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

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• 作者：Pawel Stasiak (1)
  Malgorzata Sznitowska (1)
  Carsten Ehrhardt (2)
  Maria Luczyk-Juzwa (3)
  Pawel Grieb (4)
  
• 关键词：drug conjugates ; ibuprofen ; oligo(3 ; hydroxybutyrates) ; pharmacokinetics ; pro ; drugs
• 刊名：AAPS PharmSciTech
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：11
• 期：4
• 页码：1636-1641
• 全文大小：137KB
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• 作者单位：Pawel Stasiak (1)
  Malgorzata Sznitowska (1)
  Carsten Ehrhardt (2)
  Maria Luczyk-Juzwa (3)
  Pawel Grieb (4)
  
  1. Department of Pharmaceutical Technology, Medical University of Gdansk, ul. Hallera 107, 80-416, Gdansk, Poland
  2. School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
  3. Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Zabrze, Poland
  4. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
  

文摘

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.