PURPOSE: It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated. METHODS: The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated. RESULTS: Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4. CONCLUSIONS: The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.
PURPOSE: It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated. METHODS: The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated. RESULTS: Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4. CONCLUSIONS: The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.
Authors: Hans-Joachim Lehmler; Ling Xu; Sandhya M Vyas; Vivian A Ojogun; Barbara L Knutson; Gabriele Ludewig Journal: Int J Pharm Date: 2007-11-17 Impact factor: 5.875
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