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 IV Formulations during in Vitro Digestion

Hywel D. Williams; Mette U. Anby; Philip Sassene; Karen Kleberg; Jean-Claude Bakala-N’Goma; Marilyn Calderone; Vincent Jannin; Annabel Igonin; Anette Partheil; Delphine Marchaud; Eduardo Jule; Jan Vertommen; Mario Maio; Ross Blundell; Hassan Benameur; Frédéric Carrière; Anette Müllertz; Colin W. Pouton; Christopher J. H. Porter

doi:10.1021/mp300331z

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 IV Formulations during in Vitro Digestion

Hywel D. Williams, Mette U. Anby, Philip Sassene, Karen Kleberg, Jean-Claude Bakala-N’Goma, Marilyn Calderone, Vincent Jannin, Annabel Igonin, Anette Partheil, Delphine Marchaud, Eduardo Jule, Jan Vertommen, Mario Maio, Ross Blundell, Hassan Benameur, Frédéric Carrière, Anette Müllertz, Colin W. Pouton, Christopher J. H. Porter

88 Citations (Scopus)

Abstract

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 (AP _DIGEST). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 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 AP _DIGEST 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 (SR^M) attained on initiation of digestion. SR^M defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP_DIGEST (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 SR^M was evident, regardless of formulation composition and drug solubilization reduced markedly above SR^M > 2.5. The threshold SR^M may prove to be an effective tool in discriminating between LBFs based on performance.

Original language	Undefined/Unknown
Journal	Molecular Pharmaceutics
Volume	9
Issue number	11
Pages (from-to)	3286-3300
Number of pages	15
ISSN	1543-8384
DOIs	https://doi.org/10.1021/mp300331z
Publication status	Published - 5 Nov 2012

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Williams, H. D., Anby, M. U., Sassene, P., Kleberg, K., Bakala-N’Goma, J.-C., Calderone, M., Jannin, V., Igonin, A., Partheil, A., Marchaud, D., Jule, E., Vertommen, J., Maio, M., Blundell, R., Benameur, H., Carrière, F., Müllertz, A., Pouton, C. W., & Porter, C. J. H. (2012). 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 IV Formulations during in Vitro Digestion. Molecular Pharmaceutics, 9(11), 3286-3300. https://doi.org/10.1021/mp300331z

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 IV Formulations during in Vitro Digestion. / Williams, Hywel D.; Anby, Mette U.; Sassene, Philip et al.
In: Molecular Pharmaceutics, Vol. 9, No. 11, 05.11.2012, p. 3286-3300.

Research output: Contribution to journal › Journal article › Research › peer-review

Williams, HD, Anby, MU, Sassene, P, Kleberg, K, Bakala-N’Goma, J-C, Calderone, M, Jannin, V, Igonin, A, Partheil, A, Marchaud, D, Jule, E, Vertommen, J, Maio, M, Blundell, R, Benameur, H, Carrière, F, Müllertz, A, Pouton, CW & Porter, CJH 2012, '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 IV Formulations during in Vitro Digestion', Molecular Pharmaceutics, vol. 9, no. 11, pp. 3286-3300. https://doi.org/10.1021/mp300331z

Williams HD, Anby MU, Sassene P, Kleberg K, Bakala-N’Goma JC, Calderone M et al. 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 IV Formulations during in Vitro Digestion. Molecular Pharmaceutics. 2012 Nov 5;9(11):3286-3300. doi: 10.1021/mp300331z

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abstract = "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 (AP DIGEST). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 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 AP DIGEST 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 {"}pressure{"} 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.",

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AU - Williams, Hywel D.

AU - Anby, Mette U.

AU - Sassene, Philip

AU - Kleberg, Karen

AU - Bakala-N’Goma, Jean-Claude

AU - Calderone, Marilyn

AU - Jannin, Vincent

AU - Igonin, Annabel

AU - Partheil, Anette

AU - Marchaud, Delphine

AU - Jule, Eduardo

AU - Vertommen, Jan

AU - Maio, Mario

AU - Blundell, Ross

AU - Benameur, Hassan

AU - Carrière, Frédéric

AU - Müllertz, Anette

AU - Pouton, Colin W.

AU - Porter, Christopher J. H.

PY - 2012/11/5

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N2 - 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 (AP DIGEST). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 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 AP DIGEST 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 "pressure" 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.

AB - 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 (AP DIGEST). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 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 AP DIGEST 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 "pressure" 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.

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