In vivo assessment of enhanced topical delivery of terbinafine to human stratum corneum.

PURPOSE: The objective of this study was to evaluate, using attenuated total reflectance Fourier transform infrared spectroscopy, the stratum corneum (SC) bioavailability of terbinafine (TBF) following topical treatment with four different formulations. METHODS: Four skin sites on the ventral forearms of five healthy volunteers were treated for 2 h using one of four formulations based on a vehicle consisting of 50% ethanol and 50% isopropyl myristate. Three of these formulations included a percutaneous penetration enhancer: either 5% oleic acid, 10% 2-pyrrolidone or 1% urea. The SC concentration profile of TBF was measured by repeated infrared spectroscopic measurements while sequentially stripping off the layers of this barrier membrane with adhesive tape. This method was validated by HPLC analysis of TBF extracted from the stripped tapes. Transepidermal water loss (TEWL) measurements were also performed, to permit facile estimation of SC thickness. RESULTS: The SC concentration profiles of TBF were fitted to the appropriate solution of Fick's second law of diffusion, thereby allowing determination of the characteristic diffusion and partitioning parameters of the permeating drug. This analysis enabled the efficacies of the different formulations tested to be compared to the no-enhancer control. While it was found that the formulation containing 5% oleic acid significantly enhanced the SC availability of TBF, the other formulations did not improve the apparent drug delivery. CONCLUSIONS: A facile and minimally invasive methodology to evaluate an important aspect of topical drug bioavailability has been described. The analytical methods used (infrared spectroscopy and HPLC) allow estimates of both relative and absolute drug bioavailability in the SC and may be useful, therefore, in the critical determination of bioequivalence between topical formulations.

Poly(ethylene carbonate) microspheres: manufacturing process and internal structure characterization.

The granulocyte-macrophage colony stimulating factor (GM-CSF), a water-soluble cytokine, was encapsulated in poly(ethylene carbonate) microspheres (MS) by a double emulsion w(1)/o/w(2) solvent evaporation method. Poly(ethylene carbonate) is a new polymer of high molecular weight (MW) and forms polymer matrices that are exclusively surface bioerodible. In the frame of this study, the influence of the polymer molecular weight and the polymer concentration in the organic phase on the physico-chemical characteristics of the microspheres were investigated. Ninety percent of the microspheres had a diameter ranging between 4 and 136 microm, with a mean value of 30 microm. The encapsulation ratios ranged from 2.22 to 2.51% (w/w) depending on the molecular weight of the polymer corresponding to an encapsulation efficiency of 70 to 100%, respectively. Independent of the polymer molecular weight used, the in vitro drug release was very low, ranging from 5.61 to less than 1% of the total encapsulated GM-CSF amount. Scanning electron microscopy (SEM) analysis showed microparticles with spherical shapes and smooth surfaces containing a few small globules. The inner structure of the microspheres appeared to consist of a polymeric matrix surrounding numerous globules. These globules have different sizes, shape and distribution in the polymeric matrix, depending on the concentration of the polymer solution and on the polymer molecular weight. In addition, it was demonstrated that the GM-CSF lowered the interfacial tension between the GM-CSF aqueous solution and the methylene chloride organic phase. The active critical concentration was as low as 0.008 mg/ml. It was therefore suggested that this particular behavior contributed to the stabilization of the primary emulsion during the formation of the microspheres, leading to rather high encapsulation efficiency.

Use of in vitro release tests for the prediction of the in vivo behavior and the development of flucytosine controlled-release capsules.

The antifungal substance flucytosine (5-fluorocytosine) was chosen as a model drug for studying the development of a controlled-release capsule dosage form based mainly on in vitro drug release tests. A solution and various capsule formulations of flucytosine were orally administered to beagle dogs, and the resulting plasma concentration-time profiles were determined. Special attention was directed to multiple-unit hard-gelatin capsules that exhibited a controlled-release effect in vitro, but not in vivo. The respective plasma profile was treated by the technique of numerical deconvolution to obtain the corresponding in vivo release profile (i.e., the drug release from the dosage form in the gastrointestinal tract of the dog). The influence of different experimental conditions of the USP paddle method on the release profile was investigated. By adding surfactant to the dissolution medium and omission of the sinker device, which is used to prevent the capsule from floating, the in vitro release rate markedly increased and correlated well with the in vivo release. Based on this adjusted in vitro test, the formulation was modified to achieve a more pronounced controlled-release effect. The plasma profile resulting from the reformulated multiple-unit capsules was in good agreement with the predictions made by numerical convolution of the in vitro release profile.

Matrix type controlled release systems: I. Effect of percolation on drug dissolution kinetics.

Matrix type controlled release tablets were prepared by compression of binary mixtures of a soluble brittle model drug (caffeine) and a plastic matrix substance (ethyl cellulose). The drug content of the tablets was varied from 10% to 100% (weight/weight) and the drug dissolution from one flat side of the tablets was studied. By means of percolation theory the release kinetics could be explained over the whole range of drug loadings. For low drug concentrations up to the lower percolation threshold the release was incomplete because most of the drug was encapsulated by the matrix substance. For drug loadings between the lower and the upper percolation threshold the release was matrix-controlled. For high drug loadings a change to zero order dissolution kinetics was observed. Close to the percolation threshold the diffusion coefficient obeys a scaling law, from which a simple equation to estimate the value of the lower percolation threshold was derived and applied to the measured dissolution data. The critical porosity (lower percolation threshold) was found to be 0.35, corresponding to a drug content of about 28% (weight/weight).