CN103211787A - Glipizide film-controlled slow-release pellet capsule - Google Patents
Glipizide film-controlled slow-release pellet capsule Download PDFInfo
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- CN103211787A CN103211787A CN2012100143557A CN201210014355A CN103211787A CN 103211787 A CN103211787 A CN 103211787A CN 2012100143557 A CN2012100143557 A CN 2012100143557A CN 201210014355 A CN201210014355 A CN 201210014355A CN 103211787 A CN103211787 A CN 103211787A
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Abstract
The invention relates to a glipizide film-controlled slow-release pellet capsule. A slow-release film of the glipizide film-controlled slow-release pellet utilizes Eurdragit RL 30D as a film-formation material. A pellet core of the glipizide film-controlled slow-release pellet contains sodium carboxymethyl starch having high expansibility, and also contains pharmaceutically-acceptable common excipients for the slow-release pellet, wherein preferably, the excipients comprise microcrystalline cellulose, lactose and sodium dodecyl sulfate, and the pellet core comprises 5 to 20wt% of sodium carboxymethyl starch. The slow-release film comprises Eurdragit RL 30D, triethyl citrate as a plasticizer and talcum powder as an antiplastering aid, wherein preferably, a ratio of Eurdragit RL 30D to triethyl citrate to talcum powder is 30: 3: 4 and a film weight increasing ratio is in a range of 17 to 36%. The glipizide film-controlled slow-release pellet comprises the pellet core containing sodium carboxymethyl starch having high water expansibility and thus after absorbing water, the glipizide film-controlled slow-release pellet obviously 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 glipizide film-controlled 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 glipizide film-controlled slow-release pellet capsule, specifically, relate to the glipizide film-controlled slow-release pellet capsule that a kind of ball core contains carboxymethyl starch sodium, belong to field of pharmaceutical preparations.
Background technology
Glipizide is the sulfonylurea oral antidiabetic drug, can promote the beta Cell of islet excreting insulin, strengthen the effect of insulin to target tissue; Also can stimulate alpha Cell of islet that glucagon secretion is suppressed, still have the hepatic glycogen of inhibition to decompose, promote the effect of muscle utilization and consumption of glucose, be used for the treatment of type 2 diabetes mellitus.
Glipizide is almost insoluble in water, and Shang Shi ordinary preparation need be taken 3 times every day the earliest, and blood concentration fluctuation is big, and peak concentration is too high, and untoward reaction is serious.
Pfizer's glipizide osmotic pump controlled release tablet (trade name: Glipizide XL) of having gone on the market, can accomplish that zero level discharges, release is even, the semipermeable membrane that shortcoming is to use macromolecular material to form is easily aging, drug residue is big, therefore must feed intake by 115% at least, just can guarantee to imitate the release in the end of term, make the osmotic pumps technology be difficult to be used widely.
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.
Glipizide 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 30D, Eurdragit RS 30D, Eurdragit NE30D and Aquacoat Aquacoat and Surelease, yet we find: the glipizide 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 glipizide film controlling type slow-release micro-pill that solves aqueous dispersion coating preparation, the invention provides a kind of film controlling type Glipizide 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 carboxymethyl starch sodium 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 RL 30D for example, macromolecular material 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 plasticizer, antiplastering aid etc. mixes, 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 Glipizide sustained-release 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, often the later stage discharges obviously slack-off.
At above-mentioned mechanism, the inventor is surprised to find that by research: if the glipizide film controlling type slow-release micro-pill of aqueous dispersion coating adopts the ball core of the carboxymethyl starch sodium that contains high-expansion, because the carboxymethyl starch sodium imbibition is to 300% of original volume, 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 glipizide film-controlled slow-release micropill of aqueous dispersion coating so greatly.Because the high-expansion of carboxymethyl starch sodium 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, glipizide film-controlled slow-release pellet capsule of the present invention, the extended release coatings film of its micropill adopts Eurdragit RL 30D as filmogen, the carboxymethyl starch sodium that contains high-expansion in the ball core, and other pharmaceutically acceptable slow-release micro-pill excipient commonly used, the preferred filler microcrystalline Cellulose of described excipient, lactose and solubilizing agent sodium lauryl sulphate, wherein, to account for the percentage ratio of ball core weight be 5～20% to carboxymethyl starch sodium in the ball core.The extended release coatings film comprises Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci, and its ratio is preferably Eurdragit RL 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is preferably 17～36%.
As one of preferred implementation of the present invention, the micropill of glipizide 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 17～36%.
The present invention provides a kind of method of improving the glipizide 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 RL 30D as filmogen, the ball core contains the excipient that carboxymethyl starch sodium and other slow-release micro-pill are used, the preferred filler microcrystalline Cellulose of described excipient, lactose and solubilizing agent sodium lauryl sulphate, wherein the percentage ratio that carboxymethyl starch sodium accounts for ball core weight in the ball core is 5～20%, the extended release coatings film comprises aqueous dispersion Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci, weight ratio is Eurdragit RL 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is 17～36%.Said method preferred is by 1000 capsules, and micropill adopts following prescription:
One, ball core prescription
Two, extended release coatings film prescription
The weightening finish of extended release coatings film coating is 17～36%.
The preparation method of film controlling type Glipizide sustained-release 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 glipizide film-controlled slow-release pellet capsule.
Film controlling type Glipizide 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 RL 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 carboxymethyl starch sodium 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 carboxymethyl starch sodium, 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 Glipizide 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, No. 0 stomach dissolution type gelatine capsule shell is 1000.
Two, preparation technology:
1, ball core preparation technology:
(1) glipizide is crossed 80 mesh sieves;
(2) take by weighing glipizide, microcrystalline Cellulose PH101, lactose, the sodium lauryl sulphate of recipe quantity, put mix homogeneously in the wet granulator;
(3) with 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 of recipe quantity, stirs, and adds the Pulvis Talci of recipe quantity again, stirs and shears evenly, adds Eurdragit RL 30 D at last and mixes evenly, 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 12.8%.
4, heat treatment:
With the micropill of wrapping extended release coatings in fluid bed, heat treatment under 40 ℃/2h condition.
5, filled capsules:
Coated micropill is filled promptly on capsule filling machine.
Three, release, assay and result
Release is got this product, according to drug release determination method (Chinese Pharmacopoeia version appendix in 2005 X D first method), adopting dissolution method second subtraction unit (Chinese Pharmacopoeia version appendix in 2005 X C), capsule is put in the sedimentation basket, is solvent with the phosphate buffer 900ml of pH6.8, rotating speed is that per minute 50 changes, operation in the time of 4,8 and 16 hours, is got solution 10ml respectively in accordance with the law, filter, and instant release medium of in process container, replenishing uniform temp, equal volume; Get subsequent filtrate,, measure trap respectively at the wavelength place of 276nm according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A); Other gets the about 50mg of glipizide reference substance, the accurate title, decide, and puts in the 100ml measuring bottle, adds methanol 20ml supersound process, make dissolving, be diluted to scale with methanol, shake up, as stock solution, phosphate buffer with pH6.8 is a solvent, by following dilution process, get a certain amount of stock solution and add proper amount of solvent, be diluted to certain density glipizide reference substance solution:
| Reference substance solution | Dilution process | Glipizide concentration (μ g/ml) |
| 1# | Get stock solution 1ml solubilizer to 200ml | 2.5 |
| 2# | Get stock solution 1ml solubilizer to 100ml | 5.0 |
| 3# | Get stock solution 3ml solubilizer to 100ml | 15.0 |
| 4# | Get reference substance solution 1#25ml solubilizer to 50ml | 1.25 |
| 5# | Get reference substance solution 3#25ml solubilizer to 50ml | 7.5 |
| 6# | Get reference substance solution 4#25ml solubilizer to 50ml | 0.625 |
Get above-mentioned reference substance solution respectively and measure trap, the drawing standard curve with method.Calculate the burst size of every capsules according to standard curve at different time.The every capsules of this product should be respectively 4,8,16 hours burst size and be not more than more than 30%, 30～70% and 85% of labelled amount, all should be up to specification.
Average rate of release is got this product, according to assay method test under the release item, got solution 10ml respectively and operate (carrying out simultaneously with the release inspection) in accordance with the law in the time of 4,8 and 12 hours, calculates the average rate of release of every capsules in different time respectively.The every capsules of this product is in 4～8 hours and 8～12 hours, and per hour average rate of release is equivalent to 7～12% of labelled amount, all should be up to specification.
Other should meet every regulation relevant under the capsule item (two appendix I of Chinese Pharmacopoeia version in 2005 A).
[assay] measured according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D).
The test of chromatographic condition and system suitability is a filler with octadecylsilane chemically bonded silica, and (with sodium hydroxide adjusting pH value to 6.00 ± 0.05 of 2mol/L)-methanol (55: 45) is mobile phase with the sodium dihydrogen phosphate of 0.1mol/L: the detection wavelength is 225nm.Get glipizide reference substance and 4-[2-(5-methylpyrazine-2-formamido) ethyl] benzsulfamide (impurity I) reference substance, add dissolve with methanol and dilution and make the mixed solution of each 0.5mg and 2.5 μ g among every 1ml, get 20 μ l and inject chromatograph of liquid, number of theoretical plate calculates by the glipizide peak and is not less than 2000, and the separating degree at glipizide peak and impurity I peak should meet the requirements.
Algoscopy is got 5 of this product, incline and content, the accurate title, decide, and fully grinds, and quantitatively is transferred in 100ml (5mg specification) or 200ml (10mg specification) measuring bottle with methanol, make dissolving with methanol is ultrasonic, be diluted to scale with the 0.1mol/L sodium dihydrogen phosphate, shake up, centrifugal back filters, precision is measured subsequent filtrate 10ml and is diluted to 50ml with the 0.1mol/L sodium dihydrogen phosphate, as need testing solution; Other gets glipizide reference substance 20mg, and accurate the title decides, and puts in the 200ml measuring bottle, add methanol 100ml and make dissolving, be diluted to scale, shake up with the 0.1mol/L sodium dihydrogen phosphate, precision is measured 25ml and is diluted to 50ml with the 0.1mol/L sodium dihydrogen phosphate, in contrast product solution.Precision is measured each 20 μ l injection chromatograph of liquid of above-mentioned two kinds of solution respectively, and the record chromatogram is pressed external standard method with calculated by peak area, promptly.Result such as table 1:
Table 1 embodiment 1 discharges the result
The result shows that embodiment 1 ball core does not contain the Glipizide sustained-release 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 4h, 8h, 16h 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 Glipizide sustained-release pellet capsule of high-expansion 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 Glipizide sustained-release pellet capsule of 5% carboxymethyl starch sodium
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) glipizide is crossed 60 mesh sieves;
(2) take by weighing glipizide, microcrystalline Cellulose PH101, lactose, carboxymethyl starch sodium, the sodium lauryl sulphate of recipe quantity, put mix homogeneously in the wet granulator;
(3) with 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 17.2%.
4, heat treatment: with embodiment 1
5, 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 the result
The result shows, the ball core of embodiment 2 contains that the Glipizide sustained-release pellet capsule initial release performance of high-expansion material carboxymethyl starch sodium 5% 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 Glipizide sustained-release pellet capsule of high-expansion material carboxymethyl starch sodium 5%, 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 Glipizide sustained-release pellet capsule of 10% carboxymethyl starch sodium
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 22.1%, 26.8%.
4, heat treatment: with embodiment 1
5, 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 the result
The result shows, the ball core contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 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, 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 Glipizide sustained-release pellet capsule of carboxymethyl starch sodium 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 4 contains the Glipizide sustained-release pellet capsule of 15% carboxymethyl starch sodium
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 30.9%.
4, heat treatment: with embodiment 1.
5, 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 the result
The result shows, the ball core contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 15% 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 Glipizide sustained-release pellet capsule of carboxymethyl starch sodium 15%, 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 5 contains the Glipizide sustained-release pellet capsule of 20% carboxymethyl starch sodium
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 33.8%.
4, heat treatment: with embodiment 1.
5, 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 the result
The result shows, the ball core contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 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 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 Glipizide sustained-release pellet capsule of carboxymethyl starch sodium 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.
The Glipizide sustained-release pellet capsule (10mg specification) of embodiment 6 common ball cores
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 1.
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 14.1%.
4, heat treatment: with embodiment 1.
5, filled capsules: with embodiment 1.
Three, release, assay and result
Method: with embodiment 1, result such as table 11:
Table 11 embodiment 6 discharges the result
The result shows that embodiment 6 ball cores do not contain the Glipizide sustained-release 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:, the results are shown in Table 12 with embodiment 1:
Expansion rate result after the long-term placement of table 12 room temperature
Experimental result shows that the ball core does not contain the Glipizide sustained-release 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 7 contains the Glipizide sustained-release pellet capsule of 5% carboxymethyl starch sodium
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 19.4%.
4, heat treatment: with embodiment 1.
5, filled capsules: with embodiment 1.
Three, release, assay and result
Assay method:, the results are shown in Table 13 with embodiment 1:
Table 13 embodiment 7 discharges the result
The result shows, the ball core of embodiment 7 contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 5% 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 14 with embodiment 1:
Expansion rate result after the long-term placement of table 14 room temperature
Experimental result shows that the ball core contains the Glipizide sustained-release pellet capsule of intumescent material carboxymethyl starch sodium 5%, 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 8 contains the Glipizide sustained-release pellet capsule of 10% carboxymethyl starch sodium
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 24.8%, 28.9%.
4, heat treatment: with embodiment 1.
5, filled capsules: with embodiment 1.
Three, release, assay and result
Assay method:, the results are shown in Table 15 with embodiment 1:
Table 15 embodiment 8 discharges the result
The result shows, the ball core contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 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, expansion rate experiment
Experimental technique:, the results are shown in Table 16 with embodiment 1:
Expansion rate result after the long-term placement of table 16 room temperature
Experimental result shows that the ball core contains the Glipizide sustained-release pellet capsule of carboxymethyl starch sodium 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 9 contains the Glipizide sustained-release pellet capsule of 15% carboxymethyl starch sodium
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 32.3%.
4, heat treatment: with embodiment 1.
5, filled capsules: with embodiment 1.
Three, release, assay and result
Assay method:, the results are shown in Table 17 with embodiment 1:
Table 17 embodiment 9 discharges the result
The result shows, the ball core contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 15% 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 18 with embodiment 1:
Expansion rate after the long-term placement of table 18 room temperature
The result shows that the ball core contains the Glipizide sustained-release pellet capsule of carboxymethyl starch sodium 15%, 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 10 contains the Glipizide sustained-release pellet capsule of 20% carboxymethyl starch sodium
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 36.0%.
4, heat treatment: with embodiment 1.
5, filled capsules: with embodiment 1.
Three, release, assay and result
Assay method:, the results are shown in Table 19 with embodiment 1:
Table 19 embodiment 10 discharges the result
The result shows, the ball core contains that the Glipizide sustained-release pellet capsule initial release performance of carboxymethyl starch sodium 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 20 with embodiment 1:
Expansion rate after the long-term placement of table 20 room temperature
The result shows that the ball core contains the Glipizide sustained-release pellet capsule of carboxymethyl starch sodium 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.
Claims (10)
1. glipizide film-controlled slow-release pellet capsule is characterized in that the extended release coatings film of micropill adopts Eurdragit RL 30D as filmogen, and the ball core contains the excipient that carboxymethyl starch sodium and other pharmaceutically acceptable slow-release micro-pill are used.
2. glipizide film-controlled slow-release pellet capsule according to claim 1, feature is that the excipient that described other pharmaceutically acceptable slow-release micro-pill are used comprises filler microcrystalline Cellulose, lactose and solubilizing agent sodium lauryl sulphate.
3. glipizide film-controlled slow-release pellet capsule as claimed in claim 1 or 2 is characterized in that the percentage ratio that carboxymethyl starch sodium in the ball core of micropill accounts for ball core weight is 5～20%.
4. as glipizide 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 Eurdragit RL30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci.
5. as glipizide film-controlled slow-release pellet capsule as described in the claim 4, the composition weight ratio that it is characterized in that the extended release coatings film of micropill is Eurdragit RL 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is 17～36%.
6. glipizide 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 17～36%.
7. method of improving the glipizide 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 RL 30D as filmogen, and the ball core of micropill contains the excipient that carboxymethyl starch sodium and other pharmaceutically acceptable slow-release micro-pill are used.
8. as method as described in the claim 7, it is characterized in that the excipient that described other pharmaceutically acceptable slow-release micro-pill are used is filler microcrystalline Cellulose, lactose and solubilizing agent sodium lauryl sulphate.
9. as method as described in claim 7 or 8, it is characterized in that the percentage ratio that carboxymethyl starch sodium in the ball core of micropill accounts for ball core weight is 5～20%, the extended release coatings film of micropill comprises Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid Pulvis Talci and weight ratio is Eurdragit RL 30D: triethyl citrate: Pulvis Talci=30: 3: 4, the coating weightening finish is 17～36%.
10. as method as described in the claim 9, it is characterized in that by 1000 capsules, described micropill adopts following prescription:
Ball core prescription:
Extended release coatings film prescription:
The weightening finish of extended release coatings film coating is 17～36%.
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| CN201210014355.7A CN103211787B (en) | 2012-01-18 | 2012-01-18 | Glipizide film-controlled slow-release micro pill capsule |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020236083A1 (en) * | 2019-05-22 | 2020-11-26 | Agency For Science, Technology And Research | Oral formulations, methods of manufacture and uses thereof |
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| US20030157166A1 (en) * | 2001-03-16 | 2003-08-21 | Chen Chih Ming | Controlled release sulfonylurea formulation |
| CN1600296A (en) * | 2003-09-22 | 2005-03-30 | 北京德众万全药物技术开发有限公司 | Method for preparing tiny pellets of difficult soluble drugs and formulation containing the pellets |
| CN101410091A (en) * | 2002-01-04 | 2009-04-15 | Ivax研究公司 | Drug delivery system for sustained delivery of glipizide |
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| US20030157166A1 (en) * | 2001-03-16 | 2003-08-21 | Chen Chih Ming | Controlled release sulfonylurea formulation |
| CN101410091A (en) * | 2002-01-04 | 2009-04-15 | Ivax研究公司 | Drug delivery system for sustained delivery of glipizide |
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| WO2020236083A1 (en) * | 2019-05-22 | 2020-11-26 | Agency For Science, Technology And Research | Oral formulations, methods of manufacture and uses thereof |
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