CN1025548C - Process for the preparation of miniature intestine dissolving capsule - Google Patents
Process for the preparation of miniature intestine dissolving capsule Download PDFInfo
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- CN1025548C CN1025548C CN 88105144 CN88105144A CN1025548C CN 1025548 C CN1025548 C CN 1025548C CN 88105144 CN88105144 CN 88105144 CN 88105144 A CN88105144 A CN 88105144A CN 1025548 C CN1025548 C CN 1025548C
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- microcapsule
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Abstract
The present invention relates to a process for preparing an intestine-dissolving microcapsule preparation by different solid medicinal powder irritating the stomach. The method is characterized in that solid powder medicine and proper auxiliary materials are mixed and suspended in an aqueous solution of an intestine-dissolving capsule materials; in a spray drier, medicinal particles are encapsulated into the intestine-dissolving microcapsule by spray and drying. Thereby, the process provides children, particularly infants, with a novel medicament preparation of the intestine-dissolving microcapsule, which has low cost, high encapsulation efficiency, small particle size, easy swallow and hard chewing.
Description
The invention belongs to a kind of preparation method of the solid drugs powder being made the miniature intestine dissolving capsule preparation.
The enteric solubility preparation that all lacks children taking so far both at home and abroad, medicine that the child uses always such as erythromycin etc. have stronger zest to stomach, in order to overcome this drawback, people have made enteric coated tablet and capsule etc. with it, but these two kinds all are unsuitable for the child, especially be unsuitable for the child and take, solid preparation because the child can not swallow.Australia good fortune youngster decides company (FauldingCo) similar medicines such as erythromycin is made enteric coated particles, reinstalls in the capsule, makes moderate progress though discharge the performance of medicine, but still is unsuitable for children taking.People sneak into this granule fruit jam again and give children taking, but thick because of its granule, particle diameter is about 1 millimeter, is easily chewed by the child, loses enteric solubility.
The method for preparing microcapsule commonly used, for example single coacervation, complex coacervation etc., because of its envelop rate to medicine low, and be unsuitable for commercial production, though existing technology with the spray drying method for preparation microcapsule has solved the problem of envelop rate, but only limit to the oily drug encapsulation is become microcapsule, the for example microcapsule of vitamin A etc., and the capsule material that uses does not have acid resistance, under one's belt with regard to rapid delivery of pharmaceuticals, have among the preparation technology of the granule of slow release medicine and microsphere at some, all need adopt ethanol, organic solvents such as isopropyl alcohol, production cost were both high, dangerous again, be unfavorable in commercial production, applying.So far do not see as yet the fine powder of solid drugs enteric solubility capsule material, in the aqueous solvent system, prepare the report of enteric-coated microcapsule with drying process with atomizing.
The object of the present invention is to provide that a kind of cost is low, envelop rate is high, microcapsule diameter is little, can be used for the aqueous solvent system, and the fine powder of solid drugs is encapsulated as the new technology of miniature intestine dissolving capsule with spray drying method.This technology is applicable in aqueous solvent system indissoluble, needs the solid drugs fine powder of enteric to be encapsulated as microcapsule, for example erythromycin, nitrofurantoin, midecamycin, tetracycline etc.
The object of the present invention is achieved like this: the solid powdery medicine is suspended in the aqueous solution of enteric capsule material, and in spray dryer, spray-dried and the microgranule of medicine is encapsulated as enteric-coated microcapsule.Now with the suspension of capsule material solution, the capsule heart, the capsule heart and capsule material, details are as follows for the preparation of microcapsule and the processing of microcapsule etc.:
One, the preparation of the capsule heart and capsule material solution
Enteric capsule material can be selected Eudragit or III number, hydroxypropylmethyl cellulose phthalate class and hydroxypropyl emthylcellulose succinic acid acetate etc. for use, the dissolution characteristics of above-mentioned enteric solubility material is to dissolve in multiple organic solvent and water insoluble and pH value is lower than in 5 the acidic buffer solution, so far with above-mentioned material to tablet etc. when enteric coated, all be with organic solvent or blended organic solvent dissolution, and make solution.But the cost of organic solvent was not only high, but also dangerous, most organic solvents are harmful, often need control its residual quantity etc., bring difficulty to production simultaneously, are unfavorable for using in the drying process with atomizing.
In order to overcome above drawback, we utilize ammonia, meet the character of hot ammonia volatilization, and its aqueous solution is neutral characteristics again after the ammonia volatilization, and ammonia solution is introduced drying process with atomizing as solvent system, thereby have solved the difficulty that with an organic solvent production is caused.
The concentration of capsule material solution has material impact to character, quality and the system capsule technology of making microcapsule.The consumption of capsule material increases, and makes the wall thickening of microcapsule.The stripping of medicine in simulated gastric fluid reduces.Otherwise, reduce as the amount of capsule material, make the wall attenuation of microcapsule, cause the stripping quantity in simulated gastric fluid to increase, part loses enteric solubility.Therefore the aqueous solution concentration of capsule material should be 3～7%, and optium concentration is 5%, and the consumption of capsule material is too big, and the suspension concentration of the capsule material and the capsule heart is increased, and causes atomization process that difficulty takes place, and the medicament contg in the microcapsule is reduced.When granule was thicker, this influence was not too big, because the particle of solid drugs is very little in this technology, the population of the medicine of Unit Weight is many, surface area ratio is very big, and its influence is very not big, evidence, the concentration of enteric material solution is 2～5% o'clock, all can make microcapsule, microscopically is observed, and profile is good, but be lower than 5% in simulated gastric fluid stripping quantity more, be best with 5%.
Because the existence of ammonium ion, may influence capsule psychological treatment thing solubility behavior in capsule material solution when sneaking into capsule material formulations prepared from solutions suspension, therefore in this technology, answer the concentration of strict control ammonia, promptly make under the whole dissolved prerequisites of capsule material, the least possible adding ammonia, so answer the limit heated and stirred, add the slowly measure of dropping ammonia.The pH value of capsule material solution is influential to its viscosity simultaneously, and within the specific limits, pH value is higher, and its viscosity is also high.The viscosity of suspension is too high, is prone to the wire drawing phenomenon when centrifugal atomizing, influences the quality of microcapsule.
Two, the preparation of medicine suspension in capsule material solution
The present invention is applicable to the solid drugs of indissoluble in aqueous capsule material solution, should earlier medicine be crushed to the smalls that particle diameter is 30～100 μ m, if it is very few that medicine dissolves in capsule material solution, desirable fine drug powder 1～10g, add medicinal Pulvis Talci 1～3g, ground and mixed drips a small amount of Tween 80 and continues to be ground to the moistening degree that is to evenly in mortar.In capsule material solution, certain dissolubility is arranged as medicine, erythromycin etc. for example, should take special processing method, each 1～10g of fine powder of the thing of promptly getting it filled (particle diameter 30～100 μ m) and stearic acid (medicinal) puts in the beaker, and heating makes fusion and mix homogeneously slowly.Placement makes cooling, adds 1～3g Pulvis Talci, mixes, and being crushed to particle diameter is 30～100 μ m, and fine powder is placed mortar, adds a small amount of Tween 80 and is mixed into the moistening degree that is.In mixture, add a small amount of capsule material solution, grind well, in grinding, slowly add remaining capsule material solution, make homodisperse suspension.
The size of capsule heart particle diameter directly influences the size of microcapsule and the quality of microcapsule.Capsule heart particle diameter is too big, when the suspension of making at the capsule heart and capsule material solution atomizes with centrifuging, and the excessive capsule heart and the capsule material solution separating of causing of centrifugal force that produces because of the capsule heart; Capsule heart particle is thick, and the microcapsule of making is also bigger, is difficult for further being processed into homodisperse oral mixed suspension preparation, and is easily chewed and lose enteric solubility; Capsule heart particle diameter is little, and the population of Unit Weight medicine is many, surface area is big, and the capsule material that is bundled into the identical microcapsule consumption of wall thickness is many, and the content of microcapsules medicine thing is too low, has both increased the cost of preparation, increases a dose of preparation again.
This technology adds the Pulvis Talci that adds 1～3 gram man-hour at the capsule heart, its objective is and be beneficial to pulverizing, especially after adding stearic acid in the heart for the capsule of erythromycin etc., do not add Pulvis Talci and be difficult to be ground into fine powder, it is influential to the stripping property of the microcapsule made to add Pulvis Talci, it is bigger than adding talcous microcapsule to find not add the stripping quantity of talcous microcapsule in simulated gastric fluid, Pulvis Talci can be dispersed in the cyst wall, drug release is played retardation, its reason is that drug molecule is adsorbed by Pulvis Talci, its distribution in the microcapsule wall is reduced, or be filled in because of Pulvis Talci in the defective of cyst wall.When capsule material concentration is high, add Pulvis Talci and can make the burst size increase of microcapsules medicine thing in simulated gastric fluid, its reason is that Pulvis Talci itself has stronger hydrophilic, Pulvis Talci is distributed in the cyst wall, makes moisture content be easy to see through cyst wall and cause.
The effect that adds the Tween 80 in man-hour at the capsule heart is to make the capsule heart be easy to be scattered in equably in the capsule material solution, when the capsule heart adds when adding stearic acid man-hour, adds Tween 80, can improve its wettability, helps medicine and dissolves in intestinal juice.
Three, the suspension spray drying is made microcapsule
For the suspension that certain viscosity will be arranged is atomized into fine droplet, the present invention adopts " Highspeedcentrifugingandsprayingdrier ", and be about to the suspension of the capsule heart in capsule material solution and slowly splash into, and atomizing and be dried to microcapsule.Import in the spray-drying process and outlet temperature should be controlled, temperature is too high can to influence stability of drug, also influence encystation, should make that inlet temperature is low as much as possible, the import and export temperature should respectively be controlled at 120～200 ℃ and 40～90 ℃ and be advisable under can the situation of encystation, optimum temperature range is at 140～150 ℃ and 50～60 ℃.
Charging rate should be controlled, and charging rate is too fast, has little time drying, drop sticks on the wall, can not become microcapsule, and charging rate is too low, productivity ratio is low, and test shows that when usefulness QZ-5 type mobile atomizer drying machine (Chinese Wuxi County spray dryer factory), charging rate is advisable with 5～15ml/mon.Best charging rate is 10ml/min.
Sprinkler pressure (getting rid of the rotating speed of dish), the dish that gets rid of that the present invention is used is promoted by compressed air.Get rid of of the pressure control of the rotating speed of dish by air.The pressure height, the rotating speed that gets rid of dish is big; Otherwise rotating speed is little.The rotating speed that gets rid of dish is too high, and centrifugal force is excessive, makes the capsule heart and capsule material solution separating, is unfavorable for encystation; It is too low to get rid of the dish rotating speed, and the drop of formation is big, has little time drying sometimes, influence encystation or the microcapsule made thick.Evidence, pressure should be controlled at 1～3kgf/cm
2In, preferentially select 1kgf/cm for use
2
Four, the post processing of microcapsule
Collect the microcapsule that forms in the spray dryer, cross 140 mesh sieves, put in the baking oven, under 80～100 ℃ temperature, heat 1～2 hour, removing residual ammonia, and must the microcapsule finished product.
Embodiment one, nitrofurantoin enteric-coated microcapsule
Nitrofurantoin is a broad spectrum antibiotic, is usually used in urinary tract infection etc., and this product has stronger zest to stomach, and its enteric coated tablet commonly used clinically is unsuitable for children taking.After making microcapsule with drying process with atomizing of the present invention, not only may command release under one's belt, and can significantly improve release performance in simulated intestinal fluid, burst size reaches 95% in five minutes.
Experimental implementation:
Get III allyl resin or hydroxypropylmethyl cellulose phthalate 3～5g, put in the 250ml beaker, add entry 100ml, heating is stirring also, the while dropping ammonia, and the pH value of control solution is 6.0 ± 0.5, up to whole dissolvings of capsule material and one-tenth clear solution.Other gets nitrofurantoin powder 6～8g, is crushed to particle diameter less than 60 μ m, adds Pulvis Talci 1～2g, adds the 0.05g Tween 80, so that the powder moistening is degree.In the mixture of making, add a spot of capsule material and grind well, again all the other capsule material solution are added and grinding, make a suspension.Get the suspension that makes and carry out spray drying, 120～200 ℃ of drying machine inlet temperatures, 40～90 ℃ of outlet temperatures; Charging rate 10ml/min, sprinkler pressure 2kgf/cm
2By collecting the nitrofurantoin microcapsule in the cyclone separator, cross 140 mesh sieves.Microcapsule put in 80～100 ℃ of baking ovens heated 1～2 hour, remove residual ammonia.
By " bioavailability study in external dissolution test of nitrofurantoin enteric-coated microcapsule and the human body " shown: nitrofurantoin enteric-coated microcapsule dissolution rate in simulated gastric fluid obviously reduces, and in simulated intestinal fluid, stripping quantity 95% in 5 minutes, reached 97% in 10 minutes, than the not only fast of former medicated powder stripping but also fully, and its biological effectiveness also obviously improves, and peak time in advance.
Embodiment two, erythromycin enteric microcapsule
Erythromycin is the most frequently used antimicrobial drug, but stomach is had stronger zest, and therefore being made into enteric-coated microcapsule just can overcome above-mentioned drawback.
Experimental implementation: get stearic acid 3～5g and put in the beaker, heating makes fusion, the erythromycin fine powder that adds 1～3g, the limit edged stirs, and little fire heating is up to homodisperse, after placement makes cooling, pulverize, add the 1g Pulvis Talci, continue to be crushed to microscopically again and observe, the all particles footpath is all less than till the 60 μ m, make the capsule heart, get 3～5g III acrylic resin, put in the 250ml beaker, add distilled water 100ml, little fire heats and constantly stirs, and dropping ammonia is controlled pH value 6 ± 0.5 simultaneously, at any time stir up to resin and all be dissolved into clear solution, the solution final pH is 6.
Get the capsule heart that makes and put in the mortar, add tween 80 0.0.05g, so that the moistening of the capsule heart is degree, adds capsule material solution and grind well on a small quantity, in grinding, add remaining capsule material solution more slowly, make homodisperse suspension.The suspension that makes is sprayed drying one-tenth microcapsule in spray dryer.The rate of addition of suspension is controlled at 5～15ml/min, is preferably 10ml/min.Inlet temperature is controlled at 120～200 ℃, and outlet temperature is controlled at 40～90 ℃.
By " bioavailability study in outer dissolution test of erythromycin enteric microcapsule and the human body " shown: erythromycin has higher anti-gastric acid performance after making enteric-coated microcapsule, and its biological effectiveness is suitable with commercially available enteric coated tablet, and speed of action is fast.
Embodiment three, tetracycline enteric-coated microcapsule
Remove capsule material hydroxypropylmethyl cellulose phthalate, concentration is outside 7%, and operation such as the compound method of its capsule heart processing method and prescription, capsule material solution and the capsule heart suspension in capsule material solution, spray-drying process is all identical with embodiment two.
Prepared " tetracycline enteric-coated microcapsule " carried out external dissolution test to be shown: dissolution rate obviously reduces in simulated gastric fluid, c%=23.4% after 1 hour; Dissolution rate obviously improves in simulated intestinal fluid ,/hour after c%=62.5%.
Embodiment four, midecamycin enteric-coated microcapsule
Prescription: midecamycin 1g
Stearic acid 5g
Pulvis Talci 1g
III acrylic resin 7g
Tween 80 0.05g
Ammonia is an amount of
Water 100ml
Its operation is fully with embodiment one.
Prepared " midecamycin enteric-coated microcapsule " carried out external dissolution test to be shown: this microcapsule stripping c%=21.8～23.8% after 1 hour in simulated gastric fluid, and in simulated intestinal fluid stripping c%=60.5～63.2% after 1 hour.Prove that this microcapsule formulation has improved the dissolution rate of midecamycin in simulated intestinal fluid.
Claims (7)
1, a kind of technology for preparing the miniature intestine dissolving capsule of solid drugs fine powder with drying process with atomizing, this technology comprises that the fine powder with medicine is suspended in the II acrylic resin, the III acrylic resin, hydroxypropylmethyl cellulose phthalate, containing in the ammonia solution of the enteric solubility capsule material of hydroxypropyl emthylcellulose succinic acid acetate, the spray-dried then microgranule with medicine is encapsulated as enteric-coated microcapsule, the fine powder of wherein said medicine is the solid drugs of indissoluble in the aqueous capsule material solution, particle diameter is 30-100 μ m, the concentration of the aqueous solution of wherein said capsule material is 3-7%, wherein said spray drying condition is that inlet temperature is controlled at 120-200 ℃, outlet temperature is controlled at 40-90 ℃, and the control atomizing pressure is 1-3kgf/cm
2, charging rate is controlled at 5-15ml/min.
2, the technology of preparation enteric-coated microcapsule according to claim 1 is characterized in that preparation method that enteric solubility capsule material contains ammonia solution and is and adds ammonia in water to regulate pH value be 6 ± 0.5, and to form clear solution degree of being.
3, according to claim 1 and 2 described technologies, the optium concentration that it is characterized in that the aqueous solution of capsule material is 5%.
4, technology according to claim 1, the best inlet temperature that it is characterized in that spray dryer is 140-150 ℃, outlet temperature is 50-60 ℃.
5, according to claim 1 and 4 described technologies, it is characterized in that controlling the nebulizer optimum pressure is 1kgf/cm
2
6,, it is characterized in that best charging rate is 10ml/min according to claim 1 and 4 described technologies.
7, technology according to claim 1 is characterized in that microencapsulation that spray drying makes under 80-100 ℃ of temperature, heated 1-2 hour in baking oven.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 88105144 CN1025548C (en) | 1988-10-22 | 1988-10-22 | Process for the preparation of miniature intestine dissolving capsule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 88105144 CN1025548C (en) | 1988-10-22 | 1988-10-22 | Process for the preparation of miniature intestine dissolving capsule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1042073A CN1042073A (en) | 1990-05-16 |
| CN1025548C true CN1025548C (en) | 1994-08-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 88105144 Expired - Fee Related CN1025548C (en) | 1988-10-22 | 1988-10-22 | Process for the preparation of miniature intestine dissolving capsule |
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| CN (1) | CN1025548C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103263400B (en) * | 2013-01-16 | 2014-12-17 | 内蒙古金河动物药业有限公司 | Chlortetracycline microcapsule preparation and preparation method thereof |
| CN108940147B (en) * | 2018-08-22 | 2021-01-01 | 南京林业大学 | Polyethylene glycol/cellulose triacetate phase change microcapsule and preparation method thereof |
| CN117462657A (en) * | 2023-11-13 | 2024-01-30 | 广州见华医学科技有限公司 | Application of lactoferrin capsule in bacteriostasis and anti-inflammation |
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- 1988-10-22 CN CN 88105144 patent/CN1025548C/en not_active Expired - Fee Related
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| CN1042073A (en) | 1990-05-16 |
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