CN100579524C - Method of preparing simvastatin sustained-release microsphere carried series - Google Patents
Method of preparing simvastatin sustained-release microsphere carried series Download PDFInfo
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- CN100579524C CN100579524C CN200810050306A CN200810050306A CN100579524C CN 100579524 C CN100579524 C CN 100579524C CN 200810050306 A CN200810050306 A CN 200810050306A CN 200810050306 A CN200810050306 A CN 200810050306A CN 100579524 C CN100579524 C CN 100579524C
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Abstract
The invention relates to a method that a functional drug is enveloped into a polymeric material with biodegradability to form a nano-micron microsphere system. The method comprises that the polymeric material and simvastatin are dissolved in an organic liquor to form uniform dispersion which is then added into an liquor containing emulsifier Tween 80 and biologically nontoxic electrolytic polyvinyl alcohol or sodium dodecyl benzene sulfonate (SDBS), and then the obtained liquor is stirred, evaporated at a reduced pressure, centrifugalized, washed and vacuum dried, finally the simvastatin-contained delayed-release microsphere system is obtained. The surface of the microsphere is smooth and round, the granule thereof is regular without conglutination, and the granule diameter, the drug-loading rate (1-10 percent) and the encapsulation rate (above 40 percent) are all controllable, and the delayed-release time exceeds 2 months. The prepared simvastatin-contained delayed-release microsphere system can be processed into various preparations used in bony tissue absorption or bony defect parts, the microsphere system is degraded at a proper speed, thus the simvastatin can be further released; the degradation of the polymer can provide bony tissue with subsequent recuperating space to complete the repair of the bony defect parts.
Description
Technical field
The invention belongs to biological technical field, be specifically related to a kind ofly adopt emulsifying-seasoning that function medicament is encapsulated in the biodegradability polymeric material to form the method for micron microsphere system received.
Background technology
Simvastatin is the inhibitor of Hydroxymethylglutaryl list acyl coenzyme A reductase, is the present clinical common drug that is used for cholesterol reducing, angiocardiopathy preventing.(Bone morphological protein2, BMP-2) expression of gene illustrate that it has the promotion ossification to bone morphogenetic protein(BMP) 2 in reported first statinses such as Mundy energy induced osteogenesis cell and the medullary cell.
This seminar serves as to estimate the animal model that residual alveolar ridge absorbs with the rat of pulling out infradentale, having prepared with the polylactic acid-glycolic guanidine-acetic acid is carrying the simvastatin timbering material and being applied to this model of carrier, inquires into feasibility and mechanism of action thereof that simvastatin prevention residual alveolar ridge absorbs.Find that this timbering material has stronger bone repair, bone formation rate and bone amount all are better than matched group; Discover that further this timbering material is also by promoting local organization transforminggrowthfactor-(translation growth factor, TGF-β 1), BMP2 and VEGF (vascular epithelial growth factor, expression VEGF) and bring into play the promotion ossification; And, thereby simvastatin also can promote osteoblastic osterix, the OPG in rat marrow stroma cell source and the expression of PC-1mRNA to promote osteoblastic differentiation and function.
Behind the simvastatin oral administration process liver first pass metabolism, its bioavailability only is 2.4%, and the absorption meeting of osseous tissue does not still less reach the needed dosage in bone formation position far away; And widely apply simvastatin can cause muscle poison and other toxicity, side effect, and increase patient's misery and financial burden, therefore, can not satisfy experiment and requirements for clinical application.This seminar preparation carry the bioavailability that the simvastatin timbering material can partly improve simvastatin, reduce toxic and side effects, but this year the simvastatin timbering material slow release effect be not very desirable, clinical manipulation is not very convenient, requires further improvement dosage form.
Research can discharge simvastatin for a long time and can keep its bioactive slow releasing preparation significant again.Wherein, the microsphere sustained-release system has begun to be applied to tissue engineering bracket, and has obtained the certain growth of promotion cell, propagation and tissue repair effect, but the report of not studying relevant for the simvastatin slow-release microball preparation as yet.
The Biodegradable polymeric carrier material can be divided into natural, semi-synthetic and synthesized polymer material.In recent years, advantage such as synthesized polymer material is good because of its biocompatibility, and biodegradable absorption is more stable in vivo, and degradative phase is adjustable and be subjected to extensive attention is that a kind of ideal microsphere prepares material.Nano controlled-release system diameter is between 1nm~100nm, medicine and DNA etc. are wrapped in microsphere inside, perhaps by static in conjunction with absorption, adhewsive action is positioned at particle surface, discharges by cyst wall leaching, infiltration and diffusion, also can be that the corrosion of capsule and microsphere itself makes drug release wherein.Polymer support, mounting system have been applied to bone, skin, neuranagenesis, are widely used in organizational project.
Summary of the invention
The object of the present invention is to provide a kind of is substrate with the biodegradable polymer material, prepares the method for simvastatin sustained-release microsphere carried system.
This method technology is simple, easy to operate; The microspheres prepared system can be reprocessed into multiple dosage form, is applied to osseous tissue and absorbs or the bone defect; Simvastatin discharges through slow release, gives full play to it and promotes the positive role of skeletonization and avoid its toxic and side effects, improves bioavailability; Simvastatin load capacity and rate of release range of accommodation are wide, release is stable.
The preparation of simvastatin sustained-release microsphere carried system is carried out as follows:
1) be jointly to be dissolved in the organic solvent of biological nontoxic at 3~10: 1 biodegradable polymer material and simvastatin by mass ratio, form 1~10 milliliter of uniform dispersion liquid, the concentration range of simvastatin is 0.001~0.01 grams per milliliter in the solution;
2) in being the aqueous solution of biological nontoxic emulsion stabilizer of 1~2% polyvinyl alcohol (PVA) or dodecylbenzene sodium sulfonate, 10~50 milliliters, mass concentration add the emulsifier tween 80 of 2~5% volume ratios and the electrolyte of 0.1~5.5 gram biological nontoxic, the electronic stirring of 300~1000rpm continues 10~30 minutes;
3) liquid that step 1) is obtained slowly joins step 2) in the liquid that obtains, 300~1000rpm, continuous stirring 1~3 hour;
4) then in 35~45 ℃ of reduction vaporizations 1~3 hour, with the organic solvent in the abundant removal microsphere;
5) at last in centrifugal 5~10 minutes of 15000~20000rpm, washing, vacuum drying 40~60 hours, promptly get simvastatin sustained-release microsphere carried system.
The used biodegradable polymer material of the present invention comprises polylactic acid (PLA), polyglycolic acid (PLGA), polylactic acid-glycolic guanidine-acetic acid copolymer; The ratio of polylactic acid-glycolic guanidine-acetic acid copolymer is 75/25 or 50/50; Used organic solvent is dichloromethane, ethyl acetate or the mixture of the two; The electrolyte of the biological nontoxic that adopts is sodium chloride, potassium chloride or sodium sulfate.
Method provided by the invention compared with prior art has the following advantages and the salience effect: the method technology for preparing simvastatin sustained-release microsphere carried system is simple, easy to operate, does not require that medicine has very big dissolubility in water; The particle diameter that does not require the material medicine powder is very little; The microsphere features smooth surface rounding, regular particles does not have adhesion, and particle diameter is controlled, and drug loading (1~10%) and envelop rate (can reach more than 40%) are controlled, and slow-release period reached more than 2 months, and it is prominent, and to release rate lower; The microspheres prepared system can be reprocessed into multiple dosage form, is applied to osseous tissue and absorbs or the bone defect; Simvastatin discharges through slow release, gives full play to it and promotes the positive role of skeletonization and avoid toxic and side effects, improves bioavailability; Simvastatin load capacity and rate of release range of accommodation are wide, release is stable.Proper as condition control, the release of function medicament simvastatin can be near zero level, promote osteoblastic growth, propagation, differentiation and function, and osteoblast had bone guided and bone inductive effect, the suitable prompt drop of microsphere system is separated, simvastatin can further be discharged, and depolymerization can be osseous tissue follow-up reparation space is provided, and finally finishes the damaged reparation of osseous tissue.
Description of drawings
Fig. 1: simvastatin is dispersive om observation in deionized water;
Fig. 2: the om observation that carries the simvastatin microsphere system;
Fig. 3: the SEM that carries the simvastatin microsphere system observes;
Fig. 4: the degradation curve figure that carries the simvastatin microsphere system.
The observed simvastatin of Fig. 1 light microscopic (Olympus BX41M-ESD) dispersive form in deionized water, simvastatin is because of being slightly soluble in the irregular distribution that water presents, do not see this form after simvastatin wrapped into polymer, illustrate that simvastatin can be encapsulated in the degradable polymer material.
Year simvastatin microsphere system (No. 4 products in embodiment 2, the table 2) under Fig. 2 light microscopic (Olympus BX41M-ESD), the form of as seen carrying the simvastatin microsphere is regular, not of uniform size, can satisfy the different drug release rates and the needs in cycle just.
Fig. 3 SEM (FDAC, model: S-4800) observe being seen year simvastatin microsphere system (No. 5 products in embodiment 2, the table 2) microscopic pattern down, as seen carry the simvastatin microsphere features smooth surface, no adhesion, on indivedual big microspheres micropore is arranged, may cause prominent the releasing that medicine is early stage, but the negligible amounts of microsphere, can not influence the slow release effect of medicine.
Fig. 4 carries the degradation curve figure of simvastatin microsphere system (No. 8 products in embodiment 2, the table 2), illustrates that the degraded of carrying the simvastatin microsphere system discharges near zero level, and drug release reached more than 8 weeks, can satisfy the needs of bone tissue restoration, healing cycle.
The specific embodiment
The present invention prepares simvastatin sustained-release microsphere carried system by emulsifying-seasoning (being called solvent evaporation method, solvent solidification method, solvent extraction method again).Used various materials comprise: the biodegradable polymer material comprises polylactic acid, polyglycolic acid, polylactic acid-glycolic guanidine-acetic acid copolymer; The ratio of polylactic acid-glycolic guanidine-acetic acid copolymer is 75/25,50/50; Used organic solvent is a dichloromethane, ethyl acetate or the mixture of the two; Function medicament is a simvastatin; Used emulsifying agent is Tween 80 (2% volume ratio); The surfactant of biological nontoxic, emulsion stabilizer are the PVA of 1-1.5%; The electrolyte of the biological nontoxic that adopts is a sodium chloride.
Further specify the preparation method and the characteristics thereof of simvastatin sustained-release microsphere carried system of the present invention below by several exemplary embodiments.
1, the preparation of degradable polymer material blank microsphere
Embodiment 1:
0.09 gram polylactic acid (molecular weight 0.2 ten thousand) is dissolved in the 3ml dichloromethane, make into uniform mixing liquid, slowly join in the aqueous solution (containing 0.6 milliliter Tween80) of PVA of the 30ml that stirs with 700rpm speed, mass concentration 1.5%, continue to stir 1.5 hours, 37 ℃ of decompression rotary evaporations 1 hour, the Ex-all organic solvent, 18000rpm is centrifugal, deionization washing 3 times, vacuum drying 48 hours, obtain about 0.078 gram of the blank microsphere powder of polylactic acid, microsphere average grain diameter is 2100nm.
Use the polylactic acid of other molecular weight and the microsphere of the different-grain diameter that other biological degradation polyalcohol material obtains by above-mentioned steps, average particle size range the results are shown in Table 1 from 358nm to 2100nm, can satisfy the needs of the different degradation rate medicine carrying microballoonss of preparation.
Table 1: the preparation of biological degradation polyalcohol material blank microsphere
Sequence number | PVA aqueous solution (ml) | Dichloromethane (ml) | Polymer, molecular weight | Amount of polymers (g) | Microsphere average grain diameter (nm) | The quality g of blank microsphere |
1 | 30 | 3 | PLA,0.2w | 0.09 | 2100 | 0.078 |
2 | 30 | 3 | PLA,1.0w | 0.09 | 1465 | 0.07 |
3 | 30 | 3 | PLA,2.0w | 0.09 | 817 | 0.08 |
4 | 30 | 3 | PLGA7525,1w | 0.2 | 1768 | 0.2 |
5 | 30 | 3 | PLGA7525,2w | 0.2 | 1258 | 0.3 |
6 | 30 | 3 | PLGA5050,1w | 0.2 | 869 | 0.3 |
7 | 30 | 3 | PLGA5050,2w | 0.2 | 358 | 0.2 |
2, carry the preparation of simvastatin polymer microballoon system
Embodiment 2:
(1) is that 5: 1 the PLA (0.05 gram, molecular weight 1.0w) and the mixture of simvastatin (0.01 gram) are dissolved in 3 milliliters of dichloromethane with mass ratio, makes into uniform mixing liquid;
(2) above-mentioned mixed liquor is slowly joined in the PVA aqueous solution (contain 0.6 milliliter of Tween80,0.3 gram sodium chloride, 700rpm stirs after 15 minutes and uses) of 30ml in the stirring (700rpm), mass concentration 1.5%, continue to stir 1.5 hours;
(3) 37 ℃ of decompression rotary evaporations 1 hour, the Ex-all organic solvent; Centrifugal 10 minutes of 18000rpm, washing, vacuum drying 48 hours obtains to carry about 0.06 gram of simvastatin microsphere powder, and microsphere average grain diameter is 102nm, and envelop rate is 20.89%.
Get exsiccant year simvastatin microsphere powder 0.03g, add 1 milliliter of acetonitrile and 2 milliliters, 0.1M phosphate buffer, after 24 hours, the uv-spectrophotometric instrument detects, analyzes, and whether wraps into microsphere and calculates drug loading (mass ratio of contained simvastatin of microsphere and microsphere), envelop rate (ratio of actual drug loading and theoretical drug loading) to determine simvastatin.According to the aforesaid operations step, change the kind of polymer and prepare the medicine carrying microballoons of different envelop rates and particle diameter respectively with the ratio of simvastatin.
Table 2: the preparation of carrying simvastatin biological degradation polyalcohol microsphere
Sequence number | The PVA aqueous solution | Dichloromethane | Polymer molecular weight | Polymer: simvastatin | The quality g of simvastatin | Microsphere average grain diameter | Envelop rate (%) | The quality g of medicine carrying microballoons | Drug loading % |
1 | 30ml | 3ml | PLA,0.2 |
10∶1 | 0.01 | 236nm | 18.34 | 0.13 | 1.41 |
2 | 30ml | 3ml | PLA,1.0w | 5∶1 | 0.01 | 102nm | 20.89 | 0.06 | 3.48 |
3 | 30ml | 3ml | PLA,2.0w | 3∶1 | 0.01 | 61nm | 28.45 | 0.04 | 7.11 |
4 | 15ml | 1.5ml | PLGA5050 2.0w | 10∶1 | 0.01 | 8430nm | 10.97 | 0.11 | 0.99 |
5 | 15ml | 1.5ml | PLGA5050 2.0w | 5∶1 | 0.01 | 1930nm | 17.33 | 0.07 | 2.48 |
6 | 15ml | 1.5ml | PLGA5050 2.0w | 3∶1 | 0.01 | 213nm | 18.09 | 0.05 | 3.62 |
7 | 30ml | 3ml | PLGA7525 2.0w | 10∶1 | 0.01 | 3223nm | 30.56 | 0.12 | 2.55 |
8 | 30ml | 3ml | PLGA7525 2.0w | 5∶1 | 0.01 | 1400nm | 35.27 | 0.05 | 7.05 |
9 | 30ml | 3ml | PLGA7525 2.0w | 3∶1 | 0.01 | 391nm | 40.67 | 0.04 | 10.17 |
Embodiment 3:
With mass ratio be 5: 1 PLGA7525 (0.05 the gram, molecular weight 2w) mixture with simvastatin (0.01 gram) is dissolved in 3 milliliters of dichloromethane, make into uniform mixing liquid, this liquid is slowly joined in the stirring (700rpm) 30 milliliters, the PVA aqueous solution of mass concentration 1% (contain 0.6 milliliter of Tween80, sodium chloride 0.3 gram, 700rpm stirs after 15 minutes and uses) in, continue to stir 1.5 hours, 37 ℃ of decompressions, rotary evaporation 1 hour, the Ex-all organic solvent; Centrifugal 10 minutes of 18000rpm, washing, vacuum drying 48 hours obtains to carry simvastatin microsphere powder 0.062 gram, and mean diameter is 1400nm, and envelop rate is 35.27%.
Change mixing speed, under the constant situation of other conditions, the preparation microsphere is to inquire into the influence of mixing speed to the preparation microsphere.Find that through serial experiment formed microsphere average grain diameter and mixing speed are negative correlativing relation.
Table 3: year simvastatin biological degradation polyalcohol microsphere of different mixing speed preparations
Sequence number | PVA aqueous solution (ml) | Dichloromethane (ml) | Polymer molecular weight | Polymer/simvastatin | Mixing speed (rpm) | Mean diameter (nm) | Envelop rate (%) | The quality g of medicine carrying microballoons | Drug loading % |
1 | 30 | 3 | PLGA7525 20,000 | 5∶1 | 500 | 1920 | 30.56 | 0.055 | 5.56 |
2 | 30 | 3 | PLGA7525 20,000 | 5∶1 | 700 | 1400 | 35.27 | 0.062 | 5.69 |
3 | 30 | 3 | PLGA7525 20,000 | 5∶1 | 1000 | 829 | 40.67 | 0.068 | 5.98 |
Above in conjunction with specific embodiments, the present invention has been done further elaboration, rather than will limit the invention with this.Inventive point of the present invention is that side effect is big, the higher pharmaceutical pack of cost is become the sustained-release micro-spheres system with appropriate carriers materials processing, as for the other drug beyond the Application Example, use other carrier material, use different dispersants, emulsifying agent, additive etc. all in design scope of the present invention.
Claims (2)
1, the preparation method of simvastatin sustained-release microsphere carried system, its step is as follows:
1) be jointly to be dissolved in the organic solvent of biological nontoxic at 3~10: 1 biodegradable polymer material and simvastatin by mass ratio, form 1~10 milliliter of uniform dispersion soln, the concentration range of simvastatin is 0.001~0.01 grams per milliliter in the solution;
2) in being the aqueous solution of biological nontoxic emulsion stabilizer of 1~2% polyvinyl alcohol, 10~50 milliliters, mass concentration add the emulsifier tween 80 of 2~5% volume ratios and the electrolyte of 0.1~5.5 gram biological nontoxic, the electronic stirring of 300~1000rpm continues 10~30 minutes;
3) liquid that step 1) is obtained slowly joins step 2) in the liquid that obtains, 300~1000rpm, continuous stirring 1~3 hour;
4) then in 35~45 ℃ of reduction vaporizations 1~3 hour, with the organic solvent in the abundant removal microsphere;
5) at last in centrifugal 5~10 minutes of 15000~20000rpm, washing, vacuum drying 40~60 hours, promptly get simvastatin sustained-release microsphere carried system;
In the above-mentioned steps, the biodegradable polymer material is polylactic acid or polylactic acid-glycolic guanidine-acetic acid copolymer, and the organic solvent of biological nontoxic is dichloromethane, ethyl acetate or the mixture of the two; The electrolyte of biological nontoxic is sodium chloride, potassium chloride or sodium sulfate.
2, the preparation method of simvastatin sustained-release microsphere carried system as claimed in claim 1 is characterized in that: the ratio of polylactic acid-glycolic guanidine-acetic acid copolymer is 75/25 or 50/50.
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CN102499997A (en) * | 2011-12-27 | 2012-06-20 | 吉林大学 | Composite nano fiber support material, as well as preparation method and application in bone repairing aspect |
EP3242653A1 (en) * | 2015-01-05 | 2017-11-15 | Boston Scientific Scimed Inc. | Biodegradable drug eluting microsphere for the treatment of solid tumors |
CN104906047B (en) * | 2015-05-19 | 2017-12-12 | 南方医科大学 | A kind of preparation method of pravastatin sodium long-acting slow-release microballoon |
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CN108096213B (en) * | 2017-12-25 | 2020-06-30 | 河北科技大学 | Preparation method of simvastatin microspheres wrapped by hydroxyethyl starch 130/0.4 |
CN109248338A (en) * | 2018-11-16 | 2019-01-22 | 张浩淼 | Absorbable membrane and its preparation method and application, dental implant |
CN114129537A (en) * | 2021-10-21 | 2022-03-04 | 广东省科学院健康医学研究所 | Hydrophobic drug microsphere controlled release agent and preparation method and application thereof |
CN114129542A (en) * | 2021-10-21 | 2022-03-04 | 广东省科学院健康医学研究所 | Polymer composite microsphere and preparation method and application thereof |
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