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

Abstract

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.

Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

“…Basic compounds, with the exception of astemizole and noscapine, should be taken with food (Table 1), as their solubility and IDR values increase in the fed state. Examples are cinnarizine and carvedilol, with a higher solubility and IDR in FeSSIF than in FaSSIF observed here, and the positive food effect also recently reported in literature [63,64]. All compounds with no reported food effect are either neutral or acids (Table 1) in agreement with our IDR data.…”

Suitability of Artificial Membranes in Lipolysis-Permeation Assays of Oral Lipid-Based Formulations

“…LBF has also been shown to increase the bioavailability of BCS (biopharmaceutics classification system) class II and IV drugs (5)(6)(7)(8), possibly by circumventing the dissolution step in the intestine. However, several studies have shown that an API does not necessarily have to be fully dissolved within an LBF, but that co-administration with crystalline material can be sufficient to increase the amount of solubilized drug and bioavailability (9,10), in a phenomenon sometimes described as the "chasing principle" (11). This effect means that dissolution prior to administration might not be necessary for effective drug delivery via LBF.…”

“…In the in vitro lipolysis assay, the amount of API solubilizedor available for absorptionis expected to correlate to the in vivo performance, because the APIs are typically highly permeable. However, when comparing LBFs of different compositions, the in vitro in vivo relationship (IVIVR) of drug release with bioavailability fails to reach even rank-order in many cases (9,13,14); the reader is advised to read the review by Feeney et al (15) for further details. This observation suggests that the mechanisms of action for LBFs are not necessarily as simple as increasing apparent solubility within the intestinal media or supersaturation effects driving permeation.…”

“…Recently, an in vitro method was published in which effectiveness of LBFs was gauged by adding simultaneous absorption via a Caco-2 monolayer to the in vitro lipolysis assay (19). This method has shown good IVIVR by assessing mass transfer across the monolayer (9,19), a promising step towards a more efficient development process for LBFs. However, cultured cells are not compatible with all formulations or digestive agents (20,21).…”

Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems

“…In addition, they are limited in detecting any mechanisms other than drug solubilization that influence the fed/fasting responses of su-SEDDSs. The establishment of a more powerful in vitro model, such as a simultaneously combined digestion-permeation experimental set-up, may provide a better indication of various mechanisms critical to the negation of food effects and the enhancement of overall systemic drug exposure [191,192]. Moreover, a recent research reported in vitro digestion-in vivo permeation model which called in situ perfusion [193].…”