Models for Predicting Drug Absorption From Oral Lipid-Based Formulations

Alskär, Linda C.; Bergström, Christel A. S.

doi:10.1007/s40610-015-0023-1

Cited by 12 publications

(9 citation statements)

References 51 publications

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“…The complex relationship between intestinal formulation processing and absorption of drug and lipid products complicates the establishment of robust IVIVC for LBFs. [5,32] The standard in vitro lipolysis method (without an absorptive sink) [33,34] as well as initial droplet size of the formulation [6,7,35] results in poor and inconsistent in vivo correlations. Thus, in the current study a newly developed lipolysis-permeation device, that enables simultaneous study of digestion and absorption was assessed for its potential to produce IVIVC.…”

Section: Discussionmentioning

confidence: 99%

Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

Alskär

Parrow

Keemink

et al. 2019

Journal of Controlled Release

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Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly watersoluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipid-based drug formulation containing the predissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acid) and bile salt. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acid and bile salt in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in solid form, e.g. due to chemical instability in the lipid vehicle. Finally, the in vitro lipolysispermeation used herein established IVIVC for carvedilol in the presence of LBFs.

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Section: Discussionmentioning

confidence: 99%

Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

Alskär

Parrow

Keemink

et al. 2019

Journal of Controlled Release

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“…This may explain, at least in part, the additive solubility effect of the excipients included in an LBF that has been observed experimentally. 20 The simulations indicate that each of the included excipients forms local nanostructures in the dry LBF and that the interaction between the excipients is minimal. Hence, based on the results from the simulations, we speculate that, when drug molecules dissolve in the LBF, they simply saturate each of the included components.…”

Section: Discussionmentioning

confidence: 90%

Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach

2017

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The internal molecular structure of lipid-based formulations (LBFs) is poorly understood. In this work we aimed at establishing coarse-grained molecular dynamics simulations as a tool for rapid screening and investigation of the internal environment of these formulations. In order to study complex LBFs composed of different kinds of lipids we simulated a number of systems containing either medium-chain or long-chain lipids with varying proportions of tri-, di-, and monoglycerides. Structural and dynamic measurements and analyses identified that the internal environment in a mixture of lipids was locally ordered even in the absence of water, which might explain some of the previously reported effects on drug solubility in these systems. Further, phase changes occurring upon water dispersion are well captured with coarse-grained simulations. Based on these simulations we conclude that the coarse-grained methodology is a promising in silico approach for rapid screening of structures formed in complex formulations. More importantly it facilitates molecular understanding of interactions between excipients and water at a feasible time scale and, hence, opens up for future virtual drug formulation studies.

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“…It has been tried before to directly apply a "mixture rule" to predict drug solubility in an LBF based on solubility in the individual components. 4,17 There are of course limits to any simple mixture rule for property prediction of a complex formulation. It may fail theoretically in cases where a single component dominates the mixture property.…”

Section: Resultsmentioning

confidence: 99%

A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery

Niederquell

Dujovny²,

Probst³

et al. 2019

Journal of Pharmaceutical Sciences

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Drug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, ε r. Diverse solvents and lipid-based excipients were then experimentally tested for ε r and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an ε r range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained ε r was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.

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Models for Predicting Drug Absorption From Oral Lipid-Based Formulations

Cited by 12 publications

References 51 publications

Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach

A Relative Permittivity Approach for Fast Drug Solubility Screening of Solvents and Excipients in Lipid-Based Delivery

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