CN1140263C - Medicine release-controlled microcapsule with dual-layer membrane and its preparing process - Google Patents
Medicine release-controlled microcapsule with dual-layer membrane and its preparing process Download PDFInfo
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- CN1140263C CN1140263C CNB011043644A CN01104364A CN1140263C CN 1140263 C CN1140263 C CN 1140263C CN B011043644 A CNB011043644 A CN B011043644A CN 01104364 A CN01104364 A CN 01104364A CN 1140263 C CN1140263 C CN 1140263C
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Abstract
The present invention relates to a double-film medicine release-controlled microcapsule which is a sodium alginate/chitosan microcapsule with a double-film structure. In the preparation method of the microcapsule, the sodium alginate/chitosan microcapsule with a double-film structure is prepared by a secondary film forming reaction. The microcapsule uses natural polymer sodium alginate and chitosan which have good biocompatibility, good degradable performance and good film forming characteristics as main materials which are rich in the natural world. Thus, the present invention has the advantage of low cost and is suitable for mass production.
Description
Technical field
The present invention relates to a kind of medicine release-controlled microcapsule with dual-layer membrane and preparation method thereof.
Background technology
Controlled-release technology is that chemical substance or biochemical are slowly discharged to reach the technology of effective utilization and reduction toxic and side effects target, has all shown wide application prospect in fields such as medicine, pesticide, chemical fertilizer, household chemicalss.Wherein, the microencapsulation technology is the main direction of controlled release carrier research always, particularly shows good performance in the medicine controlled releasing field.The development of recombinant DNA technology make gene engineering peptides and protein medicaments realize large-scale production and be widely used in clinical, the very important effect of performance in the treatment of a lot of major diseases.For example, be used for the treatment of the interleukin II of tumor, the interferon of treatment viral hepatitis, the insulin of treatment diabetes etc.Problems such as yet this class medicine exists, and the body internal stability is poor, the half-life is short.Therefore, researcher is constantly explored new controlled drug delivery system (J.Pharm.Pharmacol.1996,48 (3): 258-62, J.Pharm.1999,177 (2): 211-20).Wish to keep stability of drug, improve the drug utilization degree, reduce dosage and toxic and side effects, realize target administration according to diseased region simultaneously by this controlled release system.
Two kinds of natural polymers of sodium alginate and chitosan have excellent biological compatibility, and can under temperate condition, carry out polyelectrolyte complex reaction formation microcapsule, be beneficial to and keep the especially activity of protein medicaments of medicine, therefore paid close attention to by numerous researcher as the ideal carrier of medicine controlled releasing.Utilize alginate microcapsule (hereinafter to be referred as the ACA microcapsule) must obtain good strength character and controlled release properties as medicine controlled release carrier.Film-strength is most important to safety in utilization, and the cracking of microcapsule membrane can cause the rapid release of embedding medicinal, thereby causes a series of bad pharmacological reaction of human body, even drug intoxication, and is very dangerous in clinical practice.Controlled release properties decision drug release rate and associated blood drug level level.Film-strength and controlled release properties are not only relevant with the character of chitosan material such as molecular weight, deacetylation, and with the closely related (J.Appl.Polym.Sci.1994 of preparation route, process conditions of microcapsule, 51:1427-32, J.Pharm.Sci.1994,83:178-85).According to existing bibliographical information, at present the ACA microcapsule is selected at material, all there are certain problem in preparation route and process conditions, fails to solve the contradiction that microcapsule membrane intensity and controlled release properties can not be unified.
Summary of the invention
The objective of the invention is to overcome the existing problem of above-mentioned microcapsule, a kind of medicine release-controlled microcapsule with dual-layer membrane is provided, this microcapsule has high strength and good controlled release properties.In addition, the present invention also provides the method for preparing this medicine release-controlled microcapsule with dual-layer membrane and preparation thereof.
To achieve these goals, the present invention proposes the imagination that calcium alginate gel beads and chitosan solution carry out the two-step film forming reaction, and the prescription and the technology of two-step film forming are provided, prepared double-deck ACA film microcapsule with high strength and good controlled release properties.In the microcapsule preparation process, film forming characteristics according to different molecular weight, different deacetylation chitosans, consider that simultaneously different pharmaceutical changes very responsive characteristics to temperature, pH environment etc., under the prerequisite that guarantees higher entrapment efficiency, selection is prepared as follows route and the film formation reaction condition obtains medicine release-controlled microcapsule with dual-layer membrane.
Specifically, medicine release-controlled microcapsule with dual-layer membrane of the present invention is a kind of medicine controlled releasing microcapsule, it is characterized in that it being the alginate microcapsule of double membrane structure.Wherein film forming is under 15-35 ℃ for the first time, press calcium alginate and chitosan solution volumetric usage than 1: 2-8 reaction 10-50 minute, film forming is to be the sodium alginate soln rubber cover bead surface of 0.1-1.5% with the 2-5 volumetric concentration earlier for the second time, again with chitosan solution reaction 10-30 minute; Used chitosan solution concentration is 0.1-2%, and the chitosan molecule amount is 10,000-800,000, and deacetylation is 60-98%.
In the medicine controlled releasing microcapsule of the above, the interval that it is characterized in that described chitosan molecule amount is 10,000-800,000, and deacetylation is 60-98%.
In the medicine controlled releasing microcapsule of the above, the interval that it is characterized in that described chitosan molecule amount is 10,000-150,000, and the second layer is 150,000-800,000, and deacetylation is 60-98%.
Also have, the preparation method of medicine controlled releasing microcapsule of the present invention is the poly-capsule of sodium alginate/shell that becomes double membrane structure through the two-step film forming prepared in reaction.
In the preparation method of above-mentioned medicine controlled releasing microcapsule, it is characterized in that the used microencapsulation material of film formation reaction is sodium alginate, chitosan and polylysine, Polyethylene Glycol.
In addition, in above-mentioned preparation method, film formation reaction condition: under 15-35 ℃, by calcium alginate and chitosan solution volumetric usage than 1: 2-8 carries out the film formation reaction 10-50 minute first time, be the sodium alginate soln rubber cover bead surface of 0.1-1.5% then with the 2-5 volumetric concentration, carry out the film formation reaction 10-30 minute second time with chitosan solution again; Used chitosan solution concentration is 0.1-2%, and the chitosan molecule amount is 10,000-800,000, and deacetylation is 60-98%.
In addition, in the preparation method of above-mentioned medicine controlled releasing microcapsule, it is characterized in that described chitosan molecule amount the first time film formation reaction be 10,000-150,000, and for the second time film formation reaction is 150,000-800,000 chitosan.
Medicine release-controlled microcapsule with dual-layer membrane of the invention described above and preparation method thereof has following characteristics:
1. microcapsule is a main material with natural polymer sodium alginate and the chitosan with good biocompatibility, degradability and film forming characteristics, and occurring in nature content is abundant, and cost is low, is suitable for large-scale production.
2. the microencapsulation material that adopts of microcapsule is not had an effect with albumen, and gentle microcapsule film formation reaction condition makes the protein medicaments of embedding keep original activity in the microencapsulation process, and effectively shields taste.Behind the oral administration, microcapsule membrane makes medicine avoid enzymatic degradation in the digestive tract.
3. preparation double membrane structure microcapsule is the unification that has realized film-strength and controlled release properties, and it can be used for the preparation of other same type of material microcapsule except that the ACA microencapsulation material.
4. Zhi Bei double membrane structure microcapsule has high strength and good controlled release properties, and can control release rate of drugs by the adjusting of membrane structure.
5. Zhi Bei double membrane structure microcapsule has the good biological adhesiveness, it can be with the hydration mucomembranous cell on human body intestinal canal top layer sticking and, by oral administering mode can the prolong drug carrier in holdup time of these mucomembranous surfaces, medicine can directly be absorbed by human body through mucosa simultaneously, significantly improves bioavailability of medicament.
6. the microcapsule of this technology preparation has made full use of the swelling behavior and the pH sensitivity characteristic of gel, can control the dissolving out capability of medicine in different pH environment by the control microcapsule structure, promptly in simulation stomach, intestinal juice, show different dissolving out capability, outstanding intestinal canal administration advantage.
Description of drawings
Give simple explanation to accompanying drawing below.
Fig. 1 is the microcapsule photo with double membrane structure.
Fig. 2 for the microcapsule bovine hemoglobin discharge 7 hours after photo.
Fig. 3 is the influence curve figure that dissolution medium discharges bovine hemoglobin.
Fig. 4 is the stripping curve of insulin in simulated intestinal fluid.
The specific embodiment
Give further instruction below by embodiment to technology of the present invention.
The preparation of embodiment 1 double membrane structure ACA microcapsule
Under 20 ℃ of conditions, press calcium alginate and chitosan solution volumetric usage than 1: 2 film formation reaction 25 minutes, be 0.2% sodium alginate soln rubber cover bead surface then with 2.5 volumes, concentration, carry out the film formation reaction second time with chitosan solution again, the time is 20 minutes.Chitosan solution concentration wherein: 0.2%, the chitosan molecule amount: for the first time 70,000, for the second time: 200,000, deacetylation: 85%.Prepared double membrane structure ACA microcapsule (Fig. 1) with high strength and good controlled release properties.
Embodiment 2 application tests (I)
The double membrane structure microcapsule of embodiment 1 preparation, being placed in the simulation gastro-intestinal Fluid dispose procedure does not have breakage.And this microcapsule taken to mice, in mouse small intestine, stop and do not find capsule in 48 hours.
Embodiment 3 application tests (II)
Microencapsulated bovine hemoglobin in simulation gastro-intestinal Fluid the release prepared the method for pressing embodiment 1 still had a large amount of albumen (Fig. 2) that do not discharge after 7 hours in the microcapsule.
Embodiment 4 application tests (III)
Have only 15% by the embodiment 1 prepared release rate of ACA microencapsulated bovine hemoglobin in simulated gastric fluid, and release rate can reach more than 80% in simulated intestinal fluid, and release profiles at this moment discharges near zero level very much, and (the Y=0.0562x+0.1669 linear regression coeffficient is: R
2=0.9538) (as Fig. 3).This release behavior of ACA microcapsule can protect medicine not destroyed by the acid condition in the gastric juice, wants in the small intestinal of absorption site and arrive drug main smoothly.
In external stripping experiment, obtained the experimental result (as Fig. 4) that approximate zero level discharges by embodiment 1 prepared ACA microencapsulation insulin.Equation of linear regression is y=0.0365x+0.1027, linear regression coeffficient R
2=0.9869.Show that ACA microencapsulation insulin almost is a constant release in external stripping experiment.
Result by the foregoing description can see that the present invention has following outstanding advantage.
1. the material of the present invention's employing is degradable natural macromolecular material, and is without any side effects to human body, stable to property of protein simultaneously, promptly can finish the microencapsulation process under room temperature, neutral pH environment, satisfied the specific (special) requirements of medicine to carrier.
2. the present invention is according to the film forming characteristics of heterogeneity macromolecular material, and the ACA microcapsule with double membrane structure of development has high strength and good controlled release properties.
3. the stripping behavior of the ACA microcapsule of the present invention's preparation in the simulation gastro-intestinal Fluid can finely be satisfied medicine in the systemic requirement of small intestinal.
Claims (6)
1. medicine controlled releasing microcapsule, it is characterized in that it being the alginate microcapsule of double membrane structure, wherein film forming is under 15-35 ℃ for the first time, press calcium alginate and chitosan solution volumetric usage than 1: 2-8 reaction 10-50 minute, film forming is to be the sodium alginate soln rubber cover bead surface of 0.1-1.5% with the 2-5 volumetric concentration earlier for the second time, again with chitosan solution reaction 10-30 minute; Used chitosan solution concentration is 0.1-2%, and the chitosan molecule amount is 10,000-800,000, and deacetylation is 60-98%.
2. medicine controlled releasing microcapsule according to claim 1, the interval that it is characterized in that described chitosan molecule amount is 10,000-800,000, deacetylation is 60-98%.
3. medicine controlled releasing microcapsule according to claim 2, the interval that it is characterized in that described chitosan molecule amount is 10,000-150,000, and the second layer is 150,000-800,000, and deacetylation is 60-98%.
4. the preparation method of a medicine controlled releasing microcapsule, this method is: under 15-35 ℃, by calcium alginate and chitosan solution volumetric usage than 1: 2-8 carries out the film formation reaction 10-50 minute first time, be the sodium alginate soln rubber cover bead surface of 0.1-1.5% then with the 2-5 volumetric concentration, carry out the film formation reaction 10-30 minute second time with chitosan solution again;
Used chitosan solution concentration is 0.1-2%, and the chitosan molecule amount is 10,000-800,000, and deacetylation is 60-98%.
5. preparation method according to claim 4 is characterized in that the used microencapsulation material of film formation reaction is sodium alginate, chitosan and polylysine, Polyethylene Glycol.
6. preparation method according to claim 4, it is characterized in that described chitosan molecule amount the first time film formation reaction be 10,000-150,000, and for the second time film formation reaction is 150,000-800,000 chitosan.
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| CNB011043644A CN1140263C (en) | 2001-02-28 | 2001-02-28 | Medicine release-controlled microcapsule with dual-layer membrane and its preparing process |
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| CNB011043644A CN1140263C (en) | 2001-02-28 | 2001-02-28 | Medicine release-controlled microcapsule with dual-layer membrane and its preparing process |
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| CN1140263C true CN1140263C (en) | 2004-03-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100364517C (en) * | 2005-09-28 | 2008-01-30 | 浙江大学 | Water-soluble medicine degradable polymer microcapsule injecta and preparing method |
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| CN100418523C (en) * | 2005-08-30 | 2008-09-17 | 中南大学湘雅二医院 | Prepn process of double-layer catechin microcapsule |
| CN100436525C (en) * | 2006-02-16 | 2008-11-26 | 武汉理工大学 | Prepn of sodium alginate/chitosan mixture gel |
| CN1973901B (en) * | 2006-12-07 | 2010-05-19 | 浙江大学 | Composite microsphere preparation of lactic acid-hydroxyacetic acid copolymer and its preparation process |
| CN101703804B (en) * | 2009-11-25 | 2013-03-13 | 复旦大学附属中山医院 | Porous bone replacing material for control release of antibioticsand preparation method thereof |
| CN102755662B (en) * | 2012-07-25 | 2014-01-08 | 福州乾正药业有限公司 | Medical gel film prepared by compounding chitosan and preparation method of same |
| CN104888670B (en) * | 2015-06-05 | 2017-03-01 | 武汉理工大学 | A kind of method that natural polymer bilayered microcapsule is prepared using gas-liquid fluid channel |
| CN105594725B (en) * | 2015-11-09 | 2017-10-27 | 中国农业大学 | A kind of athomin double-layer microcapsule sustained release agent using chitosan as carrier and preparation method thereof |
| CN106702597B (en) * | 2016-12-20 | 2019-06-18 | 华南理工大学 | A kind of nuclear shell structured nano tunica fibrosa and its preparation method and application |
| CN107397212B (en) * | 2017-08-21 | 2021-03-19 | 西华大学 | White fungus thick soup microcapsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100364517C (en) * | 2005-09-28 | 2008-01-30 | 浙江大学 | Water-soluble medicine degradable polymer microcapsule injecta and preparing method |
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