CN102805741A - Compound micro-capsule and preparation method thereof - Google Patents
Compound micro-capsule and preparation method thereof Download PDFInfo
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- CN102805741A CN102805741A CN2012102734443A CN201210273444A CN102805741A CN 102805741 A CN102805741 A CN 102805741A CN 2012102734443 A CN2012102734443 A CN 2012102734443A CN 201210273444 A CN201210273444 A CN 201210273444A CN 102805741 A CN102805741 A CN 102805741A
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Abstract
The invention relates to a compound micro-capsule and a preparation method thereof. The compound micro-capsule comprises inner capsules and an outer capsule. The compound micro-capsule mainly comprises any of sodium alginate, calcium chloride, barium chloride, chitosan, poly left lysine and sodium citrate. The compound micro-capsule can be used to capsulate chemicals, traditional Chinese medicine, biological medicine, biological cells or tissues. Each inner capsule is prepared by a high voltage electrostatic method. The outer capsule is coated outside the multiple inner capsules by dropping preparation. The preparation method is simple. By the compound micro-capsule, slow release of the medicine is achieved. The compound micro-capsule is also applicable to in vitro culture and in vivo transplantation of the biological cells or tissues.
Description
Technical field
The present invention relates to medical technical field, exactly it is a kind of compound microcapsule and preparation method thereof.The compound microcapsule of this invention can be used for wrapping up chemicals, Chinese medicine, biological medicine, cell, piece of tissue etc.; Can control after drug oral or the injection speed that release fraction medicine in vivo discharges; And cultivate the inside and outside that can be used for cell, tissue; Fixing of enzyme transplanted in the blood vessel of bio-pharmaceutical.
Background technology
Microcapsule is nearly more than 20 years technology of rising, and has obtained abroad using widely.Except industries such as spice, cosmetics, weavings, microcapsule also is widely used on medicine, health product, processes oral rapidly disintegrating agent and easy oxidation, is prone to decomposition, the not good medicine of taste such as being used to.
Microcapsule system utilize natural or synthetic macromolecular material (being referred to as the capsule material) as cyst membrane wall shell, will be solid-state or liquid drug wrap up and become Drug Storage type microencapsulation.The advantage of microcapsule comprises: can be made into multiple pharmaceutical preparation; Liquid drug can be changed system into solid dosage forms; Delay drug release, preparation slow release long-acting preparation; Cover the bad flavor of smelling of medicine, can be easy to swallow; The compatibility that reduces compound medicine changes; Improve the side reaction of oral drugs digestive tract; Improve stability of drug, reduce the incompatibility of compound preparation; Medicine is worked at target site; The semi permeability microcapsule also has special effect to enzyme preparation,, as is made into and does not dissolve the semi permeability microcapsule the immunoreation of human body tool like asparaginase, and blood can be done in order to treat leukemia through semipermeable membrane and asparaginase; Microcapsule also can improve the physical characteristic of some drugs, like compressibility and flowability.Using maximum microcapsule advantages is to form sustained-release preparation and targeting preparation through microencapsulation method; Some microcapsules can also be wrapped in living cells or bioactive substance in the capsule.The capsule material of microcapsule want nontoxic non-stimulated, chemical property is stablized, have suitable release property, certain intensity is arranged, qualified characteristics such as viscosity are arranged; Capsule material commonly used mainly contains natural polymer ascus material, like gelatin, arabic gum, agar, alginic acid and salt, chitosan etc.; Semi-synthetic high score ascus material is like sodium carboxymethyl cellulose, cellulose acetate carbonic ester, ethyl cellulose, methylcellulose, hydroxypropyl cellulose; Synthetic high polymer capsule material comprises biodegradable carbon ester, polyamino acid, poly lactose, lactide glycolide copolymer, polylactic acid-polyglycol block copolymer, nonbiodegradable polyamide, the silicone rubber etc. of gathering.
The profile of microcapsule can be depending on the character of core material and the cohesion mode and the skilled operation degree of capsule material, and scrotiform can be spherical entity or be level and smooth spherical putamina shape, beading shape and surface smoothing, folding irregular structure etc.The diameter of different shape microcapsule, the dust head is several microns～tens microns.The microcapsule of processing can supply the basic material of various dosage form preparations such as powder, capsule, granule, electuary, tablet, pill, injection, implant and ointment.
Bioactive substances such as enzyme, protein and hormone are encapsulated in the selective permeation film, form spherical microcapsule, be referred to as " bio-microcapsule ".Selection through microcapsule membrane sees through effect; The outer material greater than a certain molecular weight of capsule can not be diffused into; And the micromolecule product of bioactive substance or the emiocytosis microcapsule of can freely coming in and going out in nutritional labeling in the biotic environment and the capsule, thereby reach immune isolation purpose.
Microcapsule can be expanded the application of oils raw material in industry and daily life.Utilize common process to be difficult to be processed into solid formulation like beta-carotene, vitamin A, vitamin E, fish oil, Radix Oenotherae erythrosepalae oil, Semen Vitis viniferae oil, Fructus Perillae wet goods oily substance; And utilize microcapsule can oils be processed into solid formulation, thereby further be processed into tablet, solid product such as capsule even powder.
In addition, utilize the microcapsule technology also can with other various health care oils raw materials be processed into tasteless powder and join milk, coffee, etc. in the food, thereby expanded the range of application of oils health product such as fish oil greatly.
Along with the development that material technology is maked rapid progress, some cheap and good-quality new materials are developed successively becomes the new raw material that is fit to be processed into the microcapsule shell, and the production cost of microcapsule begins to decline to a great extent.By the difference of its character, the capsule casing material of having developed use at present abroad mainly contains following 6 types:
1, polysaccharide/water-setting gelatin substance is like starch, Algin, agar, pectin, carrageenan (carrageenin) and other glue class.
2, protein and albumin are like gelatin, tyramine, zein, soybean protein and albumin etc.
3, fat and fatty acid are like monoglyceride, glycerol dibasic acid esters and triglyceride, lauric acid, sad, Palmic acid, stearic acid and salt thereof.
4, cellulose esters is like methylcellulose, ethyl cellulose, CMC, HPMC or the like.
5, hydrophilic and lipophile wax are like Lac, Cera Flava, Brazil wax and macromole Polyethylene Glycol etc.
6, sucrose derivative, like sucrose fatty acid ester etc., this type material has good water-solubility and good film forming fastness, so very suitable fish oil, Radix Oenotherae erythrosepalae oil and VE, VA and other oily raw material are processed into microcapsule.
The process of preparation microcapsule is called microencapsulation, and microencapsulation method commonly used has physico-chemical process, physical mechanical method, chemical method.Traditional microcapsule process technology adopts water law processing, promptly utilizes twin-jet nozzle will spray the droplet-like microcapsule and falls in the Sheng dish that cooling water is housed in advance through freely falling body.Softish hot microcapsule is cooling rapidly in cooling water, becomes the round bead shape utricule automatically owing to the tension force effect of water, after drying promptly becomes finished product.This technology is still being used in all over the world many enterprises at present; Because of its technology is simple, need not complicated drying equipment, adopt so be fit to very much middle-size and small-size drugmaker.
Because the range of application of microcapsule enlarges gradually; So its technological exploitation is also constantly deepened thereupon; Such as microcapsule being processed into the only ultra micro microcapsule about 1 micron of diameter; Can be used for being developed further into the oral cavity and dissolve brand-new dosage form such as sheet, fast disintegrating tablet or enteric coatel tablets soon, this lays a good foundation for the smooth exploitation of new drug.
The microcapsule process technology has the great development space in medicine, health product production or other all trades and professions, some raw material can improve its practicality greatly after being processed into microcapsule.At foreseeable future, microcapsule will become one of modal product on the international medical market, and its market prospect is extremely bright.
Domestic research to microcapsule; Polymers such as useful Resina persicae, CAP, CMC and gelatin etc. are as the capsule material; Also obtain certain progress with the complex coacervation encapsulation and with gelatin or the single cohesion of CAP microcapsule process; And carried out water soluble drug such as chondroitin sulfate, and polyethylene glycol 6000 carries out the research of encapsulation for the capsule material, desk study the extracorporeal releasing test of taeniafuge agrimophol microcapsule; Aspect Chinese medicine preparation, also adopted complex coacervation, Oleum Viticis Negundo has been processed the Oleum Viticis Negundo microencapsule tablet.The unit that has is in addition also studied Folium Viticis Negundo oil, Filifolium sibiricum (Linn.) Kitam. wet goods; The unit that has is studied contained 0.2% volatile oil in the Bulbus Allii; Allicin and allicin are prone to oxidation and gastrointestinal mucosal are had zest in the oil under light, temperature effect, after Bulbus Allii volatile oil is processed the garlicin microcapsule, not only make liquid drug become solid dosage; And improved stability; Covered strong impulse and smelt pungent, and through clinical observation 155 routine acute and chronic bacillary dysentery, effective percentage reaches 94.2%.
Since the physiological Study chamber Lim of University of Toronto in 1980 and Sun Mianfang (A.M.Sun) professor have invented APA (alginate-polylysine-alginate; APA) since the microcapsule, the APA microencapsulation of biological activity cell or tissue is transplanted has become the most promising experimental technique that carries out the interior relevant internal organs of biological cell or tissue transplantation treatment body or function of organization's disappearance disease clinically.But the activity of the size of microcapsule, intensity, permeability and transplanted cells is directly connected to a series of fundamental issues such as the time, side effect of in vivo transplantation site of cell or tissue, survival.If microcapsule is too little, then cell possibly wrap up not goodly, and the ratio of defects of microcapsule also diminishes along with the microcapsule scrotiform and increases, and transplantation site is selected difficulty, little microcapsule insufficient strength, and microcapsule breaks and causes cell to leak, and will inevitably cause rejection; The scrotiform ratio of defects of big microcapsule is less, and intensity is higher, but the difficult growth of the exchange of nutrient substance and cell, volume also can cause being prone to cause the rejection of body greatly; The big microcapsule liquefaction capsule heart is relatively poor, also is prone to cause permeability bad, and the immunity that directly influences microcapsule is isolated and to the response effect of endogenous material.
Chitosan is a kind of multifunctional material; Nontoxic, chemical stability good; Preparation calcium alginate-chitosan microcapsules normally is suspended in the calcium alginate core particle that makes in the chitosan calcium salt colloid solution for preparing and forms film, and preparation condition is gentle, does not need organic solvent; Be suitable for having bioactive protein drug, good application also arranged at chemical industry, Food Science etc.But the permeability of its cyst membrane and mechanical strength still are two big factors of its extensive use of puzzlement.Bibliographical information Ca
2+And Ba
2+Also all can with the chitosan film forming, be used for preparing microcapsule.
The present invention has combined the advantage of little microcapsule and big microcapsule, has prepared a kind of compound microcapsule, and compound microcapsule external capsule diameter can be 1～5mm; And the folliculus diameter can be 50～800 μ m; Two kinds of microencapsulated materials are the common used material of microcapsule preparation, and the advantage of external capsule is that intensity height, good in integrity, isolation effect are good, and that the advantage of capsula interna is a dead volume is little, specific surface area is big, entrapment efficiency is high; But capsula interna exists breakage rate big because volume is less; Shortcomings such as the immunity isolation effect is poor, and intensity is poor slightly can be remedied by external capsule; External capsule also can delay the release of capsula interna Chinese medicine; Avoid the rapid release of capsula interna Chinese medicine; Increased the immune isolation effect of capsula interna; Envelop rate, drug loading, the stability of medicine are further improved, and the multiple capsule of parcel cell or biological tissue also can further reduce the destruction of some small-molecule substances to cell in the capsula interna.
With this compound microcapsule for preparing, has following advantage: 1, can realize dead volume less in the capsula interna and bigger reference area, when histiocyte is survived, keep active preferably in capsula interna; 2, outer capsule volume increases, and approach increased when it was used in vivo and in vitro, can be made into oral sustained-release preparation; In case 3 external capsules break or there is distortion on the surface, cause permeability to increase, immune system can not produce rejection to the transplanted cells in the capsula interna at once yet; 4, because the obstruct of external capsule, even so external capsule shrinkage capsula interna can not flow out to outside the big capsule yet, can prevent the outflow of material in the capsula interna; 5, parcel cell or biological tissue carry out the multiple capsule of transplanting in In vitro culture or the body; Because the obstruct of external capsule and capsula interna; Can get into trophocyst inner cell in the capsula interna with intravital nutrient substance in the culture fluid; In host's the immune shielding system capsula interna then more difficult to get access, make immune isolation effect better, the active substance of the nucleus tissue secretion in the capsula interna can produce therapeutic effect; 6, can wrap up chemicals, Chinese medicine, biological cell or tissue respectively in external capsule and the capsula interna, materials such as anticoagulant, somatomedin can help graft survival and increase the anti-anticoagulant effect of coagulating.And single medicine capsule rate of release is very fast, and the ratio of defects of little microcapsule is also bigger.
For the preparation of compound Emulsion, domestic existing stable double emulsion (200880021575.4), this patent is studied the preparation of emulsion; All the other (1) by the method (00128884.9) of multi-emulsion method manufacturing slow-releasing microsphere, (2) multi-emulsion method prepares magnetic macromolecular microsphere (200310113439.7) etc., also all is the method for preparinies with emulsion, prepares relevant slow control-release microsphere; The patent of other relevant microcapsules also has: (1) utilizes the method (02116987.X) of sodium alginate-chitose-sodium alginate microcapsule embedding cell or tissue; (2) curcuma zedoary oil nano capsule freeze dried ampoule powder for injection and preparation technology thereof multinomial patent applications such as (01131732.9); Be prepared into single capsule but be, preparation technology is simple, but changes still such as the envelop rate of medicine, stability, release are bigger; Prescription, complex process, even do not have slow controlled-release effect.
The drug-supplying system of this compound microcapsule preparation is compared with single capsule preparation and emulsion preparation; Have the medicament selection scope big, discharge more controlled, prescription is simple, good stability, preparation technology is simple, repetitive rate is high, cost is low, the efficient advantages of higher; The compound microcapsule of basis system is insoluble in simulated gastric fluid, and drug release is slower, slowly dissolves at the simulated intestinal fluid Chinese medicine; Also slower in the water drug release, medicine can slowly be discharged in gastrointestinal tract and other positions of body.
Summary of the invention
To the objective of the invention is that a kind of preparation is simple, the medicament selection scope is wide in order providing, and to make compound microencapsulated delivery system that drug slow discharges and preparation method thereof.Compare with single capsule, the present invention is with the obvious advantage in medicine sustained and controlled release and inside and outside application, and its immune isolation effect has obtained improving greatly.
The objective of the invention is to realize like this:
A kind of compound microcapsule of the present invention and preparation method thereof; Its compound microcapsule by 1-100 capsula interna again 1 layer of external capsule of outsourcing constitute; One or more combination in capsula interna parcel chemicals, Chinese medicine, biological cell and the tissue sample, external capsule is the one or more combination in parcel capsula interna, chemicals, Chinese medicine, biological cell and the tissue sample.
Described a kind of compound microcapsule and preparation method thereof; It further is suspended in the external capsule encystation solution on the basis that capsula interna is accomplished, and carries out the secondary encystation; Outside several capsula internas, form one deck external capsule, the interpolation freeze drying protectant carries out lyophilization or adds cell culture fluid and carry out In vitro culture.
Described a kind of compound microcapsule and preparation method thereof; The one-tenth capsule material of its capsula interna is: with sodium alginate, calcium chloride, barium chloride, chitosan, gather left lysine etc. for becoming capsule material; Sodium alginate is edible and the pharmaceutic adjuvant that meets the U.S. and Chinese Pharmacopoeia; As the sizing agent and the printing paste of textile, be widely used in the food industry as thickening agent, stabilizing agent, emulsifying agent simultaneously; China's regulation can be used for varieties of food items, needs an amount of the use by production.Have the cholesterol of making and excrete, suppress Pb, Cd, Sr is absorbed by the body and protects gastrointestinal tract, whole intestinal, fat-reducing, hypoglycemic effect.Main as suspending agent, stabilizing agent, emulsifying agent, thickening agent, sticky dose, the capsule material of dispersant, gellant, fruit glaze agent, suspending agent, microcapsule etc. on medicament; Being prepared as of capsula interna: use earlier the sodium alginate soln of distilled water compound concentration as 0.5%-3.0%; With medicine or biological tissue and its mixing, through HV generator and Micropump, adjustment voltage, tack pin and syringe needle are from liquid level; Drip a kind of to in two kinds of solution of calcium chloride, barium chloride of the 25-200mmol/1 of magnetic agitation; Obtaining size is the glue pearl of 50-800 μ m, removes supernatant behind the reaction 10min, with normal saline washing 2 times; The glue pearl thrown one of gather in chitosan two solution of left lysine solution, 0.05%-1.0% the person to 0.01%-0.5% and continue to stir 5min; Remove supernatant and with normal saline washing 2 times; And then be fed in the sodium alginate soln of 0.05%-0.5% and stir 5min, remove supernatant and obtain capsula interna with after the normal saline washing 2 times.
Described a kind of compound microcapsule and preparation method thereof; The another kind of method for preparing of its capsula interna is: with the sodium alginate parcel of above-mentioned process 0.05%-0.5% and the capsula interna after the normal saline washing; Throw again to the sodium citrate solution of 20-100mM and stir; 3～10min with normal saline washing 2 times, obtains capsula interna.
Described a kind of compound microcapsule and preparation method thereof, the one-tenth capsule material of its external capsule is: with sodium alginate, calcium chloride, barium chloride, chitosan, gather left lysine etc. for becoming capsule material; Being prepared as of external capsule: use distilled water that sodium alginate is made into the solution of concentration as 0.5%-3.0% earlier, with the one or more combination in capsula interna, chemicals, Chinese medicine, biological cell and the tissue sample and this sodium alginate soln mixing; Adopt dropper; The sodium alginate soln that is mixed with capsula interna is dripped a kind of to in two kinds of solution of calcium chloride, barium chloride of the 25-200mmol/1 of magnetic agitation; Remove supernatant behind the reaction 10min, obtaining size is the glue pearl of 1-5imm, with normal saline washing 2 times; The glue pearl thrown one of gather in chitosan two solution of left lysine solution, 0.05%-1.0% the person to 0.01%-0.5% and continue to stir 5min, remove supernatant and with normal saline washing 2 times; And then be fed in the sodium alginate soln of 0.05%-0.5% and stir 5min, remove supernatant and obtain compound microcapsule with after the normal saline washing 2 times; Compound microcapsule is placed freeze drying protectant lactose, sodium chloride, and the one or more combination in the mannitol solution is carried out lyophilization; Or add cell culture solution, in 37 ± 0.5 ℃ of incubators, cultivate.
Described a kind of compound microcapsule and preparation method thereof; The another kind of method for preparing of its external capsule is: by the sodium alginate soln of the above-mentioned 0.05%-0.5% of being fed into and with obtaining compound microcapsule after the normal saline washing; Throw again to the sodium citrate solution of 20-100mM and stir 3～20min; With normal saline washing 2 times, obtain compound microcapsule; Compound microcapsule is placed freeze drying protectant lactose, sodium chloride, and the one or more combination in the mannitol solution is carried out lyophilization; Or add cell culture solution, in 37 ± 0.5 ℃ of incubators, cultivate.
Description of drawings:
Fig. 1 is a compound microcapsule sketch map of the present invention
Fig. 2 is the drug release curve chart according to the compound microcapsule of indomethacin of embodiment 1 preparation
Fig. 3 is the drug release curve chart according to the compound microcapsule of indomethacin of embodiment 3 preparations
The specific embodiment:
See Fig. 1, this compound microcapsule is made up of external capsule 1 and capsula interna 2, and this compound microcapsule can be used for wrapping up chemicals, Chinese medicine, biological cell and tissue etc., and ability control drug release speed improves stability of drug, improves the immune isolation effect of biological cell and tissue.
Embodiment 1:
The preparation of the compound microcapsule of indomethacin-ACA-Ca-Ca:
(1) preparation of capsula interna:
A, indomethacin is crossed 100 mesh sieves, and be drawn to the 20ml syringe behind the sodium alginate soln mixing of 1-1.5ml1.8%.
B, use the high-pressure electrostatic method, adjustment voltage, adopt 6# tack syringe needle and syringe needle, the sodium alginate solution of pastille is splashed into the CaCl of the 80ml100mM of band magnetic agitation from liquid level 2cm
2In the solution, form the insoluble calcium alginate microsphere of particle diameter 500-700 μ m, remove supernatant behind the 10min,, obtain the glue pearl with normal saline washing 2 times.
C, the glue pearl thrown to 0.3% chitosan solution continue to stir 5min, remove supernatant and with normal saline washing 2 times.
D, will wrap up glue pearl behind the chitosan and be fed in 0.15% the sodium alginate soln and stir 5min, and remove supernatant and, remove normal saline as far as possible, promptly get the pastille capsula interna with normal saline washing 2 times.
(2) preparation of external capsule:
A, with the above-mentioned pastille capsula interna for preparing once more with 1.8% sodium alginate uniform mixing of 2 times of volumes.
B, employing disposable plastic dropper drop to the sodium alginate soln that is mixed with the indomethacin capsula interna 100mM CaCl that is with magnetic agitation
2In the solution, reaction 10min forms the calcium alginate microballon that contains the APA microcapsule; With normal saline washing 2 times.
C, the abandoning supernatant of trying one's best add to microcapsule among the 0.3% chitosan solution 10m1, and reaction 5min is with normal saline washing 2 times, abandoning supernatant.
D, micro gel bead is suspended among 0.15% the sodium alginate soln 15ml, reaction 5min washes 2 times with normal saline, removes unnecessary sodium alginate, and abandoning supernatant obtains containing the compound ACA-Ca-Ca microcapsule of indomethacin.
(3) drug release test
Get 10 in the multiple capsule that contains indomethacin, throw to the commentaries on classics basket of medicament dissolution instrument.According to two drug release determination method first methods of Pharmacopoeia of the People's Republic of China version in 2010, with the 250ml anti-cold distilled water that newly boils, adding 1% sodium lauryl sulphate is release medium, rotating speed 100rmin
-1, medium temperature (37.04 ± 0.5) ℃ is respectively at different time sampling 5mL; Replenishing equal-volume equality of temperature release medium simultaneously, survey absorbance in the 265nm place behind the 0.45 μ m filtering with microporous membrane excessively, is blank with the release medium; Calculate the cumulative release percentage rate of medicine, and the drug release curve that draws.The release profiles of medicine is seen Fig. 2; Wherein 1 is the drug release of the compound microcapsule of indomethacin-ACA-Ca-Ca, and 2 is the drug release of the single capsule of indomethacin-ACA-Ca, visible by figure; Medicine wraps up to the compound microcapsule of ACA-Ca-Ca, and have prolongation than the indomethacin in parcel to single capsule release time.
Embodiment 2:
The preparation of the compound microcapsule of rat Langerhans islet-APA-Ca-Ca:
(1) preparation of capsula interna:
Be drawn to the 20ml syringe behind A, the sodium alginate soln mixing with rat Langerhans islet behind the purification and 1-1.5ml1.8%.
B, with high-pressure electrostatic method (or claim orifice-coagulating bath method), adjustment voltage, adopt 9# tack pin and syringe needle from liquid level 2cm, the sodium alginate solution that will contain islets of langerhans splashes into the CaCl of the 80ml100mM of band magnetic agitation
2In the solution, form the insoluble calcium alginate microsphere of particle diameter 400-600 μ m, remove supernatant behind the 10min, with normal saline washing 2 times.
C, the glue pearl is fed into 0.05% gathers and continue in the left lysine solution (PLL) to stir 5min, remove supernatant and with normal saline washing 2 times.
D, will wrap up glue pearl behind the PLL and throw and to 0.15% sodium alginate soln, stir 5min, remove supernatant and with normal saline washing 2 times.Eliminate normal saline as far as possible, promptly get the APA-Ca capsula interna that contains rat Langerhans islet.
(2) preparation of external capsule:
A, 1.8% sodium alginate be through 0.45 μ m, and the filtering with microporous membrane of 0.22 μ m is with 1.8% sodium alginate uniform mixing of the above-mentioned capsula interna for preparing and 2 times of volumes.
B, employing glass dropper drop to 100mM CaCl with the sodium alginate soln that is mixed with rat Langerhans islet-APA microcapsule
2In the solution, disperse with magnetic stirrer), reaction 10min forms the calcium alginate microballon that contains the APA capsula interna; With normal saline washing 2 times.
C, the abandoning supernatant of trying one's best add to 0.05% with microcapsule and gather among the left lysine solution 10ml, reaction 5min.With normal saline washing 2 times, abandoning supernatant.
D, micro gel bead is suspended among 0.15% the sodium alginate soln 15ml, reaction 5min washes 2 times with normal saline, removes unnecessary sodium alginate, abandoning supernatant.
E, microsphere is suspended in the citric acid soln of 55mM reaction 10min, the liquefaction capsule heart; With normal saline washing 2 times; The post precipitation abandoning supernatant is removed excessive citric acid and liquid seaweed acid sodium, obtains containing the compound APA-Ca-Ca microcapsule of rat Langerhans islet-APA-Ca capsula interna.
F, compound microcapsule is placed RPMI1640 solution, 37 ± 0.5 ℃ of overnight incubation.
(3) sugar stimulates the insulin release experiment
The islets of langerhans of compound microencapsulation is put in 24 well culture plates 37 ℃ of incubators by the amount of 50IEQ cultivates 24h, discard culture fluid after, fill it up with the RPMI1640 culture fluid of LG (2.22mmol/L); Behind 37 ℃ of static cultivation 1h; Exhaust culture fluid, every pipe 1ml ,-20 ℃ of preservations; Fill it up with high glucose (22.2mmol/L) RPMI1640 culture fluid again, exhaust culture fluid behind 37 ℃ of static cultivation 1h, every pipe 1ml ,-20 ℃ of preservations are exempted from the kit measurement insulin concentration with the rat insulin enzyme, calculate SI (SI) by following formula simultaneously:
The result: the insulin secretion concentration of islets of langerhans under low sugar is 15.51 ± 2.68mIU/L, and high sugared insulin secretion concentration down is 27.85 ± 3.64mIU/L, and insulin release was 1.8 times that low sugar stimulates under high sugar stimulated, and the SI value is 1.80 ± 0.49.Explaining behind the compound microencapsulation of rat Langerhans islet still has activity, and the release of insulin can be arranged under the stimulation of glucose.
Embodiment 3:
The preparation of the compound microcapsule of indomethacin-ACA-Ba-Ba:
1, the preparation of capsula interna:
A, be drawn to the 20ml syringe after indomethacin crossed behind 100 mesh sieves sodium alginate soln mixing with 1-1.5m11.8%.
B, use the high-pressure electrostatic method, adjustment voltage, adopt 4# tack syringe needle and syringe needle, sodium alginate solution is splashed into the BaCl of the 80ml25mM of band magnetic agitation from liquid level 1cm
2In the solution, form insoluble calcium alginate microsphere, remove supernatant behind the 10min,, obtain the glue pearl with normal saline washing 2 times.
C, the glue pearl thrown to 0.5% chitosan solution continue to stir 8min, remove supernatant and with normal saline washing 2 times.
D, will wrap up glue pearl behind the chitosan and be fed in 0.15% the sodium alginate soln and stir 5min, and remove supernatant and, eliminate normal saline as far as possible, promptly get indomethacin-ACA-Ba capsula interna with normal saline washing 2 times.
2, the preparation of external capsule:
A, with 1.8% sodium alginate uniform mixing of the above-mentioned capsula interna for preparing and 2 times of volumes.
B, employing disposable plastic dropper drop to 100mMBaCl with the sodium alginate soln that is mixed with indomethacin-ACA-Ba microcapsule
2In the solution, disperse with magnetic stirrer, reaction 10min forms the compound microballon of alginic acid barium that contains ACA-Ba-Ba; With normal saline washing 2 times.
C, the abandoning supernatant of trying one's best add to microcapsule among the 0.8% chitosan solution 10ml, reaction 5min.With normal saline washing 2 times, abandoning supernatant.
D, micro gel bead is suspended among 0.15% the sodium alginate soln 15ml, reaction 5min washes 2 times abandoning supernatant with normal saline.
E, compound microsphere is suspended in the citric acid soln of 55mM, reaction 10min, the liquefaction capsule heart, with normal saline washing 2 times, the post precipitation abandoning supernatant obtains the compound microcapsule of indomethacin-ACA-Ba-Ba.
F, add an amount of mannitol solution, place-20 ℃ of refrigerators to freeze reality, carry out lyophilization again at microcapsule.
Take out the freeze dried multiple capsule that contains indomethacin, throw to the commentaries on classics basket of medicament dissolution instrument.According to two drug release determination method first methods of Pharmacopoeia of the People's Republic of China version in 2010, with the 250ml anti-cold distilled water that newly boils, adding 1% sodium lauryl sulphate is release medium, rotating speed 100rmin
-1, medium temperature (37.0 ± 0.5) ℃ is respectively at different time sampling 5mL; Replenishing equal-volume equality of temperature release medium simultaneously, survey absorbance in the 265nm place behind the 0.45 μ m filtering with microporous membrane excessively, is blank with the release medium; Calculate the cumulative release percentage rate of medicine, and the drug release curve chart that draws.The release profiles of medicine is seen Fig. 3; Wherein 1 is the drug release of the single capsule of indomethacin-ACA-Ba, and 2 is the drug release of the compound microcapsule of indomethacin-ACA-Ba-Ba, visible by Fig. 3; Medicine wraps up to the compound microcapsule of ACA-Ba-Ba, and greatly prolong than the indomethacin in parcel to single capsule release time.
Claims (5)
1. compound microcapsule; Form by capsula interna and external capsule; It is characterized in that: by 1-100 capsula interna again 1 layer of external capsule of outsourcing constitute; One or more combination in capsula interna parcel chemicals, Chinese medicine, biological cell and the tissue sample, external capsule is the one or more combination in parcel capsula interna, chemicals, Chinese medicine, biological cell and the tissue sample.
2. a kind of compound microcapsule according to claim 1 and preparation method thereof is characterized in that: capsula interna with sodium alginate, calcium chloride, barium chloride, chitosan, gather one or more combination in the left lysine for becoming capsule material; The method for preparing of capsula interna is: use earlier the sodium alginate soln of distilled water compound concentration as 0.5%-3.0%; With medicine or biological tissue and its mixing, through HV generator and Micropump, adjustment voltage, tack pin and syringe needle are from liquid level; Drip a kind of to in two kinds of solution of calcium chloride, barium chloride of the 25-200mmol/1 of magnetic agitation; Obtaining size is the glue pearl of 50-800 μ m, removes supernatant behind the reaction 10min, with normal saline washing 2 times; The glue pearl thrown one of gather in chitosan two solution of left lysine solution, 0.05%-1.0% the person to 0.01%-0.5% and continue to stir 5min; Remove supernatant and with normal saline washing 2 times; And then be fed in the sodium alginate soln of 0.05%-0.5% and stir 5min, remove supernatant and obtain capsula interna with after the normal saline washing 2 times;
3. a kind of compound microcapsule according to claim 2 and preparation method thereof; It is characterized in that: the another kind of method for preparing of capsula interna is: the capsula interna that obtains by claim 2 is thrown to the sodium citrate solution of 20-100mM again and is stirred 3～10min; With normal saline washing 2 times, obtain capsula interna.
4. a kind of compound microcapsule according to claim 1 and preparation method thereof, it is characterized in that: the one-tenth capsule material of external capsule is: with sodium alginate, calcium chloride, barium chloride, chitosan, gather one or more combination in the left lysine for becoming capsule material; The method for preparing of external capsule is: use distilled water that sodium alginate is made into the solution of concentration as 0.5%-3.0% earlier, with the one or more combination in capsula interna, chemicals, Chinese medicine, biological cell and the tissue sample and this sodium alginate soln mixing; Adopt dropper; The sodium alginate soln that is mixed with capsula interna is dripped a kind of to in two kinds of solution of calcium chloride, barium chloride of the 25-200mmol/1 of magnetic agitation; Remove supernatant behind the reaction 10min, obtaining size is the glue pearl of 1-5mm, with normal saline washing 2 times; The glue pearl thrown one of gather in chitosan two solution of left lysine solution, 0.05%-1.0% the person to 0.01%-0.5% and continue to stir 5min, remove supernatant and with normal saline washing 2 times; And then be fed in the sodium alginate soln of 0.05%-0.5% and stir 5min, remove supernatant and obtain compound microcapsule with after the normal saline washing 2 times; Compound microcapsule is placed freeze drying protectant lactose, sodium chloride, and the one or more combination in the mannitol solution is carried out lyophilization; Or add cell culture solution, in 37 ± 0.5 ℃ of incubators, cultivate.
5. a kind of compound microcapsule according to claim 4 and preparation method thereof; It is characterized in that: the another kind of method for preparing of external capsule is: the compound microcapsule that obtains by claim 4 is thrown to the sodium citrate solution of 20-100mM again and is stirred 3～20min; With normal saline washing 2 times, obtain compound microcapsule; Compound microcapsule is placed freeze drying protectant lactose, sodium chloride, and the one or more combination in the mannitol solution is carried out lyophilization; Or add cell culture solution, in 37 ± 0.5 ℃ of incubators, cultivate.
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| CN2012102734443A CN102805741A (en) | 2012-08-02 | 2012-08-02 | Compound micro-capsule and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103788606A (en) * | 2014-02-07 | 2014-05-14 | 上海应用技术学院 | Modified polylactic acid composite material containing peach gum powder and preparation method thereof |
| CN106036829A (en) * | 2016-05-27 | 2016-10-26 | 天津科技大学 | Compound mature vinegar micro-capsules as well as preparation method and application thereof |
| CN106606804A (en) * | 2015-10-22 | 2017-05-03 | 四川蓝光英诺生物科技股份有限公司 | Preparation method of composite structure |
| CN113679842A (en) * | 2021-06-22 | 2021-11-23 | 重庆理工大学 | Preparation method and application of two-phase drug-loaded gel beads |
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2012
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| S.M. CHIA ET AL: "Multi-layered microcapsules for cell encapsulation", 《BIOMATERIALS》 * |
| 吕超等: "ACA 微囊的处方和工艺因素对囊膜通透性及强度的影响", 《温州医学院学报》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103788606A (en) * | 2014-02-07 | 2014-05-14 | 上海应用技术学院 | Modified polylactic acid composite material containing peach gum powder and preparation method thereof |
| CN106606804A (en) * | 2015-10-22 | 2017-05-03 | 四川蓝光英诺生物科技股份有限公司 | Preparation method of composite structure |
| CN106606804B (en) * | 2015-10-22 | 2020-05-12 | 四川蓝光英诺生物科技股份有限公司 | Method for preparing composite structure |
| CN106036829A (en) * | 2016-05-27 | 2016-10-26 | 天津科技大学 | Compound mature vinegar micro-capsules as well as preparation method and application thereof |
| CN113679842A (en) * | 2021-06-22 | 2021-11-23 | 重庆理工大学 | Preparation method and application of two-phase drug-loaded gel beads |
| CN113679842B (en) * | 2021-06-22 | 2022-11-15 | 重庆理工大学 | Preparation method and application of two-phase drug-loaded gel beads |
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Application publication date: 20121205 |