Co-solubilization of poorly soluble drugs by micellization and complexation.

The use of combined approach of surfactants and cyclodextrins in solubilization of poorly soluble drugs has been described in literature. In this report, a mathematical model has been developed to provide the quantitative basis for this approach. First, by way of hypothetical examples and simulations, the influence of various interaction parameters on the phase solubility profile is presented. Additionally, the model results are compared with (a) results reported by Yang et al., with NSC-639829, sodium lauryl sulfate (SLS) and sulfobutyl-ether-beta-cyclodextrin ((SBE)(7M)-beta-CD) and (b) solubility of methylprednisolone, a model poorly soluble drug, in the presence of its water-soluble 'surfactant-like' prodrug, methylprednisolone 21-hemisuccinate, and (SBE)(7M)-beta-CD. The model shows good agreement with experimental data. Furthermore, theoretical simulations show that the combined solubility is less than the sum of the individual solubility values in cyclodextrins and surfactants. Based on the hypothetical case and the two examples, the factors affecting the phase solubility profile in mixed solutions of surfactants and cyclodextrins are presented. Finally, the limitations of the model to explain co-solubilization by surfactants and cyclodextrins are discussed.

Comparison of oil-in-water emulsions manufactured by microfluidization and homogenization.

The purpose of this study was to compare drug-free model submicron oil-in-water (o/w) emulsions manufactured by high-speed homogenization and microfluidization. The study was aimed at evaluating the influence of these two manufacturing processes on the stability of the emulsions with respect to emulsifier concentration. Stability was defined in terms of dispersed droplet diameter growth over time. The study was also directed towards identifying the minimum emulsifier concentrations required by either processing method within the same model o/w systems to produce emulsions viable throughout the study period of three months. The Microfluidizer 110L was found to be more effective than the homogenizer in producing stable o/w submicron emulsions using triglycerides of caprylic/capric acid as the oil phase and combinations of emulsifiers (polyoxyethylene sorbitan oleate with high HLB and sorbitan monooleate with low HLB) at low emulsifier concentrations. Submicron emulsions prepared by the microfluidization process had smaller droplet diameters and exhibited less droplet diameter growth over time compared to high-speed homogenization. At emulsifier concentrations below 20% w/w, the droplet diameter or stability of the dispersed phase of the sub-micron emulsions prepared by either process was found to be dependent on the emulsifier content.

Formulation approaches for orally administered poorly soluble drugs.

Despite having pharmacodynamic or target activity, many drugs fail in the drug development process due to poor bioavailability, and presently marketed conventional dosage forms of poorly soluble drugs employ high doses leading to potential toxicity. The introduction of the Biopharmaceutic Classification System (BCS) has provided a basis to categorize drugs based on the two major parameters affecting absorption, solubility and permeability. Several techniques can be employed to enhance the absorption and bioavailability of poorly soluble and poorly permeable drugs based on the BCS concept. This article is an attempt to summarize the development of various formulation approaches that are currently employed to enhance bioavailability of orally administered poorly soluble drugs.

Stearoyl CoA desaturase 1 is elevated in obesity but protects against fatty acid-induced skeletal muscle insulin resistance in vitro.

AIMS/HYPOTHESIS: Stearoyl CoA desaturase 1 (SCD1) is implicated in mediating obesity and insulin resistance. Paradoxically, SCD1 converts saturated fatty acids, the lipid species implicated in mediating insulin resistance, to monounsaturated fatty acids. The aim of the present study was to assess the molecular mechanisms that implicate SCD1 in the aetiology of fatty acid-induced insulin resistance. METHODS: SCD1 protein was transiently decreased or increased in rat L6 skeletal muscle myotubes using SCD1 short interfering RNA (siRNA) or liposome-mediated transfection of pcDNA3.1/Hygro-mSCD1, respectively. RESULTS: Reducing SCD1 protein resulted in marked esterification of exogenous fatty acids into diacylglycerol (DAG) and ceramide. Insulin-stimulated Akt activity and phosphorylation and 2-deoxyglucose uptake were reduced with SCD1 siRNA. Exposure of L6 myotubes to palmitate abolished insulin-stimulated glucose uptake in both control and SCD1 siRNA myotubes. Overexpression of SCD1 resulted in triacylglycerol esterification but attenuated ceramide and DAG accumulation and protected myotubes from fatty acid-induced insulin resistance. CONCLUSIONS/INTERPRETATION: SCD1 protects from cellular toxicity in L6 myotubes by preventing excessive accumulation of bioactive lipid metabolites.