Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 1: Method Parameterization and Comparison of In Vitro Digestion Profiles Across a Range of Representative Formulations

doi:10.1002/jps.23205

Journal of Pharmaceutical Sciences

Volume 101, Issue 9, September 2012, Pages 3360-3380

https://doi.org/10.1002/jps.23205 Get rights and content

ABSTRACT:

The Lipid Formulation Classification System Consortium is an industry–academia collaboration, established to develop standardized in vitro methods for the assessment of lipid-based formulations (LBFs). In this first publication, baseline conditions for the conduct of digestion tests are suggested and a series of eight model LBFs are described to probe test performance across different formulation types. Digestion experiments were performed in vitro using a pH-stat apparatus and danazol employed as a model poorly water-soluble drug. LBF digestion (rate and extent) and drug solubilization patterns on digestion were examined. To evaluate cross-site reproducibility, experiments were conducted at two sites and highly consistent results were obtained. In a further refinement, bench-top centrifugation was explored as a higher throughput approach to separation of the products of digestion (and compared with ultracentrifugation), and conditions under which this method was acceptable were defined. Drug solubilization was highly dependent on LBF composition, but poorly correlated with simple performance indicators such as dispersion efficiency, confirming the utility of the digestion model as a means of formulation differentiation. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association

Section snippets

INTRODUCTION

The issue of low aqueous drug solubility continues to hinder the robust testing of new chemical entities during drug discovery and development. Of the many formulation strategies that have been used to address the obstacles associated with low solubility, lipid-based formulations (LBFs) have generated significant interest.¹ The composition of LBFs can vary widely, although common design features include the presence of molecularly dispersed drug within a blend of various polar and nonpolar oils

Materials

Details of the lipidic excipients used within the LFCS Consortium can be found in Table 1. Danazol was kindly supplied by Sterling Pharmaceuticals (Sydney, Australia) and Indis (Aartselaar, Belgium). Preliminary studies revealed that the two different batches of this drug showed comparable solubility in pH 6.5 Tris-maleate buffer (0.7–1.2 µg/mL), and the values obtained were within the range of previously reported values.²⁵ Sodium taurodeoxycholate >95% (NaTDC), 4-bromophenylboronic acid, and

Danazol Equilibrium Solubility in the Series of LFCS LBFs

The eight LBFs investigated were chosen to provide examples of all classes of formulations currently contained within the LFCS.² As a result, investigation of their solvent capacity and properties during dispersion and digestion was expected to provide a broad indication of the likely performance of a range of LBFs.

The equilibrium solubility of danazol in the eight LBFs is shown in Figure 1. A trend toward increasing solubility with increasing polarity of the formulation was observed, giving

DISCUSSION

Several recent studies suggest that changes to the solubilization properties of LBF as they are processed in the GI tract are key determinant of in vivo performance.¹²,¹⁹,²⁰,⁴⁵ The major changes imparted by GI processing are formulation dilution, formulation digestion, and the interaction of formulation components and digestion products with biliary secretions—all of which are expected to impact on patterns of drug solubilization.⁵ Recent studies have suggested that in vitro lipid digestion

CONCLUSIONS

Standardized baseline conditions for the evaluation of LBF using in vitro lipid digestion tests have been proposed and a broad range of LBF types examined. The data obtained under a consistent set of in vitro digestion conditions provide an opportunity to directly compare LBF performance and permit initial identification of key experimental variables. Experiments were conducted at pH 6.5, using 2 mM Tris-maleate buffer containing 150 mM NaCl, 1.4 mM CaCl₂, 3 mM NaTDC, and 0.75 mM PC. To better

Acknowledgements

This study results from a joint collaboration between members of the LFCS Consortium funded primarily by Capsugel, Sanofi R&D, Gattefossé, and Merck Serono with additional funding from NiCox, Roche, Bristol-Myers Squibb, and Actelion. The authors would like to acknowledge Rhiannon Smythe and Samuel Wood for determining danazol solubilities in pure lipid excipients.

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Pharmaceutics, Preformulation and Drug DeliveryToward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 1: Method Parameterization and Comparison of In Vitro Digestion Profiles Across a Range of Representative Formulations

ABSTRACT:

Section snippets

INTRODUCTION

Materials

Danazol Equilibrium Solubility in the Series of LFCS LBFs

DISCUSSION

CONCLUSIONS

Acknowledgements

Eur J Pharm Sci

Adv Drug Deliv Rev

Eur J Pharm Sci

J Pharm Sci

Adv Drug Deliv Rev

J Pharm Sci

J Pharm Sci

J Control Release

Int J Pharm

Food Chem

Int J Pharm

Eur J Pharm Sci

Biochim Biophys Acta

Eur J Pharm Sci

J Colloid Interface Sci

Eur J Pharm Sci

Biochim Biophys Acta

Biochim Biophys Acta

Comp Biochem Physiol B Biochem Mol Biol

Eur J Pharm Sci

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Int J Pharm

Int J Pharm

J Pharm Sci

Int J Pharm

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Eur J Pharm Biopharm

Eur J Pharm Biopharm

FEBS Lett

Adv Drug Deliv Rev

Adv Colloid Interface Sci

J Nutr Biochem

J Lipid Res

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Enhancing the bioavailability of poorly water-soluble drugs

Pharmaceutics, Preformulation and Drug Delivery
Toward the Establishment of Standardized In Vitro Tests for Lipid-Based Formulations, Part 1: Method Parameterization and Comparison of In Vitro Digestion Profiles Across a Range of Representative Formulations