红霉素自微乳化给药系统的研究
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摘要
自微乳化给药系统(Self-microemulsifying drug delivery system, SMEDDS)是由药物、油相、非离子型乳化剂和助乳化剂组成,在温和搅拌下,可自发形成O/W型微乳,其粒径小于100nm。SMEDDS可显著提高水难溶性药物的溶出度、口服吸收率和生物利用度,是近年来药剂学研究的热点领域之一。红霉素为水难溶性药物,其口服制剂存在溶出难、口服吸收率低、生物利用度差等问题,将红霉素制成SMEDDS有望解决上述问题。
第一部分处方前研究
1.以75%浓硫酸显色、75±5℃水浴30min、482nm处为破乳和显色条件,建立了EM-SMEDDS的UV含量测定方法,红霉素在31.2～83.2μg·mL-1范围内,A482值与浓度C有良好的线性关系。
2.采用摇瓶法测定了红霉素的表观油/水分配系数,在正辛醇/0.1mol·L一1HCL、正辛醇/pH 6.8 PBS和正辛醇/蒸馏水体系中红霉素的表观油/水分配系数(P)的对数值分别为1.09、1.28和1.62,表明随着水相pH增加,红霉素在水相中的溶解度减少,表观油/水分配系数增大。
第二部分EM-SMEDDS处方筛选及其制备
1.红霉素在油相中的溶解度IPM>OLIVE-OIL、在乳化剂中的溶解度Cremophor EL略大于Tween80、在助乳化剂中的溶解度Labrasol>PEG400。
2.采用滴定法绘制了油-乳化剂/助乳化剂-水体系伪三元相图,确定了空白SMEDDS处方油相IPM(20～40%)和Cremophor EL与Labrasol混合乳化剂(其中Cremophor EL65～75%、Labrasol25～35%)的组成。
2.加料顺序对EM-SMEDDS平均粒径和粒径分布有明显影响。采用油相与混合乳化剂混合均匀后,再加入药物的加料方式,成乳后的乳滴平均粒径<50nm,粒度分布范围较窄。
3.采用均匀设计考察制备温度、混合乳化剂中Cremophor EL的比例、载药量与油相所占比例对平均粒径、粒径分布的影响,采用平均粒径、粒径分布、分散时间为评价指标,筛选出了EM-SMEDDS的优化处方:油相IPM30%、Cremophor EL与Labrasol组成的混合乳化剂70%(其中Cremophor EL 65%)、载药量为100mg/g。
第三部分红霉素自乳化微乳制剂的制剂学评价
1.采用Zetasizer Nano zeta电位仪,以水为分散介质,测得空白SMEDDS与EM-SMEDDS二者的动电电位均趋近0mV,表明SMEDDS微乳的稳定机制是界面膜位阻排斥效应。
2.采用冷热循环实验7天和常温留样观察6个月,EM-SMEDDS仍为澄清、透明溶液,无药物晶体析出,体系均一性、自乳化效率、药物含量均未受影响,说明EM-SMEDDS冷热循环7天内、常温6个月是稳定的。
3.采用总体液平衡反向透析法考察EM-SMEDDS的体外释药过程。EM-SMEDDS药物在30min内迅速溶出,累积溶出量达64.74%;随后溶出速度减慢,120min内药物累积溶出量96.65%。分别用零级方程、一级方程、Higuchi方程、Weibull方程、Hixon-Crowell方程对释药曲线进行拟和,其释药动力学Hixson-Crowell方程拟和效果最好。
第四部分红霉素自微乳化制剂体内药动学的初步研究
采用在体回流方法,考察了EM-SMEDDS和EM-混悬剂在大鼠小肠的吸收行为。EM-SMEDDS在小肠各段均有吸收,十二指肠段的吸收速率常数Ka为1.03±0.07、空肠段Ka为1.63±0.06、回肠段Ka为1.9±0.22,Ka值按十二指肠、空肠、回肠依次增加;虽然EM-混悬剂的Ka值也按十二指肠、空肠、回肠依次增加,但EM-SMEDDS在各肠段Ka均显著高于EM-混悬剂。说明EM-SMEDDS可提高EM在小肠各段的吸收率,显著改善EM口服的吸收。
Erythromycin Self-microemulsifying drug delivery system (EM-SMEDDS), choosing Erythromycin as the drug and oil and surfactants as vehicles , is thermodynamically stable SMEDDS. The Self-microemulsifying drug delivery system are described as mixtures of oil, surfactant, cosurfactant and drug. The principal characteristic of these systems form fine oil-in-water microemulsions upon mild agitation following diluted by aqueous phase, with mean droplet size less than 100nm. SMEDDS can improve the bioavailability and the absorption of poorly soluble drugs. In recent years, much attention has been paid to the study. Most oral dosage forms of Erythromycin had low bioavailability. Due to their poor solubility properties in water, Erythromycin could hardly dissolve in gastrointestinal fluids. Erythromycin is deemed unsuitable for oral administration for the poor bioavailability and low water solubility. Therefore,SMEDDS was selected as the carrier to prepare EM-SMEDDS to increase the dissolution, absorption and bioavailability of Erythromycin. The objective of our research is made up of four topics:
PART ONE PREFORMULATION STUDY
First of all, UV spectrophotometry analytic for microemulsions, Erythromycin was analyzed with the wave length at 482 nm after adding the 75% sulphuric acid solution and keeping it in 75±5℃water for 30min. The logarithm of apparent partition coefficients of Erythromycin in n-octanol/o.1mol·L-1HCL、n-octanol/pH 6.8 PBS and n-octanol/Water system were 1.09、1.28 and 1.62 respectively, The Log P reduces with the pH of aqueous phase means that the solubility of Erythromycin in aqueous phase increases.
PART TWO THE OPTIMIZATION OF FORMULATION AND PREPARATION FOR EM-SMEDDS
The balance solubility of EM in different oil Phase,surfactant and cosurfactant were assayed, which higher than another were selected. Pseudo-ternary phase diagrams were constructed. The optimal SMEDDS were obtained by comparing the self-emulsifying domain and by the evaluation of the resultant emulsion’s appearance. The optimal SMEDDS was IPM (30~40%),the mixed surfactant was made up of Cremopher EL and LAS (Cremopher EL 65~75%).Through the uniform design, we investigated the effects of the vehicle contents,temperature,and drug loading on the self-emulsifying efficiency, which self-emulsifying efficiency included the self-emulsifying time, mean droplet size and the distribution of droplet size .All results brought us a best formulation of EM-SEDDS.
PART THREE THE EVALUATION OF PHARMACY FOR EM-SMEDDS
The zeta potential of blank SMEDDS and EM-SMEDDS in water are both close to 0mV, which indicated the stabilization of them. The present findings introduced the hot-cold cycle for 7 days and observed at room temperature for 6 months, which the physico-chemical property of EM-SMEDDS was stabilitated.
We study the dissolution of EM-SMEDDS by bulk-equilibrium reverse dialysis bag technique. The results show that the formulations could release fast and completely, and the cumulated release of the formulations were above 64.74% at 30min, above 96.65% at 120min ,and drug release slowly after 30 min. Zero-order equation, frist-order equation, higuchi equation, weibull equation, Hixon-Crowell were used to calculate drug release kinetics. The results showed that the drug release elucidating with Hixon-Crowell equation were best.
PART FOUR THE INITIAL STUDY IN PHARMACOKINETICS OF EM-SMEDDS
The absorption kinetics and permeability rate constants (ka) were investigated by the in situ perfusing method in rats,and the concentration of EM was determined by UV.The results indicated that EM-SEDDS can be absorbed in the whole small intestinal segments. And the ka of EM-SMEDDS at duodenum, jejunum and ileum were 1.03±0.07, 1.63±0.06 and 1.9±0.22h-1 respectively. The results also showed that the Ka of EM-SMEDDS was step-by-step increase successively according to duodenum, jejunum and ileum. Compared the Ka of EM-SMEDDS with EM-suspension, we found that EM-SMEDDS can be better absorbed than EM-suspension in the small intestine, which demonstrated the SMEDDS will improve the absorption of EM by oral administration.
第一部分处方前研究
1.以75%浓硫酸显色、75±5℃水浴30min、482nm处为破乳和显色条件,建立了EM-SMEDDS的UV含量测定方法,红霉素在31.2～83.2μg·mL-1范围内,A482值与浓度C有良好的线性关系。
2.采用摇瓶法测定了红霉素的表观油/水分配系数,在正辛醇/0.1mol·L一1HCL、正辛醇/pH 6.8 PBS和正辛醇/蒸馏水体系中红霉素的表观油/水分配系数(P)的对数值分别为1.09、1.28和1.62,表明随着水相pH增加,红霉素在水相中的溶解度减少,表观油/水分配系数增大。
第二部分EM-SMEDDS处方筛选及其制备
1.红霉素在油相中的溶解度IPM>OLIVE-OIL、在乳化剂中的溶解度Cremophor EL略大于Tween80、在助乳化剂中的溶解度Labrasol>PEG400。
2.采用滴定法绘制了油-乳化剂/助乳化剂-水体系伪三元相图,确定了空白SMEDDS处方油相IPM(20～40%)和Cremophor EL与Labrasol混合乳化剂(其中Cremophor EL65～75%、Labrasol25～35%)的组成。
2.加料顺序对EM-SMEDDS平均粒径和粒径分布有明显影响。采用油相与混合乳化剂混合均匀后,再加入药物的加料方式,成乳后的乳滴平均粒径<50nm,粒度分布范围较窄。
3.采用均匀设计考察制备温度、混合乳化剂中Cremophor EL的比例、载药量与油相所占比例对平均粒径、粒径分布的影响,采用平均粒径、粒径分布、分散时间为评价指标,筛选出了EM-SMEDDS的优化处方:油相IPM30%、Cremophor EL与Labrasol组成的混合乳化剂70%(其中Cremophor EL 65%)、载药量为100mg/g。
第三部分红霉素自乳化微乳制剂的制剂学评价
1.采用Zetasizer Nano zeta电位仪,以水为分散介质,测得空白SMEDDS与EM-SMEDDS二者的动电电位均趋近0mV,表明SMEDDS微乳的稳定机制是界面膜位阻排斥效应。
2.采用冷热循环实验7天和常温留样观察6个月,EM-SMEDDS仍为澄清、透明溶液,无药物晶体析出,体系均一性、自乳化效率、药物含量均未受影响,说明EM-SMEDDS冷热循环7天内、常温6个月是稳定的。
3.采用总体液平衡反向透析法考察EM-SMEDDS的体外释药过程。EM-SMEDDS药物在30min内迅速溶出,累积溶出量达64.74%;随后溶出速度减慢,120min内药物累积溶出量96.65%。分别用零级方程、一级方程、Higuchi方程、Weibull方程、Hixon-Crowell方程对释药曲线进行拟和,其释药动力学Hixson-Crowell方程拟和效果最好。
第四部分红霉素自微乳化制剂体内药动学的初步研究
采用在体回流方法,考察了EM-SMEDDS和EM-混悬剂在大鼠小肠的吸收行为。EM-SMEDDS在小肠各段均有吸收,十二指肠段的吸收速率常数Ka为1.03±0.07、空肠段Ka为1.63±0.06、回肠段Ka为1.9±0.22,Ka值按十二指肠、空肠、回肠依次增加;虽然EM-混悬剂的Ka值也按十二指肠、空肠、回肠依次增加,但EM-SMEDDS在各肠段Ka均显著高于EM-混悬剂。说明EM-SMEDDS可提高EM在小肠各段的吸收率,显著改善EM口服的吸收。
Erythromycin Self-microemulsifying drug delivery system (EM-SMEDDS), choosing Erythromycin as the drug and oil and surfactants as vehicles , is thermodynamically stable SMEDDS. The Self-microemulsifying drug delivery system are described as mixtures of oil, surfactant, cosurfactant and drug. The principal characteristic of these systems form fine oil-in-water microemulsions upon mild agitation following diluted by aqueous phase, with mean droplet size less than 100nm. SMEDDS can improve the bioavailability and the absorption of poorly soluble drugs. In recent years, much attention has been paid to the study. Most oral dosage forms of Erythromycin had low bioavailability. Due to their poor solubility properties in water, Erythromycin could hardly dissolve in gastrointestinal fluids. Erythromycin is deemed unsuitable for oral administration for the poor bioavailability and low water solubility. Therefore,SMEDDS was selected as the carrier to prepare EM-SMEDDS to increase the dissolution, absorption and bioavailability of Erythromycin. The objective of our research is made up of four topics:
PART ONE PREFORMULATION STUDY
First of all, UV spectrophotometry analytic for microemulsions, Erythromycin was analyzed with the wave length at 482 nm after adding the 75% sulphuric acid solution and keeping it in 75±5℃water for 30min. The logarithm of apparent partition coefficients of Erythromycin in n-octanol/o.1mol·L-1HCL、n-octanol/pH 6.8 PBS and n-octanol/Water system were 1.09、1.28 and 1.62 respectively, The Log P reduces with the pH of aqueous phase means that the solubility of Erythromycin in aqueous phase increases.
PART TWO THE OPTIMIZATION OF FORMULATION AND PREPARATION FOR EM-SMEDDS
The balance solubility of EM in different oil Phase,surfactant and cosurfactant were assayed, which higher than another were selected. Pseudo-ternary phase diagrams were constructed. The optimal SMEDDS were obtained by comparing the self-emulsifying domain and by the evaluation of the resultant emulsion’s appearance. The optimal SMEDDS was IPM (30~40%),the mixed surfactant was made up of Cremopher EL and LAS (Cremopher EL 65~75%).Through the uniform design, we investigated the effects of the vehicle contents,temperature,and drug loading on the self-emulsifying efficiency, which self-emulsifying efficiency included the self-emulsifying time, mean droplet size and the distribution of droplet size .All results brought us a best formulation of EM-SEDDS.
PART THREE THE EVALUATION OF PHARMACY FOR EM-SMEDDS
The zeta potential of blank SMEDDS and EM-SMEDDS in water are both close to 0mV, which indicated the stabilization of them. The present findings introduced the hot-cold cycle for 7 days and observed at room temperature for 6 months, which the physico-chemical property of EM-SMEDDS was stabilitated.
We study the dissolution of EM-SMEDDS by bulk-equilibrium reverse dialysis bag technique. The results show that the formulations could release fast and completely, and the cumulated release of the formulations were above 64.74% at 30min, above 96.65% at 120min ,and drug release slowly after 30 min. Zero-order equation, frist-order equation, higuchi equation, weibull equation, Hixon-Crowell were used to calculate drug release kinetics. The results showed that the drug release elucidating with Hixon-Crowell equation were best.
PART FOUR THE INITIAL STUDY IN PHARMACOKINETICS OF EM-SMEDDS
The absorption kinetics and permeability rate constants (ka) were investigated by the in situ perfusing method in rats,and the concentration of EM was determined by UV.The results indicated that EM-SEDDS can be absorbed in the whole small intestinal segments. And the ka of EM-SMEDDS at duodenum, jejunum and ileum were 1.03±0.07, 1.63±0.06 and 1.9±0.22h-1 respectively. The results also showed that the Ka of EM-SMEDDS was step-by-step increase successively according to duodenum, jejunum and ileum. Compared the Ka of EM-SMEDDS with EM-suspension, we found that EM-SMEDDS can be better absorbed than EM-suspension in the small intestine, which demonstrated the SMEDDS will improve the absorption of EM by oral administration.
引文
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[2] 中国药典 2005 年版(二部).化学工业出版社,2005.222-224
[3] 吴钟琪,周宏灏,许树梧.全科医学临床药物学[M].科学出版社,2001:816-819
[4] Shah NH,Carvajal MT,et a1.Self-emulsifying drug delivery systems (SEDDS)with polyglycolzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drug [J].Int.J.Pharm.1994,106(1):15
[5] Constantinides, PP. Lipid microemulsions for improving drug disso1ution and oral absorption: physical and biopharmaceutical aspects [J]. Pharm Res.1995, 12(11):1561
[6] 欧阳净,黄华.自乳化释药系统的研究进展[J].中国药房.2005,16(19):1499-1501
[7] 陆彬.药剂学实验[M].人民卫生出版社,1994.3-5
[8] 郑俊民.经皮给药剂型[M].人民卫生出版社,1997.276-279
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