伊维菌素微球的制备及其药动学与药效学研究
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摘要
伊维菌素作为体内外驱虫或杀虫剂,在国内外得到广泛应用,各种制剂都有研究报道。为了研究伊维菌素的缓释制剂,采用溶剂挥发法,利用聚乳酸(分子量25000、50000、87000,分别缩称为PLA2.5、PLA5、PLA8.7)、乙交酯丙交酯共聚物(PLGA)、乙基纤维素(EC)作载体制备伊维菌素聚合物微球,探索其制备工艺。经筛选试验认为,合理的制备工艺是,以含1.5%PVA(乳化剂)的水溶液为连续相即水相(W),以溶解药物和聚合物的二氯甲烷为分散相即油相(O),药物与聚合物之比为0.43 : 1,分散相在连续相中的浓度为10%,将分散相缓慢加入到连续相中,在300～500rpm速度搅拌下形成O/W型乳状液,继续不断搅拌6～7h,乳滴干燥成球。另外还采用化学交联固化法制备了伊维菌素的明胶微球。聚合物微球药物包封率大多数在80%以上,明胶微球的包封率只有2.2%。
利用普通显微镜和电子显微镜分别观察了微球的形态和表面结构。微球呈圆球状,表面有较多的微孔,除明胶微球表面平滑外,其它微球可见凹凸不平,PLA5微球有明显的皱褶。当搅拌速度为300、400和500rpm时,可得到平均粒径为298、112和105μm的PLGA微球,平均粒径为184、124和105μm的PLA5微球。当搅拌速度为600rpm时,得到平均粒径为36μm的EC微球。转速越快,粒径越小,粒径范围越窄。转速为300rpm和400rpm时,微球粒径呈正态分布。
以95%乙醇-pH7.4磷酸盐缓冲液(4:6)作为溶出介质,研究不同平均粒径的PLA5微球、PLGA微球和EC微球的体外释药特点。除EC微球释药太快外,其它微球与药物原晶体比较,具有明显的缓释作用,用Higuchi、一级和零级释放方程模拟,相关系数都在0.9以上,相关系数平均值以零级模
Ivermectin, which several kinds of its formulations were studied by otherresearchers, has been used as endectocide widely in the world.
In present studies, a solvent evaporation process was applied to preparepolymers microsphere containing ivermectin, using 250ml water containing1.5% polyvinyl alcohol (PVA) as water phase, 25ml methylene chloridecontaining ivermectin/polymer (0.43:1) as oil phase. The oil phase was slowlyadded into water phase while stirring at 300~500rpm, after 6~7 hours, thestirring was stopped, the microspheres were collectted. The gelatin microspherewas prepared by emulsion-crosslinking method. The embedding rates of polymerand gelatin microspheres were more than 80% and 2.2%, respectively.
The sizes, shapes and surface of microspheres were studied using lightmicroscope and electronic microscope. It was showed that, microsphere'ssurfaces were smooth with many small pores on it, the mean diameters obtainedof lactic/glycolic acid copolymer (PLGA) and polylactic acid (PLA, mw:50000)microspheres were 298, 112, 105 micrometer and 184, 124, 105 micrometer,
repectively, when the stirring rate was 300, 400 and 500 rpm. The mean diameterof ethylcellulose (EC) microspheres was 36 μm.In vitro release characteristics of PLGA, PLA and EC microspheres werestudied by using a solution consisted of 95% alcohol and pH7.4 phosphate buffer(4:6) as release medium, the goodness of fit for Higuchi, first order and zeroorder equation was evaluated by the correlative index. The result showed that therelease profile fitted best to zero-order release equation, but the differencesbetween the microspheres with the same mean diameters in another parallelgroups were also observed, microspheres released ivermectin slower than rawcrystalline significantly. The time for 50% of acumulative release for ivermectinraw crystalline, PLA microspheres (184, 124, 105μm), PLGA microspheres (298,112, 105μm) and EC microsphere were 10.6, 213.9, 363.4, 263.5, 1445.7, 281.0and 216.5 hours. The microspheres with larger mean diameter released slowly,but it was not significant when the diameters differred not largely. Burst releasesfor microspheres in 12 hours were 7.41% to 52.54%.Pharmacokinetic studies were carried out in beagle dogs and goats usingHPLC with fluorescence detector for measuring plasma concentration ofivermectin. The plasma concentration versa time curves obtained after singledose S.C. injection of ivermectin in each individual animal was analysed withone or two-compartment open modal, the pharmacokinetic parameters werecalculated. That obtained after injection of microspheres was analysed withnon-compartment modal, AUC were calculated with trapezoidal rule. Theparameters for ivermecin with dose of 0.3mg/kg in dogs, t1/2ka, Tmax, Cmax, t1/2keand AUC0~∞ were 0.17d, 1.33d, 44.31ng/ml, 4.96d, and 323.26ng.d/mlrespectively, in goats, Cmax, AUC and t1/2ke were 11.31ng/ml, 70.29 ng.d/ml and8.73d. The parameters for PLGA (298μm) and PLA (184μm) microspheres withdose 3.0 mg/kg as ivermectin calculated in dogs, Tmax, Cmax, AUC0~t, AUC0~∞,
were 0.83d, 56.17ng/ml, 518.18ng.d/ml, 4121.54ng.d/ml and 0.81d, 48.59ng/ml,540.77ng.d/ml, 6860.47ng.d/ml, respectively. The AUC for microspheres weresignificantly larger than that for ivermectin injection. In goats, AUC for PLA,PLGA, EC and gelatin microspheres were 275.91, 408.11, 93.45 and162.84ng.d/ml respectively.The efficacy against nematodes in goats and scabies in pig were studied.The egg reduce percent rate for PLA, PLGA, EC, gelatin microspheres andivermectin injection at the day 14 after treatment were 100%, 100%, 91.1%,42.9% and 100%, and persistent efficacy of PLA and PLGA microspheres wereabout 120 days. The efficacy of PLGA microsphere against scabies in pigs waslike as that of ivermectin injection.The present results suggested that, PLA and PLGA microspheres possessedthe sustained release potency to persist the plasma level of ivermectin above1ng/ml for about 120 days, its efficacy against nematodes was consistent withthe plasma concentration.
利用普通显微镜和电子显微镜分别观察了微球的形态和表面结构。微球呈圆球状,表面有较多的微孔,除明胶微球表面平滑外,其它微球可见凹凸不平,PLA5微球有明显的皱褶。当搅拌速度为300、400和500rpm时,可得到平均粒径为298、112和105μm的PLGA微球,平均粒径为184、124和105μm的PLA5微球。当搅拌速度为600rpm时,得到平均粒径为36μm的EC微球。转速越快,粒径越小,粒径范围越窄。转速为300rpm和400rpm时,微球粒径呈正态分布。
以95%乙醇-pH7.4磷酸盐缓冲液(4:6)作为溶出介质,研究不同平均粒径的PLA5微球、PLGA微球和EC微球的体外释药特点。除EC微球释药太快外,其它微球与药物原晶体比较,具有明显的缓释作用,用Higuchi、一级和零级释放方程模拟,相关系数都在0.9以上,相关系数平均值以零级模
Ivermectin, which several kinds of its formulations were studied by otherresearchers, has been used as endectocide widely in the world.
In present studies, a solvent evaporation process was applied to preparepolymers microsphere containing ivermectin, using 250ml water containing1.5% polyvinyl alcohol (PVA) as water phase, 25ml methylene chloridecontaining ivermectin/polymer (0.43:1) as oil phase. The oil phase was slowlyadded into water phase while stirring at 300~500rpm, after 6~7 hours, thestirring was stopped, the microspheres were collectted. The gelatin microspherewas prepared by emulsion-crosslinking method. The embedding rates of polymerand gelatin microspheres were more than 80% and 2.2%, respectively.
The sizes, shapes and surface of microspheres were studied using lightmicroscope and electronic microscope. It was showed that, microsphere'ssurfaces were smooth with many small pores on it, the mean diameters obtainedof lactic/glycolic acid copolymer (PLGA) and polylactic acid (PLA, mw:50000)microspheres were 298, 112, 105 micrometer and 184, 124, 105 micrometer,
repectively, when the stirring rate was 300, 400 and 500 rpm. The mean diameterof ethylcellulose (EC) microspheres was 36 μm.In vitro release characteristics of PLGA, PLA and EC microspheres werestudied by using a solution consisted of 95% alcohol and pH7.4 phosphate buffer(4:6) as release medium, the goodness of fit for Higuchi, first order and zeroorder equation was evaluated by the correlative index. The result showed that therelease profile fitted best to zero-order release equation, but the differencesbetween the microspheres with the same mean diameters in another parallelgroups were also observed, microspheres released ivermectin slower than rawcrystalline significantly. The time for 50% of acumulative release for ivermectinraw crystalline, PLA microspheres (184, 124, 105μm), PLGA microspheres (298,112, 105μm) and EC microsphere were 10.6, 213.9, 363.4, 263.5, 1445.7, 281.0and 216.5 hours. The microspheres with larger mean diameter released slowly,but it was not significant when the diameters differred not largely. Burst releasesfor microspheres in 12 hours were 7.41% to 52.54%.Pharmacokinetic studies were carried out in beagle dogs and goats usingHPLC with fluorescence detector for measuring plasma concentration ofivermectin. The plasma concentration versa time curves obtained after singledose S.C. injection of ivermectin in each individual animal was analysed withone or two-compartment open modal, the pharmacokinetic parameters werecalculated. That obtained after injection of microspheres was analysed withnon-compartment modal, AUC were calculated with trapezoidal rule. Theparameters for ivermecin with dose of 0.3mg/kg in dogs, t1/2ka, Tmax, Cmax, t1/2keand AUC0~∞ were 0.17d, 1.33d, 44.31ng/ml, 4.96d, and 323.26ng.d/mlrespectively, in goats, Cmax, AUC and t1/2ke were 11.31ng/ml, 70.29 ng.d/ml and8.73d. The parameters for PLGA (298μm) and PLA (184μm) microspheres withdose 3.0 mg/kg as ivermectin calculated in dogs, Tmax, Cmax, AUC0~t, AUC0~∞,
were 0.83d, 56.17ng/ml, 518.18ng.d/ml, 4121.54ng.d/ml and 0.81d, 48.59ng/ml,540.77ng.d/ml, 6860.47ng.d/ml, respectively. The AUC for microspheres weresignificantly larger than that for ivermectin injection. In goats, AUC for PLA,PLGA, EC and gelatin microspheres were 275.91, 408.11, 93.45 and162.84ng.d/ml respectively.The efficacy against nematodes in goats and scabies in pig were studied.The egg reduce percent rate for PLA, PLGA, EC, gelatin microspheres andivermectin injection at the day 14 after treatment were 100%, 100%, 91.1%,42.9% and 100%, and persistent efficacy of PLA and PLGA microspheres wereabout 120 days. The efficacy of PLGA microsphere against scabies in pigs waslike as that of ivermectin injection.The present results suggested that, PLA and PLGA microspheres possessedthe sustained release potency to persist the plasma level of ivermectin above1ng/ml for about 120 days, its efficacy against nematodes was consistent withthe plasma concentration.
引文
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