CN103211787B - Glipizide film-controlled slow-release micro pill capsule - Google Patents
Glipizide film-controlled slow-release micro pill capsule Download PDFInfo
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Abstract
The present invention relates to a kind of Glipizide film-controlled slow-release micro pill capsule, the sustained release clothing film of its micropill is using Eurdragit RL 30D as filmogen, sodium carboxymethyl starch containing high-expansion in capsule core, and the conventional excipient of other pharmaceutically acceptable sustained release pellets, preferably microcrystalline cellulose, lactose and lauryl sodium sulfate, wherein, the percentage that sodium carboxymethyl starch accounts for capsule core weight in capsule core is 5~20%.Sustained release clothing film includes Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid talcum powder, and its ratio is preferably Eurdragit RL 30D: triethyl citrate: talcum powder=30: 3: 4, coating weight gain is preferably 17~36%.Due to containing the capsule core with the sodium carboxymethyl starch for meeting water high-expansion, can substantially be expanded after water suction, sustained release clothing film is caused to be stretched, thickness is thinning, and the aperture of permeable micropore becomes big, and permeability improves, the permeability that compensate for the aging generation of film declines, so that middle and later periods rate of release substantially constant, latter stage residual is small, can before the deadline remain the release performance of stabilization.
Description
Technical field
The present invention relates to a kind of Glipizide film-controlled slow-release micro pill capsule, it particularly relates to a kind of capsule core contains carboxylic first
The Glipizide film-controlled slow-release micro pill capsule of base sodium starch, belongs to field of pharmaceutical preparations.
Background technology
Glipizide is sulfonylurea OHA, can promote islet β cell insulin, enhancing insulin to target
The effect of tissue；Also alpha Cell of islet can be stimulated makes glucagon secretion suppressed, still there is suppression hepatic glycogenolytic, promotes flesh
Meat utilizes the effect with consumption of glucose, for treating diabetes B.
Glipizide is almost insoluble in water, and the ordinary preparation of listing need to take 3 times, blood concentration fluctuation daily earliest
Greatly, Cmax is too high, and adverse reaction is serious.
Pfizer has listed glipizide osmotic pump controlled release tablet (trade name：Glipizide XL), Zero order release can be accomplished, release the drug
Uniformly, have the disadvantage that the pellicle for using macromolecular material to constitute is easily aging, medicament residue is big, it is therefore necessary at least thrown by 115%
Material, just can ensure that the drug release in the effect end of term so that osmotic pumps technology is difficult to be used widely.
Sustained release pellet is that medicine is made into multiunit slow-release system, general to load oral, capsule dissolving after capsule
Afterwards, sustained release pellet can extensively, be evenly distributed in intestines and stomach.Distribution area of the medicine on stomach and intestine surface increases, and is ensureing medicine
Thing can also effectively reduce stimulation of the medicine to intestines and stomach while uniformly release.Micropill preparation particle diameter is smaller, turning in intestines and stomach
Fortune is not influenceed by the food conveying rhythm and pace of moving things, though when pyloric sphincter is closed, remain to by pylorus, therefore particulate is in intestines and stomach
Absorption do not influenceed by gastric emptying typically.What is more important, the drug release behavior of micropill system is each of one dosage of composition
The summation of individual micropill drug release behavior, error or defect of indivedual micropills in preparation will not be produced to the drug release behavior of whole preparation
Have a strong impact on, therefore better than the slow, Dospan being made up of a unit in terms of the reappearance and uniformity of drug release rule.
Glipizide is suitable to be made sustained-release pellet preparation, and the effective blood drug concentration duration is long, blood concentration fluctuation is small, pair
The small, individual difference of effect is small, patient compliance is good.
The most frequently used implementation method of sustained release pellet is to use film controlling type, i.e., the outside solution coating method in capsule core wraps one
Layer sustained release clothing film, sustained release clothing film contains filmogen, plasticizer, antiplastering aid etc..It is many in one's early years that sustained release is prepared using organic solvent
The coating solution of clothing film, because organic solvent coating solution has pollution and safety issue, in order to overcome organic solvent coating solution
Defect, aqueous dispersion packaging technique is used widely, and conventional aqueous dispersion has Aquacoat, acrylic acid tree
Lipid aqueous dispersion, polyvinyl acetate ester aqueous dispersion etc., such as polyvinyl acetate ester aqueous dispersion Kollicoat SR 30D,
Crylic acid resin aqueous dispersion Eurdragit RL 30D, Eurdragit RS 30D, Eurdragit NE30D and ethyl
Cellulose aqueous dispersions Aquacoat and Surelease, however we have found that：The Glipizide for preparing is coated using aqueous dispersion
Film controlling type sustained-release micro-pill capsules, within a period of time for just having prepared, its release performance is good, but after storage a period of time,
Its release performance begins to decline, and storage time is more long, declines more obvious, the term of validity latter half for often specifying in medicine, release
Performance is decreased obviously.Analysis reason because coating membrane during placement because aqueous dispersion particulate continues to be combined with each other
Cause gradually to compact, cause membrane permeability to decline, make release slack-off, popular saying is aging.
The content of the invention
It is coated under the aging release for bringing of film of the Glipizide film controlling type sustained release pellet for preparing to solve aqueous dispersion
The problem of drop, the invention provides a kind of film controlling type Glipizide of the release performance that can before the deadline remain stabilization
Sustained-release micro-pill capsules, feature be micropill capsule core in containing have meet water high-expansion sodium carboxymethyl starch, by water suction
Expansion causes that sustained release coating film is deformed upon, so as to counteract the aging of film.
The conventional aqueous dispersion type coating material of the current slow controlled release micro pill of film controlling type, such as Eurdragit RL 30D, bag
Macromolecular material in clothing material is in itself and water insoluble, but is dispersed in water in particulate form, with plasticizer, antiplastering aid etc.
Aqueous dispersion coating solution is obtained after mixing, micropill surface is sprayed on through spray gun, this operation is referred to as being coated；When being coated firm beginning,
These aqueous dispersions on micropill surface exist with substantial amounts of discontinuous particle shape, increase as coating solution is sprayed into, these
Grain contacts with each other, deforms, condensing, last mutually partial fusion, forms a discontinuous film；Then it is heat-treated, water is waved
After hair, polymer beads are then connected with each other, fusion completely forms coating membrane.It is heat-treated the film-controlled slow-release being coated to aqueous dispersion micro-
The release performance influence of ball is very big：Not enough, such as time is too short or temperature is too low, polymer in coatings for heat treatment
Also contain micro water between particle, it may proceed to evaporate within follow-up storage period, continuing with film becomes between particle
Obtain and more compact, permeability declines causes release slack-off；In order to avoid such case, generally using the side of increase heating strength
Method overcomes, for example, increase heat treatment time or improve heat treatment temperature, but this treatment easily lead to it is heat treated
Head, causes film excessively to dry and compact, even if initial stage release is qualified, but it is within follow-up storage period, the film for compacting originally
Can become loose due to the water suction from environment and the creep of film-forming high molecular material, permeability rises, and causes release to accelerate.It is real
Trample and show, for film controlling type Glipizide sustained-release micropill, because insoluble drug release is completely by diffusion, thus aging to film cause
Permeability decline very sensitive, accomplish just right to ensure to remain before the deadline stabilization by Technology for Heating Processing
Release performance is highly difficult, and often later stage release is substantially slack-off.
For above-mentioned mechanism, the present inventor is surprised to find that by research：If the Glipizide film that aqueous dispersion is coated
Control type sustained release pellet uses the capsule core of the sodium carboxymethyl starch containing high-expansion, due to sodium carboxymethyl starch water swelling to original
The 300% of volume, can substantially expand after capsule core water suction so that micropill volume becomes big, causes release membranes to be stretched, and thickness is thinning,
The aperture of permeable micropore becomes big, and permeability improves, and can compensate heat treatment deficiency causes the aging produced permeability of film to decline,
So that middle and later periods rate of release substantially constant, latter stage remains small.Heat treatment can additionally be eliminated excessive causes film undue
The influence compacted, it is to avoid the day change of release performance that comes of caudacoria Relaxation Zone, so that insoluble drug release speed in the whole term of validity
Degree substantially constant.The ageing resistace of the Glipizide film-controlled slow-release micropill of aqueous dispersion coating can so be greatly improved.By
The high-expansion of sodium carboxymethyl starch in capsule core, expansive force is very big, as standing time increases, the expansion rate after micropill water suction
It is basically unchanged, can causes that release membranes occur irreversible plastic deformation after being stretched, no matter how film changes (becomes loose or become
Compact) can support and arrive similar degree greatly, so as to ensure that the permeability of film is basically unchanged.
Preferably, Glipizide film-controlled slow-release micro pill capsule of the invention, the sustained release clothing film use of its micropill
Eurdragit RL 30D as filmogen, the sodium carboxymethyl starch containing high-expansion in capsule core, and other are pharmaceutically
The conventional excipient of acceptable sustained release pellet, the excipient is preferably filled with agent microcrystalline cellulose, lactose and solubilizer 12
Sodium alkyl sulfate, wherein, the percentage that sodium carboxymethyl starch accounts for capsule core weight in capsule core is 5~20%.Sustained release clothing film is included
Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid talcum powder, its ratio are preferably Eurdragit RL
30D: triethyl citrate: talcum powder=30: 3: 4, coating weight gain is preferably 17~36%.
As one of the preferred embodiment of the present invention, at the micropill of Glipizide film-controlled slow-release micro pill capsule of the invention
Side is as follows：
First, capsule core prescription (1000 meters)
2nd, it is sustained clothing film prescription
It is preferred that sustained release clothing film coating weightening is 17~36%.
It is anti-aging invention also provides a kind of Glipizide film-controlled slow-release micro pill capsule for improving aqueous dispersion coating
The method of performance, it is characterized in that the sustained release clothing film of micropill uses aqueous dispersion Eurdragit RL 30D as filmogen, ball
Core contains the excipient of sodium carboxymethyl starch and other sustained release pellets, and the excipient is preferably filled with agent microcrystalline cellulose, breast
Sugar and solubilizer lauryl sodium sulfate, the percentage that sodium carboxymethyl starch accounts for capsule core weight wherein in capsule core are 5~20%, are delayed
Release clothing film and include aqueous dispersion Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid talcum powder, weight ratio is
Eurdragit RL 30D: triethyl citrate: talcum powder=30: 3: 4, coating weight gain is 17~36%.The above method it is excellent
Choosing, is that based on 1000 capsules, micropill uses following prescription：
First, capsule core prescription
2nd, it is sustained clothing film prescription
Sustained release clothing film coating weightening is 17~36%.
The preparation method of film controlling type Glipizide sustained-release micropill of the present invention, can be according to film controlling type in the prior art
Delay the general technology of controlled release micro pill to prepare, including batch mixing, pill core, the slow clothing film of bag etc., it is preferred to use extrusion spheronization method
Prepare capsule core.The sustained release pellet that will be made loads common stomach dissolution type gelatine capsule, that is, obtain Glipizide film-controlled slow-release micropill glue
Capsule.
Film controlling type Glipizide sustained-release micro pill capsule of the present invention has the following advantages：
1) confrontation sustained release clothing film is aging：With aqueous dispersion Eurdragit RL 30D+ triethyl citrates+talcum powder group
Into sustained release clothing film can be aging, reason is that aqueous dispersion particulate is combined and promotes film aging, causes membrane permeability to reduce, and contain tool
There is the capsule core of the sodium carboxymethyl starch for meeting water high-expansion, can substantially be expanded after water suction, cause sustained release clothing film to be stretched, thickness becomes
Thin, the aperture of permeable micropore becomes big, and permeability improves, and the permeability that compensate for the aging generation of film declines, so that the middle and later periods
Rate of release substantially constant, latter stage residual is small, can before the deadline remain the release performance of stabilization.
2) supporting role：Using the capsule core of the sodium carboxymethyl starch with water swelling, can be substantially expanded after water suction
To supporting role, burst drug release caused by the extruding by intestines and stomach can be avoided in intestines and stomach operation process in vivo.
Specific embodiment
The Glipizide sustained-release micro pill capsule of the common capsule core of embodiment 1
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology：
1st, capsule core preparation technology：
(1) Glipizide is crossed into 80 mesh sieves；
(2) Glipizide, microcrystalline cellulose PH101, lactose, the lauryl sodium sulfate of recipe quantity are weighed, wet method system is put
It is well mixed in grain machine；
(3) with the ethanol solution softwood of 2% sodium carboxymethylcellulose 10%；
(4) put and extruded on extruder, mesh size is 1.0mm, extruded velocity is 20~30rpm；
(5) round as a ball, round as a ball speed is 900~1000rpm, is dried in fluid bed；
(6) sieve, take the capsule core between 16~30 mesh.
2nd, it is sustained clothing film coating liquid preparing process：
The triethyl citrate for weighing recipe quantity puts the water of recipe quantity, stirs, and adds the talcum powder of recipe quantity,
Stirring shearing is uniform, is eventually adding the D of Eurdragit RL 30 and mixes uniformly, obtains final product.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 12.8%.
4th, it is heat-treated：
The micropill of extended release coatings will be wrapped in fluid bed, be heat-treated under the conditions of 40 DEG C/2h.
5th, capsule is filled：
Coating micro-pill is obtained final product in filling on capsule filling machine.
3rd, release, assay and result
Release takes this product, according to drug release determination method (the first methods of China's coastal port annex X D), using dissolution rate
The subtraction unit of determination method second (China's coastal port annex X C), by capsule put sedimentation basket in, with the phosphate of pH6.8
Buffer solution 900ml is solvent, and rotating speed is 50 turns per minute, is operated in accordance with the law, during through 4,8 and 16 hours, solution 10ml is taken respectively, is filtered
Cross, and supplement mutually synthermal, same volume dissolution medium in process container immediately；Subsequent filtrate is taken, according to UV-vis spectroscopy
Photometry (two annex IV A of China's coastal port), trap is determined at the wavelength of 276nm respectively；Separately take lattice row pyrrole
Piperazine reference substance about 50mg, it is accurately weighed, in putting 100ml measuring bottles, plus methyl alcohol 20ml ultrasonically treated, make dissolving, with methanol dilution extremely
Scale, shakes up, and used as stock solution, the phosphate buffer with pH6.8, by following dilution process, takes a certain amount of storage as solvent
Standby liquid adds appropriate solvent, is diluted to certain density Glipizide reference substance solution：
| Reference substance solution | Dilution process | Glipizide concentration (μ g/ml) |
| 1# | Take stock solution 1ml solubilizers to 200ml | 2.5 |
| 2# | Take stock solution 1ml solubilizers to 100ml | 5.0 |
| 3# | Take stock solution 3ml solubilizers to 100ml | 15.0 |
| 4# | Take reference substance solution 1#25ml solubilizers to 50ml | 1.25 |
| 5# | Take reference substance solution 3#25ml solubilizers to 50ml | 7.5 |
| 6# | Take reference substance solution 4#25ml solubilizers to 50ml | 0.625 |
Above-mentioned reference substance solution is taken respectively and is measured in the same method trap, draw standard curve.Calculated often according to standard curve
Burst size of the grain capsule in different time.Every capsule of this product should be respectively no more than labelled amount in the burst size of 4,8,16 hours
30%, 30~70% and more than 85%, regulation all should be met.
Average rate of release takes this product, according to the lower assay method experiment of release, takes solution at 4,8 and 12 hours respectively
10ml operates (with release inspection while carrying out) in accordance with the law, and average release speed of the every capsule in different time is calculated respectively
Rate.Every capsule of this product in 4~8 hours and 8~12 hours, per hour average rate of release equivalent to labelled amount 7~
12%, regulation all should be met.
Other should meet relevant every regulation (two annex I A of China's coastal port) under capsule.
【Assay】Determined according to high performance liquid chromatography (two annex V D of China's coastal port).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, with the phosphorus of 0.1mol/L
Acid dihydride sodium solution (adjusting pH value to 6.00 ± 0.05 with the NaOH of 2mol/L)-methyl alcohol (55: 45) is mobile phase：Detection
Wavelength is 225nm.Take Glipizide reference substance and 4- [2- (5- methylpyrazine -2- formamidos) ethyl] benzsulfamide (impurity
I) reference substance, plus methyl alcohol dissolves and dilutes the mixed solution for being made each 0.5mg and 2.5 μ g in every 1ml, takes 20 μ l injection liquid phase colors
Spectrometer, number of theoretical plate is calculated by Glipizide peak and is not less than 2000, and Glipizide peak should be conformed to the separating degree at impurity I peaks
Ask.
Determination method takes this product 5, pours out content, accurately weighed, is fully ground, and 100ml is quantitatively transferred to methyl alcohol
In (5mg specifications) or 200ml (10mg specifications) measuring bottle, dissolving is made with methyl alcohol ultrasound, it is dilute with 0.1mol/L sodium dihydrogen phosphates
Release to scale, shake up, filtered after centrifugation, precision measures subsequent filtrate 10ml 0.1mol/L sodium dihydrogen phosphates and is diluted to
50ml, as need testing solution；It is another to take Glipizide reference substance 20mg, it is accurately weighed, in putting 200ml measuring bottles, plus methyl alcohol 100ml
Make dissolving, scale is diluted to 0.1mol/L sodium dihydrogen phosphates, shake up, precision measures 25ml 0.1mol/L biphosphates
Sodium solution is diluted to 50ml, used as reference substance solution.Precision measures each 20 μ l injections liquid chromatograph of above two solution respectively,
Record chromatogram, by external standard method with calculated by peak area, obtains final product.Result such as table 1：
The releasing result of 1 embodiment of table 1
Result shows that Glipizide sustained-release micro pill capsule of the capsule core of embodiment 1 without intumescent material, initial release is good,
As standing time increases, film is constantly aging, and rate of release is slack-off, and residual substantially increases.
4th, expansion rate is determined
Assay method：37 DEG C of distillation appropriate amount of water is preheated to being added in 100ml measuring bottles, is dipped in 37 DEG C of water-baths and with steaming
Distilled water constant volume is to standby after scale；3 500ml beakers are taken, the distilled water that 300ml is preheated to 37 DEG C is separately added into, 37 are immersed in
It is standby in DEG C water-bath；Take capsule to be measured 10, remove capsule shells, micropill in capsule is poured out, it is fast in putting above-mentioned 100ml measuring bottles
Speed minimum scale value be 0.01ml pipette, extract measuring bottle in distilled water until liquid level is fallen after rise to measuring bottle scale, then accurately
The volume of water in pipette is read, the average external volume of micropill in every capsule is calculated, V is designated as0.30 capsules to be measured are taken, is divided into 3
Group, removes capsule shells by every group 10, and micropill in capsule is poured out, and immersion in above-mentioned 3 500ml beakers is put respectively, exists respectively
4h, 8h, 16h respectively take out 1 group, filtration, and the water of micropill surface residual is blotted with filter paper, and that has been put again that constant volume crosses is above-mentioned
In the measuring bottle of 100ml, rapidly with distilled water in above-mentioned pipette, extract measuring bottle until liquid level is fallen after rise to measuring bottle scale, then accurately
The volume of water in pipette is read, the average external volume of micropill in every capsule is calculated, V is designated asT.When being calculated as follows each sampling
Between put expansion rate, the results are shown in Table 2.
Computing formula：Expansion rate (%)=(VT-V0)/V0× 100%
Expansion rate result after the placement for a long time of the room temperature of table 2
Test result indicate that, capsule core without high-expansion material Glipizide sustained-release micro pill capsule, micropill expansion rate compared with
It is small, and as room temperature is placed for a long time, expansion rate reduces therewith, the effect aging without sustained release clothing film is offset.
Glipizide sustained-release micro pill capsule of the embodiment 2 containing 5% sodium carboxymethyl starch
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000
2nd, preparation technology：
1st, capsule core preparation technology：
(1) Glipizide is crossed into 60 mesh sieves；
(2) Glipizide, microcrystalline cellulose PH101, lactose, sodium carboxymethyl starch, the dodecyl sulphur of recipe quantity are weighed
Sour sodium, puts in wet granulator and is well mixed；
(3) with the ethanol solution softwood of 2% sodium carboxymethylcellulose 10%；
(4) put and extruded on extruder, mesh size is 1.0mm, extruded velocity is 20~30rpm；
(5) round as a ball, round as a ball speed is 900~1000rpm, is dried in fluid bed；
(6) sieve, take the capsule core between 16~30 mesh.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 17.2%.
4th, it is heat-treated：With embodiment 1
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,3 are the results are shown in Table：
The releasing result of 3 embodiment of table 2
Result shows, the Glipizide sustained-release micropill of capsule core material containing the high-expansion sodium carboxymethyl starch 5% of embodiment 2
Capsule initial release performance is good, and as standing time increases, still very well, end point discharges the equal very little of residual to releasing effect.
4th, swelling rate test
Experimental technique：With embodiment 1,4 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 4
Test result indicate that, the Glipizide sustained-release micro pill capsule of capsule core material containing high-expansion sodium carboxymethyl starch 5%,
Micropill expansion rate is larger, and under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Glipizide sustained-release micro pill capsule of the embodiment 3 containing 10% sodium carboxymethyl starch
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1.
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology：
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 22.1%, 26.8%.
4th, it is heat-treated：With embodiment 1
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,5 are the results are shown in Table；
The releasing result of 5 embodiment of table 3
Result shows that Glipizide sustained-release micro pill capsule initial release performance of the capsule core containing sodium carboxymethyl starch 10% is good
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,6 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 6
Test result indicate that, Glipizide sustained-release micro pill capsule of the capsule core containing sodium carboxymethyl starch 10%, micropill expansion rate
Larger, under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Glipizide sustained-release micro pill capsule of the embodiment 4 containing 15% sodium carboxymethyl starch
First, prescription
1. capsule core prescription (1000)
2. clothing film coating liquid prescription is sustained：With embodiment 1.
No. 3.0 stomach dissolution type gelatine capsule shells 1000.
2nd, preparation technology
1st, capsule core preparation technology：With embodiment 2
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 30.9%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,7 are the results are shown in Table
The releasing result of 7 embodiment of table 4
Result shows that Glipizide sustained-release micro pill capsule initial release performance of the capsule core containing sodium carboxymethyl starch 15% is good
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,8 are the results are shown in Table：
Expansion rate after the placement for a long time of the room temperature of table 8
Result shows that Glipizide sustained-release micro pill capsule of the capsule core containing sodium carboxymethyl starch 15%, micropill expansion rate is larger,
Under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Glipizide sustained-release micro pill capsule of the embodiment 5 containing 20% sodium carboxymethyl starch
First, prescription
1. capsule core prescription (1000)
2. clothing film coating liquid prescription is sustained：With embodiment 1
No. 3.0 stomach dissolution type gelatine capsule shells 1000
2nd, preparation technology
1st, capsule core preparation technology：With embodiment 2
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 33.8%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,9 are the results are shown in Table：
The releasing result of 9 embodiment of table 5
Result shows that Glipizide sustained-release micro pill capsule initial release performance of the capsule core containing sodium carboxymethyl starch 20% is good
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,10 are the results are shown in Table：
Expansion rate after the placement for a long time of the room temperature of table 10
Result shows that Glipizide sustained-release micro pill capsule of the capsule core containing sodium carboxymethyl starch 20%, micropill expansion rate is larger,
Under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
The Glipizide sustained-release micro pill capsule (10mg specifications) of the common capsule core of embodiment 6
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1.
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology：
1st, capsule core preparation technology：With embodiment 1.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 14.1%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Method：With embodiment 1, as a result such as table 11：
The releasing result of 11 embodiment of table 6
Result shows that Glipizide sustained-release micro pill capsule of the capsule core of embodiment 6 without intumescent material, initial release is good,
As standing time increases, film is constantly aging, and rate of release is slack-off, and residual substantially increases.
4th, expansion rate is determined
Assay method：With embodiment 1,12 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 12
Test result indicate that, Glipizide sustained-release micro pill capsule of the capsule core without intumescent material, micropill expansion rate is smaller,
And as room temperature is placed for a long time, expansion rate reduces therewith, the effect aging without sustained release clothing film is offset.
Glipizide sustained-release micro pill capsule of the embodiment 7 containing 5% sodium carboxymethyl starch
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000
2nd, preparation technology：
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 19.4%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,13 are the results are shown in Table：
The releasing result of 13 embodiment of table 7
Result shows that the capsule core of embodiment 7 contains the Glipizide sustained-release micro pill capsule initial release of sodium carboxymethyl starch 5%
Performance is good, and as standing time increases, still very well, end point discharges the equal very little of residual to releasing effect.
4th, swelling rate test
Experimental technique：With embodiment 1,14 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 14
Test result indicate that, the Glipizide sustained-release micro pill capsule of capsule core sodium carboxymethyl starch containing intumescent material 5% is micro-
Ball expansion rate is larger, and under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Glipizide sustained-release micro pill capsule of the embodiment 8 containing 10% sodium carboxymethyl starch
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1.
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology：
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 24.8%, 28.9%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,15 are the results are shown in Table：
The releasing result of 15 embodiment of table 8
Result shows that Glipizide sustained-release micro pill capsule initial release performance of the capsule core containing sodium carboxymethyl starch 10% is good
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,16 are the results are shown in Table：
Expansion rate result after the placement for a long time of the room temperature of table 16
Test result indicate that, Glipizide sustained-release micro pill capsule of the capsule core containing sodium carboxymethyl starch 10%, micropill expansion rate
Larger, under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Glipizide sustained-release micro pill capsule of the embodiment 9 containing 15% sodium carboxymethyl starch
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1.
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology
1st, capsule core preparation technology：With embodiment 2
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 32.3%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,17 are the results are shown in Table：
The releasing result of 17 embodiment of table 9
Result shows that Glipizide sustained-release micro pill capsule initial release performance of the capsule core containing sodium carboxymethyl starch 15% is good
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,18 are the results are shown in Table：
Expansion rate after the placement for a long time of the room temperature of table 18
Result shows that Glipizide sustained-release micro pill capsule of the capsule core containing sodium carboxymethyl starch 15%, micropill expansion rate is larger,
Under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Glipizide sustained-release micro pill capsule of the embodiment 10 containing 20% sodium carboxymethyl starch
First, prescription
1st, capsule core prescription (1000)
2nd, it is sustained clothing film coating liquid prescription：With embodiment 1.
3rd, No. 0 stomach dissolution type gelatine capsule shell 1000.
2nd, preparation technology
1st, capsule core preparation technology：With embodiment 2.
2nd, it is sustained clothing film coating liquid preparing process：With embodiment 1.
3rd, it is coated (sustained release clothing film)：
Capsule core is placed in fluid bed and is coated, control clothing film weightening, coating weight gain is 36.0%.
4th, it is heat-treated：With embodiment 1.
5th, capsule is filled：With embodiment 1.
3rd, release, assay and result
Assay method：With embodiment 1,19 are the results are shown in Table：
The releasing result of 19 embodiment of table 10
Result shows that Glipizide sustained-release micro pill capsule initial release performance of the capsule core containing sodium carboxymethyl starch 20% is good
Good, as standing time increases, still very well, the release equal very little of residual is put at end to releasing effect.
4th, expansion rate experiment
Experimental technique：With embodiment 1,20 are the results are shown in Table：
Expansion rate after the placement for a long time of the room temperature of table 20
Result shows that Glipizide sustained-release micro pill capsule of the capsule core containing sodium carboxymethyl starch 20%, micropill expansion rate is larger,
Under room temperature is placed for a long time, expansion rate keeps constant, counteracts the aging of sustained release clothing film.
Claims (4)
1. it is a kind of improve aqueous dispersion be coated Glipizide film-controlled slow-release micro pill capsule ageing resistace method, it is characterized in that
The sustained release clothing film of micropill using Eurdragit RL 30D as filmogen, the capsule core of micropill contain sodium carboxymethyl starch and its
The excipient of his pharmaceutically acceptable sustained release pellet.
2. method as claimed in claim 1, it is characterized in that the excipient of other pharmaceutically acceptable sustained release pellets is
Filler microcrystalline cellulose, lactose and solubilizer lauryl sodium sulfate.
3. method as claimed in claim 1 or 2, it is characterized in that sodium carboxymethyl starch accounts for the percentage of capsule core weight in the capsule core of micropill
Than being 5~20%, the sustained release clothing film of micropill includes Eurdragit RL 30D, plasticizer triethyl citrate and antiplastering aid talcum
Powder and weight ratio are Eurdragit RL 30D: triethyl citrate: talcum powder=30: 3: 4, coating weight gain is 17~36%.
4. method as claimed in claim 3, it is characterized in that based on 1000 capsules, the micropill uses following prescription：
Capsule core prescription：
Sustained release clothing film prescription：
Sustained release clothing film coating weightening 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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| CN201210014355.7A CN103211787B (en) | 2012-01-18 | 2012-01-18 | Glipizide film-controlled slow-release micro pill capsule |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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2012
- 2012-01-18 CN CN201210014355.7A patent/CN103211787B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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| Title |
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| 格列吡嗪缓释微丸的制备及体外释放度考察;袁伟栋等;《中国药剂学杂志》;20091130;第7卷(第6期);第409-416页，尤其是第409页摘要，第410页第2.1、2.2节，第411页第2.4.1、2.4.3节 * |
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