CN102106828A - 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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- CN102106828A CN102106828A CN2011100461470A CN201110046147A CN102106828A CN 102106828 A CN102106828 A CN 102106828A CN 2011100461470 A CN2011100461470 A CN 2011100461470A CN 201110046147 A CN201110046147 A CN 201110046147A CN 102106828 A CN102106828 A CN 102106828A
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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 the excretory a kind of important T lymphocyte regulatory factor of thymus, 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 chronic HBV infection person has 300,000,000 approximately, and is wherein most of in the area, Asia.The Chronic HBV carrier accounts for 10%-15% in the population of China, and annual generation liver cirrhosis and hepatocarcinoma person account for 2 % and 1% respectively 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 a lyophilized injectable powder, its recommended amounts at the treatment chronic hepatitis B is every pin 1.6mg subcutaneous injection secondary weekly, 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 compliance of patients is very poor, and therefore developing the sustained release microsphere agents that can be administered once in every month can improve compliance of patients 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 the 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 big 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 thymalfasin sustained release microsphere agents of action time in vivo, 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%.Microsphere wherein of the present invention is meant 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 Acetic acid, hydroxy-, bimol. cyclic ester and lactide a kind of macromolecular material of forming of block copolymerization is in varing proportions arranged, have excellent biological compatibility and degradability, its final catabolite is carbon dioxide and water.Vicryl Rapide described in the present invention is an 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 ideal drug loading, it is used clinically becomes a kind of possibility.The inventor studies the physicochemical property and the prescription factor of thymalfasin, the result finds unexpectedly, adopt thymalfasin 0.1%-10%, Vicryl Rapide 85%-99%, prescription be prepared into 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 on 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 a kind of in human serum albumin, gelatin, trehalose or the mannitol or its two or more compositions arbitrarily.
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 the density and the viscosity of water increase in protectant concentration can cause because consumption is excessive greater than 5.0% the time, and the particle diameter of prepared colostrum can increase, and further cause the particle diameter of the sustained-release micro-spheres that finally obtains to become greatly, are unfavorable for controlled delivery of pharmaceutical agents release.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 the drug loading of sustained-release micro-spheres simultaneously.
Find that by contrast the drug loading to microsphere of the acetic acid content in the thymalfasin has remarkable influence, test find content be respectively 0.23%, 0.56%, 1% and the drug loading of 3.2% o'clock pairing microsphere be respectively: 6.1%, 5.8%, 4.5% and 0.9%.Thymalfasin of the present invention is an 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, Vicryl Rapide concentration be 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, 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) treat organic solvent volatilization after, obtain being enclosed with the sustained-release micro-spheres of thymalfasin.
Step 3) described " getting colostrum " can adopt 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 " emulsion ", aqueous phase got emulsion outside colostrum joined 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, thus the drug loading of raising 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 surfactants is a 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; Taking by weighing the 4g Vicryl Rapide is dissolved in the dichloromethane of 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; Taking by weighing the 8g Vicryl Rapide is dissolved in the dichloromethane of 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 the foregoing description preparation is carried out the mensuration of release in vitro, assay method is: precision takes by weighing pastille microsphere 100mg and places 10ml tool plug test tube, with pH is that 7.4 phosphate buffer (contains 0.02% Hydrazoic acid,sodium salt as antibacterial, 0.05% Tween 80 is a 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 release in vitro degree 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 the prepared thymalfasin sustained release microsphere agents of embodiment 1,2.By Fig. 1,2 as can be seen, the prepared thymalfasin sustained release microsphere agents of the present invention has the good slow release effect, prominent the releasing all less than 20% in 1 day.Its slow release cycle is one month.
Above content be in conjunction with concrete preferred implementation to further describing that the present invention did, can not assert that concrete enforcement 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 (10)
1. thymalfasin sustained release microsphere agents, it is characterized in that, comprise thymalfasin, Vicryl Rapide, its mass percent is respectively: thymalfasin 0.1%-10%, Vicryl Rapide 85%-99%, described Vicryl Rapide is an 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.
2. a kind of thymalfasin sustained release microsphere agents according to claim 1; it is characterized in that; comprise the protective agent that mass percent is 0.1-5.0%, this protective agent is a kind of in human serum albumin, gelatin, trehalose or the mannitol or its two or more compositions arbitrarily.
3. a kind of thymalfasin sustained release microsphere agents according to claim 1 is characterized in that described thymalfasin is an acetate, the content of its acetic acid greater than 0% less than 1.0%.
4. a kind of thymalfasin sustained release microsphere agents according to claim 2 is characterized in that described thymalfasin is an acetate, the content of its acetic acid greater than 0% less than 1.0%.
5. according to any described a kind of thymalfasin sustained release microsphere agents of claim 1 to 4, it is characterized in that the slow release cycle of described microball preparation is 25-35 days.
6. the preparation method as any described a kind of thymalfasin sustained release microsphere agents of claim 1 to 5 is characterized in that, may further comprise the steps:
1) Vicryl Rapide is dissolved in organic solvent, Vicryl Rapide concentration be 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, 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) treat organic solvent volatilization after, obtain being enclosed with the sustained-release micro-spheres of thymalfasin.
7. according to the preparation method of the described a kind of thymalfasin sustained release microsphere agents of claim 6, it is characterized in that described surfactant is two or more a compositions of a kind of in polyvinyl alcohol, poloxamer, enuatrol, sodium stearate or the tween or its.
8. according to the preparation method of the described a kind of thymalfasin sustained release microsphere agents of claim 7, it is characterized in that described surfactant is a polyvinyl alcohol, concentration is 0.1%-5%(W/V).
9. according to the preparation method of any described a kind of thymalfasin sustained release microsphere agents of claim 6 to 8, it is characterized in that outer aqueous pH values is 3.0-5.0.
10. according to the preparation method of any described a kind of thymalfasin sustained release microsphere agents of claim 6 to 8, it is characterized in that colostrum adopts high-speed stirred, high pressure homogenize or ultrasonication preparation.
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Cited By (7)
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| CN103126999A (en) * | 2013-02-06 | 2013-06-05 | 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 |
| CN104288185A (en) * | 2014-10-31 | 2015-01-21 | 潘霞 | Preparation method for polysaccharide nucleic acid medicine composition curing infantile eczema |
| CN104434817A (en) * | 2014-09-17 | 2015-03-25 | 黑龙江泰华源生物技术有限责任公司 | Sustained release microsphere preparation for injection of liraglutide |
| CN105935353A (en) * | 2015-06-15 | 2016-09-14 | 烟台海安药物研发有限公司 | Thymalfasin slow release microsphere preparation and preparation method thereof |
| CN109260173A (en) * | 2018-11-15 | 2019-01-25 | 朗天药业(湖北)有限公司 | A kind of thymalfasin pharmaceutical composition and preparation method thereof |
| CN111349152A (en) * | 2018-12-20 | 2020-06-30 | 深圳翰宇药业股份有限公司 | Method for preparing thymalfasin |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103126999A (en) * | 2013-02-06 | 2013-06-05 | 广东先强药业股份有限公司 | Thymalfasin chitosan / beta-cyclodextrin composite microsphere drug delivery system and preparation method |
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| 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 |
| CN111349152A (en) * | 2018-12-20 | 2020-06-30 | 深圳翰宇药业股份有限公司 | Method for preparing thymalfasin |
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