A novel chemical delivery system comprising an ocular sustained release formulation of a 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one-BIS-5-fluorouracil [correction of flourouracil] codrug

Directly compressed sustained release pellets were prepared from material consisting of a molecule of 3alpha, 17alpha, 21-trihydroxy-5beta-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...

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Bibliographic Details
Published in:Drug development and industrial pharmacy 2007-06, Vol.33 (6), p.677-682
Main Authors: Howard-Sparks, Michelle, Al-Ghananeem, Abeer M, Crooks, Peter A, Pearson, Andrew P
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - administration & dosage
Angiogenesis Inhibitors - chemical synthesis
Angiogenesis Inhibitors - pharmacokinetics
Animals
Biological Availability
Cattle
Chromatography, High Pressure Liquid
Delayed-Action Preparations
Drug Delivery Systems
Fluorouracil - administration & dosage
Fluorouracil - analogs & derivatives
Fluorouracil - chemical synthesis
Fluorouracil - chemistry
Fluorouracil - pharmacokinetics
Humans
In Vitro Techniques
Molecular Structure
Pregnanes - administration & dosage
Pregnanes - chemical synthesis
Pregnanes - pharmacokinetics
Pregnanolone - administration & dosage
Pregnanolone - analogs & derivatives
Pregnanolone - chemical synthesis
Pregnanolone - chemistry
Pregnanolone - pharmacokinetics
Prodrugs - administration & dosage
Prodrugs - chemical synthesis
Prodrugs - pharmacokinetics
Vitreous Body - metabolism
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Description
Summary:Directly compressed sustained release pellets were prepared from material consisting of a molecule of 3alpha, 17alpha, 21-trihydroxy-5beta-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 angiogenesis. 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.
ISSN:0363-9045