ABSTRACT
The feasibility of incorporating significant quantities of the anionic surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet formulation of a poorly water-soluble immunosuppressive agent was investigated. Despite the extremely poor compressibility of SDS and poor chemical stability of the drug, a commercializable, direct-compression tablet formulation with satisfactory mechanical properties and acceptable chemical stability was achieved. Optimal in vitro release of the drug from the tablet formulation was achieved by establishing the minimum molar uptake ratio necessary to achieve complete micellar solubilization of the drug, after which formulation studies were conducted to determine the influence of formulation and process variables on the rate and extent of drug release. A model-independent analysis of dissolution results in a reduced volume (250 ml) of modified simulated gastric fluid demonstrated that the rate and extent of drug release was highly dependent on the mean particle size of the bulk drug, but independent of compression force above that required to achieve a compact of acceptable mechanical strength. Employing the Korsmeyer-Peppas model of Fickian and non-Fickian drug release, it was further shown that release of the drug from the dosage form was governed largely by surface erosion of the surfactant-enriched tablet matrix.
Subject(s)
Imidazoles/administration & dosage , Immunosuppressive Agents/administration & dosage , Sodium Dodecyl Sulfate/administration & dosage , Surface-Active Agents/administration & dosage , Tacrolimus/analogs & derivatives , Administration, Oral , Chemistry, Pharmaceutical , Drug Delivery Systems , Imidazoles/chemistry , Particle Size , Solubility , Tablets , Tacrolimus/administration & dosage , Tacrolimus/chemistryABSTRACT
The isocratic, reversed-phase, high-performance liquid chromatographic (HPLC) method presented provides a simple and rapid analytical technique for the simultaneous determination of low-molecular-mass oligomers of polyethylene glycol (PEG) in aqueous polymer samples containing polar contaminants of biologic origin. In the present case, individual molecular mass species were quantitated in aqueous skin extracts arising from the investigation of PEG transport through mammalian skin. PEGs were isolated and purified by solid-phase extraction using large-pore kieselguhr (Extrelut QE) cartridges, which selectively retained polar contaminants from excised skin specimens. Sample recoveries were found to be dependent upon molecular mass, ranging from 18.28% to 86.10%, but were highly reproducible. The mean inter-sample error (n > or = 5) for the extraction of twenty-six molecular mass species of PEG was less than 3%. Satisfactory resolution of primary molecular mass components was accomplished using a base-deactivated, C8 column (Supelcosil LC-8-DB) and a mobile phase consisting of methanol and water. Corresponding run times for the complete separation of individual oligomers ranged from 8 to 30 min, while the limit of detection for a particular molecular mass species was approximately 5 micrograms/ml. The method was further employed to determine the weight-average (Mw) and number-average (Mn) molecular mass distributions and polydispersity for three commercial PEG blends, as well as to characterize the methylene chloride/water distribution coefficients for twenty-two molecular mass species ranging from 282 to 1206 Da.
Subject(s)
Chromatography, High Pressure Liquid/methods , Polyethylene Glycols/analysis , Skin/chemistry , Animals , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid/statistics & numerical data , Macromolecular Substances , Methylene Chloride , Molecular Weight , Polyethylene Glycols/chemistry , Polymers , Quality Control , Rats , Sensitivity and Specificity , WaterABSTRACT
The influence of frozen storage of hairless rat skin on the constant-current iontophoretic transport of a model weak acid, salicylic acid, was examined. Nearly a threefold increase was observed in the steady-state flux of salicylic acid through previously frozen skin (217.1 nmol h-1 cm-2) when compared with fresh, excised skin (72.3 nmol h-1 cm-2). The iontophoretic permeability of skin to salicylic acid was also found to be dependent upon the length of time skin samples remained in the frozen state. Differential scanning calorimetry studies revealed distinct differences in the thermograms for fresh and frozen skin. These results suggest that storage of skin samples in the frozen state may contribute to physical or chemical changes in skin structure.
Subject(s)
Freezing , Skin/metabolism , Animals , Calorimetry, Differential Scanning , Chromatography, High Pressure Liquid , In Vitro Techniques , Iontophoresis , Male , Rats , Salicylates/pharmacokinetics , Salicylic Acid , Skin Absorption , TemperatureABSTRACT
The electrically-assisted transport of a homologous series of polyethylene glycols (PEGs) through hairless rat skin (HRS) was examined in order to determine the relationship between the iontophoretic permeability of flexible macromolecules and their size and conformation in free solution. Using fully hydrated HRS, the anodic transport of 26 low molecular weight oligomers of PEG was studied over a 14 hour period at a current density of 0.50 mA/cm2. Analysis of the data revealed a distinct sigmoidal relationship between iontophoretic permeability and molecular size. In addition, the reflection of a relatively small molecular weight species was significant. Accordingly, a hydrodynamic model relating the convective transport of flexible macrosolutes through cylindrical pores was fit to the data generated from the iontophoretic transport of PEGs ranging in weight from 282 to 1382 daltons. A nonlinear least squares analysis of the data demonstrated that the 'effective' mean diameter of aqueous channels within HRS is approximately 36 A.
