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Ketobemidone prodrugs for buccal delivery
L B Hansen1, L L Christrup, H Bundgaard
1Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen.
Acta Pharmaceutica Nordica
|January 1, 1991
Summary
Researchers developed novel ketobemidone esters as prodrugs for improved buccal absorption. A specific ester showed promising stability in saliva and rapid plasma hydrolysis, indicating potential for effective drug delivery.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Drug Delivery
Background:
- Opioid analgesics like ketobemidone require formulations for targeted absorption.
- Prodrug strategies can enhance drug bioavailability and administration routes.
- Buccal and sublingual delivery offer alternatives to oral or parenteral administration.
Purpose of the Study:
- To synthesize and evaluate various ketobemidone esters as potential prodrugs.
- To assess the chemical stability, enzymatic hydrolysis, and lipophilicity of these esters.
- To identify a ketobemidone prodrug suitable for buccal or sublingual absorption.
Main Methods:
- Synthesis of carboxylic acid and carbonate esters of ketobemidone.
- High-performance liquid chromatography (HPLC) assay for stability and hydrolysis studies.
- Octanol-buffer partition experiments and reversed-phase chromatography for lipophilicity determination.
Main Results:
- All synthesized esters exhibited rapid hydrolysis in human plasma (half-lives 0.03-1.8 min).
- Significant enzymatic hydrolysis was observed in human saliva (half-lives 3-295 min).
- Esters demonstrated increased lipophilicity compared to the parent ketobemidone.
Conclusions:
- The 3,3-dimethylbutyryl ester of ketobemidone showed notable resistance to salivary hydrolysis.
- This ester's combination of salivary stability, rapid plasma hydrolysis, and high lipophilicity makes it a promising candidate for buccal delivery.
- Prodrug design can optimize the pharmacokinetic profile of analgesics for specific administration routes.