Summary of the invention
The problem that descends for the aging release that brings of film of the acipimox film controlling type slow-release micro-pill that solves aqueous dispersion coating preparation, the invention provides a kind of film controlling type slow-releasing acipimox pellet capsule that can remain stable release performance before the deadline, characteristics are to contain in the ball core of micropill has the low-substituted hydroxypropyl cellulose of meeting the water high-expansion, make sustained release coating film generation deformation by imbibition, thereby offset the aging of film.
Film controlling type delays controlled release micro pill aqueous dispersion build coating material commonly used at present, Eurdragit NE 30D for example, macromolecular material wherein itself is also water insoluble, but be dispersed in the water with particulate form, with make the aqueous dispersion coating solution after the mixing such as plasticizer, antiplastering aid, be sprayed on the micropill surface through spray gun, this operation is called as coating; When coating had just begun, these aqueous dispersions on micropill surface existed with a large amount of discontinuous particle shapes, and along with coating solution sprays into increase, these granules are in contact with one another, are out of shape, condense, and last partial fusion mutually forms a discontinuous film; Heat-treat then, after the water volatilization, polymer beads then is connected with each other, merges fully the formation coating membrane.Heat treatment is very big to the release performance influence of the film-controlled slow-release micropill of aqueous dispersion coating: the words that heat treatment is not enough, for example the time is too short or temperature is low excessively, the water that also contains trace in the coatings between the polymer beads, it can continue to evaporate in follow-up storage period, continue combination between the granule, film becomes and compacts more, and permeability decline causes discharging slack-off; For fear of this situation, usually adopt the method that increases heat treatment intensity to overcome, for example increase heat treatment time or improve heat treatment temperature, but this processing is easy to cause heat treatment excessive, causes film too dry and compact, and is qualified even the initial stage discharges, yet it is in follow-up storage period, the film meeting of compacting originally is slacken owing to the creep of suction and film forming macromolecular material from environment, and permeability rises, and causes discharging accelerating.Practice shows, for film controlling type slow-releasing acipimox micropill, because drug release is fully by diffusion, thereby descend very responsive to the aging permeability that causes of film, accomplish that by Technology for Heating Processing just right to guarantee to remain before the deadline stable release performance be very difficult, in most cases heat treated temperature and time is not enough, and often the later stage discharges obviously slack-off.
At above-mentioned mechanism, the inventor is surprised to find that by research: if the acipimox film controlling type slow-release micro-pill of aqueous dispersion coating adopts the ball core of the low-substituted hydroxypropyl cellulose that contains high-expansion, because the low-substituted hydroxypropyl cellulose expansion rate of water absorption is up to 500%~700%, can obviously expand behind the ball wicking absorbent, make the micropill volume become big, cause release membranes to be stretched, the thickness attenuation, it is big that the aperture of permeable micropore becomes, permeability improves, can compensate the heat treatment deficiency and cause the aging permeability that is produced of film to descend, thereby make middle and late stage rate of release substantially constant, latter stage is residual little.Can eliminate the excessive influence that causes film too to compact of heat treatment in addition, avoid the change of the lax release performance that brings of day caudacoria, thereby make interior drug releasing rate substantially constant of whole effect duration.Can improve the ageing resistace of the acipimox film-controlled slow-release micropill of aqueous dispersion coating so greatly.Because the high-expansion of low-substituted hydroxypropyl cellulose in the ball core, expansive force is very big, along with increase standing time, expansion rate after the micropill suction is constant substantially, can irreversible plastic deformation take place the back so that release membranes is stretched, no matter how film changes (become loose or become and compact) all can be supportted the big similar degree that arrives, thereby the permeability that guarantees film is constant substantially.
As preferably, acipimox film-controlled slow-release pellet capsule of the present invention, the extended release coatings film of its micropill adopts Eurdragit NE30D as filmogen, the low-substituted hydroxypropyl cellulose that contains high-expansion in the ball core, and pharmaceutically acceptable slow-release micro-pill excipient commonly used, excipient preferably microcrystalline cellulose and lactose, wherein, to account for the percentage ratio of ball core weight be 10~40% to low-substituted hydroxypropyl cellulose in the ball core.The extended release coatings film comprises Eurdragit NE 30D and antiplastering aid Pulvis Talci, and its ratio is preferably Eurdragit NE 30D: triethyl citrate: Pulvis Talci=30: 2: 4, the coating weightening finish is preferably 20~39%.
As one of preferred implementation of the present invention, the micropill of acipimox film-controlled slow-release pellet capsule of the present invention prescription is as follows:
One, ball core prescription (1000 meters)
Two, extended release coatings film prescription
Preferred extended release coatings film coating weightening finish is 20~39%.
The present invention provides a kind of method of improving the acipimox film-controlled slow-release pellet capsule ageing resistace of aqueous dispersion coating simultaneously, the extended release coatings film that it is characterized in that micropill adopts aqueous dispersion Eurdragit NE 30D as filmogen, the ball core contains low-substituted hydroxypropyl cellulose and slow-release micro-pill excipient commonly used, excipient preferably microcrystalline cellulose and lactose.Wherein the percentage ratio that low-substituted hydroxypropyl cellulose accounts for ball core weight in the ball core is 10~40%, the extended release coatings film comprises aqueous dispersion Eurdragit NE 30D and antiplastering aid Pulvis Talci, weight ratio is Eurdragit NE 30D: triethyl citrate: Pulvis Talci=30: 2: 4, the coating weightening finish is 20~39%.Said method preferred is by 1000 capsules, and micropill adopts following prescription:
One, ball core prescription (1000 meters)
Two, extended release coatings film prescription
Preferred extended release coatings film coating weightening finish is 20~39%.
The preparation method of film controlling type slow-releasing acipimox micropill of the present invention can prepare according to the general technology of the slow controlled release micro pill of film controlling type in the prior art, comprises batch mixing, pill core, the slow clothing film of bag etc., and preferred employing is extruded spheronization and prepared the ball core.With the slow-release micro-pill that the makes common stomach dissolution type gelatine capsule of packing into, promptly obtain acipimox film-controlled slow-release pellet capsule.
Film controlling type slow-releasing acipimox pellet capsule of the present invention has following advantage:
1) antagonism extended release coatings film is aging: the extended release coatings film of forming with aqueous dispersion Eurdragit NE 30D+ triethyl citrate+Pulvis Talci can wear out, reason is that the aqueous dispersion microgranule is in conjunction with promoting film aging, cause membrane permeability to reduce, and contain ball core with the low-substituted hydroxypropyl cellulose of meeting the water high-expansion, can obviously expand after the suction, cause the extended release coatings film to be stretched, the thickness attenuation, it is big that the aperture of permeable micropore becomes, permeability improves, and has compensated the aging permeability that produces of film and has descended, thereby made middle and late stage rate of release substantially constant, latter stage is residual little, can remain stable release performance before the deadline.
2) supporting role: use the ball core of low-substituted hydroxypropyl cellulose, can obviously expand after the suction and play a supporting role, avoid in the gastrointestinal tract operation process in vivo being subjected to the gastrointestinal extruding and prominent the releasing of medicine that cause with water swelling.
Specific embodiment
The slow-releasing acipimox pellet capsule of embodiment 1 common ball core
One, prescription
1, ball core prescription (1000)
2, extended release coatings film coating fluid prescription
3, No. 0 stomach dissolution type gelatine capsule shell is 1000
Two, preparation technology:
1, ball core preparation technology:
(1) acipimox is crossed 60 mesh sieves;
(2) take by weighing acipimox, microcrystalline Cellulose PH101, the lactose of recipe quantity, put mix homogeneously in the wet granulator;
(3) 1% sodium carboxymethyl cellulose 10% alcoholic solution system soft material;
(4) put on the extruder and extrude, mesh size is 1.0mm, and extruded velocity is 20~30rpm;
(5) round as a ball, round as a ball speed is 900~1000rpm, dries in the fluid bed;
(6) sieve, get the ball core between 16~30 orders.
2, extended release coatings film coating solution preparation technology:
The triethyl citrate that takes by weighing recipe quantity is put in the water of recipe quantity, stirs, and adds the Pulvis Talci of recipe quantity again, stirs and shears evenly, adds Eurdragit NE 30D at last, stirs, promptly.
3, coating (extended release coatings film):
The ball core is placed the fluid bed coating, the weightening finish of control clothing film, the coating weightening finish is 14.8%.
4, heat treatment:
With the micropill of wrapping extended release coatings in fluid bed, heat treatment under 40 ℃/2h condition.
5, filled capsules
With the coated micropill filling capsule promptly.
Three, release, assay and result
Assay is measured according to high effective liquid chromatography for measuring (two appendix V of Chinese Pharmacopoeia version in 2005 D).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Methanol-0.01mol/L tetrabutylammonium (20: 80) (regulating pH value to 6.0 with phosphoric acid) is mobile phase, the detection wavelength is 264nm, theoretical cam curve is calculated by the acipimox peak should be not less than 2000, and the separating degree of acipimox peak and adjacent impurity peaks should be up to specification.
Algoscopy is got 10 of this product, and inclining content, and content decided in accurate title, porphyrize, precision take by weighing fine powder an amount of (containing acipimox 20mg approximately), put in the 100ml measuring bottle, it is an amount of to add mobile phase, the ultrasonic principal agent that makes dissolves, and standardize solution filters, precision is measured subsequent filtrate 5ml, put in the 50ml measuring bottle, be diluted to scale, as need testing solution with mobile phase, it is an amount of that precision takes by weighing the acipimox reference substance in addition, add mobile phase and be made into the solution that 1ml contains acipimox 20 μ g approximately, product solution in contrast, precision is measured need testing solution and each 20 μ 1 of reference substance solution, inject chromatograph of liquid, the record chromatogram is pressed external standard method with calculated by peak area content, promptly.
Release is got this product, according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2005), adopt dissolution method (two appendix X of Chinese Pharmacopoeia version in 2005 C, first method) device, hydrochloric acid solution 1000ml with 0.1mol/L is a solvent, Revolution Per Minute 100 changes, operation in accordance with the law, through 1 hour, 3 hours, 10ml took a sample respectively in the time of 5 hours, filter, and the timely dissolution medium 10ml that in process container, replenishes uniform temp, precision is measured subsequent filtrate 5ml, puts in the 100ml measuring bottle, hydrochloric acid solution with 0.1mol/L is diluted to scale, as need testing solution; Other precision takes by weighing through 105 ℃ of acipimox reference substances that are dried to constant weight an amount of, and the hydrochloric acid solution that adds 0.1mol/L is made the solution that contains 7.5 μ g among every 1ml, in contrast product solution.Get need testing solution and reference substance solution respectively,, measure trap respectively, calculate every burst size at different time at the wavelength place of 269nm according to ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2005).Every of this product burst size when the 1st hour, 3 hours and 5 hours should be respectively more than 15~35%, 60~85% and 80% of labelled amount, all should be up to specification.
Result such as table 1:
Table 1 embodiment 1 discharges the result
The result shows that embodiment 1 ball core does not contain the slow-releasing acipimox pellet capsule of intumescent material, and initial release is good, and along with increase standing time, film is constantly aging, and rate of release is slack-off, residual obvious increase.
Four, expansion rate is measured
Assay method: it is an amount of to add the distilled water be preheated to 37 ℃ in the 100ml measuring bottle, is dipped in 37 ℃ of water-baths and standby behind the scale with the distilled water standardize solution; Get 3 500ml beakers, add 300ml respectively and be preheated to 37 ℃ distilled water, be immersed in 37 ℃ of water-baths standby; Get 10 of capsules to be measured, remove capsule shells, micropill in the capsule is inclined to, put in the above-mentioned 100ml measuring bottle, be that distilled water falls after rise to the measuring bottle scale until liquid level in the pipette, extract measuring bottle of 0.01ml rapidly with minimum scale value, accurately read the volume of water in the pipet then, calculate the average external volume of micropill in every capsules, be designated as V
0Get 30 capsules to be measured, be divided into 3 groups, every group 10, remove capsule shells, micropill in the capsule is inclined to, put respectively in above-mentioned 3 500ml beakers and soak, respectively take out 1 group at 1h, 3h, 5h respectively, filter, blot the remaining water in micropill surface, it is put again in the measuring bottle of the above-mentioned 100ml that standardize solution crosses with filter paper, fall after rise to the measuring bottle scale until liquid level with distilled water in the above-mentioned pipette, extract measuring bottle rapidly, accurately read the volume of water in the pipet then, calculate the average external volume of micropill in every capsules, be designated as V
TBe calculated as follows the expansion rate of each sampling time point, the results are shown in Table 2.
Computing formula: expansion rate (%)=(V
T-V
0)/V
0* 100%
Expansion rate result after the long-term placement of table 2 room temperature
Experimental result shows that the ball core does not contain the slow-releasing acipimox pellet capsule of intumescent material, and the micropill expansion rate is less, and along with room temperature is placed for a long time, expansion rate reduces thereupon, does not offset the aged effect of extended release coatings film.
Embodiment 2 contains the slow-releasing acipimox pellet capsule of 10% low-substituted hydroxypropyl cellulose
One, prescription
1, ball core prescription (1000)
2, extended release coatings film coating fluid prescription: with embodiment 1.
3, No. 0 stomach dissolution type gelatine capsule shell is 1000.
Two, preparation technology:
1, ball core preparation technology:
(1) acipimox is crossed 60 mesh sieves;
(2) take by weighing acipimox, microcrystalline Cellulose PH101, lactose, the low-substituted hydroxypropyl cellulose of recipe quantity, put mix homogeneously in the wet granulator;
(3) 1% sodium carboxymethyl cellulose 10% alcoholic solution system soft material;
(4) put on the extruder and extrude, mesh size is 1.0mm, and extruded velocity is 20~30rpm;
(5) round as a ball, round as a ball speed is 900~1000rpm, dries in the fluid bed;
(6) sieve, get the ball core between 16~30 orders.
2, extended release coatings film coating solution preparation technology: with embodiment 1
3, coating (extended release coatings film):
The ball core is placed the fluid bed coating, the weightening finish of control clothing film, the coating weightening finish is 20.1%.
4, heat treatment: with embodiment 1.
5, filled capsules: promptly with the coated micropill filling capsule.
Three, release, assay and result
Assay method:, the results are shown in Table 3 with embodiment 1:
Table 3 embodiment 2 discharges the result
The result shows, the ball core of embodiment 2 contains that the slow-releasing acipimox pellet capsule initial release performance of low-substituted hydroxypropyl cellulose 10% is all good, and along with increase standing time, releasing effect is still fine, and the end point discharges residual all very little.
Four, swelling rate test
Experimental technique:, the results are shown in Table 4 with embodiment 1:
Expansion rate result after the long-term placement of table 4 room temperature
The result shows that the ball core contains the slow-releasing acipimox pellet capsule of intumescent material low-substituted hydroxypropyl cellulose 10%, and the micropill expansion rate is bigger, and room temperature is long-term places down, and expansion rate remains unchanged, and has offset the aging of extended release coatings film.
Embodiment 3 contains the slow-releasing acipimox pellet capsule of 20% low-substituted hydroxypropyl cellulose
One, prescription
1, ball core prescription (1000)
2, extended release coatings film coating fluid prescription: with embodiment 1
3, No. 0 stomach dissolution type gelatine capsule shell is 1000
Two, preparation technology:
1, ball core preparation technology: with embodiment 2.
2, extended release coatings film coating solution preparation technology: with embodiment 1.
3, coating (extended release coatings film):
The ball core is placed the fluid bed coating, the weightening finish of control clothing film, the coating weightening finish is 26.2%, 31.6%.
4, heat treatment: with embodiment 1.
5, filled capsules: promptly with the coated micropill filling capsule.
Three, release, assay and result
Assay method:, the results are shown in Table 5 with embodiment 1:
Table 5 embodiment 3 discharges the result
The result shows, the ball core contains that the slow-releasing acipimox pellet capsule initial release performance of low-substituted hydroxypropyl cellulose 20% is all good, and along with increase standing time, releasing effect is still fine, and the end point discharges residual all very little.
Four, expansion rate experiment
Experimental technique:, the results are shown in Table 6 with embodiment 1:
Expansion rate result after the long-term placement of table 6 room temperature
The result shows that the ball core contains the slow-releasing acipimox pellet capsule of low-substituted hydroxypropyl cellulose 20%, and the micropill expansion rate is bigger, and room temperature is long-term places down, and expansion rate remains unchanged, and has offset the aging of extended release coatings film.
Embodiment 4 contains the slow-releasing acipimox pellet capsule of 30% low-substituted hydroxypropyl cellulose
One, prescription
1. ball core prescription (1000)
2. extended release coatings film coating fluid prescription: with embodiment 1.
3.0 1000 of number stomach dissolution type gelatine capsule shell.
Two, preparation technology
1, ball core preparation technology: with embodiment 2.
2, extended release coatings film coating solution preparation technology: with embodiment 1.
3, coating (extended release coatings film):
The ball core is placed the fluid bed coating, the weightening finish of control clothing film, the coating weightening finish is 35.8%.
4, heat treatment: with embodiment 1.
5, filled capsules: promptly with the coated micropill filling capsule.
Three, release, assay and result
Assay method:, the results are shown in Table 7 with embodiment 1:
Table 7 embodiment 4 discharges the result
The result shows, the ball core contains that the slow-releasing acipimox pellet capsule initial release performance of low-substituted hydroxypropyl cellulose 30% is all good, and along with increase standing time, releasing effect is still fine, and the end point discharges residual all very little.
Four, expansion rate experiment
Experimental technique:, the results are shown in Table 8 with embodiment 1:
Expansion rate after the long-term placement of table 8 room temperature
The result shows that the ball core contains the slow-releasing acipimox capsule of low-substituted hydroxypropyl cellulose 30%, and expansion rate is bigger, and room temperature is long-term places down, and expansion rate remains unchanged, and has offset the aging of extended release coatings film.
Embodiment 5 contains the slow-releasing acipimox pellet capsule of 40% low-substituted hydroxypropyl cellulose
One, prescription
1. ball core prescription (1000)
2. extended release coatings film coating fluid prescription: with embodiment 1.
3.0 1000 of number stomach dissolution type gelatine capsule shell.
Two, preparation technology
1, ball core preparation technology: with embodiment 2.
2, extended release coatings film coating solution preparation technology: with embodiment 1.
3, coating (extended release coatings film):
The ball core is placed the fluid bed coating, the weightening finish of control clothing film, the coating weightening finish is 38.7%.
4, heat treatment: with embodiment 1.
5, filled capsules: promptly with the coated micropill filling capsule.
Three, release, assay and result
Assay method:, the results are shown in Table 9 with embodiment 1:
Table 9 embodiment 5 discharges the result
The result shows, the ball core contains that the slow-releasing acipimox pellet capsule initial release performance of low-substituted hydroxypropyl cellulose 40% is all good, and along with increase standing time, releasing effect is still fine, and the end point discharges residual all very little.
Four, expansion rate experiment
Experimental technique:, the results are shown in Table 10 with embodiment 1:
Expansion rate after the long-term placement of table 10 room temperature
The result shows that the ball core contains the slow-releasing acipimox pellet capsule of low-substituted hydroxypropyl cellulose 40%, and the micropill expansion rate is bigger, and room temperature is long-term places down, and expansion rate remains unchanged, and has offset the aging of extended release coatings film.