Development of lipid-based SEDDS using digestion products of long-chain triglyceride for high drug solubility: Formulation and dispersion testing.

A self-emulsifying drug delivery system (SEDDS) containing long chain lipid digestion products (LDP) and surfactants was developed to increase solubility of two model weakly basic drugs, cinnarizine and ritonavir, in the formulation. A 1:1.2 w/w mixture of glyceryl monooleate (Capmul GMO-50; Abitec) and oleic acid was used as the digestion product, and a 1:1 w/w mixture of Tween 80 and Cremophor EL was the surfactant used. The ratio between LDP and surfactant was 1:1 w/w. Since the commercially available Capmul GMO-50 is not pure monoglyceride and contained di-and-triglycerides, the digestion product used would provide 1:2 stoichiometric molar ratio of monoglyceride and fatty acid after complete digestion in gastrointestinal fluid. Both cinnarizine and ritonavir had much higher solubility in oleic acid (536 and 72 mg/g, respectively) than that in glyceryl monooleate and glyceryl trioleate. Therefore, by incorporating oleic acid in place of glyceryl trioleate in the formulation, the solubility of cinnarizine and ritonavir could be increased by 5-fold and 3.5-fold, respectively, as compared to a formulation without the fatty acid. The formulation dispersed readily in aqueous media, and adding 3 mM sodium taurocholate, which is generally present in GI fluid, remarkably improved the dispersibility of SEDDS and reduced particle size of dispersions. Thus, the use of digestion products of long-chain triglycerides as components of SEDDS can enhance the drug loading of weakly basic compounds and increase dispersibility in GI fluids.

Evaluation of Cytotoxicity of Self-Emulsifying Formulations Containing Long-Chain Lipids Using Caco-2 Cell Model: Superior Safety Profile Compared to Medium-Chain Lipids.

Medium-chain (MC) and long-chain (LC) lipids are used for development of self-emulsifying drug delivery systems (SEDDS). MC lipids are often preferred because of their ability to form stable microemulsions with relatively high drug solubilization capacity. On the other hand, LC lipids could be more biocompatible as most endogenous and dietary lipids are LC glycerides. They also maintain high drug solubilization capacity after digestion. The present study was undertaken to determine the cytotoxicity of LC lipids and their formulations on Caco-2 cells of 1-day, 5-day, and 21-day maturity. The results were compared with the cytotoxicity profiles of MC lipids reported previously from our laboratory. The cell viability and cell membrane integrity were, respectively, determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the lactate dehydrogenase assay. The cytotoxicity was partially due to lipid surfactant-induced membrane rupture, and it was influenced by cell maturity and formulation composition. The lipid-surfactant combinations showed greater tolerance than surfactants alone, and LC-SEDDS were well-tolerated at almost 10-fold higher concentration than corresponding MC-SEDDS. Furthermore, the cytotoxicity of digestion end products of both LC and MC triglycerides in the presence of 3 mM sodium taurocholate was compared on 21-day Caco-2 cultures by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The LC lipid formulations showed better tolerance than MC lipid formulations after digestion. Thus, although MC and LC lipids are well-tolerated at doses normally administered to humans, LC lipids show much better safety than MC lipids in a cell-culture model.

Development of Solid Dispersion by Hot Melt Extrusion Using Mixtures of Polyoxylglycerides With Polymers as Carriers for Increasing Dissolution Rate of a Poorly Soluble Drug Model.

Various polyoxylglycerides have been researched extensively in the development of solid dispersions (SDs) for bioavailability enhancement of poorly water-soluble drugs. However, because of their low melting points (40°C-60°C), SDs produced are usually soft and semisolid. The objective of present study was to prepare SDs of a Biopharmaceutical Classification System class II drug, carvedilol, in mixtures of stearoyl polyoxylglycerides (Acconon® C-50; m.p. ∼50°C) with polymers by hot melt extrusion to obtain free-flowing powder upon grinding. Miscibility of carvedilol with Kollidon® VA64, hydroxypropyl methylcellulose acetate succinate, and Klucel™ EXF was first evaluated by film casting, and Kollidon® VA64 was selected for further study. SDs containing 5%-20% carvedilol, 0%-20% Acconon® C-50, and the remaining Kollidon® VA64 were prepared for hot melt extrusion. SDs were characterized by differential scanning calorimetry and powder X-ray diffraction analysis, and dissolution tests were conducted in 250 mL of pH 6.8 phosphate buffer by filling powders in capsules. Carvedilol was miscible with all polymers tested up to 50% and remained amorphous in SDs. The drug release from formulations containing 20% carvedilol and 0, 5%, 10%, and 20% Acconon® C-50 were 30%, 30%, 70%, and 90%, respectively, in 60 min. SDs containing carvedilol and Acconon® C-50, up to 20% each, as well as Kollidon® VA64, were physically stable after 3 months of storage at 25°C/60% relative humidity.

Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals.

The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q10, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q10, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87 mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250 mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200 nm. From all formulations, except that of vitamin K2, >80-90% nutraceuticals dispersed in 5-10 min and there was no precipitation of compounds during the test period of 120 min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion.