 |
The result shows that the in vitro dissolution rate of the donepezil hydrochloride tablet provided by the invention is obviously superior to that of the common tablet within 10-30 min.
Example 2
Prescription:
tableting and coating were carried out according to the preparation process of example 1, and dissolution measurement was carried out according to the measurement method of example 1, with the following measurement results:
| prescription 7 | Prescription 8 | Prescription 9 | Prescription 10 | Prescription 11 | Prescription 12 | |
| 10min | 62.22 | 62.27 | 62.45 | 62.51 | 62.23 | 62.34 |
| 15min | 100.87 | 100.45 | 100.34 | 100.56 | 100.51 | 100.46 |
| 30min | 101.31 | 100.92 | 101.21 | 101.15 | 100.88 | 100.88 |
Example 3
Prescription:
tableting and coating were carried out according to the preparation process of example 1, and dissolution measurement was carried out according to the measurement method of example 1, with the following measurement results:
| prescription 13 | Prescription 14 | Prescription 15 | Prescription 16 | Prescription 17 | Prescription 18 | |
| 10min | 63.23 | 62.37 | 63.44 | 63.41 | 63.24 | 63.34 |
| 15min | 100.83 | 100.43 | 100.32 | 100.42 | 100.34 | 100.43 |
| 30min | 101.32 | 100.93 | 101.24 | 101.15 | 100.86 | 100.87 |
Experimental example 1
The samples prepared in each of the examples 1-3 and the donepezil hydrochloride dispersible tablets prepared completely according to the prescription process of the example 1 of the Chinese patent 201410109709.5 are packaged by an aluminum-plastic bubble-cap plate and then subjected to stability examination synchronously. Placing at 25 deg.C RH 75% and 25 deg.C RH 92.5%, sampling for 5 and 10 days respectively, and determining the dissolution data by adopting the average value of formula 1-18.
Appearance results were as follows:
the cumulative percent dissolution at 15 minutes results were as follows:
Claims (11)
1. the common donepezil hydrochloride tablet consists of donepezil hydrochloride, a disintegrant, a filler, an adhesive, a lubricant and a glidant, and is characterized in that the content of the disintegrant is less than 30% by weight, the disintegrant consists of carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose, the mass ratio of the carboxymethyl starch sodium to the low-substituted hydroxypropyl cellulose is 1: 0.4-0.8, the filler is lactose and microcrystalline cellulose, and the adhesive is povidone.
2. The donepezil hydrochloride ordinary tablet according to claim 1, wherein the mass ratio of the carboxymethyl starch sodium to the low-substituted hydroxypropyl cellulose is selected from 1:0.5 to 0.7.
3. The donepezil hydrochloride ordinary tablet according to claim 1, wherein the mass ratio of the carboxymethyl starch sodium to the low-substituted hydroxypropyl cellulose is selected from 1: 0.6.
4. The donepezil hydrochloride ordinary tablet according to claim 1, wherein the mass ratio of lactose to microcrystalline cellulose is selected from 1:0.5 to 1.
5. The donepezil hydrochloride ordinary tablet according to claim 1, wherein the mass ratio of lactose to microcrystalline cellulose is selected from 1:0.7 to 0.8.
6. The donepezil hydrochloride ordinary tablet according to claim 1, wherein the mass ratio of lactose to microcrystalline cellulose is selected from 1: 0.75.
7. Donepezil hydrochloride generic tablet according to claim 1, characterized in that the lubricant is selected from magnesium stearate or sodium stearyl fumarate and the glidant is selected from silicon dioxide.
8. The donepezil hydrochloride ordinary tablet according to claim 1, which comprises, by weight: 1-10% of donepezil hydrochloride, 60-85% of filler, 10-30% of disintegrant, 1-10% of adhesive, 0.1-10% of lubricant and 0.1-10% of glidant.
9. The donepezil hydrochloride ordinary tablet according to claim 1, which comprises, by weight: 2-4% of donepezil hydrochloride, 70-80% of filler, 10-20% of disintegrant, 1-5% of adhesive, 0.1-2% of lubricant and 0.1-3% of glidant.
10. The donepezil hydrochloride ordinary tablet according to claim 1, which contains donepezil hydrochloride in an amount of 5mg per unit formulation.
11. A method for preparing the donepezil hydrochloride ordinary tablet formulation of any one of claims 1 to 10, comprising the steps of:
1) premixing: uniformly mixing donepezil hydrochloride, a disintegrating agent and a filling agent;
2) and (3) wet granulation: adding a binding agent for wet granulation, and performing wet granulation after the granulation is finished;
3) drying and granulating: drying and finishing wet granules;
4) total mixing: adding a lubricant and a glidant for total mixing;
5) tabletting;
6) and (4) coating.
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| CN1608623A (en) * | 2004-11-05 | 2005-04-27 | 贵州圣济堂制药有限公司 | Enteric coated donepezil hydrochloride tablet and its perpn process |
| JP5269894B2 (en) * | 2007-06-27 | 2013-08-21 | ハンミ ファーム． シーオー．， エルティーディー． | Method for producing fast-dissolving preparation for oral administration, its production, and packaging device |
| CN101480378A (en) * | 2008-01-09 | 2009-07-15 | 浙江华海药业股份有限公司 | Solid preparation of Donepezil hydrochloride and technique for preparing the same |
| CN101756917A (en) * | 2008-10-24 | 2010-06-30 | 北京科信必成医药科技发展有限公司 | Donepezil hydrochloride orally disintegrating tablet and preparation method thereof |
| CN102885798B (en) * | 2011-07-21 | 2015-04-22 | 成都康弘药业集团股份有限公司 | Orally disintegrating tablet |
| CN103919740A (en) * | 2014-03-24 | 2014-07-16 | 张绪伟 | Donepezil hydrochloride oral tablet |
| CN103877046A (en) * | 2014-03-24 | 2014-06-25 | 张绪伟 | Donepezil hydrochloride dispersible tablet and preparation method thereof |
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