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首页> 外文学位 >Characterization of polymorphic forms and in vitro release of etoposide from poly-DL-lactic and poly-DL-lactic-co-glycolic acid micromatrices.
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Characterization of polymorphic forms and in vitro release of etoposide from poly-DL-lactic and poly-DL-lactic-co-glycolic acid micromatrices.

机译：依托泊苷从聚-DL-乳酸和聚-DL-乳酸-共-乙醇酸微基质的多晶型形式表征和体外释放。

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摘要

Etoposide has been shown to be effective in the treatment of testicular and small-cell lung cancers, lymphoma, leukemia and Kaposi's sarcoma. Several clinical investigations have suggested that the prolonged maintenance of greater than 1 {dollar}mu{dollar}g/ml concentration in plasma would provide better therapeutic response in patients. Thus use of a sustained/controlled release formulation of etoposide was indicated. This investigation focused on the potential for the development of a sustained/controlled release dosage form of etoposide for a 7-15 day delivery using selected polylactic and polylactic-co-glycolic acid polymers. During the course of studies involving the enhancement of aqueous solubility of etoposide in our laboratory evidence of a potential thermally induced polymorphic transition was detected. Therefore, further characterization of this phenomenon was also included in this investigation.; Thermal behavior of etoposide was characterized by differential scanning calorimetry, thermal gravimetric analysis, X-ray diffractometry, mass spectroscopy, IR spectra and HPLC analyses. A method for the preparation of micromatrices of etoposide was developed utilizing a suspension and solvent evaporation technique. DSC, IR and NMR investigations did not indicate any potential etoposide-polymer interaction.; Etoposide I, a monohydrate, underwent a dehydration reaction between 85-115{dollar}spcirc{dollar}C to yield Etoposide Ia, which upon further heating melted at 198{dollar}spcirc{dollar}C and crystallized to a new polymorph, Etoposide IIa at 206{dollar}spcirc{dollar}C. Etoposide IIa was found to melt at 269{dollar}spcirc{dollar}C and converted to its hydrated form, Etoposide II when exposed to atmosphere at room temperature. The polymorphic transition was found to be irreversible and monotropic. Etoposide I, the currently marketed drug was used in all delivery systems examined. Formulation studies with polylactic acid polymers indicated that the molecular weight of the polymer was a key parameter in influencing the percent of drug entrapped in the micromatrices, particles size distribution and the drug release profiles. Glycolide-containing polymers demonstrated control of etoposide release only at low drug loadings: larger micromatrices showing better control. Polylactic acid 50,000 at 1:5 and 1:15 drug to polymer ratios exhibited maximum rate of drug release of 1.57 mg/hr. At this release rate, a delivery system containing 350 mg of etoposide could be expected to maintain a plasma concentration of 1.08 {dollar}mu{dollar}g/ml over a period of 7 days. Additionally, drug release profile of polylactide-co-glycolide (85:15, 75-180 {dollar}mu{dollar}m) microsphere formulation with 1:10 drug to polymer ratio, was found to be more appropriate for a 15-day release system based upon 700 mg of etoposide.
机译：依托泊苷已被证明可有效治疗睾丸癌和小细胞肺癌，淋巴瘤，白血病和卡波济氏肉瘤。几项临床研究表明，血浆中浓度长期维持在1美元/微克/毫升以上可为患者提供更好的治疗反应。因此表明使用了依托泊苷的缓释/控释制剂。这项研究集中在开发使用选定的聚乳酸和聚乳酸-共-乙醇酸聚合物的依托泊苷缓释/控释剂型7-15天递送的潜力。在涉及依托泊苷的水溶性增加的研究过程中，在我们的实验室中发现了潜在的热诱导多晶型转变的证据。因此，这项研究还包括对该现象的进一步表征。依托泊苷的热行为通过差示扫描量热法，热重分析，X射线衍射法，质谱，IR光谱和HPLC分析来表征。利用悬浮液和溶剂蒸发技术开发了一种依托泊苷微基质的制备方法。 DSC，IR和NMR研究没有表明任何潜在的依托泊苷-聚合物相互作用。一水合物依托泊苷I在85-115 {sp} {dol} C之间进行脱水反应，得到依托泊苷Ia，依托泊苷Ia进一步加热至198 {sp} {dol} C熔化并结晶成新的多晶型物依托泊苷IIa在206 {dollar} spcirc {dollar} C。发现依托泊苷IIa在室温下于269℃熔化并转化成其水合形式依托泊苷II。发现多晶型转变是不可逆的并且是单向的。依托泊苷I，目前市售的药物被用于所有检查的递送系统中。用聚乳酸聚合物进行的配方研究表明，聚合物的分子量是影响药物在微基质中截留的百分比，粒径分布和药物释放曲线的关键参数。含乙醇酸内酯的聚合物仅在低载药量时显示了依托泊苷释放的控制：较大的微基质显示出更好的控制。药物与聚合物的比例为1：5和1:15的聚乳酸50,000显示出最大的药物释放速率为1.57 mg / hr。在该释放速率下，预期包含350 mg依托泊苷的递送系统在7天内将维持1.08 {μg}美元/ g的血浆浓度。另外，发现药物与聚合物的比例为1:10的聚丙交酯-共-乙交酯（85:15，75-180 {μmol}μm}）微球制剂的药物释放曲线更适合15天释放系统基于700毫克依托泊苷。

著录项

  • 作者

    Jasti, Bhaskara Rao.;

  • 作者单位

    University of the Pacific.;

  • 授予单位 University of the Pacific.;
  • 学科 Health Sciences Pharmacy.; Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 1995
  • 页码 147 p.
  • 总页数 147
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药剂学;药物化学;
  • 关键词

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