In Vivo Assessment of Parenteral Formulations of Oligo(3-Hydroxybutyric Acid) Conjugates with the Model Compound Ibuprofen

• Published in: AAPS PharmSciTech Vol. 11; no. 4; pp. 1636 - 1641
• Main Authors: Stasiak, Pawel, Sznitowska, Malgorzata, Ehrhardt, Carsten, Luczyk-Juzwa, Maria, Grieb, Pawel
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-12-2010
• Subjects: 3-Hydroxybutyric Acid - chemistry; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Area Under Curve; Biochemistry; Biological Availability; Biomedical and Life Sciences; Biomedicine; Biotechnology; Brief/Technical Note; Dosage Forms; Drug Compounding; Drug Delivery Systems; Excipients; Female; Ibuprofen - administration & dosage; Ibuprofen - chemistry; Ibuprofen - pharmacokinetics; Indexing in process; Injections, Intramuscular; Male; Pharmaceutical Solutions; Pharmacology/Toxicology; Pharmacy; Prodrugs; Rabbits; Reproducibility of Results; Therapeutic Equivalency; pharmacokinetics; pro-drugs; oligo(3-hydroxybutyrates); ibuprofen; drug conjugates
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-010-9545-2

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 μg/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.