The apparent solubilizing capacity of simulated intestinal fluids for poorly water-soluble drugs.

Drug solubility testing in biorelevant media has become an indispensable tool in pharmaceutical development. Despite this importance, there is still an incomplete understanding of how poorly soluble compounds interact with these media. The aim of this study was to apply the concept of the apparent solubilization capacity to fasted and fed state simulated intestinal fluid (FaSSIF and FeSSIF, respectively). A set of non-ionized poorly soluble compounds was studied in biorelevant media prepared from an instantly dissolving complex (SIF(™) Powder) at 37°C. The values of the solubilization capacity were different between FaSSIF and FeSSIF but correlated. Drug inclusion into the mixed micelles was highly specific for a given compound. The ratio of the FeSSIF to FaSSIF solubility was in particular considered and discussed in terms of the apparent solubilizing capacity. The apparent solubilization concept appears to be useful for the interpretation of biorelevant solubility tests. Further studies are needed to explore acidic and basic drugs.

Absorption of poorly water soluble drugs subject to apical efflux using phospholipids as solubilizers in the Caco-2 cell model.

The purpose of this work was to determine the influence of liposomal solubilization of poorly water soluble drugs exhibiting apical efflux on permeation kinetics and cell toxicity in Caco-2 cells. The HIV-protease inhibitors indinavir and saquinavir were incorporated in phosphatidylcholine liposomes at maximal drug-to-lipid mass ratios and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using purely aqueous drug solutions as reference. A novel mathematical model was developed to quantitatively delineate the contribution of passive membrane permeation and carrier mediated efflux to transport across the cell monolayer and passive permeability coefficient and maximal efflux rate and affinity constant of the transporter system were determined. Cell toxicity of phospholipids was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and the lactate dehydrogenase (LDH) assay. Cell integrity was not significantly affected by phospholipid concentrations of up to 150 mg/ml with respect to the used standard tests. Maximum drug concentration was increased 10- and 750-fold for indinavir and saquinavir, respectively, by the use of liposomes. The passive membrane permeability coefficient differed between the two drugs in accordance with their lipophilicity and the affinity for apical efflux transporters was on average 4-fold greater for saquinavir than for indinavir. Liposomal solubilization diminished the passive permeability coefficient of both drugs but the passive apical-to-basal delivery rate was increased by the liposomes compared to the purely aqueous solutions at maximal donor concentrations for at least one of the two drugs. Efflux rate reached a maximum for the liposomal formulations reflecting transporter saturation. Hence, liposomal solubilization considerably increased drug concentration in the media and altered absorption behavior by affecting both the passive diffusion and the carrier mediated efflux components of cell monolayer permeation.

Lipophilic drug transfer between liposomal and biological membranes: what does it mean for parenteral and oral drug delivery?

This review presents the current knowledge on the interaction of lipophilic, poorly water soluble drugs with liposomal and biological membranes. The center of attention will be on drugs having the potential to dissolve in a lipid membrane without perturbing them too much. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid-based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics of lipophilic drugs after parenteral as well as oral administration.

Instant solubilization of poorly water-soluble drugs by in-situ loading of aqueous phospholipid dispersions suitable for parenteral administration.

The features of a new, in situ method for solubilizing poorly soluble drugs (SupraVail Instant Solubilization) are demonstrated. The resulting formulations are suitable for parenteral administration in preclinical and clinical studies. The technique avoids drug precipitation upon dilution and circumvents the need for co-administration of high organic solvent concentrations. The method involves mixing a sterile solution of a poorly water-soluble drug in a water-miscible organic solvent (the "transfer medium") with an excess of a sterile, stable, phospholipid dispersion prepared by high-shear homogenization. The influence of several mixing parameters which may affect the utility and viability of the method for two drugs, namely diazepam or cyclosporine A, are examined in detail. The resulting transparent dispersions were analyzed for presence of insoluble particles, transmission, particle size, and degree of solubilization. It is found that solubilizing efficiency is mainly determined by the drug and the phospholipid-to-drug ratio in the final dispersion. Complete and instant solubilization is obtained by using negatively charged phospholipids in the transfer medium. Variations in the mixing conditions, such as fast addition compared to slow addition, no shaking (agitation) versus shaking during mixing, stirring after mixing, and temperature variations of the lipid dispersion do not significantly affect the reproducibility of the method.

Characteristics of a novel phospholipid-based depot injectable technology for poorly water-soluble drugs.

Phospholipid concentrates in a water miscible solvent were explored as injectable formulations for the poorly water-soluble drugs, using the anti-infective PHA 244 as model substance. Formulations containing up to 70% w/v phospholipid could dissolve 15% PHA 244. The formulations showed excellent syringe-ability and no precipitation of the drug after dilution in an excess of water. The local tolerability and pharmacokinetics of the formulations were explored after subcutaneous injection into cattle. A slow release pattern over a 2-week period and excellent local tolerability at the injection site were observed. Considering the low manufacturing costs, related to the production of solutions, this SupraVail MLM (Membrane Lipid Matrix) technology is a cost-effective alternative to more expensive depot technologies for poorly water-soluble drugs with similar release characteristics, like sterile aqueous and oily drug substance suspensions, as cited in the literature.