A Novel Chemical Delivery System Comprising an Ocular Sustained Release Formulation of a 3α, 17α, 21-trihydroxy-5β-pregnan-20-one-BIS-5-Flourouracil Codrug

ABSTRACT

Directly compressed sustained release pellets were prepared from material consisting of a molecule of 3α, 17α, 21-trihydroxy-5β-pregnan-20-one (trihydroxy steroid, THS) covalently linked via carbonate moieties to two molecules of 5-flourouracil (5FU) to form a novel THS-BIS-5FU codrug for the treatment of angiogenisis. Dissolution and drug release was tested in vitro in 0.1M phosphate buffer (pH 7.4), human serum, and vitreous humor. The results suggest that neat THS-BIS-5FU codrug pellets are useful for sustained release ocular delivery of the parent compounds, and that the unique physicochemical properties of the codrug allow slow dissolution and rapid release of the two parent drugs. This codrug formulation is regarded as a “chemical delivery” system that involves dissolution of the codrug as the rate-limiting step followed by rapid hydrolysis of the carbonate ester linkages to release the parent drugs via sustained delivery.

KEYWORDS:

• Codrug
• Chemical delivery
• Sustained release
• 5-Fluorouracil
• Trihydroxy steroid
• Angiogenesis