罗红霉素缓释微丸的研究
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摘要
罗红霉素(Roxithromycin,RXM)是一种半合成大环内酯类抗生素，对常见的革兰氏阳性菌、部分革兰氏阴性菌、部分厌氧菌等均具有良好的抗菌活性。临床上主要用于呼吸道感染、泌尿道感染、皮肤和软组织感染等，是目前呼吸道感染，特别是小儿呼吸道感染的首选药。但其不良反应发生率仍然达4.0％以上，一日服用2次亦不便于提高儿童患者的依从性。本文以减少副作用，增加儿童用药的顺应性，提高生物利用度为目的，研制了粒径为0.5mm左右的罗红霉素缓释微丸。
采用HPLC法进行微丸中药物的含量测定，比色法对释放度进行测定，建立了高效液相色谱紫外检测法测定家犬体内血药浓度的方法。
处方前研究表明：罗红霉素在水、生理盐水中极微溶，在各种生理pH范围内微溶或略溶；在各种生理pH范围内，随着pH值升高，油／水分配系数增加，logP值范围为0.86～2.26。说明RXM的溶出速度是其吸收的限速步骤。
用国产离心造粒机粉末层积法制备罗红霉素微丸。经处方筛选和工艺因素考察，优化处方及操作参数，结果目标粒径32～40目的微丸收率约90％，药物含量约25％，微丸收率和主药含量均达到预期效果。
用流化床悬浮包衣法对罗红霉素微丸进行缓释包衣。以释放度为指标，分别采用Eudragit NE 30D、Eudragit RS 30D和Eudragit RL 30D混合、Aquacoat和Surelease为包衣材料，对增塑剂、抗粘剂、抗静电剂、致孔剂、包衣增重以及老化时间等进行了考察。确定包衣材料采用Eudragit NE 30D。释药机制探讨表明：略有骨架，以膜控为主的控制释药模型用一级动力学方程解释较好。
家犬口服罗红霉素市售片和自制粒径为32～40目和18～24目的两种罗红霉素缓释微丸，采用统计矩的非隔室动力学理论对家犬血药数据
沈阳药科大学硕士学位论文 摘 要
进行处理，两种微丸药物药动学参数 Tm。均为“．40土 1石7）h，C。。分
别为（8．ZI士1．gi）卜g／ml和（6．52ti．44）pg／ml，MRT分别为（34．94t8．79）
h和（33．9H5．33）h，Fr分别为 100．43％和幻．43％。结果表明其体内吸
收过程具有明显的缓释特征，且体内外释药相关性良好。但小粒径罗红
霉素缓释微丸具有更高的生物利用度。
Roxithromycin(RXM) is a semisynthetic macrolides antibiotic with a broad and essentially bateriostatic action against many Gram-positive and some Gram- negative bacteria, as well as some anaerobes. Roxithromycin has been widely used clinically to treat respiratory tract infection, urogenifal infection, skin and soft tissue infections etc, especially as the first picked medicine to therapy pediatric respiratory tract infection. However, its side effect incidence is above 4%. On the other hand, twice a day administration is inconvenient to rise children's compliance. The purpose of the present study was designed to develop a kind of Roxithromycin sustained release pellets with 0.5mm diameter which would decrease adverse effects and improve its bioavailability, and which would be more convenient for patients to use.
HPLC was utilized to determine the Roxithromycin content in pellets, colorimetry for assaying release of Roxithromycin sustained release pellets. The HPLC ultraviolet method was established to monitor the plasma concentration in dogs.
The preformulation results showed that Roxithromycin is very slightly soluble in water and saline, slight or sparingly soluble in various physiological pH fluids and the octanol/water partition coefficients increase
with pH rising in various physiological pH fluids(logP:0.86-2.66). It shows that the limit drug absorption in gastrointestinal tract is the drug release from dosage form.
Roxithromycin pellets were prepared by means of power layering with the centrifugal granulation equipment made in China. Through the formulation filtration and process observation, it was discovered that the yield of the objective pellets (32/40 mesh cut) was about 90% and the average Roxithromycin content was 25%. The results suggested the preparation process and formulation of Roxithromycin pellets can reach the expected goals.
A fluid-bed spray processor was adopted for the coating of the pellets. The coating process variables were determined and controlled. The coating formula respectively composed of Eudragit NE 30D, Eudragit RS 30D mixed with Eudragit RL 30D, Aquacoat and Surelease were studied on plasticizers, anti-tacking agents, HPMC, static electricity-proofing, coating level and curing time, etc. Eudragit NE 30D is selected for the excelletnt drug release character and convenient process. The description of dissolution profiles suggested that among the different kinetics, the first-order became the most appropriate model to describe release kinetics.
The plasma concentration of Roxithromycin in dogs was tested after a single oral administration of commercial tablets and two kind self-made sustained release pellets(32/40 and 18/24 mesh cut). The pharmacokinetics parameters and the relative bioavailability were measured. The pharmacokinetics parameters of Roxithromycin in two sustained release pellets analyzed by non-compartment model theory were Tmax(6.40+1.67) h, Cmax(8.21+1.91)g/ml and (6.52+1.44)g/ml, MRT (34.94+8.79)h and (33.92+5.33)h, Fr 100.43% and 83.43%, respectively. The results indicated that they have satisfactory sustained release effect and there were good correlation between absorption percent in vivo and dissolution percent in
vitro. But Roxithromycin sustained release pellets with smaller size show a better bioavailability.
采用HPLC法进行微丸中药物的含量测定，比色法对释放度进行测定，建立了高效液相色谱紫外检测法测定家犬体内血药浓度的方法。
处方前研究表明：罗红霉素在水、生理盐水中极微溶，在各种生理pH范围内微溶或略溶；在各种生理pH范围内，随着pH值升高，油／水分配系数增加，logP值范围为0.86～2.26。说明RXM的溶出速度是其吸收的限速步骤。
用国产离心造粒机粉末层积法制备罗红霉素微丸。经处方筛选和工艺因素考察，优化处方及操作参数，结果目标粒径32～40目的微丸收率约90％，药物含量约25％，微丸收率和主药含量均达到预期效果。
用流化床悬浮包衣法对罗红霉素微丸进行缓释包衣。以释放度为指标，分别采用Eudragit NE 30D、Eudragit RS 30D和Eudragit RL 30D混合、Aquacoat和Surelease为包衣材料，对增塑剂、抗粘剂、抗静电剂、致孔剂、包衣增重以及老化时间等进行了考察。确定包衣材料采用Eudragit NE 30D。释药机制探讨表明：略有骨架，以膜控为主的控制释药模型用一级动力学方程解释较好。
家犬口服罗红霉素市售片和自制粒径为32～40目和18～24目的两种罗红霉素缓释微丸，采用统计矩的非隔室动力学理论对家犬血药数据
沈阳药科大学硕士学位论文 摘 要
进行处理，两种微丸药物药动学参数 Tm。均为“．40土 1石7）h，C。。分
别为（8．ZI士1．gi）卜g／ml和（6．52ti．44）pg／ml，MRT分别为（34．94t8．79）
h和（33．9H5．33）h，Fr分别为 100．43％和幻．43％。结果表明其体内吸
收过程具有明显的缓释特征，且体内外释药相关性良好。但小粒径罗红
霉素缓释微丸具有更高的生物利用度。
Roxithromycin(RXM) is a semisynthetic macrolides antibiotic with a broad and essentially bateriostatic action against many Gram-positive and some Gram- negative bacteria, as well as some anaerobes. Roxithromycin has been widely used clinically to treat respiratory tract infection, urogenifal infection, skin and soft tissue infections etc, especially as the first picked medicine to therapy pediatric respiratory tract infection. However, its side effect incidence is above 4%. On the other hand, twice a day administration is inconvenient to rise children's compliance. The purpose of the present study was designed to develop a kind of Roxithromycin sustained release pellets with 0.5mm diameter which would decrease adverse effects and improve its bioavailability, and which would be more convenient for patients to use.
HPLC was utilized to determine the Roxithromycin content in pellets, colorimetry for assaying release of Roxithromycin sustained release pellets. The HPLC ultraviolet method was established to monitor the plasma concentration in dogs.
The preformulation results showed that Roxithromycin is very slightly soluble in water and saline, slight or sparingly soluble in various physiological pH fluids and the octanol/water partition coefficients increase
with pH rising in various physiological pH fluids(logP:0.86-2.66). It shows that the limit drug absorption in gastrointestinal tract is the drug release from dosage form.
Roxithromycin pellets were prepared by means of power layering with the centrifugal granulation equipment made in China. Through the formulation filtration and process observation, it was discovered that the yield of the objective pellets (32/40 mesh cut) was about 90% and the average Roxithromycin content was 25%. The results suggested the preparation process and formulation of Roxithromycin pellets can reach the expected goals.
A fluid-bed spray processor was adopted for the coating of the pellets. The coating process variables were determined and controlled. The coating formula respectively composed of Eudragit NE 30D, Eudragit RS 30D mixed with Eudragit RL 30D, Aquacoat and Surelease were studied on plasticizers, anti-tacking agents, HPMC, static electricity-proofing, coating level and curing time, etc. Eudragit NE 30D is selected for the excelletnt drug release character and convenient process. The description of dissolution profiles suggested that among the different kinetics, the first-order became the most appropriate model to describe release kinetics.
The plasma concentration of Roxithromycin in dogs was tested after a single oral administration of commercial tablets and two kind self-made sustained release pellets(32/40 and 18/24 mesh cut). The pharmacokinetics parameters and the relative bioavailability were measured. The pharmacokinetics parameters of Roxithromycin in two sustained release pellets analyzed by non-compartment model theory were Tmax(6.40+1.67) h, Cmax(8.21+1.91)g/ml and (6.52+1.44)g/ml, MRT (34.94+8.79)h and (33.92+5.33)h, Fr 100.43% and 83.43%, respectively. The results indicated that they have satisfactory sustained release effect and there were good correlation between absorption percent in vivo and dissolution percent in
vitro. But Roxithromycin sustained release pellets with smaller size show a better bioavailability.
引文
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[15] 陈挺，陈庆华．聚合物水分散体包衣技术及其应用．中国现化应用药学杂志，2000，17(5)：339-343
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[2] 杜蕾．红霉素类抗生素的研究进展及其市场分析．中国医药情报，1999，5(2)：68-71
[3] 朱立勤．罗红霉素的应用概况．天津药学，1998，10(2)：69-70
[4] 候绍庆，黄占群，魏振平．国产罗红霉素的分析方法及制剂学研究概况．中国医药工业杂志，2000，31(4)：184-186
[5] 戴德银主编．实用新药特药手册(第二版)．人民军医出版社，1997，160-162
[6] Young RA, Gonzalez JP, Sorkin EM. Roxithromycin. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. Drugs, 1989, 37 (1): 8-41
[7] Markham A, Faulds D. Roxithromycin. An update of its antimicrobial activity, pharmacokinetic properties and therapeutic use. Drugs, 1994, 48 (2): 297-326
[8] 任淑萍，孟雅君．罗红霉素国内临床应用研究进展．中国临床药理学杂志，1997，13(2)：124-127
[9] 张宁，朱家壁．口服缓控释制剂技术发展的新动向．国外医学药学分册，2000，27(4)：239-243
[10] 陆彬主编．药物新剂型与新技术．人民卫生出版社，1998，294-298
[11] 阳长明，侯世祥，张志荣等．缓释与控释小丸的研究进展．华西药学杂志， 2001，16(2)：121-123伍成祥，徐锋．
[12] Pillay V, Fassihi R. In vitro release modulation from crosslinded pellets for site-specific drug delivery to the gastrointestinal tract Ⅰ. Comparison of pH-responsive drug release and associated kinetics. J Controlled release, 1999, 59 (2): 229-242
[13] 浅析微丸在固体口服缓释控释制剂中的应用．山东医药工业，2000，19(5)：36-38
[14] 汪芸，姜洪芳，汪国华．微丸的成型性研究进展．江西中医学院学报，2002，14(1)：59-60
[15] 陈挺，陈庆华．聚合物水分散体包衣技术及其应用．中国现化应用药学杂志，2000，17(5)：339-343
[16] 张立超，胡晋红．聚合物水分散体包衣技术进展．药学实践杂志，1999，17(3)：144-148
[17] 毕殿洲主编．药剂学第四版．人民卫生出版社，1999，13
[18] 王秋华，谢玮，陆进方．罗红霉素胶囊溶出度的HPLC测定．中国医药工业杂志，1998，29(10)：450-451
[19] 郑俊民主编．经皮给药新剂型．人民卫生出版社，1997，255
[20] 毕殿洲主编．药剂学第四版．人民卫生出版社，1999，17-20
[21] 屠锡德主编．生物药剂学．北京，中国医药科技出版社，1998：21-22
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