CN104984327A - Thymalfasin sustained release micro-sphere preparation and preparing method thereof - Google Patents
Thymalfasin sustained release micro-sphere preparation and preparing method thereof Download PDFInfo
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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Abstract
The invention provides a thymalfasin sustained release micro-sphere preparation and a preparing method thereof. The thymalfasin sustained release micro-sphere preparation comprises, by micro-sphere weight, 0.1%-30% of thymalfasin, 50%-99.9% of a biodegradable high polymer material which ranges from 5000 Dalton to 200000 Dalton in molecular weight and has the biocompatibility and 0%-20% of other acceptable auxiliary materials on pharmacy. The invention further provides the preparing method for preparing the thymalfasin sustained release micro-sphere preparation, namely a high-pressure static microcapsule molding method. By means of thymalfasin sustained release micro-spheres prepared with the method, effective embedding and sustained release of the thymalfasin are achieved, the sustained release effect can reach 40 days, the toxic and side effect of the thymalfasin can be effectively reduced, the bioavailability is improved, and the metabolic half-life is prolonged; and meanwhile, the number of drug administration times is decreased, and economic and mental burdens of a patient are relieved.
Description
Technical field
The invention belongs to sustained release microsphere agents technical field, long-acting slow-release microball preparation relating to a kind of immunomodulator and preparation method thereof, be specifically related to a kind of thymalfasin sustained release microsphere agents and preparation method thereof.
Background technology
Thymalfasin, i.e. Thymosin alpha 1 find and a kind of important T lymphocyte regulatory factor secreted by thymus for 1984, relevant with Culture in vitro.Thymalfasin is that a N holds acetylizad Acid polypeptide, is made up of, is mainly used in chronic viral hepatitis B and the immune response-enhancing agents as immune impairment patient 28 amino acid residues.
Thymalfasin is as a kind of immunomodulator, and its good efficacy is confirmed, and potential applicability in clinical practice is considerable.It is one of modal viral infection of the mankind that hepatitis B virus (HBV) infects, and whole world Patients with Chronic HBV Infection about has 300,000,000, and wherein major part is in Asia.In population of China, Chronic HBV carriers accounts for 10%-15%, and in chronic hepatitis B (CHB) patient, annual generation liver cirrhosis and hepatocarcinoma person account for 2% and 1% respectively.Obviously, active treatment HBV infection, stops it to liver cirrhosis and hepatocarcinoma development, significant.In addition, thymalfasin has good efficacy to the disease such as AIDS, malignant tumor.
Existing injection thymalfasin list marketing at present, said preparation is lyophilized injectable powder, it is every pin 1.6mg subcutaneous injection secondary weekly in the recommended amounts of Treatment chronic Hepatitis B, and two dosage are approximately separated by 3-4 day, treatment should continuous 6 months (52 pin) period not interruptible price.The compliance of such administering mode patient is very poor, therefore develops the compliance that the sustained release microsphere agents that can monthly be administered once can improve patient greatly, improves the cure rate of this disease.
The document of the preparation method of current thymalfasin sustained release microsphere agents and patent get more and more, mainly contain multi-emulsion method (W/O/W), emulsion solvent diffusion method, extrusion by melting etc., wherein multi-emulsion method is the typical method that one prepares Poly(D,L-lactide-co-glycolide (PLGA) sustained-release micro-spheres.Have employed multi-emulsion method (W/O/W) in the article that the Zhong Yanqiang of Second Military Medical University, PLA etc. deliver and patent (CN200610118413.5) and prepare thymalfasin sustained-release micro-spheres.Number of patent application is that 200310119386.X discloses a kind of method utilizing PLGA to extract, synthesize thymosin microcapsule controlled-release pin.He Yi etc., the preparation of thymosin polylactic acid microsphere and Release Performance research, Chinese Journal of Pharmaceuticals, 2006,37 (3), disclose and prepare thymosin polylactic acid microsphere with emulsified solvent volatilization, take wherein PLGA as carrier, prepare microsphere with emulsifying volatility process.Zou Liang etc., the preparation of thymosin gelatine microsphere and the feature of tablets in vitro, Journal of Chinese Hospital Pharmacy 2004,24 (9), disclose the gelatine microsphere of thymosin.The research of the thymic peptide alpha 1 microballoon prepared with emulsion-crosslinking method, with medicine A type gelatin for capsule material.Zhang Haisong, Chen Yangshu, Hu Jungao, etc., the research of oral thymus microsphere, China Dispensary, 1999,10 (2): 58, etc.Easily there is gathering in above traditional method, merge, be separated and purified product difficulty, most of the time and cost are for removing residual solvent and extra medicinal, be not suitable for suitability for industrialized production, and spray drying method, fusion method, saltings out method etc. are simple to operate, favorable reproducibility, but preparation process is fiercer, higher or the pH value of the temperature used changes greatly, higher requirement is had to the stability of medicine, be not suitable for polypeptide, protein medicaments or other heat-sensitive substances, in addition, thymalfasin sustained-release micro-spheres surface atresia prepared by above method, inner hollow or the cavity no matter led to mutually, make microsphere drug loading low, unfavorable to administration.Therefore, currently a solid porous sustained-release micro-spheres of thymalfasin that can solve above-mentioned shortcoming and preparation method thereof is needed badly.
Summary of the invention
The object of the present invention is to provide a kind of thymalfasin sustained-release micro-spheres and preparation method thereof, described method is the high-pressure electrostatic microcapsule method of forming not needing separation and purification, avoid second time emulsion and high-temperature operation, the solid porous microsphere even sized by the thymalfasin sustained-release micro-spheres that this legal system is standby, medicament contg is high, can effective prolong drug action time in vivo, reduce the administration frequency of thymalfasin.
At present domestic also do not adopt the high-pressure electrostatic microcapsule method of forming to prepare thymalfasin-polylactic acid long-acting slow-release microball preparation unit or individual, and thymalfasin sustained-release micro-spheres prepared by the present invention is the domestic surperficial perforate prepared first, thymalfasin-polylactic acid porous sustained-release micro-spheres that interior outer hole is mutually through.PLLA has excellent biocompatibility and the polymer of biological degradability, is to can be used as pharmaceutical carrier through CFDA approval, and the end product of metabolism is in vivo CO
2and H
2o, intermediate product lactic acid is also the product of normal sugar metabolism in body, can not assemble at vitals, and therefore polylactic acid microsphere obtains investigation and application widely as pharmaceutical carrier.
The present invention adopts following technical scheme:
A kind of high-pressure electrostatic microcapsule method of forming that adopts prepares thymalfasin sustained-release micro-spheres technology, specific as follows:
1) a certain amount of PLLA (PLLA) dissolves in organic solvent, obtain copolymer of poly lactic acid concentration for (1%-40%) (W/V, g/ml) oil phase, wherein organic solvent is one in dichloromethane, ethyl acetate or its arbitrary composition; Stabilizing agent is for comprising but being not limited only to Pu Langluoni F-127 (Pluronic F127), and its mass fraction is 0.01%-1.2%.
2) by thymalfasin, protective agent is molten, porogen is water-soluble, obtains the interior aqueous phase that thymalfasin is 1%-60% (W/V).
3) mixed with interior aqueous phase by above-mentioned oil phase, with cell crushing instrument ultrasonic emulsification certain hour, emulsification times is generally (0.5-2), and min (power 200W, ultrasonic 1s, interval 1s) forms even, stable W/O emulsion.
4) be that the sodium alginate of 1.5%-30% or chitosan aqueous solution add in above-mentioned emulsion as aqueous phase (W) using the mass fraction of fresh outfit, with cell crushing instrument ultrasonic emulsification certain hour, emulsification times is generally (0.5-2), and min (power 200W, ultrasonic 1s, interval 1s) forms even, stable W/O/W emulsion.
5) obtained W/O/W emulsion is loaded in syringe immediately, by high pressure microcapsule shaping device and syringe pump, be expelled in the calcium chloride water of the 5%-10% of new preparation, generate calcium alginate because sodium alginate and calcium chloride meet to react and form thymalfasin sustained-release micro-spheres.
Further; step 2) described in protective agent be mainly: one or more mixture in human serum albumin, gelatin, trehalose, mannose or mannitol etc.; wherein protectant mass fraction is generally at 0.01%-5.0%; porogen comprises but is not limited only to ammonium bicarbonate, and mass percentage is: 0.01%-1.0%.
Further, step 5) technological parameter of mesohigh microcapsule shaping device is: voltage 25KV; Fltting speed: (81-100) mm/h, 23G syringe needle, receiving range (41-60) mm.Solution 60-80min after magnetic agitation receives, filter out the White Flocculus in solution with funnel, the centrifugal 5min of 7000rpm, can collect thymalfasin-polylactic acid solid microsphere, lyophilization is to remove H
2o, dichloromethane, NH
3and CO
2, the dry solid porous sustained-release micro-spheres of thymalfasin can be obtained.
Thymalfasin porous sustained-release microsphere preparation prepared by the present invention can slow release 30-40 days.
Accompanying drawing explanation
Fig. 1 is the scanning electron microscope (SEM) photograph of thymalfasin sustained-release micro-spheres prepared by the embodiment of the present invention 1;
Fig. 2 is the scanning electron microscope (SEM) photograph of thymalfasin sustained-release micro-spheres prepared by the embodiment of the present invention 2;
Fig. 3 is the scanning electron microscope (SEM) photograph of thymalfasin sustained-release micro-spheres prepared by the embodiment of the present invention 3;
Fig. 4 is the cumulative in vitro release profiles of thymalfasin sustained release microsphere agents prepared by the embodiment of the present invention 1;
Fig. 5 is the cumulative in vitro release profiles of thymalfasin sustained release microsphere agents prepared by the embodiment of the present invention 2;
Fig. 6 is the cumulative in vitro release profiles of thymalfasin sustained release microsphere agents prepared by the embodiment of the present invention 3;
Fig. 7 is the cumulative in vitro release profiles comparison diagram of thymalfasin sustained release microsphere agents prepared by the embodiment of the present invention 1,2,3.
Detailed description of the invention
Embodiment 1
The PLLA (PLLA) of 200mg is dissolved in the dichloromethane of 5ml, obtains the oil phase of copolymer of poly lactic acid, and adds the stabilizing agent Pu Langluoni F-127 of 3mg.The gelatin of 80mg thymalfasin, 15mg, the ammonium bicarbonate of 0.5ml are dissolved in the water for injection of 600ml, oil phase is joined in aqueous phase, cell crushing instrument ultrasonic emulsification 1.5min (power 200W, ultrasonic 1s, interval 1s) is adopted to form even, stable W/O emulsion.The 1000ml mass fraction above-mentioned solution being joined new preparation is the sodium alginate aqueous solution of 2%, and with cell crushing instrument ultrasonic emulsification 1.5min, ultrasonic emulsification condition is the same, form even, stable W/O/W emulsion, obtained W/O/W emulsion is loaded in syringe immediately, by high pressure microcapsule shaped device, being expelled to the mass fraction that 500ml configures is in the calcium chloride solution of 10%, magnetic agitation emulsion 1.5 hours, White Flocculus is filtered out with funnel, the centrifugal 5min of 7000rpm, collects thymalfasin-PLLA microsphere.Namely lyophilization obtains thymalfasin porous sustained-release microsphere, and microspherulite diameter is less than 100 μm, and drug loading is 5.2%, and thymalfasin porous sustained-release microsphere scanning electron microscope is as Fig. 1.
Embodiment 2
The PLLA (PLLA) of 300mg is dissolved in the ethyl acetate of 10ml, obtains the oil phase of copolymer of poly lactic acid, and adds the stabilizing agent Pu Langluoni F-127 of 3.5mg.The trehalose of 150mg thymalfasin, 20mg, the ammonium bicarbonate of 4.0ml are dissolved in the water for injection of 1000ml, oil phase is joined in aqueous phase, cell crushing instrument ultrasonic emulsification 1.5min (power 200W, ultrasonic 1s, interval 1s) is adopted to form even, stable W/O emulsion.Above-mentioned solution being joined the mass fraction that 1500ml newly prepares is the sodium alginate aqueous solution of 5%, and with cell crushing instrument ultrasonic emulsification 1.5min, ultrasonic emulsification condition is the same, form even, stable W/O/W emulsion, obtained W/O/W emulsion is loaded in syringe immediately, by high pressure microcapsule shaped device, being expelled to the mass fraction that 1000ml configures is in the calcium chloride solution of 8%, magnetic agitation emulsion 1.5 hours, White Flocculus is filtered out with funnel, the centrifugal 5min of 7000rpm, collects thymalfasin-PLLA microsphere.Namely lyophilization obtains thymalfasin porous sustained-release microsphere, and microspherulite diameter is less than 100 μm, and drug loading is 6.0%, and thymalfasin porous sustained-release microsphere scanning electron microscope is as Fig. 2.
Embodiment 3
The PLLA (PLLA) of 400mg is dissolved in the dichloromethane of 10ml, obtains the oil phase of copolymer of poly lactic acid, and adds the stabilizing agent Pu Langluoni F-127 of 4.8mg.The trehalose of 100mg thymalfasin, 10mg, the ammonium bicarbonate of 1.0ml are dissolved in the water for injection of 800ml, oil phase is joined in aqueous phase, cell crushing instrument ultrasonic emulsification 1.5min (power 200W, ultrasonic 1s, interval 1s) is adopted to form even, stable W/O emulsion.Above-mentioned solution being joined the mass fraction that 1200ml newly prepares is the sodium alginate aqueous solution of 5%, and with cell crushing instrument ultrasonic emulsification 1.5min, emulsification condition is the same, form even, stable W/O/W emulsion, obtained W/O/W emulsion is loaded in syringe immediately, by high pressure microcapsule shaped device, being expelled to the mass fraction that 1200ml configures is in the calcium chloride solution of 6%, magnetic agitation emulsion 1.5 hours, White Flocculus is filtered out with funnel, the centrifugal 5min of 7000rpm, collects thymalfasin-PLLA microsphere.Namely lyophilization obtains thymalfasin porous sustained-release microsphere, and microspherulite diameter is less than 100 μm, and drug loading is 5.8%, and thymalfasin porous sustained-release microsphere scanning electron microscope is as Fig. 3.
Embodiment 4
The external release of thymalfasin sustained-release micro-spheres measures
The thymalfasin sustained release microsphere agents prepared by above-described embodiment carries out release in vitro mensuration, and assay method is:
Precision takes dry medicine-containing microsphere 0.100g and is placed in 10ml tool plug test tube, be that the phosphate buffer of 7.4 is (containing 0.02% Hydrazoic acid,sodium salt as antibacterial using pH, the Tween 80 of 0.05% is wetting agent) 10ml is release medium, be placed in constant temperature waters shaking table, the vitro release carrying out microsphere under earthquake speed 100rpm, temperature 37 DEG C ± 0.5 DEG C condition measures.Respectively get the content of 0.5ml release medium for high effective liquid chromatography for measuring thymalfasin at 0 hour, 3 hours, 1 day, 3 days, 5 days, 7 days, 9 days, 14 days, 18 days, 21 days, 24 days, 28 days, 30 days, 40 days respectively, and supplement fresh release medium.Fig. 4,5,6,7 is respectively vitro cumulative release profiles and the correlation curve of the thymalfasin sustained release microsphere agents prepared by embodiment 4,5,6.As can be seen from Fig. 4,5,6,7, the thymalfasin sustained release microsphere agents prepared by the present invention has good releasing effect, is all less than 20% in 7 days, and its deenergized period is 30-40 days.
Above content is in conjunction with concrete preferred implementation further description made for the present invention, can not assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, done any amendment, equivalent replacement, improvement etc., all should be considered as belonging to protection scope of the present invention.
Claims (10)
1. a thymalfasin sustained release microsphere agents, it is characterized in that: it is the daltonian biodegradable and macromolecular material of tool biocompatibility of 5000-200000 by the molecular weight of the thymalfasin of the 0.1%-30% of microspheres weight and the 50%-99.9% of microspheres weight, and the preparation that other adjuvants pharmaceutically acceptable accounting for microspheres weight 0%-20% are prepared from, described sustained-release micro-spheres mean diameter is 50-100 μm.
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 one in human serum albumin, gelatin, alginic acid sugar or mannitol or wherein arbitrary composition.
3. a kind of thymalfasin sustained release microsphere agents according to claim 1, it is characterized in that, described degradable has the macromolecular material of biocompatibility, is selected from one or both and above any mixture in polymeric polyglycolide-polylactide, gelatin, PLLA, polylactic acid-glycollic acid, polyglycolic acid, polyvinyl alcohol, Polyethylene Glycol, hydroxyacetic acid, polylactic acid-polyglycol, poly butyric ester-hydroxyl pentanoate copolymer.
4. a kind of thymalfasin sustained release microsphere agents according to claim 3, it is characterized in that, described degradable has the macromolecular material of biocompatibility, the one in preferred PLLA, polymeric polyglycolide-polylactide, polylactic acid-polyglycol, take PLLA as the best.
5. a kind of thymalfasin sustained release microsphere agents according to claim 1, is characterized in that, described degradable has the macromolecular material of biocompatibility, and molecular weight ranges is all 5000-200000 dalton.
6. a kind of thymalfasin sustained release microsphere agents according to claim 1, is characterized in that, the slow release cycle of described thymalfasin is 30-40 days.
7. a preparation method for a kind of thymalfasin sustained release microsphere agents as described in claim 1 to 6 any one, is characterized in that, comprise the following steps:
1) PLLA is dissolved in organic solvent, and adds a certain amount of stabilizing agent, obtain PLA concentration for the oil phase of (1%-40%) (W/V, g/ml), wherein organic solvent is one in dichloromethane, ethyl acetate or its arbitrary composition; Stabilizing agent is for comprising but being not limited only to Pu Langluoni F-127(Pluronic F127), its mass fraction is 0.01%-1.2%;
2) by thymalfasin, protective agent is molten, porogen is water-soluble, thymalfasin be 1%-60%(W/V) interior aqueous phase, wherein protective agent is one in human serum albumin, gelatin, alginic acid sugar or mannitol or wherein arbitrary composition, and mass percent is 0.01%-5.0%; Porogen comprises but is not limited only to ammonium bicarbonate, and mass percentage is: 0.01%-1.0%;
3) above-mentioned oil phase is mixed with interior aqueous phase, with cell crushing instrument ultrasonic emulsification certain hour, phaco time is generally (0.5-2) min(power 200W, ultrasonic 1s, interval 1s) form even, stable W/O emulsion
4) be that the sodium alginate of 1.5%-30% or chitosan aqueous solution add in above-mentioned emulsion as aqueous phase (W) using the mass fraction newly prepared, with cell crushing instrument ultrasonic emulsification certain hour, emulsification times is (0.5-2) min(power 200W, ultrasonic 1s, interval 1s) form even, stable W/O/W emulsion;
5) by above-mentioned steps 4) in obtained W/O/W emulsion load immediately in syringe, by high pressure microcapsule shaping device, be expelled in the calcium chloride water of the 5%-10% of new preparation, generate calcium alginate because sodium alginate and calcium chloride meet to react and form microsphere;
6) high pressure microcapsule shaping device injection contacts mixing with receiving liquid and reacts, and magnetic agitation 50-80min, filters out the White Flocculus in solution with funnel, the centrifugal 5min of 7000rpm, can collect thymalfasin-polylactic acid microsphere, and lyophilization is to remove H
2o, dichloromethane, NH
3and CO
2, dry thymalfasin porous sustained-release microsphere can be obtained.
8. the preparation method of a kind of thymalfasin sustained release microsphere agents according to claim 7, the technological parameter of high pressure microcapsule shaping device is: voltage 25KV; Fltting speed: (81-100) mm/h, 23G syringe needle, receiving range (41-60) mm.
9., in the step 6) of the preparation method of a kind of thymalfasin sustained release microsphere agents according to claim 7, the magnetic agitation time is preferably (61-70) min, take 65min as the best.
10. the thymalfasin sustained release microsphere agents prepared of preparation method described in claim 1-9 any one.
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| CN201510329245.3A CN104984327A (en) | 2015-06-15 | 2015-06-15 | Thymalfasin sustained release micro-sphere preparation and preparing method thereof |
| CN201610387160.5A CN105935353A (en) | 2015-06-15 | 2016-06-02 | Thymalfasin slow release microsphere preparation and preparation method thereof |
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| CN106039291A (en) * | 2016-06-08 | 2016-10-26 | 上海上药第生化药业有限公司 | Microemulsion preparation containing thymalfasin and preparation method of microemulsion preparation |
| 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 |
| CN111714469A (en) * | 2019-03-22 | 2020-09-29 | 苏州特瑞药业有限公司 | Thymalfasin preparation and preparation method thereof |
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| CN109847091A (en) * | 2018-12-29 | 2019-06-07 | 苏州恒瑞迦俐生生物医药科技有限公司 | A kind of controllable grain size range embolism microball and preparation method thereof |
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| CN101244259B (en) * | 2007-02-14 | 2011-03-30 | 成都地奥九泓制药厂 | Thymus gland peptide alpha1sustained-release microsphere preparation for injection and preparation thereof |
| CN101947212B (en) * | 2010-09-08 | 2012-10-10 | 华侨大学 | Micro-embedded medicament carrier and preparation method thereof |
| CN102106828B (en) * | 2011-02-25 | 2013-04-24 | 深圳翰宇药业股份有限公司 | Thymalfasin sustained-release microsphere preparation and preparation method thereof |
| KR101541822B1 (en) * | 2011-12-29 | 2015-08-05 | 주식회사 삼양바이오팜 | Method for the preparation of microspheres of biodegradable polylactic acid derivative with no use of organic solvents |
| CN102941043B (en) * | 2012-10-12 | 2015-08-05 | 华侨大学 | High-pressure electrostatic anti-dissolving agent process prepares the method for porous polymer bead |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106039291A (en) * | 2016-06-08 | 2016-10-26 | 上海上药第生化药业有限公司 | Microemulsion preparation containing thymalfasin and preparation method of microemulsion preparation |
| 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 |
| 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 |
| CN111714469A (en) * | 2019-03-22 | 2020-09-29 | 苏州特瑞药业有限公司 | Thymalfasin preparation and preparation method thereof |
| CN111714469B (en) * | 2019-03-22 | 2023-10-03 | 苏州特瑞药业股份有限公司 | Thymalfasin preparation and preparation method thereof |
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Application publication date: 20151021 |