CN105935353A - Thymalfasin slow release microsphere preparation and preparation method thereof - Google Patents
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- 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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- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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Abstract
The invention provides a thymalfasin slow release microsphere preparation and a preparation method thereof. The thymalfasin slow release microsphere preparation is a preparation prepared from thymalfasin accounting for 0.1-30% of the weight of microspheres, a biodegradable and biocompatible polymer material accounting for 50-99.9% of the weight of the microspheres and having a molecular weight of 5000-200000dalton, and other pharmaceutically acceptable auxiliary materials accounting for 0-20% of the weight of the microspheres. The invention also provides the preparation method of the thymalfasin slow release microsphere preparation. The method is a high-voltage electrostatic microcapsule molding method. The thymalfasin slow release microsphere preparation realizes effective embedding and slow releasing of thymalfasin, can continuously release for 40d, and also has the advantages of effectively reduction of the toxic and side effects of thymalfasin, improvement of the bioavailability, prolongation of the metabolism half life, administration frequency reduction, and reduction of the economy and spirit burden of patients.
Description
Technical field
The invention belongs to sustained release microsphere agents technical field, relate to the long-acting of a kind of immunomodulator
Sustained release microsphere agents and preparation method thereof, be specifically related to a kind of thymalfasin sustained release microsphere agents and
Its preparation method.
Background technology
Thymalfasin, i.e. Thymosin alpha 1, be a kind of weight finding for 1984 and being secreted by thymus
The T lymphocyte regulatory factor wanted, relevant with Culture in vitro.Thymalfasin is a N
Hold acetylizad Acid polypeptide, be made up of 28 amino acid residues, be mainly used in chronic viral hepatitis B
And the immune response-enhancing agents as immune impairment patient.
Thymalfasin is confirmed as a kind of immunomodulator, its good efficacy, clinical
Application prospect is considerable.It is that the modal virus of the mankind is sexy that hepatitis B virus (HBV) infects
One of dye, whole world Patients with Chronic HBV Infection there are about 300,000,000, and wherein most is in Asia.
In population of China, Chronic HBV carriers accounts for 10%-15%, and chronic hepatitis B (CHB) is suffered from
In person, annual generation liver cirrhosis and hepatocarcinoma person account for 2% and 1% respectively.Obviously, actively control
Treat HBV infection, stop it to develop to liver cirrhosis and hepatocarcinoma, significant.Additionally,
Thymalfasin has good efficacy to the disease such as AIDS, malignant tumor.
Having injection thymalfasin list marketing at present, said preparation is lyophilized injectable powder, its
Recommended amounts at treatment chronic hepatitis B is every pin 1.6mg subcutaneous injection secondary weekly, two doses
Amount is about separated by 3-4 day, and treatment should can not be interrupted continuous 6 months (52 pin) period.This
The compliance of the administering mode patient of sample is very poor, and be therefore developed to monthly to be administered once is slow
Release microball preparation and can improve the compliance of patient greatly, improve the cure rate of this disease.
The document of the preparation method of current thymalfasin sustained release microsphere agents gets more and more with patent,
Mainly there are multi-emulsion method (W/O/W), emulsion solvent diffusion method, extrusion by melting etc., Qi Zhongfu
Breast method is the typical case side that one prepares Poly(D,L-lactide-co-glycolide (PLGA) sustained-release micro-spheres
Method.Article that the Zhong Yanqiang of Second Military Medical University, PLA etc. deliver and patent
(CN200610118413.5) have employed multi-emulsion method (W/O/W) in and be prepared for thymalfasin
Sustained-release micro-spheres.Number of patent application is that 200310119386.X discloses one and utilizes PLGA to carry
The method taking, synthesizing thymosin microcapsule controlled-release pin.He Yi etc., the system of thymosin polylactic acid microsphere
Standby and Release Performance research, Chinese Journal of Pharmaceuticals, 2006,37 (3), disclose with newborn
Change solvent volatilization and prepare thymosin polylactic acid microsphere, wherein with PLGA as carrier, wave with emulsifying
The method of sending out prepares microsphere.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.With breast
Change the research of thymic peptide alpha 1 microballoon prepared by cross-linking method, with medicine type A gelatin as capsule material.Zhang Hai
Pine, Chen Yangshu, Hu Jungao, etc., the research of oral thymus microsphere, China Dispensary, 1999,
10 (2): 58, etc..Easily there is gathering, merge in above traditional method, separates and purification
Product difficulty, most of the time and cost are used for removing residual solvent and extra medicinal, are not suitable for
Industrialized production, and simple to operate, the favorable reproducibility such as spray drying method, fusion method, salting out method,
But preparation process is fiercer, the temperature used is higher or pH value changes greatly, to medicine
Stability have higher requirement, be not suitable for polypeptide, protein medicaments or other heat-sensitive substances,
Additionally, thymalfasin sustained-release micro-spheres surface atresia prepared by above method, inner hollow or mutual
The most logical cavity so that microsphere drug loading is low, unfavorable to being administered.Therefore, one is currently needed badly
Money solid porous sustained-release micro-spheres of thymalfasin that can solve disadvantages mentioned above and preparation method thereof.
Summary of the invention
It is an object of the invention to provide a kind of thymalfasin sustained-release micro-spheres and preparation method thereof, institute
The method of stating be need not isolated and purified, avoid second time emulsion and the high-pressure electrostatic of high-temperature operation
The microcapsule method of forming, uniform, medicament contg sized by thymalfasin sustained-release micro-spheres prepared by this method
High solid porous microsphere, can effectively extend medicine action time in vivo, reduce thymus method
New administration frequency.
The most domestic the high-pressure electrostatic microcapsule method of forming is not the most used to prepare thymalfasin-poly-
The unit of lactic acid long-acting slow-release microball preparation or individual, and thymalfasin slow release prepared by the present invention
Microsphere is the domestic surface perforate prepared first, the thymalfasin that interior outer hole is mutually communicated-poly-
Lactic acid porous sustained-release microsphere.PLLA is to have excellent biocompatibility and biological degradability
Polymer, be to can be used as pharmaceutical carrier through CFDA approval, the final product of metabolism in vivo
Thing is CO2And H2O, intermediate product lactic acid is also the product of internal normal sugar metabolism, Bu Hui
Vitals are assembled, and therefore polylactic acid microsphere has obtained studying widely and answering as pharmaceutical carrier
With.
The present invention adopts the following technical scheme that
A kind of employing high-pressure electrostatic microcapsule method of forming prepares thymalfasin sustained-release micro-spheres technology, tool
Body is as follows:
1) a certain amount of PLLA (PLLA) dissolves in organic solvent, obtains poly-breast
Acid copolymer concentration is the oil phase of (1%-40%) (W/V, g/ml), and wherein organic solvent is
One in dichloromethane, ethyl acetate or its arbitrary composition；Stabilizer for comprise but not only
Being limited to Pu Langluoni F-127 (Pluronic F127), its mass fraction is 0.01%-1.2%.
2) molten to thymalfasin, protective agent, porogen being dissolved in water, obtaining thymalfasin is 1%-60%
(W/V) interior aqueous phase.
3) above-mentioned oil phase is mixed with interior aqueous phase, with cell crushing instrument ultrasonic emulsification certain time,
Emulsification times is generally (0.5-2) min (power 200W, ultrasonic 1s are spaced 1s) and is formed
Uniformly, stable W/O emulsion.
4) by water-soluble to the sodium alginate that mass fraction is 1.5%-30% or the chitosan of fresh outfit
Liquid adds in above-mentioned emulsion as aqueous phase (W), with cell crushing instrument ultrasonic emulsification certain time,
Emulsification times is generally (0.5-2) min (power 200W, ultrasonic 1s are spaced 1s) and is formed
Uniformly, stable W/O/W emulsion.
5) prepared W/O/W emulsion is loaded in syringe immediately, by high pressure microcapsule
Shaped device and syringe pump, be expelled in the calcium chloride water of 5%-10% newly prepared, because of
Sodium alginate and calcium chloride meet to react and generate calcium alginate and form thymalfasin sustained-release micro-spheres.
Further, step 2) described in protective agent predominantly: human serum albumin, gelatin,
One or more mixture in trehalose, mannose or mannitol etc., the most protectant matter
Amount mark is typically at 0.01%-5.0%, and porogen comprises but is not limited only to ammonium hydrogen carbonate, quality
Percentage composition 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 reception, filters out the white in solution with funnel
Floccule, 7000rpm is centrifuged 5min, can collect thymalfasin-polylactic acid solid microsphere,
Lyophilization is to remove H2O, dichloromethane, NH3And CO2, the thymus method being dried can be obtained
New solid porous sustained-release micro-spheres.
Thymalfasin porous sustained-release microsphere preparation prepared by the present invention can be with slow release 30-40 days.
Accompanying drawing explanation
Fig. 1 is the scanning electron microscope (SEM) photograph of the thymalfasin sustained-release micro-spheres of the embodiment of the present invention 1 preparation；
Fig. 2 is the scanning electron microscope (SEM) photograph of the thymalfasin sustained-release micro-spheres of the embodiment of the present invention 2 preparation；
Fig. 3 is the scanning electron microscope (SEM) photograph of the thymalfasin sustained-release micro-spheres of the embodiment of the present invention 3 preparation；
Fig. 4 is the external tired of the thymalfasin sustained release microsphere agents of the embodiment of the present invention 1 preparation
Long-pending release profiles；
Fig. 5 is the external tired of the thymalfasin sustained release microsphere agents of the embodiment of the present invention 2 preparation
Long-pending release profiles；
Fig. 6 is the external tired of the thymalfasin sustained release microsphere agents of the embodiment of the present invention 3 preparation
Long-pending release profiles；
Fig. 7 is the body of the thymalfasin sustained release microsphere agents of the embodiment of the present invention 1,2,3 preparation
Outer cumulative release curve comparison figure.
Detailed description of the invention
Embodiment 1
The PLLA (PLLA) of 200mg is dissolved in the dichloromethane of 5ml, is gathered
The oil phase of lactic acid copolymer, and add the stabilizer Pu Langluoni F-127 of 3mg.By 80mg
Thymalfasin, the gelatin of 15mg, the ammonium hydrogen carbonate of 0.5ml are dissolved in the water for injection of 600ml,
Oil phase is joined in aqueous phase, employing cell crushing instrument ultrasonic emulsification 1.5min (power 200W,
Ultrasonic 1s, is spaced 1s) form uniform, stable W/O emulsion.Above-mentioned solution is joined
The sodium alginate aqueous solution that 1000ml mass fraction is 2% of new preparation, and use cell crushing instrument
Ultrasonic emulsification 1.5min, ultrasonic emulsification condition ibid, forms uniform, stable W/O/W breast
Liquid, loads in syringe immediately by prepared W/O/W emulsion, is filled by high pressure microcapsule molding
Putting, be expelled in the calcium chloride solution that mass fraction is 10% that 500ml configures, magnetic force stirs
Mixing emulsion 1.5 hours, filter out White Flocculus with funnel, 7000rpm is centrifuged 5min, receives
Collection thymalfasin-PLLA microsphere.Lyophilization i.e. obtains thymalfasin porous sustained-release microsphere, micro-
Spherolite footpath is less than 100 μm, and drug loading is 5.2%, thymalfasin porous sustained-release microsphere scanning electricity
Mirror such 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 add the stabilizer Pu Langluoni F-127 of 3.5mg.Will
150mg thymalfasin, the trehalose of 20mg, the ammonium hydrogen carbonate of 4.0ml are dissolved in 1000ml's
In water for injection, oil phase is joined in aqueous phase, use cell crushing instrument ultrasonic emulsification 1.5min
(power 200W, ultrasonic 1s are spaced 1s) forms uniform, stable W/O emulsion.Will
Above-mentioned solution joins the sodium alginate aqueous solution that mass fraction is 5% that 1500ml newly prepares,
And by cell crushing instrument ultrasonic emulsification 1.5min, ultrasonic emulsification condition ibid, is formed uniformly, steady
Fixed W/O/W emulsion, loads prepared W/O/W emulsion immediately in syringe, passes through
High pressure microcapsule shaped device, is expelled to the calcium chloride that mass fraction is 8% that 1000ml configures
In solution, magnetic agitation emulsion 1.5 hours, filter out White Flocculus, 7000rpm with funnel
Centrifugal 5min, collects thymalfasin-PLLA microsphere.It is many that lyophilization i.e. obtains thymalfasin
Hole sustained-release micro-spheres, microspherulite diameter is less than 100 μm, and drug loading is 6.0%, thymalfasin porous
Sustained-release micro-spheres scanning electron microscope such 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 add the stabilizer Pu Langluoni F-127 of 4.8mg.Will
100mg thymalfasin, the trehalose of 10mg, the ammonium hydrogen carbonate of 1.0ml are dissolved in 800ml's
In water for injection, oil phase is joined in aqueous phase, use cell crushing instrument ultrasonic emulsification 1.5min
(power 200W, ultrasonic 1s are spaced 1s) forms uniform, stable W/O emulsion.Will
Above-mentioned solution joins the sodium alginate aqueous solution that mass fraction is 5% that 1200ml newly prepares,
And by cell crushing instrument ultrasonic emulsification 1.5min, emulsification condition ibid, is formed uniform, stable
W/O/W emulsion, loads in syringe immediately by prepared W/O/W emulsion, micro-by high pressure
Capsule shaped device, is expelled in the calcium chloride solution that mass fraction is 6% that 1200ml configures,
Magnetic agitation emulsion 1.5 hours, filters out White Flocculus with funnel, and 7000rpm is centrifuged 5min,
Collect thymalfasin-PLLA microsphere.Lyophilization i.e. obtains thymalfasin porous sustained-release microsphere,
Microspherulite diameter is less than 100 μm, and drug loading is 5.8%, and thymalfasin porous sustained-release microsphere scans
Electronic Speculum such 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,
Assay method is:
Precision weighs dry medicine-containing microsphere 0.100g and is placed in 10ml tool plug test tube, with pH
Be 7.4 phosphate buffer (containing 0.02% Hydrazoic acid,sodium salt as antibacterial, 0.05% tell
Temperature 80 is for wetting agent) 10ml is release medium, it is placed in the shaking table of constant temperature waters, earthquake speed
The vitro release carrying out microsphere under the conditions of degree 100rpm, temperature 37 DEG C ± 0.5 DEG C measures.Point
Not 0 hour, 3 hours, 1 day, 3 days, 5 days, 7 days, 9 days, 14 days, 18 days,
Within 21 days, 24 days, 28 days, 30 days, 40 days, respectively take 0.5ml release medium for efficient liquid phase
The content of chromatography determination thymalfasin, and supplement fresh release medium.Fig. 4,5,6,
7 vitro cumulative being respectively the thymalfasin sustained release microsphere agents prepared by embodiment 4,5,6
Release profiles and correlation curve.By Fig. 4,5,6,7 it can be seen that prepared by the present invention
Thymalfasin sustained release microsphere agents has good releasing effect, is respectively less than 20% in 7 days, its
Deenergized period is 30-40 days.
Above content is that to combine concrete preferred implementation made for the present invention further in detail
Describe in detail bright, it is impossible to assert the present invention be embodied as be confined to these explanations.For the present invention
For person of an ordinary skill in the technical field, without departing from the inventive concept of the premise,
Done any modification, equivalent substitution and improvement etc., are regarded as belonging to the protection of the present invention
Scope.
Claims (10)
1. a thymalfasin sustained release microsphere agents, it is characterized in that: it be the molecular weight of the 50%-99.9% of the thymalfasin by the 0.1%-30% of microspheres weight and microspheres weight be 5000-200000 daltonian biodegradable and tool biocompatibility macromolecular material, 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.
A kind of thymalfasin sustained release microsphere agents the most according to claim 1; it is characterized in that; comprising the protective agent that mass percent is 0.1%-5.0%, this protective agent is the one in human serum albumin, gelatin, alginic acid sugar or mannitol or wherein arbitrary composition.
A kind of thymalfasin sustained release microsphere agents the most according to claim 1, it is characterized in that, described degradable has the macromolecular material of biocompatibility, one or both and any of the above 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.
A kind of thymalfasin sustained release microsphere agents the most according to claim 3, it is characterized in that, described degradable has the one in the macromolecular material of biocompatibility, preferably PLLA, polymeric polyglycolide-polylactide, polylactic acid-polyglycol, is optimal with PLLA.
A kind of thymalfasin sustained release microsphere agents the most according to claim 1, it is characterised in that described degradable has the macromolecular material of biocompatibility, and molecular weight ranges is all 5000-200000 dalton.
A kind of thymalfasin sustained release microsphere agents the most according to claim 1, it is characterised in that the slow release cycle of described thymalfasin is 30-40 days.
7. the preparation method of a kind of thymalfasin sustained release microsphere agents as described in claim 1 to 6 any one, it is characterised in that comprise the following steps:
1) PLLA is dissolved in organic solvent, and adds a certain amount of stabilizer, obtain the oil phase that PLA concentration is (1%-40%) (W/V, g/ml), the one during wherein organic solvent is dichloromethane, ethyl acetate or its arbitrary composition；Stabilizer is not limited only to Pu Langluoni F-127(Pluronic F127 for comprising), its mass fraction is 0.01%-1.2%；
2) molten to thymalfasin, protective agent, porogen are dissolved in water; thymalfasin be 1%-60%(W/V) interior aqueous phase; one during wherein protective agent is human serum albumin, gelatin, alginic acid sugar or mannitol or wherein arbitrary composition, mass percent is 0.01%-5.0%；Porogen comprises but is not limited only to ammonium hydrogen carbonate, and weight/mass percentage composition is: 0.01%-1.0%；
3) above-mentioned oil phase is mixed with interior aqueous phase, with cell crushing instrument ultrasonic emulsification certain time, phaco time generally (0.5-2) min(power 200W, ultrasonic 1s, is spaced 1s) form uniform, stable W/O emulsion；
4) sodium alginate that mass fraction is 1.5%-30% newly prepared or chitosan aqueous solution are added in above-mentioned emulsion as aqueous phase (W), with cell crushing instrument ultrasonic emulsification certain time, emulsification times is (0.5-2) min(power 200W, ultrasonic 1s, is spaced 1s) form uniform, stable W/O/W emulsion；
5) by above-mentioned steps 4) in the W/O/W emulsion for preparing load immediately in syringe, by high pressure microcapsule shaping device, be expelled in the calcium chloride water of 5%-10% newly prepared, because the reaction of meeting of sodium alginate and calcium chloride generates calcium alginate and forms microsphere；
6) high pressure microcapsule shaping device injection contacts mixing react with receiving liquid, and magnetic agitation 50-80min filters out the White Flocculus in solution with funnel, and 7000rpm is centrifuged 5min, can collect thymalfasin-polylactic acid microsphere, and lyophilization is to remove H2O, dichloromethane, NH3And CO2, the thymalfasin porous sustained-release microsphere being dried can be obtained.
The preparation method of a kind of thymalfasin sustained release microsphere agents the most 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.
In the step 6) of the preparation method of a kind of thymalfasin sustained release microsphere agents the most according to claim 7, the magnetic agitation time is preferably (61-70) min, is optimal with 65min.
10. the thymalfasin sustained release microsphere agents that prepared by preparation method described in claim 1-9 any one.
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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 |
| 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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