Design, synthesis, and pharmacokinetic evaluation of a chemical delivery system for drug targeting to lung tissue

• Published in: Journal of pharmaceutical sciences Vol. 85; no. 5; p. 496
• Main Authors: Saah, M, Wu, W M, Eberst, K, Marvanyos, E, Bodor, N
• Format: Journal Article
• Language: English
• Published: United States 01-05-1996
• Subjects: Animals; Anti-Asthmatic Agents - administration & dosage; Anti-Asthmatic Agents - chemistry; Anti-Asthmatic Agents - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Chemical Phenomena; Chemistry, Physical; Chlorambucil - administration & dosage; Chlorambucil - chemistry; Chlorambucil - pharmacokinetics; Chromatography, High Pressure Liquid; Cromolyn Sodium - administration & dosage; Cromolyn Sodium - chemistry; Cromolyn Sodium - pharmacokinetics; Drug Carriers; Drug Delivery Systems; Drug Stability; Evaluation Studies as Topic; Hydrolysis; Lung - metabolism; Male; Organ Specificity; Rabbits; Rats; Rats, Sprague-Dawley; Thioctic Acid - administration & dosage; Thioctic Acid - chemistry; Thioctic Acid - pharmacokinetics; Tissue Distribution
• ISSN: 0022-3549
• DOI: 10.1021/js9504200

We espouse the application of a novel chemical delivery system (CDS) approach to a delivery mechanism for drug targeting to lung tissue using the 1,2-dithiolane-3-pentyl moiety of lipoic acid as the "targetor moiety". The synthesis and the physicochemical and pharmacokinetic evaluation of a CDS modeling the lipoyl and other ester derivatives of chlorambucil (an antineoplastic agent) and cromolyn (a bischromone used in antiasthma prophylaxis) as compared with their respective parent drugs are described. The chlorambucil CDS was synthesized by esterifying the alcohol derivative of lipoic acid with chlorambucil using dicyclohexylcarbodiimide as the coupling agent. The cromolyn CDS was prepared by a multistep synthetic procedure culminating in the reaction of the alkyl bromide derivative of lipoic acid with the disodium salt of the bischromone compound. All the esters were highly lipophilic unlike the parent compounds. The in-vitro kinetic and in-vivo pharmacokinetic studies showed that the respective CDSs were sufficiently stable in buffer and biological media, hydrolyzed rapidly into the respective active parent drugs, and significantly enhanced delivery and retention of the active compound to lung tissue in comparison with the underivatized parent compounds used in conventional therapy.