Studies On Thymosin α₁ Tablets For Colon-targeted Drug Delivery

Thymosin α₁ (Tα₁) is a polypeptide composed of 28 amino acids. As a biologic response modifier, Tα₁ can induce T-cell differentiation and maturation with increases in CD4⁺, CD8⁺ and CD3⁺ cells, as well as interferon gamma (γ-IFN), interleukin-2 (IL-2) and interleukin-3 (IL-3). What's more, Antigen-stimulated expression of IL-2 receptors was also observed. Tα₁ is being used for treating chronic hepatitis B, hepatitis C, malignant melanoma and hepatocellular carcinoma. At present, there is only one dosage form—freeze-dried powder for injection of Tα₁, which is inconvenient for patients' long-term administration. Oral colon-targeted drug delivery system (OCDDS) is a new route to enhance the oral bio-availability of protein and polypeptide drugs. This study was designed to prepare Tα₁ tablets for colon-targeted drug delivery, with absorption enhancer and protease inhibitor being used to improve the colonic absorption of Tα₁, and chitosan hydrochloride, a bacterial-triggered colon-targeted material was used as the inner coating, while Eudragit L100-55 was the outer enteric coating. Thus, the preparation released little drug in stomach and small intestine, while in the colon, the release was markedly increased.The study first investigated the absorption of Tα₁ from colon in rats through in situ perfusion or ligation method, and the effects of differentabsorption enhancers or protease inhibitor on Toil's colonic absorption were compared, including sodium deoxycholate (SDC), carbomer 940, water-soluble chitosan and bacitracin. The results shew the colonic absorption of Tα₁, is up to 60% within 3h, the blood concentration of Tot, got a notable rise, all the absorption enhancers or protease inhibitor could improve Toil's absorption in rats' colon by different degree, and the combination of SDC and bacitracin was most effective, which doubled the blood concentration of Tα₁.With the confirmation of the colonic absorption of Tα₁, the study prepared Tα₁ colon-targeted tablets, and the in vitro drug release was evaluated. Tα₁, mixed with SDC, bacitracin and other additives, was directly compressed to tablet cores, then chitosan hydrochloride and Eudragit L100-55 were used to coat the tablet cores respectively. Single factor experiment and L₉(3³) orthogonal experiment were carried out to screen the optimization formulations of the tablet cores and coatings. On the other hand, Fluorescein isothiocyanate-labeled dextran (FD-4), instead of Tα₁, was chosen as a model compound to prepare the FD-4 colon-targeted tablets by the same methods, and the in vitro drug-release experiment in the artificial gastric juice , small and large intestinal juice was carried out. As the results shew, the accumulated release of the preparation was less than 23% within 6h in the artificial gastric and small intestinal juice, while in the artificial large intestinal juice for 4h, the...