乳化技术提高难溶性药物口服生物利用度的研究
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摘要
新型乳剂微乳和干乳都具有分散度高,利于难溶性药物口服吸收的特点。多烯紫杉醇和阿托伐他汀钙都属于难溶性药物,而且口服生物利用度低。本研究以多烯紫杉醇和阿托伐他汀钙为模型药物,分别系统研究了多烯紫杉醇口服微乳及阿托伐他汀钙干乳的处方和制备技术,考察并筛选药物的增溶剂和口服吸收促进剂,以提高药物的口服生物利用度。
首先在多烯紫杉醇体外分析方法建立的基础上,考察了多烯紫杉醇在不同油及乳化剂中的溶解度,结果表明,多烯紫杉醇在油Capryol 90和助乳化剂Transcutol中的溶解度都大于100 mg/mL,为下一步微乳油相的选择提供了依据。
以Capryol 90为油相,采用滴定法绘制由油相,乳化剂/助乳化剂,水相组成的伪三元相图,初步筛选了微乳系统。并通过粒径、粘度和药物含量等指标筛选出了三个微乳处方,分别为:Capryol 90:Cremophor EL/PG:water=30:39:31(M-1);Capryol 90:CremophorRH40/Transcutol:water=28:36:36(M-2);Capryol 90:Cremophor EL/Transcutol:water=29:37:34(M-3)。
分别考察了上述微乳处方的制剂学性质:多烯紫杉醇微乳肉眼观察为澄清半透明流动性良好的液态;采用透射电镜观察为球形;电泳光散射法测定其平均粒径均在30 nm左右;粒径分布较窄(p.d.＜0.12);ζ电位绝对值小于10。多烯紫杉醇微乳在室温25℃,100 r/min下所测定的粘度分别为98 cP、76 cP和79 cP。染色法确定微乳均为o/w型。
微乳中油相对多烯紫杉醇具有良好的增溶作用,在三个微乳中其含量分别高达22.76、32.24、和29.25 mg/mL。即使在稀释条件下放置24 h也不析出结晶。而且具有良好的体外释放特征,透析袋法12 h内释放80%以上的药物,明显高于市售处方,释放曲线与Weibull模型拟合的最好。
稳定性研究结果显示,多烯紫杉醇微乳在室温避光条件下,稳定性良好,保存6个月,其粒径、粘度及药物含量都没有明显变化。在强光及高温条件下,微乳的粒径及粘度没有显著变化,但多烯紫杉醇含量随时间降低。建议多烯紫杉醇微乳在室温下避光保存。建立了Caco-2细胞单层膜透过实验模型,考察了微乳对P-糖蛋白的抑制作用。与市售处方相比,微乳中多烯紫杉醇的A-B累积透过量明显增大,其顺序为:M-3＞M-2＞M-1＞TE＞Control group,其中M-3的累积透过量是对照组的40倍(0.62μg/cm~2 vs0.016μg/cm~2)。同时,M-2和M-3能显著地抑制P-糖蛋白的外排作用,多烯紫杉醇B-A方向的累积外排量明显降低,大小顺序为:Control group＞TE＞M-1＞M-2＞M-3,其中M-3的累积外排量是对照组的1/1.3(0.61μg/cm~2 vs 0.87μg/cm~2)。同时微乳的A-B及B-A方向P_(app)值也相应地增大和降低。
建立了大鼠血浆中多烯紫杉醇的高效液相色谱分析方法。口服药动学结果表明,M-2和M-3可以显著地提高多烯紫杉醇的口服生物利用度。微乳M-2和M-3的C_(max)明显增大,分别为131.95 ng/mL和270.48 ng/mL,是对照组46.39 ng/mL的2.8和5.8倍;平均AUC分别为389.43 ng·h/mL和193.43 ng·h/mL,为对照组的5.19倍和2.58倍;口服生物利用度也显著增大分别从对照组的6.63%提高到了17.09%和34.42%。
同时,建立了阿托伐他汀钙的高效液相色谱分析方法,溶解度测定结果表明,其在PlurolOleique CC 497中的溶解度最大,为干乳油相的选择提供了依据。
在处方筛选过程中,以干乳收率、粒径、药物含量、粒子形态为考察指标,并采用正交试验设计法确定了干乳的处方及制备条件。优化处方以Plurol Oleique CC 497为油相,Poloxamer 188为乳化剂,Dextrin为载体材料。最佳的喷雾干燥条件为:进口温度为120℃,出口温度为90℃,真空度为100%,喷雾速度为5 mL/min,喷嘴气流速度为800 Nl/min。
对阿托伐他汀钙干乳制剂学性质的考察结果表明:优化干乳呈圆整球形,具有良好的分散性及流动性;药物良好地分散于干乳中,长期保存没有晶体析出;显著提高了阿托伐他汀钙的溶解度;具有良好的体外释放行为及稳定性。
建立了Ussing Chamber扩散池体外吸收模型,考察了阿托伐他汀钙在空肠、回肠及结肠的体外吸收情况,结果表明,干乳显著的促进了阿托伐他汀钙的体外小肠吸收,为其提高口服生物利用度的应用奠定了基础。
Microemulsion and dry emulsion exhibit high dispersibility and benefical improvement of oral bioavailability of poorly water-soluble drugs.Docetaxel and atorvastatin calcium are both poorly water-soluble drugs with low bioavailability.Therefore,they were selected as the model drugs which were formulated into microemulsion and dry emulsion respectively to improve their solubility,gastrointestinal permeability and even oral bioavailability.
Firstly,based on the HPLC analysis method,the solubility determination of docetaxel in various vehicles showed that its solubility in Capryol 90 and Transcutol was both over 100 mg/mL which contributed to the oil selection.
Capryol 90 was fixed as the oil phase of the microemulsions and other components were selected by pseudo ternary phase diagrams.Three microemulsions with wide microemulsion area in phase diagrams,low droplet size,viscosity as well as high drug content were optimized which were:Capryol 90:Cremophor EL/PG:water=30:39:31(M-1);Capryol 90:Cremophor RH40/Transcutol:water=28:36:36(M-2);Capryol 90:Cremophor EL/Transcutol:water=29: 37:34(M-3),respectively.
The microemulsions were clear and semi-transparent liquid visually observed and well spherical particles could be observed by TEM.The average droplet size was around 30 nm with narrow distribution and low polydispersity index(p.d.＜0.12).While the absolute zeta potential values of microemulsions were lower than 10.At room temperature,the viscosity of each microemulsion formulation was 98,76 and 79 cP respectively with well fluidity.
Microemulsions studied in this research exhibited potential solubilization capacity towards docetaxel and its content was improved to 22.76,32.24 and 29.25 mg/mL by M-1,M-2 and M-3 respectively.Additionally,no precipitation determined as long as 24 h in diluted condition. Docetaxel could release well from microemulsions(more than 80%at 12 h) by dialysis membrane method.Docetaxel microemulsions presented well stability at room temperature at least for 6 months with stable droplet size,viscosity and drug content.However,docetaxel content decreased in highlight or high temperature and it was suggested that microemulsions should be stored at room temperature protecting from highlight.
Caco-2 cell monolayer was utilized to perform the transport study to reveal the inhibition effect of microemulsions against P-gp.It was shown that the A-B transport of docetaxel was much improved by microemulsions compared to that of the control group and the A-B transported amount from M-3 was as much as 40 times higher than that of control group (0.62μg/cm~2 vs 0.016μg/cm~2).On the other hand,the P-gp effiux of docetaxel was inhibited by microemulsions and the efflux amount from M-3(0.61μg/cm~2) was significantly lower than that of the control group(0.87μg/cm~2).The A-B and B-A P_(app) values also exhibited significant deviation compared to that of the control group or TE.
An effective HPLC method was developed for the determination of docetaxel in plasma samples.For oral administration,The C_(max) was enhanced 5.8-fold in M-3 as compared with that of the orally administrated TE(46.39 ng/mL vs.270.48 ng/mL,p＜0.01).The AUC of docetaxel in M-3 increased 5.2-fold compared with that of orally administrated TE(389.43 ng·h/mL vs. 74.98 ng·h/mL,p＜0.01).Additionally,M-2 and M-3 significantly improved the absolute oral bioavailability of docetaxel(17.09%and 34.42%),compared to that of orally administered TE (6.63%).
Atorvastatin calcium was analyzed by HPLC method and its solubility in Plurol Oleique CC 497 was the highest among the oils detected which was higher than 16 mg/mL.
To optimize the atorvastatin calcium dry emulsion formulations,orthogonal design was used with the determination of dry emulsion recovery,droplet size,drug content,appearance.The optimized formulation was composed of Plurol Oleique CC 497,Poloxamer 188 and dextrin. Additionally,the selected spry drying condition was:inlet temperature 120℃,aspiration of 100%,drying air flow at 800 N1/h,and feeding rate of the emulsion at 5 ml/min.
The optimized formulation was well separated spherical particles with low reconstituted droplet size,improved atorvastatin calcium content,well dispersity,good stability and release.
Ussing Chamber was used to study the in vitro permeability of atorvastatin calcium across rat intestine and the cumulative permeated amount was significantly improved by its dry emulsion formulations compared with that of its suspension.
首先在多烯紫杉醇体外分析方法建立的基础上,考察了多烯紫杉醇在不同油及乳化剂中的溶解度,结果表明,多烯紫杉醇在油Capryol 90和助乳化剂Transcutol中的溶解度都大于100 mg/mL,为下一步微乳油相的选择提供了依据。
以Capryol 90为油相,采用滴定法绘制由油相,乳化剂/助乳化剂,水相组成的伪三元相图,初步筛选了微乳系统。并通过粒径、粘度和药物含量等指标筛选出了三个微乳处方,分别为:Capryol 90:Cremophor EL/PG:water=30:39:31(M-1);Capryol 90:CremophorRH40/Transcutol:water=28:36:36(M-2);Capryol 90:Cremophor EL/Transcutol:water=29:37:34(M-3)。
分别考察了上述微乳处方的制剂学性质:多烯紫杉醇微乳肉眼观察为澄清半透明流动性良好的液态;采用透射电镜观察为球形;电泳光散射法测定其平均粒径均在30 nm左右;粒径分布较窄(p.d.＜0.12);ζ电位绝对值小于10。多烯紫杉醇微乳在室温25℃,100 r/min下所测定的粘度分别为98 cP、76 cP和79 cP。染色法确定微乳均为o/w型。
微乳中油相对多烯紫杉醇具有良好的增溶作用,在三个微乳中其含量分别高达22.76、32.24、和29.25 mg/mL。即使在稀释条件下放置24 h也不析出结晶。而且具有良好的体外释放特征,透析袋法12 h内释放80%以上的药物,明显高于市售处方,释放曲线与Weibull模型拟合的最好。
稳定性研究结果显示,多烯紫杉醇微乳在室温避光条件下,稳定性良好,保存6个月,其粒径、粘度及药物含量都没有明显变化。在强光及高温条件下,微乳的粒径及粘度没有显著变化,但多烯紫杉醇含量随时间降低。建议多烯紫杉醇微乳在室温下避光保存。建立了Caco-2细胞单层膜透过实验模型,考察了微乳对P-糖蛋白的抑制作用。与市售处方相比,微乳中多烯紫杉醇的A-B累积透过量明显增大,其顺序为:M-3＞M-2＞M-1＞TE＞Control group,其中M-3的累积透过量是对照组的40倍(0.62μg/cm~2 vs0.016μg/cm~2)。同时,M-2和M-3能显著地抑制P-糖蛋白的外排作用,多烯紫杉醇B-A方向的累积外排量明显降低,大小顺序为:Control group＞TE＞M-1＞M-2＞M-3,其中M-3的累积外排量是对照组的1/1.3(0.61μg/cm~2 vs 0.87μg/cm~2)。同时微乳的A-B及B-A方向P_(app)值也相应地增大和降低。
建立了大鼠血浆中多烯紫杉醇的高效液相色谱分析方法。口服药动学结果表明,M-2和M-3可以显著地提高多烯紫杉醇的口服生物利用度。微乳M-2和M-3的C_(max)明显增大,分别为131.95 ng/mL和270.48 ng/mL,是对照组46.39 ng/mL的2.8和5.8倍;平均AUC分别为389.43 ng·h/mL和193.43 ng·h/mL,为对照组的5.19倍和2.58倍;口服生物利用度也显著增大分别从对照组的6.63%提高到了17.09%和34.42%。
同时,建立了阿托伐他汀钙的高效液相色谱分析方法,溶解度测定结果表明,其在PlurolOleique CC 497中的溶解度最大,为干乳油相的选择提供了依据。
在处方筛选过程中,以干乳收率、粒径、药物含量、粒子形态为考察指标,并采用正交试验设计法确定了干乳的处方及制备条件。优化处方以Plurol Oleique CC 497为油相,Poloxamer 188为乳化剂,Dextrin为载体材料。最佳的喷雾干燥条件为:进口温度为120℃,出口温度为90℃,真空度为100%,喷雾速度为5 mL/min,喷嘴气流速度为800 Nl/min。
对阿托伐他汀钙干乳制剂学性质的考察结果表明:优化干乳呈圆整球形,具有良好的分散性及流动性;药物良好地分散于干乳中,长期保存没有晶体析出;显著提高了阿托伐他汀钙的溶解度;具有良好的体外释放行为及稳定性。
建立了Ussing Chamber扩散池体外吸收模型,考察了阿托伐他汀钙在空肠、回肠及结肠的体外吸收情况,结果表明,干乳显著的促进了阿托伐他汀钙的体外小肠吸收,为其提高口服生物利用度的应用奠定了基础。
Microemulsion and dry emulsion exhibit high dispersibility and benefical improvement of oral bioavailability of poorly water-soluble drugs.Docetaxel and atorvastatin calcium are both poorly water-soluble drugs with low bioavailability.Therefore,they were selected as the model drugs which were formulated into microemulsion and dry emulsion respectively to improve their solubility,gastrointestinal permeability and even oral bioavailability.
Firstly,based on the HPLC analysis method,the solubility determination of docetaxel in various vehicles showed that its solubility in Capryol 90 and Transcutol was both over 100 mg/mL which contributed to the oil selection.
Capryol 90 was fixed as the oil phase of the microemulsions and other components were selected by pseudo ternary phase diagrams.Three microemulsions with wide microemulsion area in phase diagrams,low droplet size,viscosity as well as high drug content were optimized which were:Capryol 90:Cremophor EL/PG:water=30:39:31(M-1);Capryol 90:Cremophor RH40/Transcutol:water=28:36:36(M-2);Capryol 90:Cremophor EL/Transcutol:water=29: 37:34(M-3),respectively.
The microemulsions were clear and semi-transparent liquid visually observed and well spherical particles could be observed by TEM.The average droplet size was around 30 nm with narrow distribution and low polydispersity index(p.d.＜0.12).While the absolute zeta potential values of microemulsions were lower than 10.At room temperature,the viscosity of each microemulsion formulation was 98,76 and 79 cP respectively with well fluidity.
Microemulsions studied in this research exhibited potential solubilization capacity towards docetaxel and its content was improved to 22.76,32.24 and 29.25 mg/mL by M-1,M-2 and M-3 respectively.Additionally,no precipitation determined as long as 24 h in diluted condition. Docetaxel could release well from microemulsions(more than 80%at 12 h) by dialysis membrane method.Docetaxel microemulsions presented well stability at room temperature at least for 6 months with stable droplet size,viscosity and drug content.However,docetaxel content decreased in highlight or high temperature and it was suggested that microemulsions should be stored at room temperature protecting from highlight.
Caco-2 cell monolayer was utilized to perform the transport study to reveal the inhibition effect of microemulsions against P-gp.It was shown that the A-B transport of docetaxel was much improved by microemulsions compared to that of the control group and the A-B transported amount from M-3 was as much as 40 times higher than that of control group (0.62μg/cm~2 vs 0.016μg/cm~2).On the other hand,the P-gp effiux of docetaxel was inhibited by microemulsions and the efflux amount from M-3(0.61μg/cm~2) was significantly lower than that of the control group(0.87μg/cm~2).The A-B and B-A P_(app) values also exhibited significant deviation compared to that of the control group or TE.
An effective HPLC method was developed for the determination of docetaxel in plasma samples.For oral administration,The C_(max) was enhanced 5.8-fold in M-3 as compared with that of the orally administrated TE(46.39 ng/mL vs.270.48 ng/mL,p＜0.01).The AUC of docetaxel in M-3 increased 5.2-fold compared with that of orally administrated TE(389.43 ng·h/mL vs. 74.98 ng·h/mL,p＜0.01).Additionally,M-2 and M-3 significantly improved the absolute oral bioavailability of docetaxel(17.09%and 34.42%),compared to that of orally administered TE (6.63%).
Atorvastatin calcium was analyzed by HPLC method and its solubility in Plurol Oleique CC 497 was the highest among the oils detected which was higher than 16 mg/mL.
To optimize the atorvastatin calcium dry emulsion formulations,orthogonal design was used with the determination of dry emulsion recovery,droplet size,drug content,appearance.The optimized formulation was composed of Plurol Oleique CC 497,Poloxamer 188 and dextrin. Additionally,the selected spry drying condition was:inlet temperature 120℃,aspiration of 100%,drying air flow at 800 N1/h,and feeding rate of the emulsion at 5 ml/min.
The optimized formulation was well separated spherical particles with low reconstituted droplet size,improved atorvastatin calcium content,well dispersity,good stability and release.
Ussing Chamber was used to study the in vitro permeability of atorvastatin calcium across rat intestine and the cumulative permeated amount was significantly improved by its dry emulsion formulations compared with that of its suspension.
引文
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