Figure 3 The concentration of drug in the aqueous phase in the long chain triglycerides (LCT) studies with (■) and without (□) addition of lipase (n > 3, ±S.D). (A) Flupentixol (added at 200% (w/w) of the maximum solubility in LCT); (B) LU 28-179 (added at 80% (w/w) of the maximum solubility in LCT); (C) Probucol (added at 80% (w/w) of the maximum solubility in LCT). Source: From Ref. 40.
and solvent properties. The dynamic lipolysis model, employing LCT as a model dietary lipid, has proven valuable for studying food effect in vitro.
Simulating Hydrolysis of Lipid-Based Formulations by Use of the Lipolysis Model
Development of a lipid-based formulation almost always involves the identification of lipid and surfactant excipients in which the drug can be fully solubilized (55). Development of SEDDS formulations requires additional formulation optimization to confer adequate resistance to drug precipitation following dispersion in vivo. Another factor not routinely addressed in formulation development involves the impact of in vivo lipid digestion on drug solubilization and formulation performance. Studies conducted with the dynamic lipolysis model, in the presence of relevant amounts of dietary and formulation-derived lipid substrates, can be useful in achieving this objective.
The first attempt to use an in vitro lipolysis model to predict the in vivo performance of lipid-based formulations was described in 1988 by Reymond and Sucker
(44,56). However, no in vitro-in vivo correlation (IVIVC) was found, possibly due to an in vitro TG hydrolysis rate that was lower than that occurring in vivo.
An IVIVC has been demonstrated for the oral absorption of LU 28-179 in dogs and the drug release observed in the lipolysis model from a hydroxypropyl-^-cyclodextrin reference solution, a SMEDDS formulation, oil solutions, and dry emulsion formulations containing either LCT or MCT (57). Compared to the reference solution, the absorption of LU 28-179 in dogs was substantially greater for the SMEDDS and dry emulsion formulations, which correlated with the rate and extent of drug release observed in the in vitro lipolysis model.
De Smidt et al. (16) investigated the influence of vehicle dispersion and digestibility on the GI absorption in rats of the poorly soluble drug, penclomedine, in rats administered as either an undispersed solution in MCT and D-a-tocopheryl polyethyleneglycol 1000 succinate or in emulsions prepared to contain oil droplet sizes of 160 or 720 nm. When coadministered with the lipase inhibitor tetrahydro-lipstatin (THL), the emulsion droplet size had minimal impact on drug absorption; however, drug absorption from the undispersed solution was substantially reduced in the presence of THL. Although in vitro lipolysis studies were not conducted on these formulations, the influence of in vivo lipolysis on formulation performance is evident from the results.
Porter et al. (47) characterized LC-SMEDDS and MC-SMEDDS formulations of danazol containing comparable amounts of either long (LC) or medium chain (MC) TG. Following approximately 200-fold dilution in 0.1N HCl, lipid droplet sizes of approximately 40 nm were formed, with the droplet size being independent of the TG fatty acid chain length. In addition, dispersion of these formulations in test media containing 5mM BS and 1.25 mM PL resulted in minimal drug precipitation. However, 30 minutes after the initiation of lipolysis, 69% of the drug precipitated from the MC-SMEDDS, as compared to only 6% from the LC-SMEDDS. The degree of drug precipitation was inversely correlated with danazol bioavailability in dogs, which was 5.7-fold greater from the LC-SMEDDS formulation relative to the MC-SMEDDS formulation. Studies conducted with the antimalarial drug halofantrine showed a similar relationship between drug precipitation resistance during in vitro lipolysis and superior bioavailability (46).
Several published studies of SEDDS formulations have described an inverse correlation between lipid droplet size and degree of drug absorption (58-61). However, it should be noted that the formulations investigated in these studies were not controlled for either surfactant or lipid type or amount. Since it has been well documented that SEDDS formulations of different qualitative or quantitative composition, but similar lipid droplet size frequently result in different bioavailabilities for a particular drug, no clear-cut conclusion with regard to impact of droplet size on bioavailability can be drawn (47,62,63). To further investigate the effect of droplet size on drug absorption, two SEDDS formulations containing probucol were developed, which differed only in the lipid droplet size. One formulation, a self-nanoemulsifying drug delivery system (SNEDDS), contained lipid droplets of 45 ± 3.4nm in size, while a SMEDDS formulation contained droplets of 4.58 ± 0.84 ^m in size (54). The dynamic lipolysis model was used to evaluate the lipolysis rate and release of probucol from both of these formulations in comparison to a simple oil solution formulation of the drug (64). The solubilization of probucol by the aqueous phase was substantially lower from the oil solution compared to either the SNEDDS or SMEDDS formulations, for which drug solubilization was essentially identical. An in vitro-in vivo relationship was demonstrated between the drug release profiles obtained in vitro using the dynamic lipolysis model, and the drug plasma concentration profiles obtained in a previous bioavailability study conducted in mini-pigs (52). While these initial results are very encouraging, more work is needed in order to further define the lipolysis model with the goal of consistently generating reliable and reproducible projections of formulation performance in man.
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