Toward the Establishment of Standardized in Vitro Tests for Lipid-Based Formulations. 2. The Effect of Bile Salt Concentration and Drug Loading on the Performance of Type I, II, IIIA, IIIB, and
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- 作者：Hywel D. Williams ; Mette U. Anby ; Philip Sassene ; Karen Kleberg ; Jean-Claude Bakala-N鈥橤oma ; Marilyn Calderone ; Vincent Jannin ; Annabel Igonin ; Anette Partheil ; Delphine Marchaud ; Eduardo Jule ; Jan Vertommen ; Mario Maio ; Ross Blundell ; Hassan Benameur ; Fr茅d茅ric Carri猫re ; Anette M眉llertz ; Colin W. Pouton ; Christopher J. H. Porter
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：November 5, 2012
- 年：2012
- 卷：9
- 期：11
- 页码：3286-3300
- 全文大小：715K
- 年卷期：v.9,no.11(November 5, 2012)
- ISSN：1543-8392
文摘
The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (APDIGEST). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations 鈮? mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in APDIGEST increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SRM) attained on initiation of digestion. SRM defines the supersaturation 鈥減ressure鈥?in the system and is calculated from the maximum attainable concentration in the APDIGEST (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SRM was evident, regardless of formulation composition and drug solubilization reduced markedly above SRM > 2.5. The threshold SRM may prove to be an effective tool in discriminating between LBFs based on performance.