CN103211786A - Choline fenofibrate film-controlled enteric slow-release pellet capsule - Google Patents
Choline fenofibrate film-controlled enteric slow-release pellet capsule Download PDFInfo
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- CN103211786A CN103211786A CN2012100143542A CN201210014354A CN103211786A CN 103211786 A CN103211786 A CN 103211786A CN 2012100143542 A CN2012100143542 A CN 2012100143542A CN 201210014354 A CN201210014354 A CN 201210014354A CN 103211786 A CN103211786 A CN 103211786A
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Abstract
The invention relates to a choline fenofibrate film-controlled enteric slow-release pellet capsule. A slow-release film of the choline fenofibrate film-controlled enteric slow-release pellet utilizes Eurdragit RS 30D as a film-formation material. A pellet core of the choline fenofibrate film-controlled enteric slow-release pellet contains low-substituted hydroxypropyl cellulose having high expansibility, and also contains a pharmaceutically acceptable common excipient for the slow-release pellet, wherein preferably, the excipient comprises microcrystalline cellulose, and the pellet core comprises 10 to 40wt% of the low-substituted hydroxypropyl cellulose. The slow-release film comprises Eurdragit RS 30D, triethyl citrate as a plasticizer and talcum powder as an antiplastering aid, wherein preferably, a ratio of urdragit RS 30D to triethyl citrate to talcum powder is 30: 3: 4 and a film weight increasing ratio is in a range of 20 to 38%. The choline fenofibrate film-controlled enteric slow-release pellet comprises the pellet core containing low-substituted hydroxypropyl cellulose having high water expansibility and thus after absorbing water, the choline fenofibrate film-controlled enteric slow-release pellet expands so that the slow-release film is stretched; the thickness of the slow-release film is reduced; the water-permeable micropore size is increased; and permeability is improved and the permeability reduction caused by film aging is counteracted. Therefore, in middle and later stages, the choline fenofibrate film-controlled enteric slow-release pellet release rate is basically constant; in the last stage, residues are less; and stable release performances can be kept in the period of validity.
Description
Technical field
The present invention relates to a kind of choline fenofibrate film control enteric sustained-release pellet capsule, specifically, relate to the choline fenofibrate film control enteric sustained-release pellet capsule that a kind of ball core contains low-substituted hydroxypropyl cellulose, belong to field of pharmaceutical preparations.
Background technology
The choline fenofibrate is a lipid lowerers, and by peroxide activator enzyme paraphyte activated receptor alpha (PPAR-α), it is synthetic with minimizing apoC III to activate lipolytic enzyme, makes fat acid decomposition and obviously increase of triglyceride removing in the blood plasma, thereby brings into play effect for reducing fat.Share with statins, be used for the treatment of mixed dyslipidemia; Single medicine is used to treat serious hypertriglyceridemia etc.Clinical basic demand to this class medicine is can long-acting controlling symptoms.
The dissolubility of choline fenofibrate in water is fine, the choline fenofibrate capsule of Abbott's listing is a kind of enteric coated capsule, because the dissolubility of fenofibrate in gastric acid is low, dissolubility height under intestinal pH value condition, make the bioavailability that enteric coated preparation can improve fenofibrate, can also reduce the gastrointestinal stimulation, shortcoming is that onset is slow, peak reaching time of blood concentration is 4-5 hour, and 8 days blood drug level just can reach stable state after the administration.
Slow-release micro-pill is that medicine is made multiunit slow release medicine-releasing system, and it is oral generally to incapsulate the back, and after the capsule dissolves, slow-release micro-pill can be extensively, be evenly distributed in the gastrointestinal tract.Medicine increases at the distribution area on gastrointestinal surface, is guaranteeing that can also effectively reduce medicine when medicine evenly discharges stimulates gastrointestinal.The pellet particle diameter is less, and the transhipment unable to take food thing in gastrointestinal tract is carried the influence of the rhythm and pace of moving things, even when sphincter of pylorus is closed, still can pass through pylorus, so microgranule absorbs the influence that generally is not subjected to gastric emptying at gastrointestinal.What is more important, the drug release behavior of micropill system is a summation of forming each micropill drug release behavior of a dosage, error or the defective of indivedual micropills in preparation can not produce the drug release behavior of whole preparation and have a strong impact on, and therefore is being better than aspect the repeatability of release rule and the concordance by delaying of forming of a unit, controlled release tablet.
The choline fenofibrate is suitable for making sustained-release pellet preparation, and the effective blood drug concentration longer duration, blood concentration fluctuation is little, side effect is little, individual variation is little, patient's compliance is good.
The most frequently used implementation method of slow-release micro-pill is to adopt film controlling type, promptly wraps one deck extended release coatings film in the outside of ball core with the solution coating method, and the extended release coatings film contains filmogen, plasticizer, antiplastering aid etc.In one's early years coating solutions that adopt organic solvent to prepare the extended release coatings film more, because existing, pollutes and safety issue the organic solvent coating solution, in order to overcome the defective of organic solvent coating solution, the aqueous dispersion packaging technique is used widely, aqueous dispersion commonly used has Aquacoat, the crylic acid resin aqueous dispersion, polyvinyl acetate ester aqueous dispersion etc., polyvinyl acetate ester aqueous dispersion Kollicoat SR 30D for example, crylic acid resin aqueous dispersion Eurdragit RL/RS 30D, Eurdragit NE30D and Aquacoat Aquacoat and Surelease, yet we find: the choline fenofibrate film controlling type sustained-release micro-pill capsules that adopts the preparation of aqueous dispersion coating, in a period of time that has just prepared, its release performance is good, yet after storing a period of time, its release performance begins to descend, storage time is long more, it is obvious more to descend, often in latter half effect duration of medicine regulation, release performance obviously descends.The analysis reason is because coating membrane causes compacting gradually owing to the aqueous dispersion microgranule continues to interosculate in the process of placing, and causes membrane permeability to descend, and makes release slack-off, and popular saying is for aging.
Summary of the invention
The problem that descends for the aging release that brings of film of the choline fenofibrate film controlling type enteric sustained-release pellet that solves aqueous dispersion coating preparation, the invention provides a kind of film controlling type choline fenofibrate enteric sustained-release 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 RS 30D for example, macromolecule in the coating material 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 choline fenofibrate enteric sustained-release pellet, 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, often the later stage discharges obviously slack-off.
At above-mentioned mechanism, the inventor is surprised to find that by research: if the choline fenofibrate film controlling type enteric sustained-release pellet of 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 choline fenofibrate film control enteric sustained-release pellet of aqueous dispersion coating so greatly.Because the high-expansion of low-substituted hydroxypropyl cellulose in the ball core, expansive force is very big, even increase standing time, expansion rate after the micropill suction is also 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, choline fenofibrate film-controlled slow-release pellet capsule of the present invention, the extended release coatings film of its micropill adopts Eurdragit RS30D as filmogen, the low-substituted hydroxypropyl cellulose that contains high-expansion in the ball core of micropill, and the excipient used of other pharmaceutically acceptable slow-release micro-pill, described excipient preferably microcrystalline cellulose; To account for the percentage ratio of ball core weight be 10～40% to low-substituted hydroxypropyl cellulose in the ball core of micropill; The extended release coatings film comprises Eurdragit RS 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci, and its ratio is preferably Eurdragit RS 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is preferably 20～38%.The enteric coating film comprises polyacrylic resin II, stearic acid, triethyl citrate, Pulvis Talci, and weight ratio is polyacrylic resin II: stearic acid: triethyl citrate: Pulvis Talci=30: 1: 1: 2, and coating weightening finish 19～21%.
As one of preferred implementation of the present invention, the micropill of choline fenofibrate 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
The weightening finish of extended release coatings film coating is 20～38%.
Three, enteric coating film prescription
Enteric coating film weightening finish: 19～21%.
The present invention provides a kind of method of improving the choline fenofibrate 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 RS 30D as filmogen, the ball core of micropill contains low-substituted hydroxypropyl cellulose and other slow-release micro-pill excipient commonly used, described excipient preferably microcrystalline cellulose.To account for the percentage ratio of ball core weight be 10～40% to low-substituted hydroxypropyl cellulose in the ball core of micropill, the extended release coatings film of micropill comprises aqueous dispersion Eurdragit RS 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci, weight ratio is Eurdragit RS 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is 20～38%.The enteric coating film comprises polyacrylic resin II, stearic acid, triethyl citrate, Pulvis Talci, and weight ratio is polyacrylic resin II: stearic acid: triethyl citrate: Pulvis Talci=30: 1: 1: 2, and coating weightening finish 19～21%.Said method preferred is by 1000 capsules, adopts following prescription:
One, ball core prescription (1000 meters)
Two, extended release coatings film prescription
Preferred extended release coatings film coating weightening finish is 20～38%.
Four, enteric coating film prescription
Preferred enteric coating film weightening finish: 19～21%.
The preparation method of film controlling type choline fenofibrate enteric sustained-release pellet 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, comprise batch mixing, pill core, the slow clothing film of bag, enteric coated film etc., preferred employing is extruded spheronization and is prepared the ball core.With the enteric sustained-release pellet that the makes common stomach dissolution type gelatine capsule of packing into No. 0, promptly obtain choline fenofibrate film control enteric sustained-release pellet capsule.
Film controlling type choline fenofibrate enteric sustained-release 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 RS 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 choline fenofibrate enteric sustained-release pellet capsule of embodiment 1 common ball core
One, prescription
1, ball core prescription (1000)
2, extended release coatings film coating fluid prescription
3, enteric coating film coating fluid prescription
4, No. 0 stomach dissolution type gelatine capsule shell is 1000
Two, preparation technology:
1, ball core preparation technology:
(1) the choline fenofibrate is crossed 60 mesh sieves;
(2) take by weighing choline fenofibrate, the microcrystalline Cellulose PH101 of recipe quantity, put mix homogeneously in the wet granulator;
(3) 2% 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 in the recipe quantity, stirs, and adds the Pulvis Talci of recipe quantity again, stirs and shears evenly, adds Eurdragit RS 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 15.3%;
4, heat treatment:
With the micropill of wrapping extended release coatings in fluid bed, heat treatment under 40 ℃/2h condition;
5, the preparation of enteric coating:
Polyacrylic resin II is dissolved in 95% ethanol, adds stearic acid, triethyl citrate and Pulvis Talci again, stir and shear evenly, stir promptly;
6, enteric coated:
Place fluid bed enteric coated the heat-treatment micropill, weightening finish is to 19.4%;
7, filled capsules:
With the coated micropill filling capsule promptly.
Three, release, assay and result
[acid-resistant strength] gets this product, according to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2005, the second method method 1), adopt dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005) second subtraction unit, 500ml is a release medium with 0.05mol/L sodium phosphate buffer (pH3.5), and rotating speed is that per minute 50 changes, operation in accordance with the law, after 120 minutes, sampling 10ml filters, and replenishes the release medium of uniform temp, equal volume immediately.According to ultraviolet visible spectrophotometry, measure absorption value at the wavelength place of 298nm; It is an amount of that other gets choline fenofibrate reference substance, the accurate title, decide, add the also quantitative dilution of 0.05mol/L sodium phosphate buffer (pH3.5) dissolving and make the solution that contains fenofibrate acid 10 μ g among every 1ml approximately, measure with method, calculate every burst size, the burst size that this product is every must not be greater than 10%, should be up to specification.
[release] continues to add 0.05mol/L sodium phosphate buffer 400ml in the stripping rotor that contains acid release medium, be adjusted to pH6.8, operation in accordance with the law, 10ml took a sample respectively in the time of 2.5 hours, 3.5 hours, 6 hours, filter, and replenish the release medium of uniform temp, equal volume immediately, precision is measured subsequent filtrate 2ml and is put in 10ml (45mg) measuring bottle or precision is measured subsequent filtrate 1.5ml and put in 25ml (135mg) measuring bottle, adds release medium and is diluted to scale; It is an amount of that precision takes by weighing choline fenofibrate reference substance in addition, the accurate title, decide, add the also quantitative dilution of 0.05mol/L sodium phosphate buffer (pH6.8) dissolving and make the solution that contains fenofibrate acid 10 μ g among every 1ml approximately, measure, calculate every burst size at different time with method.Every burst size in the time of 2.5 hours, 3.5 hours, 6 hours of this product should be respectively below 30% of labelled amount, and 50～70% and greater than 80%.
[content] gets 20 of this product, takes out content, and accurate the title decides, porphyrize is got fine powder an amount of (being equivalent to fenofibrate acid 25mg approximately), puts in the 100ml measuring bottle, be dissolved in water and be diluted to scale, shake up, filter, precision is measured subsequent filtrate 1ml, put in the 25ml measuring bottle, thin up according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version appendix in 2005 IVA), is measured trap at the wavelength place of 298nm to scale; It is an amount of that in addition precision takes by weighing choline fenofibrate reference substance, accurately claims surely, is dissolved in water and dilutes and make the solution that contains fenofibrate acid 10 μ g among every 1ml approximately, measures with method, calculates promptly.
Result such as table 1:
Table 1 embodiment 1 discharges and content results
The result shows that the ball core of embodiment 1 does not contain the choline fenofibrate enteric sustained-release pellet capsule of high-expansion material, and initial release is good, at room temperature places, 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 solution 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 2.5h, 3.5h, 6h respectively, filter, blot the remaining solution 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 solution 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 choline fenofibrate enteric sustained-release pellet of high-expansion material, and expansion rate is very little, 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 choline fenofibrate enteric sustained-release 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, enteric coating film coating fluid prescription: with embodiment 1
4, No. 0 stomach dissolution type gelatine capsule shell is 1000
Two, preparation technology:
1, ball core preparation technology:
(1) the choline fenofibrate is crossed 60 mesh sieves;
(2) take by weighing choline fenofibrate, microcrystalline Cellulose PH101, the low-substituted hydroxypropyl cellulose of recipe quantity, put mix homogeneously in the wet granulator;
(3) 2% 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, the preparation of enteric coating: with embodiment 1
6, enteric coated:
Place fluid bed enteric coated the heat-treatment micropill, weightening finish is to 19.8%
7, filled capsules: with embodiment 1
Three, release, assay and result
Assay method:, the results are shown in Table 3 with embodiment 1
Table 3 embodiment 2 discharges and content results
The result shows that the ball core of embodiment 2 contains the choline fenofibrate enteric sustained-release pellet capsule of low-substituted hydroxypropyl cellulose 10%, and the initial release performance 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
Experimental result shows that the ball core contains the choline fenofibrate enteric sustained-release pellet of intumescent material low-substituted hydroxypropyl cellulose 10%, 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 3 contains the choline fenofibrate enteric sustained-release 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, enteric coating film coating fluid prescription: with embodiment 1
4, No. 0 stomach dissolution type gelatine capsule shell is 1000
Two, preparation technology:
1, ball core preparation technology:
(1) the choline fenofibrate is crossed 60 mesh sieves;
(2) take by weighing choline fenofibrate, microcrystalline Cellulose PH101, the low-substituted hydroxypropyl cellulose of recipe quantity, put mix homogeneously in the wet granulator;
(3) 2% 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 26.8%, 31.7%.
4, heat treatment: with embodiment 1
5, the preparation of enteric coating: with embodiment 1
6, enteric coated:
Place fluid bed enteric coated the heat-treatment micropill, weightening finish is to 20.4%
7, filled capsules: with embodiment 1
Three, release, assay and result
Assay method:, the results are shown in Table 5 with embodiment 1
Table 5 embodiment 3 discharges and content results
The result shows that the ball core contains the choline fenofibrate enteric sustained-release pellet capsule of low-substituted hydroxypropyl cellulose 20%, and the initial release performance 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
Experimental result shows that the ball core contains the choline fenofibrate enteric sustained-release pellet of intumescent material low-substituted hydroxypropyl cellulose 20%, 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 4 contains the choline fenofibrate enteric sustained-release 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. enteric coating film coating fluid prescription: with embodiment 1
4.0 1000 of number stomach dissolution type gelatine capsule shell
Two, preparation technology
1, ball core preparation technology:
(1) the choline fenofibrate is crossed 60 mesh sieves;
(2) take by weighing choline fenofibrate, microcrystalline Cellulose PH101, the low-substituted hydroxypropyl cellulose of recipe quantity, put mix homogeneously in the wet granulator;
(3) 2% 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 35.6%.
4, heat treatment: with embodiment 1
5, the preparation of enteric coating: with embodiment 1
6, enteric coated:
Place fluid bed enteric coated the heat-treatment micropill, weightening finish is to 20.9%
7, filled capsules: with embodiment 1
Three, release, assay and result
Assay method:, the results are shown in Table 7 with embodiment 1
Table 7 embodiment 4 discharges and content results
The result shows that the ball core contains the choline fenofibrate enteric sustained-release pellet capsule of low-substituted hydroxypropyl cellulose 30%, and the initial release performance 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 micropill contains the choline fenofibrate enteric sustained-release pellet 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 choline fenofibrate enteric sustained-release 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, enteric coating film coating fluid prescription: with embodiment 1
4, No. 0 stomach dissolution type gelatine capsule shell is 1000
Two, preparation technology
1, ball core preparation technology:
(1) the choline fenofibrate is crossed 60 mesh sieves;
(2) take by weighing choline fenofibrate, microcrystalline Cellulose PH101, the low-substituted hydroxypropyl cellulose of recipe quantity, put mix homogeneously in the wet granulator;
(3) 2% 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 37.5%.
4, heat treatment: with embodiment 1
5, the preparation of enteric coating: with embodiment 1
6, enteric coated:
Place fluid bed enteric coated the heat-treatment micropill, weightening finish is to 20.1%
7, filled capsules: with embodiment 1
Three, release, assay and result
Assay method:, the results are shown in Table 9 with embodiment 1
Table 9 embodiment 5 discharges and content results
The result shows that the ball core contains the choline fenofibrate enteric sustained-release pellet capsule of low-substituted hydroxypropyl cellulose 40%, and the initial release performance 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 choline fenofibrate enteric sustained-release pellet of low-substituted hydroxypropyl cellulose 40%, 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.
Claims (10)
1. a choline fenofibrate film-controlled slow-release pellet capsule is characterized in that the extended release coatings film of micropill adopts Eurdragit RS 30D as filmogen, and the ball core contains low-substituted hydroxypropyl cellulose and other pharmaceutically acceptable slow-release micro-pill excipient commonly used.
2. choline fenofibrate film-controlled slow-release pellet capsule according to claim 1, feature is that described pharmaceutically acceptable slow-release micro-pill excipient commonly used is a microcrystalline Cellulose.
3. choline fenofibrate film-controlled slow-release pellet capsule as claimed in claim 1 or 2 is characterized in that the percentage ratio that low-substituted hydroxypropyl cellulose in the ball core accounts for ball core weight is 10-40%.
4. as choline fenofibrate film-controlled slow-release pellet capsule as described in the claim 3, it is characterized in that the extended release coatings film of micropill comprises EurdragitRS 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci.
5. as choline fenofibrate film-controlled slow-release pellet capsule as described in the claim 4, it is characterized in that the extended release coatings film Eurdragit RS30D of micropill: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is preferably 20～38%.
6. choline fenofibrate film-controlled slow-release pellet capsule is characterized in that by 1000 capsules, described micropill has following prescription:
Ball core prescription:
Extended release coatings film prescription:
The weightening finish of extended release coatings film coating is 20～38%;
Enteric coating film prescription:
Enteric coating film weightening finish: 19～21%.
7. method of improving the choline fenofibrate film-controlled slow-release pellet capsule ageing resistace of aqueous dispersion coating, the extended release coatings film that it is characterized in that micropill adopts Eurdragit RS 30D as filmogen, and the ball core contains low-substituted hydroxypropyl cellulose and pharmaceutically acceptable slow-release micro-pill excipient commonly used.
8. as method as described in the claim 7, it is characterized in that described pharmaceutically acceptable slow-release micro-pill excipient commonly used is a microcrystalline Cellulose.
9. as method as described in claim 7 or 8, it is characterized in that the percentage ratio that low-substituted hydroxypropyl cellulose in the ball core accounts for ball core weight is 10-40%, the extended release coatings film comprises Eurdragit RS 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci and weight ratio is Eurdragit RS 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is 20～38%.
10. as method as described in the claim 9, it is characterized in that adopting following prescription by 1000 capsules:
Ball core prescription:
Extended release coatings film prescription:
The weightening finish of extended release coatings film coating is 20～38%;
Enteric coating film prescription:
Enteric coating film weightening finish: 19～21%.
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| CN104721148A (en) * | 2013-12-18 | 2015-06-24 | 江苏豪森药业股份有限公司 | Enteric-coated slow release pellet or particle solid preparation and production method thereof |
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