CN103877063A - Rivastigmine hydrogen tartrate capsule and preparation method thereof - Google Patents
Rivastigmine hydrogen tartrate capsule and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a rivastigmine hydrogen tartrate capsule and a preparation method thereof. The rivastigmine hydrogen tartrate capsule comprises the following components in parts by weight: 1.5-6 parts of rivastigmine hydrogen tartrate, 50-100 parts of low-substituted hydroxypropyl cellulose, 1-10 parts of cross-liked polyvinylpolypyrrolidone, 1-5 parts of sodium lauryl sulfate, 1-10 parts of povidone K30 and 1-3 parts of magnesium stearate. The rivastigmine hydrogen tartrate capsule disclosed by the invention can be used for effectively treating mild and moderate alzheimer disease (AD), and is a first-line medicament for treating AD. The rivastigmine hydrogen tartrate capsule has the advantages of reasonable formula, feasible process, stable and reliable quality and good stability, solubility and bioavailability, is prepared by adopting a wet granulation process, adopts a proper method by adding the solubilizer sodium lauryl sulfate, is proper in adhesive concentration, belongs to powder with good fluidity, and can meet the requirement of filling capsules. The rivastigmine hydrogen tartrate capsule is short in production cycle and low in production cost, and is easy for industrial production.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to senile disease field, i.e. a kind of rivastigmine-hydrogentartrate capsule and preparation method thereof, and be used for the treatment of senile dementia, i.e. Alzheimer disease.
Background of invention
Aging trend allows patients with Alzheimer disease quantity increase, and China will enter aging society, and the sickness rate of a very important problem-AD of simultaneous is increasing year by year.Investigation is found: northern China suffer from mean age of AD be 75,76 years old, the ratio of suffering from AD in over-65s crowd reaches more than 15%.AD patient's activity of daily living declines, and they are not familiar with spouse, children, wears the clothes, has a meal, defecation all can not take care of oneself, the inconvenience of particularly taking medicine; The auditory hallucination hallucination in addition having, brings endless misery and worried to people own and around.Patient's AD mean survival time (MST) is 5.5 years, and AD disease, after cardiovascular diseases, cerebrovascular and cancer, has become " the fourth-largest killer " of aged health.
Rivastigmine be a kind of selectively acting in the acetylcholinesteraseinhibitors inhibitors of brain, be used for the treatment of mild or moderate Alzheimer (AD), be treatment AD first-line drug.
Disintegrating agent is often referred to and can makes tablet in gastro-intestinal Fluid, be fragmented into rapidly the material of fine particle, thereby makes the rapid solution absorption of active component, plays a role.This class material mostly has good water absorption and dilatancy, thereby realizes the disintegrate of tablet.
Due to very easily moisture absorption of disintegrating agent itself, in tablet, add a large amount of disintegrating agents can cause the easy moisture absorption of tablet, in storage process, moisture raises, and rivastigmine-hydrogentartrate raw material is clamminess after meeting water, cause hardness to become large, cause slice, thin piece disintegrate difficulty, dissolution rate is slack-off.Thereby finished fabric is easily stored.The former sheet motilium (Johnson & Johnson) that grinds, at 6 ℃, is placed 10 days under 90% relative humidity condition, or at 40 ℃, placed discovery in 3 months under 75% relative humidity, it is very hard that slice, thin piece becomes, cannot disintegrate.
The stripping that prior art improves rivastigmine-hydrogentartrate by increasing the consumption of disintegrating agent or the kind of increase disintegrating agent conventionally.The first object of the present invention is to provide a kind of rivastigmine-hydrogentartrate capsule, this capsule only uses a kind of disintegrating agent, not only make product there is good stability, guarantee that product is after accelerated test, not obvious variation of its disintegrating property, the stripping of product is still qualified, and has better bioavailability.
Summary of the invention
The first object of the present invention is to provide a kind of rivastigmine-hydrogentartrate capsule, this capsule only uses a kind of disintegrating agent, not only make product there is good stability, guarantee that product is after accelerated test, not obvious variation of its disintegrating property, the stripping of product is still qualified, and has better bioavailability.
The second object of the present invention is to provide the preparation method of described rivastigmine-hydrogentartrate capsule, and its preparation technology is simple, convenient, feasible, favorable reproducibility, and said composition has stronger practicality.
The object of the present invention is to provide a kind of capsule preparations that can improve rivastigmine-hydrogentartrate stability and preparation method thereof, and through repetition test, each component screening is arrived to weight ratio of the present invention, be surprised to find that the dispersible tablet steady quality obtaining, stripping is fast, in body, distribute rapidly, bioavailability is high.
On the one hand, the invention provides a kind of rivastigmine-hydrogentartrate capsule, wherein, described rivastigmine-hydrogentartrate capsule is made up of following component:
1.5～6 parts of rivastigmine-hydrogentartrates
50～100 parts of low-substituted hydroxypropyl celluloses
5～10 parts of polyvinylpolypyrrolidone
2～5 parts of sodium lauryl sulphates
1～5 part of PVP K30
1～3 part of magnesium stearate.
Some embodiments therein, rivastigmine-hydrogentartrate capsule of the present invention, wherein, described rivastigmine-hydrogentartrate capsule is made up of following component:
3 parts of rivastigmine-hydrogentartrates
60 parts of low-substituted hydroxypropyl celluloses
5 parts of polyvinylpolypyrrolidone
2 parts of sodium lauryl sulphates
5 parts of PVP K30s
3 parts of magnesium stearate.
In other embodiments, rivastigmine-hydrogentartrate capsule of the present invention, wherein, described rivastigmine-hydrogentartrate capsule is made up of following component:
3 parts of rivastigmine-hydrogentartrates
100 parts of low-substituted hydroxypropyl celluloses
5 parts of polyvinylpolypyrrolidone
5 parts of sodium lauryl sulphates
10 parts of PVP K30s
3 parts of magnesium stearate.
On the other hand, the present invention relates to a kind of preparation method of rivastigmine-hydrogentartrate capsule, described method comprises the steps: 1) binding agent preparation: take sodium lauryl sulphate and the PVP K30 of described consumption, be dissolved in water, be mixed with the solution of 10% PVP K30; 2) sieve: adjuvant low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate are crossed respectively 60 mesh sieves; 3) granulate with dry: the rivastigmine-hydrogentartrate crude drug that takes described consumption is put in mixer, adds above-mentioned binding agent soft material processed, then granulate with granulator; Wet granular is dry after 1～3 hour at 40 ℃～45 ℃, granulate; 4) mix: above-mentioned granule is put in mixer, added low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and the magnesium stearate of described consumption, mix sampling and measuring content and loss on drying 30 minutes; 5) filling: calculate average loading amount by particle content measuring result, filling, controls content uniformity in scholar 5%; 6) packing: intermediate products after testing content uniformity, content and dissolution qualified after, aluminum-plastic packaged, then through outer package, obtain above-mentioned rivastigmine-hydrogentartrate capsule.
Some embodiments therein, preparation method of the present invention, wherein, described sodium lauryl sulphate is dissolved in PVP K30, in wet-granulation process, adds; Described low-substituted hydroxypropyl cellulose adopts granule to add outward.
Some embodiments therein, preparation method of the present invention, wherein, described method also comprises carries out pretreated process to rivastigmine-hydrogentartrate, described pretreatment refers to that rivastigmine-hydrogentartrate first carries out following pretreatment inserting before mixer: i) rivastigmine-hydrogentartrate is dissolved in ethanol, obtains rivastigmine-hydrogentartrate alcoholic solution; Ii) get the PVP K30 PVP K30 aqueous solution that is made into soluble in water; Iii) step I PVP K30 aqueous solution i) is inserted in ice-water bath, under ultrasonic condition, rivastigmine-hydrogentartrate alcoholic solution Uniform speed is added dropwise in PVP K30 aqueous solution, become muddy to solution system, leave standstill, filter, dry, pulverize and sieve.
In other embodiments, preparation method of the present invention, wherein, step I) in the concentration of rivastigmine-hydrogentartrate alcoholic solution be 0.01g/ml.
In other embodiments, preparation method of the present invention, wherein, the step I i) concentration of PVP K30 solution is 5%.
In other embodiments, preparation method of the present invention, wherein, step I ii) described in ultrasonic frequency be 0.4KW; The temperature of described ice-water bath is 0-5 ℃, and the speed that described Uniform speed drips is 1.5ml/min, described leaving standstill as leave standstill 6 hours at 0-5 ℃, described in sieve as crossing 80 mesh sieves.
In the component of rivastigmine-hydrogentartrate capsule of the present invention, wherein, described sodium lauryl sulphate is dissolved in PVP K30, in wet-granulation process, adds.
Crude drug rivastigmine-hydrogentartrate is almost insoluble in water, in the present invention's prescription, select adjuvant sodium lauryl sulphate as solubilizing agent, its consumption is 0.5～5 part, consumption own is very little, if adopt powder directly to add, its solubilizing effect is very poor, if be dissolved in binding agent, in wet-granulation process, add, can guarantee that it is well dispersed in crude drug surface, solve the excessively strong shortcoming of rivastigmine-hydrogentartrate crude drug hydrophobicity, thereby medicated powder fully contacts with dissolution medium after guaranteeing capsule shells disintegrate, reach the object of accelerating drug-eluting.Therefore, the present invention adopts wet granulation technology, and sodium lauryl sulphate is dissolved in binding agent and is added.
In the component of rivastigmine-hydrogentartrate capsule of the present invention, wherein, the mode that described low-substituted hydroxypropyl cellulose adopts granule to add outward adds.
In the present invention, select polyvinylpolypyrrolidone as disintegrating agent, this supplementary product consumption is generally 2～5%, and the present invention selects 2%, 3%, 5% 3 kind of consumption tested respectively, to confirm the impact of disintegrating agent on drug dissolution.
In binding agent, approximately contain 5% sodium lauryl sulphate and 10% PVP K30, get rivastigmine-hydrogentartrate crude drug, add binding agent to mix by prescription, 20 mesh sieves are granulated, put in baking oven 40 ℃ dry, after granulate with all the other auxiliary materials and mixing, incapsulate by 0.15g/ grain, respectively at 5min and 30min sampling and measuring dissolution, result shows, polyvinylpolypyrrolidone is not obvious on the impact of product dissolution of the present invention as disintegrating agent.
Rivastigmine-hydrogentartrate capsule of the present invention is adopted preparation with the following method:
1) binding agent preparation: take sodium lauryl sulphate and the PVP K30 of described consumption, be dissolved in water, be mixed with the solution of 10% PVP K30;
2) sieve: adjuvant low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate are crossed respectively 60 mesh sieves;
3) granulate with dry: the rivastigmine-hydrogentartrate crude drug that takes described consumption is put in mixer, adds above-mentioned binding agent soft material processed, then granulate with granulator; Wet granular is dry after 1～3 hour at 40 ℃～45 ℃, granulate;
4) mix: above-mentioned granule is put in mixer, added low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and the magnesium stearate of described consumption, mix sampling and measuring content and loss on drying 30 minutes;
5) filling: calculate average loading amount by particle content measuring result, filling, controls content uniformity in ± 5%;
6) packing: intermediate products after testing content uniformity, content and dissolution qualified after, aluminum-plastic packaged, then through outer package, obtain above-mentioned rivastigmine-hydrogentartrate capsule.
In the present invention, select adjuvant sodium lauryl sulphate as solubilizing agent, its consumption is 0.5～5 part, and consumption own is very little, if adopt powder directly to add, its solubilizing effect is very poor, if be dissolved in binding agent, in wet-granulation process, adds, can guarantee that it is well dispersed in crude drug surface, solve the excessively strong shortcoming of rivastigmine-hydrogentartrate crude drug hydrophobicity, thereby after guaranteeing capsule shells disintegrate, medicated powder fully contacts with dissolution medium, reach the object of accelerating drug-eluting.Therefore, the present invention adopts wet granulation technology, and sodium lauryl sulphate is dissolved in binding agent and is added.
The process in leaching of oral insoluble drug is the key factor that limits its absorption and bioavailability, and in general, the dissolution rate of medicine and the particle diameter of drug particles are inverse relation, so the particle diameter that reduces insoluble drug granule is to improve its dissolution rate.Therefore in the preparation process of oral tablet and capsule all to crude drug granule size and be distributed with certain requirement.The conventional method that reduces drug particles granularity mainly contains: the methods such as low-temperature airflow comminuting method, ball-milling method, solid dispersion method.In preparation method of the present invention, rivastigmine-hydrogentartrate first carries out as above pretreatment inserting before mixer, by rivastigmine-hydrogentartrate pretreatment in PVP K30 solution, and carry out stripping contrast experiment and bioavailability experiment, find that rivastigmine-hydrogentartrate all has significant difference in stripping and bioavailability after above-mentioned preprocess method is processed pleasantly surprisedly.Analyze reason, rivastigmine-hydrogentartrate release in vitro quickening after pretreatment in surfactant solution on the one hand, may be that SURFACTANT ADSORPTION, on hydrophobic drug surface, has increased the wettability of medicine in preprocessing process.In stripping experiment, observe, untreated rivastigmine-hydrogentartrate swims in solution surface, and the rivastigmine-hydrogentartrate of processing is wetted to be distributed in dissolution medium and to go soon; On the other hand may be because rivastigmine-hydrogentartrate crude drug be under ultrasonic condition, after surfactant solution is processed, its particle diameter diminishes, and this may be the another kind of reason that improves dissolution and bioavailability.
Crude drug rivastigmine-hydrogentartrate is almost insoluble in water, in the present invention's prescription, select adjuvant sodium lauryl sulphate as solubilizing agent, its consumption is 0.8～4 part, consumption own is very little, if adopt powder directly to add, its solubilizing effect is very poor, if be dissolved in binding agent, in wet-granulation process, add, can guarantee that it is well dispersed in crude drug surface, solve the excessively strong shortcoming of rivastigmine-hydrogentartrate crude drug hydrophobicity, thereby medicated powder fully contacts with dissolution medium after guaranteeing capsule shells disintegrate, reach the object of accelerating drug-eluting.Therefore, the present invention adopts wet granulation technology, and solubilizing agent one sodium lauryl sulphate is dissolved in to be dispersed in water in principal agent, improves dissolution, in preparation process, consider that rivastigmine-hydrogentartrate exceedes 55 ℃ and can melt, and wet granular must, through dry run, be controlled at 40 ℃～45 ℃ dry by temperature.
In the preferred preparation method of the present invention, also comprise rivastigmine-hydrogentartrate is carried out to pretreated process, described pretreatment refers to that rivastigmine-hydrogentartrate first carries out following pretreatment inserting before mixer:
I) rivastigmine-hydrogentartrate is dissolved in ethanol, obtains rivastigmine-hydrogentartrate alcoholic solution;
Ii) get the PVP K30 PVP K30 aqueous solution that is made into soluble in water;
Iii) step I PVP K30 aqueous solution i) is inserted in ice-water bath, under ultrasonic condition, rivastigmine-hydrogentartrate alcoholic solution is at the uniform velocity added dropwise in PVP K30 aqueous solution, become muddy to solution system, leave standstill, filter, dry, pulverize and sieve.
According to aforesaid preparation method, wherein, step I) in the concentration of rivastigmine-hydrogentartrate alcoholic solution be 0.12g/ml.
According to aforesaid preparation method, wherein, the step I i) concentration of middle PVP K30 solution is 5%.
According to aforesaid preparation method, wherein, step I ii) described in ultrasonic frequency be 0.4KW; The temperature of described ice-water bath is 0-5 ℃, described at the uniform velocity drip speed be 1.5ml/min, described leave standstill at 0-5 ℃ leave standstill 6 hours, described in sieve into cross 80 mesh sieves.
In preferred version provided by the present invention, first adopt the method for the invention to carry out as above pretreatment inserting before mixer rivastigmine-hydrogentartrate, under ultrasonic condition, by the pretreatment in PVP K30 solution of rivastigmine-hydrogentartrate crude drug, by stripping contrast experiment and bioavailability experiment, find that rivastigmine-hydrogentartrate all has significant difference in dissolution and bioavailability after above-mentioned preprocess method is processed pleasantly surprisedly.
The specific embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1
Prescription:
Rivastigmine-hydrogentartrate 3g
Low-substituted hydroxypropyl cellulose 100g
Polyvinylpolypyrrolidone 5g
Sodium lauryl sulphate 5g
PVP K30 10g
Magnesium stearate 3g
Make 1000
Preparation method:
(1) binding agent preparation: take sodium lauryl sulphate and the PVP K30 of recipe quantity, be dissolved in water, be mixed with the solution of 10% PVP K30;
(2) sieve: adjuvant low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate are crossed respectively 60 mesh sieves;
(3) granulate with dry: take recipe quantity rivastigmine-hydrogentartrate crude drug and put in mixer, add above-mentioned binding agent soft material processed, then granulate with granulator; Wet granular is dry after 1～3 hour at 40 ℃～45 ℃, granulate;
(4) mix: above-mentioned granule is put in mixer, added low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and the magnesium stearate of recipe quantity, mix sampling and measuring content and loss on drying 30 minutes;
(5) filling: calculate average loading amount by particle content measuring result, filling, controls content uniformity in ± 5%;
(6) packing: intermediate products after testing content uniformity, content and dissolution qualified after, aluminum-plastic packaged, then through outer package, obtain above-mentioned rivastigmine-hydrogentartrate capsule.
Embodiment 2
Prescription:
Rivastigmine-hydrogentartrate 3g
Low-substituted hydroxypropyl cellulose 60g
Polyvinylpolypyrrolidone 5g
Sodium lauryl sulphate 2g
PVP K30 5g
Magnesium stearate 3g
Make 1000
Preparation method is with embodiment 1.
Embodiment 3
Prescription:
Rivastigmine-hydrogentartrate 3g
Low-substituted hydroxypropyl cellulose 80g
Polyvinylpolypyrrolidone 3g
Sodium lauryl sulphate 3g
PVP K30 7g
Magnesium stearate 2g
Make 1000
Preparation method is with embodiment 1.
Biological test
Test example 1
The rivastigmine-hydrogentartrate capsule that the embodiment of the present invention is prepared is checked, and its result is as follows:
Table 1 embodiment assay
Above-mentioned assay shows, embodiment sample all conforms to quality requirements, show that rivastigmine-hydrogentartrate capsule prescription of the present invention is reasonable, feasible process, stable, product quality is controlled, show simultaneously, the rivastigmine-hydrogentartrate capsule dissolubility making after preprocess method pretreatment of the present invention is high, and single assorted and always assorted content is less than undressed, and active component content is high.
Test example 2
The mensuration of dissolution
1, reagent
Be subject to test preparation 1: the rivastigmine-hydrogentartrate capsule of the embodiment of the present invention 1.
Be subject to test preparation 2: the rivastigmine-hydrogentartrate capsule of the embodiment of the present invention 2.
Reference preparation: commercially available rivastigmine-hydrogentartrate capsule (Exelon, Novartis).
2, assay method
Get this product, according to dissolution method (two appendix of Chinese Pharmacopoeia version in 2005) (C first method), take the phosphate buffer 900ml of pH6.8 as solvent, rotating speed is per minute 100 to turn, operation in accordance with the law, 5, 10, 15, 30, 45, 60 minutes, getting solution 10ml filters, and the phosphate buffer 1 0ml of the pH6.8 of supplementary uniform temp, precision measures subsequent filtrate 2ml and puts in 10ml measuring bottle, add the phosphate buffer of pH6.8 to scale, shake Uniform, according to spectrophotography (two appendix IV A of Chinese Pharmacopoeia version in 2005), wavelength place at 251nm measures trap, separately get rivastigmine-hydrogentartrate reference substance appropriate, accurately weighed, dissolve and be diluted in every 1ml the approximately solution containing 20 μ g with the phosphate buffer of pH6.8, be measured in the same method, calculate accumulation stripping quantity.Measurement result is in table 2.
Table 2 rivastigmine-hydrogentartrate capsule accumulation dissolution (%)
| Product | 5min | 10min | 15min | 20min | 30min | 45min |
| Be subject to test preparation 1 | 85.6 | 88.7 | 91.4 | 92.6 | 97.8 | 99.8 |
| Be subject to test preparation 2 | 83.4 | 84.9 | 88.7 | 89.9 | 97.4 | 99.6 |
| Reference preparation | 33.6 | 46.7 | 64.8 | 84.7 | 96.5 | 99.7 |
Can find out from the above results, being subject to test preparation 1 and being subject to test preparation 2 is that the accumulation dissolution of rivastigmine-hydrogentartrate capsule of the embodiment of the present invention 1 and embodiment 2 is apparently higher than reference preparation, and being subject to the accumulation dissolution of test preparation 2 again lower than being subject to test preparation 1, visible crude drug rivastigmine-hydrogentartrate its release in vitro after preprocess method of the present invention is processed is accelerated.Its reason may be that in preprocessing process, surfactant is adsorbed on hydrophobic drug surface, has increased the wettability of medicine.From dissolution test observe to, untreated rivastigmine-hydrogentartrate swims in solution surface, pretreated rivastigmine-hydrogentartrate is wetted to be distributed in dissolution medium and to go soon.
The rivastigmine-hydrogentartrate capsule of the embodiment of the present invention 3 has also been carried out to above-mentioned identical test, and the result of its acquisition is similar.
Test example 3
Accelerated test
Adopt the method pilot-scale (1000) of the embodiment of the present invention 1 to prepare a batch sample by commercially available back, simultaneously with commercially available rivastigmine-hydrogentartrate capsule (claiming in the present invention reference preparation), 40 ℃ of temperature, under the condition of relative humidity 75%, place 6 months, sample respectively 1st month, 2 months, 3 months, 6 the end of month at duration of test, sample for reference outward appearance, dissolution, related substance, content etc., with comparison in 0 month, the results are shown in following table 3:
Table 3 accelerated test result
Can find out from the above results, compared with commercially available rivastigmine-hydrogentartrate capsule, rivastigmine-hydrogentartrate capsule of the present invention has better stability, after the accelerated test of 6 months, there are no significant changes for the character of rivastigmine-hydrogentartrate capsule of the present invention, dissolution, content etc., and reference preparation demonstrates larger variation.
The rivastigmine-hydrogentartrate capsule of the embodiment of the present invention 1 and 3 has also been carried out to above-mentioned identical test, and the result of its acquisition is similar.
Claims (9)
1. a rivastigmine-hydrogentartrate capsule, wherein, described rivastigmine-hydrogentartrate capsule is made up of following component:
1.5～6 parts of rivastigmine-hydrogentartrates
50～100 parts of low-substituted hydroxypropyl celluloses
5～10 parts of polyvinylpolypyrrolidone
2～5 parts of sodium lauryl sulphates
1～5 part of PVP K30
1～3 part of magnesium stearate.
2. rivastigmine-hydrogentartrate capsule according to claim 1, wherein, described rivastigmine-hydrogentartrate capsule is made up of following component:
3 parts of rivastigmine-hydrogentartrates
60 parts of low-substituted hydroxypropyl celluloses
5 parts of polyvinylpolypyrrolidone
2 parts of sodium lauryl sulphates
5 parts of PVP K30s
3 parts of magnesium stearate.
3. rivastigmine-hydrogentartrate capsule according to claim 1, wherein, described rivastigmine-hydrogentartrate capsule is made up of following component:
3 parts of rivastigmine-hydrogentartrates
100 parts of low-substituted hydroxypropyl celluloses
5 parts of polyvinylpolypyrrolidone
5 parts of sodium lauryl sulphates
10 parts of PVP K30s
3 parts of magnesium stearate.
4. the preparation method of the rivastigmine-hydrogentartrate capsule described in a claim 1-3 any one, described method comprises the steps: 1) binding agent preparation: the sodium lauryl sulphate and the PVP K30 that take described consumption, be dissolved in water, be mixed with the solution of 10% PVP K30; 2) sieve: adjuvant low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate are crossed respectively 60 mesh sieves; 3) granulate with dry: the rivastigmine-hydrogentartrate crude drug that takes described consumption is put in mixer, adds above-mentioned binding agent soft material processed, then granulate with granulator; Wet granular is dry after 1～3 hour at 40 ℃～45 ℃, granulate; 4) mix: above-mentioned granule is put in mixer, added low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and the magnesium stearate of described consumption, mix sampling and measuring content and loss on drying 30 minutes; 5) filling: calculate average loading amount by particle content measuring result, filling, controls content uniformity in scholar 5%; 6) packing: intermediate products after testing content uniformity, content and dissolution qualified after, aluminum-plastic packaged, then through outer package, obtain above-mentioned rivastigmine-hydrogentartrate capsule.
5. preparation method according to claim 4, wherein, described sodium lauryl sulphate is dissolved in PVP K30, in wet-granulation process, adds; Described low-substituted hydroxypropyl cellulose adopts granule to add outward.
6. preparation method according to claim 4, wherein, described method also comprises carries out pretreated process to rivastigmine-hydrogentartrate, described pretreatment refers to that rivastigmine-hydrogentartrate first carries out following pretreatment inserting before mixer: i) rivastigmine-hydrogentartrate is dissolved in ethanol, obtains rivastigmine-hydrogentartrate alcoholic solution; Ii) get the PVP K30 PVP K30 aqueous solution that is made into soluble in water; Iii) step I PVP K30 aqueous solution i) is inserted in ice-water bath, under ultrasonic condition, rivastigmine-hydrogentartrate alcoholic solution Uniform speed is added dropwise in PVP K30 aqueous solution, become muddy to solution system, leave standstill, filter, dry, pulverize and sieve.
7. preparation method according to claim 6, wherein, step I) in the concentration of rivastigmine-hydrogentartrate alcoholic solution be 0.01g/ml.
8. preparation method according to claim 6, wherein, the step I i) concentration of PVP K30 solution is 5%.
9. preparation method according to claim 6, wherein, step I ii) described in ultrasonic frequency be 0.4KW; The temperature of described ice-water bath is 0-5 ℃, and the speed that described Uniform speed drips is 1.5ml/min, described leaving standstill as leave standstill 6 hours at 0-5 ℃, described in sieve as crossing 80 mesh sieves.
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Application publication date: 20140625 |