In Vitro Release Testing (IVRT) of Topical Hydrocortisone Acetate Creams: A Novel Approach Using Positive and Negative Controls

Abstract

The objective was to develop and validate an in vitro release testing (IVRT) method to assess the release of hydrocortisone acetate (HCA) from five topical formulations. A marketed generic cream containing 1% HCA was used as the reference product. Vertical diffusion cells (VDCs) were used to assess and compare the release rates of HCA from cream formulations containing 0.5%, 1%, and 1.5% HCA. The study describes a novel approach to test the discriminatory power by including both positive and negative controls to declare pharmaceutical equivalence or inequivalence. The validated method was found to be sensitive, linear, precise, reproducible, robust, and selective for the analysis of HCA from topical cream products. Equivalence or inequivalence was established based on SUPAC-SS acceptance criteria using a 90% CI with limits of 75–133.33%. The IVRT method was shown to have discriminatory ability to appropriately measure significant differences in drug release from various cream formulations. This approach also provides useful information for the future development of acceptable IVRT methods to assess topical dosage forms for local action containing different drugs. INTRODUCTION Since an in vitro release rate can reflect numerous and combined effects of several physical and chemical parameters, including solubility, particle size of the active pharmaceutical ingredient (API) and rheological properties of the dosage form, in vitro release testing (IVRT) has been recommended by the United States Food and Drug Administration (US FDA) as a test to assess pharmaceutical equivalence/inequivalence between preand post-approval product changes (1, 2). The utility of IVRT was extended in 2012 when the US FDA published a draft guidance for assessing bioequivalence (BE) of acyclovir topical ointment, which was the first such publication recommending IVRT for use as a waiver of BE studies for a locally acting topical product (3). This particular guidance provided useful and promising information for the future application of IVRT as a method for assessment of the sameness of topical formulations intended for local action. Subsequently, the US FDA has published several draft guidances using in vitro methods for biowaivers for topical products (3– 8). In addition, a recent draft guideline published by the European Medicines Agency (EMA) also makes provision to use IVRT for the approval of generic products (9). However, a comprehensive validation of the IVRT method is imperative to ensure that the resulting method has the requisite attributes of sensitivity, precision, selectivity, and reproducibility necessary to detect differences relating to qualitative (Q1) and quantitative (Q2) properties and the microstructure and arrangement of matter (Q3) between products (10, 11). In light of the above, an IVRT method was developed and validated to assess creams containing 1% hydrocortisone acetate (HCA). Two marketed products containing 1% HCA and three additional creams specifically manufactured to contain 0.5%, 1%, and 1.5% HCA were studied. A positive control was included to ensure that the method had the necessary capability to confirm sameness, and negative controls ensured the method had the requisite discriminatory power to detect significant differences. MATERIALS AND METHODS Chemicals and Formulations Hydrocortisone acetate (HCA) was obtained from SigmaAldrich (St. Louis, MO, USA). High-performance liquid chromatography (HPLC) grade acetonitrile was obtained from Romil Ltd (200 UV ROMIL-SpS Super Purity Solvent, Waterbeach, Cambridge, UK) and ethanol (95%) was purchased from Merck Laboratories (Wadeville, Gauteng, South Africa). The water used for chromatography was dx.doi.org/10.14227/DT270120P6 e-mail: I.Kanfer@ru.ac.za * Corresponding author.