Surfactants lipid formulations

Solubility enhancement systems lipid-based systems, nanoparticles, surfactants, semisolid formulations... 

Drug A is a large, peptide-like molecule (MW 700 g/mol) and is highly lipophilic and poorly water soluble. It is a BCS Class II drugs. Its oral bioavailability in capsules and conventional tablet formulations is low, yielding practically undetected blood levels. A novel lipid formulation containing a solvent, a high HLB nonionic surfactant, and a fatty acid were developed with sufLcient oral bioavailability for use in the clinic. 

Sek, L., et al., Examination of the impact of a range of pluronic surfactants nmvtfo solubilization behavior and oral bioavailability of lipidic formulations of atovaquodepharm. Pharmacql 58,... 

Microemulsions are defined as isotropic, transparent, and thermodynamically stable (in contrast to conventional emulsions) mixtures of a hydrophobic phase (lipid), a hydrophilic phase (often water), a surfactant, and in many cases a co-surfactant. From a lipid formulation perspective, microemulsions are generally regarded as the ultimate extension of the decreased particle size/increased surface area mantra, because emulsion particle sizes are usually less than 50 nm. Microemulsions also have additional pharmaceutical advantages in terms of their solubilizing capacity [54, 55], thermodynamic stability, and capacity for stable, infinite dilution. 

Researchers at Tienzyme, Inc. (B.W. Bogan, principal investigator) in State College, Pennsylvania, are investigating the use of surfactant- or surfactant/lipid-based formulations to enhance the removal of HMW PAHs from creosote- and tar-contaminated soils by bioremediation involving white-rot fungi. 

Note Produced with Dynasan 114 as matrix lipid and poloxamer 407 and sodium cholate as surfactants. The formulations were produced in three sizes (small, medium, large) to assess the influence of the size on the degradation of the nanoparticles. Both 5% lipid and 0.5% surfactant were used. 

Nanosuspensions consist of the pure poorly water-soluble drug without any matrix material suspended in dispersion. It is sub-micron colloidal dispersion of pure particles of drug stabilized by surfactants. By formulating nanosuspensions, problems associated with the delivery of poorly water-soluble drugs and poorly water-soluble and lipid-soluble drugs can be solved. Nanosuspensions differ from nanoparticles, " which are polymeric colloidal carriers of drugs (nanospheres and nanocapsules), and from solid-lipid nanoparticles, which are lipidic carriers of drug. 

The procedure chosen for the preparation of lipid complexes of AmB was nanoprecipitation. This procedure has been developed in our laboratory for a number of years and can be applied to the formulation of a number of different colloidal systems liposomes, microemulsions, polymeric nanoparticles (nanospheres and nanocapsules), complexes, and pure drug particles (14-16). Briefly, the substances of interest are dissolved in a solvent A and this solution is poured into a nonsolvent B of the substance that is miscible with the solvent A. As the solvent diffuses, the dissolved material is stranded as small particles, typically 100 to 400 nm in diameter. The solvent is usually an alcohol, acetone, or tetrahydrofuran and the nonsolvent A is usually water or aqueous buffer, with or without a hydrophilic surfactant to improve colloid stability after formation. Solvent A can be removed by evaporation under vacuum, which can also be used to concentrate the suspension. The concentration of the substance of interest in the organic solvent and the proportions of the two solvents are the main parameters influencing the final size of the particles. For liposomes, this method is similar to the ethanol injection technique proposed by Batzii and Korn in 1973 (17), which is however limited to 40 mM of lipids in ethanol and 10% of ethanol in final aqueous suspension. 

Selective detectors tend to be employed where the analyte is present in small amounts in a complex matrix such as in bioanalytical procedures where components extracted from the biological matrix along with the analyte can cause interference. Some formulated compounds have only very poor chromophores - these include sugars, lipids, surfactants, amino acids and some classes of drugs, e.g. a number of anticholinergic drugs lack chromophores. In these cases an alternative to UV detection has to be employed. 

Another approach in using a lipid-based formulation is to micronize the lipid with the dissolved drug to create a microemulsification. This allows an increased surface area available for the dissolution of the drug from the lipid phase. In these mixtures, a surfactant is usually added to improve the ability of oil to accommodate a hydrophobic drug in solution, and the resulting liquid is almost clear. Also a surfactant can function in the GI tract to help disperse the liquid vehicle on dilution. This allows the drug (dissolved in oil droplets/surfactant) to spread readily along the GI tract. 

Cuine, J. F., W N. Charman, C. W Pouton, G. A. Edwards, andC. J. H. Porter(2007). Increasingthe proportional content of surfactant (Cremophor EL) relative to lipid in self-emulsifying lipid-based formulations of Danazol reduces oral bioavailability in beagle ddgj3arm. Res., 24 748-757. 

More importantly, lipid peroxidation can be controlled or minimized by design of formulation. While saturated lipids (e.g., MCTs) will themselves not be susceptible to peroxidation, they may contain sufLcient unsaturated impuritiesto be problematic. Similarly, monounsaturated lipids (e.g., oleic acid glycerides) are much less susceptible to peroxidation. The relative rates of peroxidation of oleic, linoleic, and linolenic acids are 6 64 100, respectively (Swern, 1995). Monounsaturated lipids may, however, may contain polyunsaturated impurities, which will catalyze the oxidation ofthe monounsaturated components (Swern, 1995). Surfactants, particularly those based on PEG, may contain peroxides that can promote lipid peroxidation thus, particular attention should be paid to the purity and source of all formulation components. 

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