Pharmacological and toxicological investigations of etodolac loaded gum katira microspheres prepared by W1/O/W2 emulsion solvent evaporation technique in rats

ABSTRACT Etodolac is a non-steroidal anti-inflammatory drug (NSAID) and approved by USFDA as a COX2 inhibitor. Although etodolac therapy provides clinical benefits, it is associated with upper gastrointestinal (GI) tract complications also. Etodolac loaded gum Katira microsphere (ELGKM) was prepared by W1/O/W2 emulsion solvent evaporation technique. The gastric irritation properties of orally administered pure etodolac, ELGKM and blank microspheres (without etodolac) were evaluated in experimental rats treated for 6 days. The stomach examination and biochemical investigation of stomach tissue of treated rats indicated that ELGKM formulation remarkably reduced ulcerogenecity as compared to pure etodolac. The anti-inflammatory activities of pure etodolac and ELGKMs were ascertained by the implantation of cotton pellets in rats for 6 days. Based on the results, ELGKMs showed significant anti-inflammatory activities (P<0.01) as compared to control group. The cotton pellets test suggested that ELGKM formulation retained more anti-inflammatory properties among the groups. The hematological changes, biochemical analysis and histopathological studies of subacute toxicity in rats revealed that ELGKM were the effective sustained release formulation in the treatment of chronic pain and inflammation. In conclusion, the physicochemical characterization, pharmacological and toxicological studies suggest that ELGKMs may represent as a potential candidate for sustained drug delivery (10-12 hours) in chronic joint pain related diseases with remarkably diminished gastrointestinal side effects.

摘要 依托度酸是一种非甾体抗炎药（non-steroidal anti-inflammatory drug, NSAID），且被美国食品药品监督管理局（USFDA）批准为环氧合酶2（cyclooxygenase 2, COX2）抑制剂。尽管依托度酸治疗可带来临床获益，但同时也会引发上消化道（GI）并发症。本研究采用W1/O/W2复乳溶剂挥发法制备了依托度酸负载刺梧桐树胶微球（ELGKM）。对连续给药6天的实验大鼠，评估了口服纯依托度酸、ELGKM及空白微球（不含依托度酸）的胃刺激性。对给药后大鼠的胃部检查及胃组织生化检测结果显示，相较于纯依托度酸，ELGKM制剂可显著降低致溃疡作用。通过大鼠棉球植入法（持续6天），评估了纯依托度酸与ELGKM的抗炎活性。结果表明，ELGKM组的抗炎活性显著优于对照组（P<0.01）。棉球植入试验提示，ELGKM制剂在各组中保留了更优的抗炎特性。对大鼠亚急性毒性的血液学变化、生化分析及组织病理学研究显示，ELGKM是一种有效的缓释制剂，可用于慢性疼痛与炎症的治疗。综上，理化表征、药理学与毒理学研究结果表明，ELGKM可作为慢性关节疼痛相关疾病的10~12小时缓释给药潜在候选制剂，且胃肠道副作用显著降低。