CN102106828B - Thymalfasin sustained-release microsphere preparation and preparation method thereof - Google Patents
Thymalfasin sustained-release microsphere preparation and preparation method thereof Download PDFInfo
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- CN102106828B CN102106828B CN2011100461470A CN201110046147A CN102106828B CN 102106828 B CN102106828 B CN 102106828B CN 2011100461470 A CN2011100461470 A CN 2011100461470A CN 201110046147 A CN201110046147 A CN 201110046147A CN 102106828 B CN102106828 B CN 102106828B
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Abstract
The invention provides a thymalfasin sustained-release microsphere preparation and a preparation method thereof. The thymalfasin sustained-release microsphere preparation comprises the following components in percentage by weight: 0.1 to 10 percent of thymalfasin, and 85 to 99 percent of poly(glycolide-co-lactide), wherein the poly(glycolide-co-lactide) is copolymer of glycolide and lactide, the ratio of the glycolide to the lactide is (25:75)-(75:25), the molecular weight of the poly(glycolide-co-lactide) is between 5,000 and 35,000 dalton, and the intrinsic viscosity is between 0.1 and 0.5dL/g. The pH value of the external water phase of the thymalfasin sustained-release microsphere preparation is between 3.0 and 5.0, and can be regulated by adopting acetic acid, hydrochloric acid, sulfuric acid and the like. The inventor discovers that by controlling the pH value of the external water phase, the stability of the thymalfasin can be improved and the entrapment rate in a preparation process also can be improved, so that the drug-loading rate of sustained-release microspheres can be improved.
Description
Technical field
The pharmaceutical preparation that the present invention relates to polypeptide drug with and preparation method thereof, relate in particular to thymalfasin sustained release microsphere agents and preparation method thereof.
Background technology
Thymalfasin (Thymosin) is to find in 1984 and by a kind of important T lymphocyte regulatory factor of thymus secretion, regulate relevant with cellular immunization.Thymalfasin is as a kind of immunomodulator, and its good efficacy has obtained conclusive evidence, and potential applicability in clinical practice is very bright.With regard to hepatitis B, it is one of human modal viral infection that hepatitis B virus (HBV) infects.Whole world Patients with Chronic HBV Infection has 300,000,000 approximately, and is wherein most of at Asia.The Chronic HBV carrier accounts for 10%-15% in the population of China, and annual generation liver cirrhosis and hepatocarcinoma person account for respectively 2 % and 1% among chronic hepatitis B (CHB) patient.Obviously, active treatment HBV infects, and stops it to liver cirrhosis and hepatocarcinoma development, and is significant.In addition, thymalfasin also has good efficacy to these human healths formidable enemies such as AIDS, malignant tumor.
The list marketing of injection thymalfasin has been arranged at present, said preparation is lyophilized injectable powder, its recommended amounts at the treatment chronic hepatitis B is weekly secondary of every pin 1.6mg subcutaneous injection, and two dosage approximately are separated by 3-4 day, and treatment should can not be interrupted during (52 pin) in continuous 6 months.Such administering mode patient's compliance is very poor, and therefore developing the sustained release microsphere agents that can be administered once per month can improve patient's compliance greatly, improves the cure rate of this medicine.
Multi-emulsion method (W/O/W) is a kind of classical way of the PLGA of preparation sustained-release micro-spheres, adopt document and the patent of multi-emulsion method (W/O/W) preparation sustained-release micro-spheres more and more, but article that the Zhong Yanqiang etc. of Second Military Medical University, PLA delivers and patent (Chinese patent application number: adopt multi-emulsion method (W/O/W) to prepare the thymalfasin sustained-release micro-spheres 200610118413.5) is only arranged at present.The drug loading of prepared thymalfasin sustained-release micro-spheres all is not more than 0.9% in its article and patent, and this brings very large difficulty to practical clinical.(every pin 1.6mg subcutaneous injection is secondary weekly for dosage during according to injection thymalfasin injectable powder treatment chronic hepatitis B, two dosage approximately are separated by 3-4 day, referring to " injection thymalfasin description ") calculate, dosage when adopting the sustained-release micro-spheres administration in January is approximately 12.8mg, calculate corresponding adjuvant total amount by 0.9% drug loading and be no less than 1422mg, contain a large amount of like this adjuvants and be can't carry out hypodermic.
Summary of the invention
The technical problem to be solved in the present invention provides and a kind ofly can effectively prolong the in vivo thymalfasin sustained release microsphere agents of action time, has reduced the administration frequency of thymalfasin.
For solving the problems of the technologies described above, the present invention is achieved through the following technical solutions:
The invention provides a kind of stable thymalfasin sustained release microsphere agents, comprise thymalfasin, Vicryl Rapide, its mass percent is respectively: thymalfasin 0.1%-10%, Vicryl Rapide 85%-99%.Wherein microsphere of the present invention refers to that medicine disperses or is attracted in macromolecule, the polymeric matrix and the microparticulate system that forms.Vicryl Rapide [poly(lactide-co-glycolide), PLGA] be that in varing proportions a kind of macromolecular material of forming of block copolymerization of Acetic acid, hydroxy-, bimol. cyclic ester and lactide is arranged, have good biocompatibility and degradability, its final catabolite is carbon dioxide and water.Vicryl Rapide described in the present invention is Acetic acid, hydroxy-, bimol. cyclic ester: lactide is the copolymer of 25:75-75:25, and its molecular weight is 5000-25000 dalton, and intrinsic viscosity is 0.1-0.5dL/g.
In order to realize that the thymalfasin sustained-release micro-spheres has desirable drug loading, it is used clinically becomes a kind of possibility.The inventor studies physicochemical property and the formulation factors of thymalfasin, the result finds unexpectedly, adopt thymalfasin 0.1%-10%, Vicryl Rapide 85%-99%, formula preparation become sustained-release micro-spheres, can realize that drug loading is the thymalfasin sustained-release micro-spheres of 4.5%-6.1%, significant minimizing adjuvant is used for prior art, makes a breakthrough at galenic pharmacy.The slow release cycle of this sustained-release micro-spheres can realize reaching 25-35 days.
Thymalfasin sustained release microsphere agents of the present invention also comprises the protective agent that mass percent is 0.1-5.0%, and this protective agent is selected from arbitrarily two or more compositions of a kind of in human serum albumin, gelatin, trehalose or the mannitol or its.
The inventor finds, when protectant concentration less than 0.1% the time, it improves a little less than the effect of thymalfasin stability, DeGrain; And increase when protectant concentration can cause because consumption is excessive the density of interior water and viscosity greater than 5.0% the time, the particle diameter of prepared colostrum can increase, and further causes the particle diameter of the sustained-release micro-spheres that finally obtains to become large, is unfavorable for the control release of medicine.The inventor finds that in research process protectant concentration is when 0.1-5.0%, owing to add the stability that protective agent can improve thymalfasin; Find to increase simultaneously the drug loading of sustained-release micro-spheres.
Find that by contrast the drug loading on microsphere of the acetic acid content in the thymalfasin has significant impact, the drug loading of corresponding microsphere was respectively when test discovery content was respectively 0.23%, 0.56%, 1% and 3.2%: 6.1%, 5.8%, 4.5% and 0.9%.Thymalfasin of the present invention is acetate, and the percentage composition of its acetic acid requires greater than 0% less than 3.0%, is preferably greater than 0% and less than 1.0%, can obtain the sustained-release micro-spheres of high drug load in this scope.
The present invention also provides multi-emulsion method (W/O/W) to prepare the method for thymalfasin sustained-release micro-spheres, may further comprise the steps:
1) Vicryl Rapide is dissolved in organic solvent, getting Vicryl Rapide concentration is 10%-40%(W/V) oil phase, wherein organic solvent is a kind of or its compositions in dichloromethane, the ethyl acetate;
2) thymalfasin, protective agent is water-soluble, getting thymalfasin concentration is 1%-30%(W/V) interior water;
3) interior water mixes with oil phase, gets colostrum, and colostrum is joined the outer aqueous phase that contains surfactant, gets emulsion;
4) after the organic solvent volatilization, obtain being enclosed with the sustained-release micro-spheres of thymalfasin.
Step 3) described " getting colostrum " can adopt the modes such as high-speed stirred, high pressure homogenize or ultrasonication to prepare, and meets the requirements as long as can guarantee the particle diameter of colostrum.Prepared colostrum will leave in the environment below 20 ℃ to increase the stability of colostrum.Described " getting emulsion " joins outer aqueous phase with colostrum and gets emulsion under the state that stirs.
The pH value of outer water of the present invention is 3.0-5.0, can adopt acetic acid, hydrochloric acid, sulphuric acid etc. to regulate pH.The inventor finds, can improve the stability of thymalfasin by the pH value of controlling outer water, can also improve the envelop rate in the preparation process, thereby improve the drug loading of sustained-release micro-spheres.
Described surfactant is selected from a kind of or its compositions in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate, tween or the span, and its concentration is 0.1%-5%(W/V).Preferred surfactant is polyvinyl alcohol, and its concentration is 0.1%-5%(W/V).
The prepared thymalfasin sustained release microsphere agents of the present invention can slow release one month.
[description of drawings]
Fig. 1 is the cumulative in vitro release profiles of thymalfasin sustained release microsphere agents of the present invention;
Fig. 2 is that the cumulative in vitro of thymalfasin sustained release microsphere agents of the present invention discharges another curve.
[specific embodiment]
Embodiment one:
Take by weighing 300mg thymalfasin and 200mg gelatin and be dissolved in the 1ml water for injection, as interior water; Take by weighing in the dichloromethane that the 4g Vicryl Rapide is dissolved in 10ml as oil phase; Oil phase is joined interior aqueous phase, adopted high-speed stirred (20000rpm) 15 seconds, get colostrum, leave in the environment below 20 ℃; This colostrum is joined 5000 milliliters of 0.5%(W/V under the state that stirs) poly-vinyl alcohol solution get emulsion, this emulsion is continued to stir flung to dichloromethane in 3 hours, centrifugal, washing is collected and is obtained microsphere, microspherulite diameter is less than 100 microns, drug loading is 6.1%.
Embodiment two:
Take by weighing the 500mg thymalfasin, the 300mg gelatin is dissolved in the 2ml water for injection, as interior water; Take by weighing in the dichloromethane that the 8g Vicryl Rapide is dissolved in 80ml as oil phase; Oil phase is joined interior aqueous phase, adopt ultrasonic cell disruption instrument (Branson S-250D) to carry out ultrasonic 10 seconds, get colostrum, leave in the environment below 20 ℃; This colostrum is joined 8000 milliliters of 1.0%(W/V under the state that stirs) poly-vinyl alcohol solution get emulsion, this emulsion is continued to stir flung to dichloromethane in 3 hours, centrifugal, washing is collected and is obtained microsphere, microspherulite diameter is less than 50 microns, drug loading is 4.5%.
Embodiment three:
The mensuration of the external release of thymalfasin sustained-release micro-spheres
The thymalfasin sustained release microsphere agents of above-described embodiment preparation is carried out the mensuration of release in vitro, assay method is: precision takes by weighing medicine-containing microsphere 100mg and places 10ml tool plug test tube, (contain 0.02% Hydrazoic acid,sodium salt as antibacterial take the phosphate buffer of pH as 7.4,0.05% Tween 80 is wetting agent) 10ml is release medium, place the water bath with thermostatic control shaking table, under hunting speed 100rpm, 37 ℃ ± 0.5 ℃ condition of temperature, carry out the vitro release of microsphere and measure.Respectively get the content that the 0.5ml release medium is used for the high effective liquid chromatography for measuring thymalfasin at 1d, 2d, 4d, 7d, 14d, 21d, 28d respectively, and replenish fresh release medium.Fig. 1,2 is respectively the cumulative in vitro release profiles of embodiment 1,2 prepared thymalfasin sustained release microsphere agents.Can be found out that by Fig. 1,2 the prepared thymalfasin sustained release microsphere agents of the present invention has good slow release effect, prominent the releasing all less than 20% in 1 day.Its slow release cycle is one month.
Above content is the further description of the present invention being done in conjunction with concrete preferred implementation, can not assert that implementation of the present invention is confined to these explanations.For the general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, can also make some simple deduction or replace, all should be considered as belonging to protection scope of the present invention.
Claims (7)
1. thymalfasin sustained release microsphere agents; it is characterized in that; comprise thymalfasin, Vicryl Rapide, protective agent; its mass percent is respectively: thymalfasin 0.1%-10%; Vicryl Rapide 85%-99%; protective agent 0.1-5.0%; described Vicryl Rapide is Acetic acid, hydroxy-, bimol. cyclic ester: lactide is the copolymer of 25:75-75:25; its molecular weight is 5000-25000 dalton; intrinsic viscosity is 0.1-0.5dL/g; described thymalfasin is acetate, the content of its acetic acid greater than 0% less than 1.0%.
2. a kind of thymalfasin sustained release microsphere agents according to claim 1 is characterized in that, described protective agent is arbitrarily two or more compositions of a kind of in human serum albumin, gelatin, trehalose or the mannitol or its.
3. the described a kind of thymalfasin sustained release microsphere agents of any one according to claim 1 and 2 is characterized in that the slow release cycle of described microball preparation is 25-35 days.
4. the preparation method such as the described a kind of thymalfasin sustained release microsphere agents of claims 1 to 3 any one is characterized in that, may further comprise the steps:
1) Vicryl Rapide is dissolved in organic solvent, getting Vicryl Rapide concentration is 10%-40%(W/V) oil phase, wherein organic solvent is a kind of or its compositions in dichloromethane, the ethyl acetate;
2) thymalfasin, protective agent is water-soluble, getting thymalfasin concentration is 1%-30%(W/V) interior water;
3) interior water mixes with oil phase, gets colostrum, and colostrum is joined the outer aqueous phase that contains surfactant, gets emulsion, and the pH value of wherein said outer water is 3.0-5.0;
4) after the organic solvent volatilization, obtain being enclosed with the sustained-release micro-spheres of thymalfasin.
5. the preparation method of described a kind of thymalfasin sustained release microsphere agents according to claim 4, it is characterized in that described surfactant is two or more compositions of a kind of in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate or the tween or its.
6. the preparation method of described a kind of thymalfasin sustained release microsphere agents according to claim 5 is characterized in that described surfactant is polyvinyl alcohol, and concentration is 0.1%-5%(W/V).
7. according to claim 4 to the preparation method of the described a kind of thymalfasin sustained release microsphere agents of 6 any one, it is characterized in that colostrum adopts high-speed stirred, high pressure homogenize or ultrasonication preparation.
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| CN103126999B (en) * | 2013-02-06 | 2014-08-20 | 广东先强药业股份有限公司 | Thymalfasin chitosan / beta-cyclodextrin composite microsphere drug delivery system and preparation method |
| CN103961320A (en) * | 2014-05-23 | 2014-08-06 | 深圳市健元医药科技有限公司 | Immunomodulator polypeptide slow-release microsphere preparation and preparation method thereof |
| CN104434817B (en) * | 2014-09-17 | 2018-02-13 | 黑龙江泰华源生物技术有限责任公司 | A kind of slow-release microshpere formulation for injection of Liraglutide |
| CN104288185B (en) * | 2014-10-31 | 2018-05-29 | 潘霞 | A kind of preparation method for the polysaccharide nucleic acid pharmaceutical composition for treating infantile eczema |
| CN104984327A (en) * | 2015-06-15 | 2015-10-21 | 烟台海安药物研发有限公司 | Thymalfasin sustained release micro-sphere preparation and preparing method thereof |
| CN109260173B (en) * | 2018-11-15 | 2019-08-20 | 朗天药业(湖北)有限公司 | A kind of thymalfasin pharmaceutical composition and preparation method thereof |
| CN111349152B (en) * | 2018-12-20 | 2022-04-05 | 深圳翰宇药业股份有限公司 | Method for preparing thymalfasin |
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| CN1398637A (en) * | 2002-07-25 | 2003-02-26 | 中国人民解放军第二军医大学 | Thymosin alpha-1 microball prepn and its prepn process |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1398637A (en) * | 2002-07-25 | 2003-02-26 | 中国人民解放军第二军医大学 | Thymosin alpha-1 microball prepn and its prepn process |
| CN1965810A (en) * | 2006-11-17 | 2007-05-23 | 中国人民解放军第二军医大学 | Sustained release microsphere formulation of thymosin alpha-1, preparation process and use thereof |
| CN101244259A (en) * | 2007-02-14 | 2008-08-20 | 成都地奥九泓制药厂 | Thymus gland peptide alpha1sustained-release microsphere preparation for injection and preparation thereof |
| CN101653598A (en) * | 2008-08-19 | 2010-02-24 | 成都地奥九泓制药厂 | Thymic peptide alpha1PLGA slow release microsphere preparation and method for preparing same |
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| CN101766807A (en) * | 2008-12-26 | 2010-07-07 | 成都地奥九泓制药厂 | Injection packaging preparation of thymosin pha1 microspheres |
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