Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide
Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide
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DOI：
10.1016/s0378-5173(99)00371-3
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发表时间：
2000-01-25
影响因子：
5.8
通讯作者：
Dunn, RL
中科院分区：
文献类型：
--
作者：
Ravivarapu, HB;Moyer, KL;Dunn, RL
本研究的目的是评价对原位形成的醋酸亮丙瑞林可注射聚合物植入剂在90天内抑制和维持动物血清睾酮水平在0.5 ng/ml范围内的有效性至关重要的制剂参数。评价的制剂含有45%（w/w）75/25聚特性粘度为0.20 dl/g的（DL-丙交酯-共-乙交酯）聚合物，溶解于55%（w/w）N-甲基-2-吡咯烷酮中，加入3%（w/w）醋酸亮丙瑞林，作为均匀溶液或两部分悬浮液（A/B）体系，其中在即将使用之前将药物分散在聚合物溶液中。本研究中评价的制剂参数包括聚合物分子量、聚合物浓度和载药量。使用大鼠和犬模型评价疗效。通过放射免疫测定法测定血清睾酮以确定功效，并通过HPLC分析研究结束时从大鼠取回的植入物的残留药物含量以确定药物释放的程度。使用候选制剂，犬中的睾酮水平在第14天降低至0.5 ng/ml的目标水平，并保持抑制直至第91天，重现了在大鼠中观察到的结果。聚合物浓度（40-50%）和载药量（3-6%（w/w））的变化对疗效的表观水平和持续时间没有显著影响。然而，采用较低分子量的聚合物降低了制剂的功效持续时间。(C)2000 Elsevier Science B. V.保留所有权利。
The objective of this study was to evaluate the formulation parameters critical to the efficacy of an injectable polymeric implant of leuprolide acetate, formed in situ, in suppressing and maintaining serum testosterone levels of animals in the range 0.5 ng/ml for over 90 days. The formulation evaluated contained 45% (w/w) 75/25 poly (DL-lactide-co-glycolide) polymer having an intrinsic viscosity of 0.20 dl/g, dissolved in 55%, (w/w) N-methyl-2-pyrrolidone with 3% (w/w) leuprolide acetate added either as a homogeneous solution or a two-part suspension (A/B) system, in which the drug was dispersed within the polymer solution immediately prior to use. The formulation parameters evaluated in this study included polymer molecular weight, polymer concentration, and drug loading. Both rat and dog models were used to evaluate efficacy. Serum testosterone was assayed by radioimmunoassay to determine efficacy, and retrieved implants from the rats at the termination of the study were analyzed by HPLC for residual drug content to determine the extent or drug release. With the candidate formulation, testosterone levels in dogs diminished to the targeted levels of 0.5 ng/ml by day 14 and remained suppressed up to day 91, reproducing the results seen in rats. Variations in polymer concentration (40-50%), and drug load (3-6% (w/w)) did not have a significant effect on the apparent level and duration of efficacy. However, employing lower molecular weight polymer decreased the duration of efficacy of the formulation. (C) 2000 Elsevier Science B.V. All rights reserved.