CN1931140A - Orally disintegrated galantamine hydrobromide tablet and its prepn process - Google Patents
Orally disintegrated galantamine hydrobromide tablet and its prepn process Download PDFInfo
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- CN1931140A CN1931140A CN 200610096693 CN200610096693A CN1931140A CN 1931140 A CN1931140 A CN 1931140A CN 200610096693 CN200610096693 CN 200610096693 CN 200610096693 A CN200610096693 A CN 200610096693A CN 1931140 A CN1931140 A CN 1931140A
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- galantamine hydrobromide
- hydrobromide
- orally disintegrated
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Abstract
The present invention discloses one kind of quickly releasing orally disintegrated galantamine hydrobromide tablet and one kind of slowly releasing orally disintegrated galantamine hydrobromide tablet and their preparation process. The quickly releasing orally disintegrated galantamine hydrobromide tablet is prepared with galantamine hydrobromide, filler, disintegrant, lubricant, etc and through mixing and direct tabletting. The slowly releasing orally disintegrated galantamine hydrobromide tablet is prepared through adsorbing galantamine hydrobromide with powdered sulfonic acid type ion resin via ion exchange, coating with coating agent, mixing with filler, disintegrant, lubricant, etc and final direct tabletting. The orally disintegrated galantamine hydrobromide tablets of the present invention have fast disintegration, good taste and raised patient's compliance.
Description
One, technical field
The present invention relates to a kind of medicine and preparation method thereof, specifically a kind of quick-releasing type and spacetabs type Orally disintegrated galantamine hydrobromide tablet and preparation method thereof.
Two, background technology
(Alzheimer disease AD) is commonly called as senile dementia to Alzheimer, is old people's a kind of common gradual function of nervous system degenerative imbalance, and clinical manifestation is based on memory loss and cognitive dysfunction.Senile dementia has had a strong impact on thousands of old peoples and has looked after their kinsfolk's life, has also increased heavy burden to society simultaneously, has caused the extensive concern of international community in recent years.Along with the aging of social population, the senile dementia sickness rate rises relatively, and the dementia prevalence of over-65s is 5%～10% at present, and still among increasing.Being only second to heart disease and cancer in U.S.'s Alzheimer, is that medical expense occupies a kind of disease of the 3rd.
Acetyl choline content is closely related with memory in the existing known brain, and the acetylcholine amount significantly reduces in the patients of senile dementia brain.Replenish the choline medicine and can improve patient's memory and think only ability, can not make that acetylcholine increases in the brain but directly give choline or lecithin, the acetylcholinesteraseinhibitors inhibitors that therefore can improve the choline level is for being hopeful most to treat a kind of selection of this disease.
Calendar year 2001, narcissus bulb stem extract galanthamine hydrobromide (Galanthamine Hydrobromide) in U.S.'s listing, is used for the treatment of mild to moderate Alzheimer's disease by the FDA approval.
Galanthamine hydrobromide belongs to second filial generation acetylcholinesteraseinhibitors inhibitors, has high selectivity and reversibility, easily sees through blood brain barrier in vivo and enters cerebral tissue, and the concentration in its brain is 2～3 times of periphery blood level.Its inhibition activity to the acetylcholinesterase in neuron and the erythrocyte is that butyrylcholine esterase in the blood plasma is suppressed active 50 times.
Galanthamine hydrobromide is ratified the back in Britain, Irish Initial Public Offering in July, 2000 by European Union, and calendar year 2001 is obtained the U.S. FDA permission and is used for the treatment of senile dementia, now 25 country's listings.In recent years, acetylcholinesterase inhibitor had become the first-line treatment medicine of senile dementia.In addition, galanthamine hydrobromide has injection, tablet, capsule listing, and is widely used in being used for the non depolarization flesh pine effect of myasthenia gravis, poliomyelitis sequela and antagonism tubocurarine chloride and similar medicine clinically.
Because the treatment senile dementia need be taken medicine for a long time, and medication crowd major part is the old people, the galanthamine hydrobromide oral formulations that is gone on the market at present is conventional formulation, as tablet and capsule, concerning the old man that swallows certain difficulty and child, use but very inconvenient, often have gerontal patient or child patient to be unwilling to take these conventional solid preparations, and the complaint medicine is difficult to swallow or block esophagus.When taking above-mentioned conventional oral formulations, also need drink water simultaneously, under the occasion of many hydropenias or inconvenience drinking-water medication just very inconvenient, thereby bring adverse effect to disease treatment.
Three, summary of the invention
The present invention is directed to the above-mentioned defective of conventional oral formulations, aiming to provide is not a kind ofly needing under the conditions of water drinking disintegrate in the oral cavity rapidly, the quick-releasing type with good taste and spacetabs type solid preparation and preparation method thereof, and technical problem to be solved is to select adjuvant and determine reasonable proportioning.
Alleged principal agent is a galanthamine hydrobromide among the present invention, its chemistry 11-methyl by name-3-methoxyl group-4 α, 5,9,10,11,12-six hydrogen-6H-benzofuran [3 α, 3,2-ef] [2] benzazepine-6-alcohol hydrobromate, molecular formula: C
17H
21NO
3HBr, molecular weight: 368.27, structural formula is:
Two kinds of different dosage forms of spacetabs type that the alleged Orally disintegrated galantamine hydrobromide tablet of the present invention has quick-releasing type and prepares on the quick-releasing type basis.
The quick-releasing type oral cavity disintegration tablet, comprise principal agent galanthamine hydrobromide and adjuvant, described adjuvant comprises filler, disintegrating agent, lubricant and correctives, adopts the powder direct compression process to prepare oral cavity disintegration tablet behind these adjuvants and the galanthamine hydrobromide mixing, and each component has following percentage by weight:
Filler 30～80%
Disintegrating agent 10～60%
Micropowder silica gel 0.5～2%
Magnesium stearate 0.5～2%
Correctives 0.01～1.0%.
Preferably:
Galanthamine hydrobromide 5～10%
Filler 50～70%
Disintegrating agent 20～40%
Micropowder silica gel 0.8～1.5%
Magnesium stearate 0.8～1.5%
Correctives 0.01～0.5%.
Described filler be selected from mannitol or/and lactose or/and microcrystalline Cellulose.Wherein the microcrystalline Cellulose good fluidity also has disintegration.
Described disintegrating agent be selected from low-substituted hydroxypropyl cellulose (L-HPC) or/and cross-linking sodium carboxymethyl cellulose (CCNa) or/and crospolyvinylpyrrolidone (CPVP).
Micropowder silica gel and magnesium stearate are lubricant, and wherein the micropowder silica gel good fluidity has the fluidizer effect.
Described correctives is an essence or/and sweeting agent, and is sweet etc. as Fructus Citri sinensis solid essence, Herba Menthae solid table, stevioside, cyclamate, A Siba.
In above compositions, also can add 1～3% gas-producing disintegrant citric acid and sodium bicarbonate, meet water generates CO2 bubble, make the rapid disintegrate of tablet.Citric acid and sodium bicarbonate equivalent, total amount satisfies 1～3%.
The quick-releasing type Orally disintegrated galantamine hydrobromide tablet adopts the direct powder compression technology, comprises pulverizing, mixing, tabletting unit process, and concrete preparation process is as follows:
Step 1: galanthamine hydrobromide and each adjuvant are crossed 50～100 mesh sieves, standby.
Step 2: take by weighing galanthamine hydrobromide and various adjuvant by proportional quantity, and with its abundant mix homogeneously.
Step 3: mixed powder is delivered to tablet machine, carry out tabletting.Relative air humidity control is lower than 40% in the tabletting process.Making finished product hardness is 20～40N, in purified water disintegrate be less than the particulate time of 710 μ m less than 60 seconds, no sand type in the oral cavity when taking medicine, and the sense of taste is good, the uncomfortable taste of no medicine.
The spacetabs type Orally disintegrated galantamine hydrobromide tablet that the present invention is alleged, be based on above-mentioned quick-releasing type oral cavity disintegration tablet, at first galanthamine hydrobromide is adsorbed and Cotton seeds successively, same then filler, disintegrating agent etc. adopt the direct powder compression technology together, comprise pulverizing, mixing and tabletting, prepare the spacetabs type Orally disintegrated galantamine hydrobromide tablet.
Described adsorption treatment, be that the sulfonic acid ion exchange resin of 100～220 mesh sieves and galanthamine hydrobromide together add in the pure water and stirred 1～24 hour under 50～70 ℃ of conditions exactly with fineness, separate then, drying, obtain the adsorbate (calling drug adsorbates in the following text) of sulfonic acid ion exchange resin absorption galanthamine hydrobromide, the weight ratio of resin and medicine is 1: 0.5～1.
Described Cotton seeds is exactly drug adsorbates to be added in the cyclohexane solution that is dissolved with coating materials stir, refluxed 0.5～1 hour, and separate the cooling back, and drying is sloughed the drug adsorbates that cyclohexane extraction just obtains coating, (calling the coated drugs adsorbate in the following text).Described coating materials is non-water-soluble ethyl cellulose or acrylic resin, and its consumption is 1～20% of a drug adsorbates weight.
Coated drugs adsorbate and employed each adjuvant of quick-releasing type oral cavity disintegration tablet are pulverized, crossed 50～100 sieves, standby.
Proportioning by the quick-releasing type oral cavity disintegration tablet takes by weighing coated drugs adsorbate (in active component) and each adjuvant and mix homogeneously.
At last, mixed powder is delivered to tablet machine, carry out tabletting.Relative air humidity control is lower than 40% in the tabletting process.Making finished product hardness is 20～40N, in purified water disintegrate be less than the particulate time of 710 μ m less than 60 seconds, no sand type in the oral cavity when taking medicine, and the sense of taste is good, the uncomfortable taste of no medicine.
Galanthamine hydrobromide is reinstated the spacetabs type Orally disintegrated galantamine hydrobromide tablet of direct powder compression preparation with adjuvant one after absorption, Cotton seeds, by " the described drug release determination method of 2005 editions appendix of Chinese pharmacopoeia is measured.Dissolution medium is a 250ml 0.4mol/L KCl solution, the slurry method, and rotating speed is 100rpm.Timing sampling is measured the galanthamine hydrobromide release, the results are shown in Table 1 and Fig. 1.
From table 1 and Fig. 1 as seen, the medicine in the spacetabs type Orally disintegrated galantamine hydrobromide tablet in dissolution medium, about 12 hours of release time.Therefore can reduce patient's medicining times, reach the purpose that makes things convenient for the patient.
Table 1 spacetabs type Orally disintegrated galantamine hydrobromide tablet release in vitro result (n=6)
| Drug release time (hour) | Average accumulated release (%) |
| 1 | 50.25 |
| 2 | 59.63 |
| 3 | 64.17 |
| 4 | 69.08 |
| 5 | 74.84 |
| 6 | 77.65 |
| 7 | 80.48 |
| 8 | 82.26 |
| 12 | 87.82 |
The invention has the advantages that:
1, the present invention fills a prescription rationally, disintegrating property is good, enter the mouth no sand type and uncomfortable taste, and sweet, the tool fruit aroma of distinguishing the flavor of.Compliance when having improved patient's medication.
2, preparation technology of the present invention adopts direct powder compression, and process is simple, be easy to control, is fit to industrial scale production.
3, the spacetabs type Orally disintegrated galantamine hydrobromide tablet among the present invention can reduce patient's medication number of times, and stabilised blood concentration level improves patient's medication compliance.
Four, description of drawings
Fig. 1: the external release curve of spacetabs type Orally disintegrated galantamine hydrobromide tablet
Five, the specific embodiment
The invention is further illustrated by the following examples:
Example 1: a kind of quick-releasing type Orally disintegrated galantamine hydrobromide tablet and preparation method
Orally disintegrated galantamine hydrobromide tablet is made up of principal agent and adjuvant, and proportioning is: principal agent 8.5%, adjuvant 91.5%.The each component proportioning is as follows:
Galanthamine hydrobromide 5.5g
Microcrystalline Cellulose 45.0g
Low-substituted hydroxypropyl cellulose 5.0g
Crospolyvinylpyrrolidone 4.5g
Micropowder silica gel 2.0g
Magnesium stearate 2.0g
Stevioside 1.0g
Fructus Citri sinensis solid essence 0.01g
Make 1000 altogether
The preparation method of this example galanthamine hydrobromide disintegrating tablet is as follows: galanthamine hydrobromide and each adjuvant are crossed 80 sieves, and standby.Take by weighing galanthamine hydrobromide and adjuvant by proportional quantity, and with its abundant mix homogeneously.Mixed powder is delivered to tablet machine, carry out tabletting, make sheet and heavily be the tablet of 65mg.Relative air humidity control is lower than 40% in the tabletting process.
Manufacture test result: tablet hardness: 35N;
Disintegration in the purified water: 15 seconds;
The intraoral disintegration time limit: disintegrate in 20 seconds;
Mouthfeel: no sand type, it is sweet to distinguish the flavor of, and Fructus Citri sinensis fragrance is arranged.
Example 2: a kind of spacetabs type Orally disintegrated galantamine hydrobromide tablet and preparation method
With 9g 200 order sulfonic acid ion exchange resin (Amberlite IRP 64, Rohm﹠amp; Hass company) be suspended in the 150ml purified water, add galanthamine hydrobromide 5.0g, 60 ℃ of heated and stirred 4 hours are filtered, and 80 ℃ of dryings obtain galanthamine hydrobromide-sulfonic acid ion exchange resin drug adsorbates.This drug adsorbates is added in the 150ml 0.5% ethyl cellulose cyclohexane solution, and heated and stirred refluxed 1 hour, was cooled to 10 ℃, filtered, and 60 ℃ of dryings 12 hours obtain the coated drugs adsorbate.
Press following formulation spacetabs type Orally disintegrated galantamine hydrobromide tablet:
Coated drugs adsorbate 14.75g
Mannitol 25.0g
Microcrystalline Cellulose 20.0g
Crospolyvinylpyrrolidone 4.0g
Low-substituted hydroxypropyl cellulose 4.0g
Micropowder silica gel 1g
Magnesium stearate 1.25g
The sweet 0.1g of A Siba
Fructus Citri sinensis solid essence 0.01g
Make 1000 altogether
Coated drugs adsorbate and each adjuvant (with identical in the quick-releasing type oral cavity disintegration tablet) are crossed 50～100 mesh sieves, get principal agent and adjuvant and with its abundant mix homogeneously by matching.Mixed powder is delivered to tablet machine, carry out tabletting, make sheet and heavily be the tablet of 70mg.Relative air humidity control is lower than 40% in the tabletting process.
Manufacture test result: tablet hardness: 40N;
Disintegration in the purified water: 10 seconds;
The intraoral disintegration time limit: disintegrate in 15 seconds;
Mouthfeel: no sand type, it is sweet to distinguish the flavor of, and Fructus Citri sinensis fragrance is arranged, and refrigerant sense is arranged slightly.
Claims (8)
1, a kind of quick-releasing type Orally disintegrated galantamine hydrobromide tablet comprises principal agent and adjuvant, it is characterized in that: each component has following percentage by weight:
Galanthamine hydrobromide 2～10%
Filler 30～80%
Disintegrating agent 10～60%
Micropowder silica gel 0.5～2%
Magnesium stearate 0.5～2%
Correctives 0.01～1.0%.
2, quick-releasing type Orally disintegrated galantamine hydrobromide tablet according to claim 1 is characterized in that:
Galanthamine hydrobromide 5～10%
Filler 50～70%
Disintegrating agent 20～40%
Micropowder silica gel 0.8～1.5%
Magnesium stearate 0.8～1.5%
Correctives 0.01～0.5%.
3, quick-releasing type Orally disintegrated galantamine hydrobromide tablet according to claim 1 and 2 is characterized in that: contain 1～3% citric acid and sodium bicarbonate in the compositions.
4, quick-releasing type Orally disintegrated galantamine hydrobromide tablet according to claim 3 is characterized in that: filler be selected from mannitol or/and lactose or/and microcrystalline Cellulose; Disintegrating agent be selected from low-substituted hydroxypropyl cellulose or/and cross-linking sodium carboxymethyl cellulose or/and crospolyvinylpyrrolidone; Correctives is that essence is or/and sweeting agent.
5, a kind of spacetabs type Orally disintegrated galantamine hydrobromide tablet, comprise be adsorbed, the principal agent and the adjuvant of coating, it is characterized in that: each weight percentages of components is as follows:
Be adsorbed, the galanthamine hydrobromide 2～10% of coating
Filler 30～80%
Disintegrating agent 10～60%
Micropowder silica gel 0.5～2%
Magnesium stearate 0.5～2%
Correctives 0.01～1.0%.
6, spacetabs type Orally disintegrated galantamine hydrobromide tablet according to claim 5 is characterized in that:
Be adsorbed, the galanthamine hydrobromide 5～10% of coating
Filler 50～70%
Disintegrating agent 20～40%
Micropowder silica gel 0.8～1.5%
Magnesium stearate 0.8～1.5%
Correctives 0.01～0.5%.
7, according to claim 5 or 6 described spacetabs type Orally disintegrated galantamine hydrobromide tablets, it is characterized in that: contain 1～3% citric acid and sodium bicarbonate in the compositions.
8, by the preparation method of the described spacetabs type Orally disintegrated galantamine hydrobromide tablet of claim 5, comprise pulverizing, mixing and tabletting, it is characterized in that: galanthamine hydrobromide through absorption, pulverize after the Cotton seeds, mixing and tabletting, described adsorption treatment is that 100～220 purpose sulfonic acid type ions are handed over resin and galanthamine hydrobromide to add in the entry in 50～70 ℃ by 1: 0.5～1 weight ratio to stir 1～24 hour, and obtained adsorbate after separation, drying with fineness exactly; Described Cotton seeds is exactly adsorbate to be added in the cyclohexane solution that is dissolved with coating materials stir, refluxed 0.5～1 hour, separate then, precipitation, drying, described coating materials are ethyl cellulose or acrylic resin, and its consumption is 1～20% of an adsorbate weight.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012063257A3 (en) * | 2010-11-10 | 2012-07-26 | Rubicon Research Private Limited | Sustained release compositions |
| CN103565761A (en) * | 2012-07-19 | 2014-02-12 | 河北智同医药控股集团有限公司 | Galanthamine hydrobromide orally disintegrating tablet |
| CN103877044A (en) * | 2014-03-24 | 2014-06-25 | 张绪伟 | Galanthamine hydrobromide dispersible tablet and preparation method thereof |
-
2006
- 2006-10-18 CN CN 200610096693 patent/CN1931140A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012063257A3 (en) * | 2010-11-10 | 2012-07-26 | Rubicon Research Private Limited | Sustained release compositions |
| CN103565761A (en) * | 2012-07-19 | 2014-02-12 | 河北智同医药控股集团有限公司 | Galanthamine hydrobromide orally disintegrating tablet |
| CN103565761B (en) * | 2012-07-19 | 2015-03-25 | 河北智同医药控股集团有限公司 | Galanthamine hydrobromide orally disintegrating tablet |
| CN103877044A (en) * | 2014-03-24 | 2014-06-25 | 张绪伟 | Galanthamine hydrobromide dispersible tablet and preparation method thereof |
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Open date: 20070321 |