title: In vivo assessment of parenteral formulations of oligo(3-hydroxybutyric Acid) conjugates with the model compound Ibuprofen.
abstract: Polymer-drug conjugates have gained significant attention as pro-drugs releasing an active substance as a result of enzymatic hydrolysis in physiological environment. In this study, a conjugate of 3-hydroxybutyric acid oligomers with a carboxylic acid group-bearing model drug (ibuprofen) was evaluated in vivo as a potential pro-drug for parenteral administration. Two different formulations, an oily solution and an o/w emulsion were prepared and administered intramuscularly (IM) to rabbits in a dose corresponding to 40 mg of ibuprofen/kilogramme. The concentration of ibuprofen in blood plasma was analysed by HPLC, following solid-phase extraction and using indometacin as internal standard (detection limit, 0.05 microg/ml). No significant differences in the pharmacokinetic parameters (C (max), T (max), AUC) were observed between the two tested formulations of the 3-hydroxybutyric acid conjugate. In comparison to the non-conjugated drug in oily solution, the relative bioavailability of ibuprofen conjugates from oily solution, and o/w emulsion was reduced to 17% and 10%, respectively. The 3-hydroxybutyric acid formulations released the active substance over a significantly extended period of time with ibuprofen still being detectable 24 h post-injection, whereas the free compound was almost completely eliminated as early as 6 h after administration. The conjugates remained in a muscle tissue for a prolonged time and can hence be considered as sustained release systems for carboxylic acid derivatives.
authors.affiliation: Department of Pharmaceutical Technology, Medical University of Gdansk, ul. Hallera 107, 80-416, Gdansk, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Stasiak
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Sznitowska
authors.forename: Carsten
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: Maria
authors.initials: M
authors.lastname: Luczyk-Juzwa
authors.forename: Pawel
authors.initials: P
authors.lastname: Grieb
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000737:chemistry*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D004304:Dosage Forms; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005079:Excipients; D005260:Female; D007052:Ibuprofen / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007273:Injections, Intramuscular; D008297:Male; D019999:Pharmaceutical Solutions; D011355:Prodrugs; D011817:Rabbits; D015203:Reproducibility of Results; D013810:Therapeutic Equivalency
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004304:Dosage Forms; D005079:Excipients; D019999:Pharmaceutical Solutions; D011355:Prodrugs; D020155:3-Hydroxybutyric Acid; D007052:Ibuprofen