Lipid Based Solid Dispersion

Many investigators have described the utility of lipid-based formulations for enhancing the bioavailability of poorly water-soluble drugs (9-12). These formulations range from simple solutions of drugs in dietary triglycerides (oil) to the use of complex mixtures of triglycerides, partial glycerides, surfactants, cosurfactants, and cosolvents to solubilize drugs. Depending on the formulation composition, they are described as nonemulsifying drug delivery systems, self-emulsifying drug delivery systems (SEDDS) or self-microemulsifying drug delivery systems (SMEDDS). Pouton attempted to provide a scientific basis of classifying various self-emulsifying lipid-based formulations based on the lipid droplet sizes formed upon mixing with aqueous media, which may range from > 100 ^m (Type I) to 50 to 100 nm (Type IIIB) (11). Despite the potential for the use of lipid-based systems to formulate many poorly water-soluble drugs, Gursoy and Benita (12) reported that there were only four lipid-based commercially marketed products available in 2004, of which two were for cyclosporine A and the other two for ritonavir and sequinavir; all of these products were encapsulated liquids. The primary limitation of lipid-based dosage forms is the requirement that the drug possess sufficient solubility in the formulation to allow delivery of a single dose in a standard oral capsule dosage form. In instances where insufficient solubility in the formulation precludes the development of a fully-solubilized lipid-based formulation, preparation of a solid dispersion of the drug in a semi-solid, lipid-based formulation could provide a viable path forward.

Most surface active and self-emulsifying excipients used in solid dispersions may be categorized as lipids or lipid-like because they are either glycerides or chemically related to the glycerides. In the present article, lipid-based solid dispersions will be discussed in broad terms by including various surface active carriers in the lipid category. Mixtures of surface active carriers with nonsurface active vehicles [e.g., polyethylene glycols (PEGs), different polymers, etc.] will also be discussed. Particular consideration will be given to the physicochemical advantages and limitations of these formulations as viable drug delivery systems as well as the different methodologies applicable to commercial product development.

The performance of nonself-emulsifying solid dispersions (e.g., those prepared using PEGs) is often limited by the relatively rapid dissolution rate of the water-soluble excipient matrix as compared to that of the dispersed drug substance. This results in the formation of a highly concentrated solution of drug, which precipitates on the surface of the dissolving excipient plug, forming a poorly soluble coating that prevents further dissolution of dispersed drug contained within the excipient matrix. For this reason, solid dispersions must be pulverized and sifted to increase their surface area in order to facilitate drug release. This is a difficult task as solid dispersions prepared with such common excipients as PEGs are usually soft and tacky and may not be readily milled. Moreover, the powders thus produced often have poor flow and mixing properties and are difficult to fill into capsules or compress into tablets.

In comparison, solid dispersion formulations prepared from surface-active lipid or lipid-like excipients prevent the formation of a poorly water-soluble drug surface layer on the excipient plug during dissolution. While a portion of the released drug may still precipitate in the dissolution medium once its dissolved concentration exceeds the saturation solubility, it would typically be present in a finely divided state due to the surface active properties of the excipient. The associated high surface area of the finely divided drug substance would facilitate its rapid dissolution in the GI fluid. This is shown schematically in Figure 2 for solid dispersions filled into hard gelatin capsules.

Figure 2 Incorporation of surface active or lipid carriers promotes dissolution of poorly water-soluble drugs administered in solid dispersions by preventing precipitation of a water insoluble, drug-rich layer on the surface of the dissolving formulation plug.

Another major advantage of solid dispersion formulations prepared from lipid or surface active excipients is realized in the relative ease with which they are manufactured. Solid dispersions prepared from these excipients may be directly filled into hard gelatin capsules in the molten state, which subsequently solidify upon cooling to ambient room temperature, thus eliminating the need for grinding, sifting, and mixing. The melting temperature of the molten excipient, however, must not exceed ~70°C, which is the maximum acceptable fill temperature for hard gelatin capsules (13).

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