Soehngen E C, Godin-Ostro E, Fielder F G, Ginsberg R S, Slusher M A, Weiner A L
Novel Delivery Systems, Liposome Company, Inc., Princeton, NJ 08540.
Arthritis Rheum. 1988 Mar;31(3):414-22. doi: 10.1002/art.1780310314.
Encapsulation of indomethacin into egg phosphatidylcholine (EPC) monophasic vesicles (MPV) or into stable plurilamellar vesicles (SPLV) before oral administration to rats substantially reduced or eliminated the gastric and intestinal ulceration normally associated with ingestion of this drug. Ulcers were assessed by the 4-hour single-dose gastric ulceration model and the 4- or 14-day repeated-dose intestinal ulceration model, using microscopic/planimetric quantitation. Oral dosages of up to 10 mg/kg of indomethacin in polyethylene glycol-400 resulted in substantial gastric ulceration, but not when given in methylcellulose suspension or as EPCMPV. Severe intestinal ulcers resulted following oral administration of indomethacin in either vehicle at daily 3-4-mg/kg doses, but did not result from EPCMPV formulations, whether dosed for 4 days or 14 days. Oral administration of pH-sensitive indomethacin liposomes constructed from cholesterol hemisuccinate resulted in loss of the protective action. Indomethacin-MPV showed both comparable bioactivity and comparable blood levels of the drug when contrasted with free drug in vehicles. Biodistribution studies demonstrated that when delivered from liposomes, drug and phospholipid are rapidly cleared through the stomach but then are differentially absorbed. Empty EPCMPV given by mouth also offered some protection against ulcers induced by systemic (subcutaneous) introduction of indomethacin, although better protective action was noted when the drug was first liposome-encapsulated and then given orally. The application of liposomes to the development of nonsteroidal antiinflammatory drugs that have minimal gastrointestinal side effects is discussed.
在给大鼠口服之前，将吲哚美辛包封到鸡蛋磷脂酰胆碱（EPC）单相囊泡（MPV）或稳定的多片层囊泡（SPLV）中，可显著减少或消除通常与摄入该药物相关的胃和肠道溃疡。使用显微镜/平面测量定量法，通过4小时单剂量胃溃疡模型和4天或14天重复剂量肠道溃疡模型评估溃疡情况。在聚乙二醇-400中口服高达10mg/kg的吲哚美辛会导致大量胃溃疡，但以甲基纤维素混悬液形式给药或制成EPCMPV时则不会。以每日3 - 4mg/kg的剂量在任何一种赋形剂中口服吲哚美辛都会导致严重的肠道溃疡，但使用EPCMPV制剂时不会，无论给药4天还是14天。口服由胆固醇半琥珀酸酯构建的pH敏感型吲哚美辛脂质体导致保护作用丧失。与赋形剂中的游离药物相比，吲哚美辛-MPV显示出相当的生物活性和相当的药物血药浓度。生物分布研究表明，当从脂质体给药时，药物和磷脂会迅速通过胃清除，但随后会有不同程度的吸收。口服空的EPCMPV对全身（皮下）注射吲哚美辛诱导的溃疡也有一定的保护作用，不过当药物先被脂质体包封然后口服时，观察到更好的保护作用。本文讨论了脂质体在开发胃肠道副作用最小的非甾体抗炎药方面的应用。
