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Tolmetin Sodium loaded thermosensitive mucoadhesive liquid suppositories for rectal delivery; strategy to overcome oral delivery drawbacks.

Research paper by Mohamed A MA Akl, Hatem R HR Ismael, Fathy I FI Abd Allah, Alla A AA Kassem, Ahmed M AM Samy

Indexed on: 12 Oct '18Published on: 12 Oct '18Published in: Drug development and industrial pharmacy



Abstract

Tolmetin sodium (TS) is a non-steroidal anti-inflammatory drug (NSAID) indicated for treatment of musculoskeletal issues. As other NSAID, TS displays a marked side effects on the gastro-intestinal (GI) tract after oral administration. Tradational solid suppositories can cause pain and discomfort for patients, may reach the end of the colon; consequently, the drug can undergo the first-pass effect. TS liquid suppository (TS-) was developed to enhance patient compliance and rectal mucosal safety in high-risk patients receiving highly NSAID therapy. This work was conducted to optimize and evaluate Poloxamer P407/P188-based thermoresponsive TS- by using mucoadhesive polymers such as methylcellulose (MC). TS- was prepared by cold method and characterized their in-vitro physicochemical properties as gelation temperature (GT), gel strength, bioadhesive properties and in-vitro release. The safety of the prepared suppository on rectum, stomach and liver was evaluated histologically. Pharmacokinetic analyses were performed to compare rectal TS- to orally Rhumtol® capsules. The results showed that the optimized TS-; composed of P407/P188/MC (21/9/0.5% w/w) displayed gelation at rectum temperature ∼ 32.90°C, gel strength of 21.35 sec and rectal retention force at the administration site of 24.25 x 10 dyne/cm. Moreover, TS- did not cause any morphological damage to the rectal tissues. Pharmacokinetic parameters of optimized TS- formulation revealed 4.6 fold increase in bioavailability as compared to Rhumtol® capsules. Taken together, the results demonstrated that liquid suppository is a potential and physically safe rectal delivery carrier for improvement rectal bioavailability and in vivo safety of TS.