Jonas C. T. Wang

Assessment of Value and Applications of In Vitro Testing of Topical Dermatological Drug Products

The FDA recently issued a guidance covering practices of scaleup and post approval changes with semisolids (SUPAC-SS). This guidance outlines the steps that must be taken by a company to maintain certification of its semisolid dermatological products after quantitative changes have been made in their compositions and/or after changes have been made in the sourcing of their key ingredients, in their processing, in their batch sizes, and/or after their site of manufacture has been relocated. A key element within the guidance is a release test to be used to determine if the diffusional release of a drug found in a formulation is the same after changes have been made to the formulation as it was prior to implementing the changes. The AAPS-FDA sponsored workshop was set up to explore this qualifying test. The stated aims of the workshop were: a) to illustrate the methodology and techniques of in vitro release testing, b) to show the sensitivity of in vitro release with respect to manufacturing variables and to variations in components and composition (of specific formulations), c) to recognize in vitro release testing as a useful procedure for SUPAC documentation, d) to highlight and evaluate other applications of in vitro release testing, e) to explore the degree to which in vitro release testing and bioavailability may be related, and f) to evaluate the role of in vitro release testing of topical dosage forms as a tool to improve product quality.

In Vitro Skin Permeation and Bioassay of Chlorhexidine Phosphanilate, a New Antimicrobial Agent

An in vitro technique was developed to study the permeation and antimicrobial activity of graded concentrations of a new antibacterial agent, chlorhexidine phosphanilate (CHP), in cream formulations using Franz diffusion cells. Formulations containing from 0.2 to 2% CHP were quantitatively applied to intact excised skin and to skin from which the stratum corneum and partial epidermis had been enzymatically removed. Receptor fluids from diffusion cells were sampled over time and assayed by HPLC methods for chlorhexidine and phosphanilic acid; 24- and 48-hr samples of the diffusate from studies with damaged skin were also bioassayed using clinical isolates of appropriate microbial species. Through intact skin almost no permeation of CHP was observed over 48 hr. The failure of CHP to penetrate intact human skin suggests that normal stratum corneum is the rate-limiting barrier to penetration by this antimicrobial agent. In damaged skin lacking stratum corneum barrier, the release of CHP from the formulation becomes the rate-determining step. Coincident with penetrating damaged skin, CHP dissociates, and the molar ratio of the chlorhexidine and phosphanilate moieties in the diffusate changes to favor phosphanilic acid. The extent of changes in the permeation rates of both moieties of CHP was directly related to the CHP concentration in cream. Both CHP moieties were found to reach equilibrium in the dermis within 24 hr after application. It was also observed that CHP creams down to 0.2% concentration yielded diffusates with activity exceeding the minimum inhibitory concentration of all test microorganisms within 24 hr.

Topical Delivery of l-Ofloxacin: Characterization of Relevant Physicochemical Properties and Evaluation of a Polymeric Delivery System

AbstractThe distribution coefficient of ofloxacin was determined between octanol and universal buffer in the pH range 3 to 10 at a constant ionic strength of 0.30. The in vitro skin permeability was studied in buffer systems ranging from pH 3 to 10 using side-by-side diffusion cells. A series of 0.05% w/w ofloxacin gels were formulated between pH 3 and 8 in a polymeric base, and their swelling and release kinetics were studied using synthetic membranes. The antimicrobial activity of ofloxacin gel formulated at pH 4 was measured in second-degree burn wounds on intact pigs. The octanol/buffer distribution coefficient was directly related to the percentage of zwitterion in the solution with a peak value at about the isoelectric point (6.70). Permeability coefficient increased with pH, with a steep rise above pH 8.00. The amount of drug in the skin also increased with pH. In the gel delivery system, the release rate of ofloxacin from various pH formulations was ranked as pH 4 > pH 3 > pH 5 > pH 6 > pH 7 > pH ...