A New Discriminative Criterion for the Development of Franz Diffusion Tests for Transdermal Pharmaceuticals

Abstract

-PURPOSE.In vitro skin/membrane permeation profiling of topical pharmaceuticals is an important overall quality attribute in the evaluation of product consistency and it is also used for IVIVR (in vitro -in vivo relationship) purposes in product development and change control. Franz diffusion cell (FDC) experiments are emerging as a generally accepted methodology in this field, where the choice of operational conditions requires a data-supported justification towards the discriminating power of the test. A response function is therefore proposed to objectively quantify the discriminating power. METHODS. We evaluated the usefulness of the proposed response function by studying one of the operational conditions, i.e. the influence of receptor medium composition, on the FDC in vitro penetration behaviour of the model compound testosterone formulated in four different topical preparations, using both artificial membranes and dermatomed human skin. A second application is a FDC test system for spilanthol. RESULTS. From the obtained cumulative amount of the active (testosterone or spilanthol) in the receptor fluid versus time curves, the permeability coefficient Kp of testosterone from each formulation was calculated. The evaluation of the discriminating power of the different media was performed using our new objective response function based upon an equal spread criterion of normalised Kp values. CONCLUSION. The proposed new criterion was found to be useful for the rational design of an in vitro diffusion test for transdermal pharmaceuticals. We demonstrated significant differences in discriminating power between the different media used: (a) for testosterone-containing formulations, it was shown that HPBCD-containing media are more discriminative compared to ethanol-or BSA-containing media; (b) for spilanthol-containing formulations, PBS containing formulations also gave better discriminating results than ethanol-based receptor media. __________________________________________________________________________________________

TRANSDERMAL FORMULATIONS CONTAINING HUMAN SEXUAL STEROIDS: DEVELOPMENT AND VALIDATION OF METHODS ANDIN VITRODRUG RELEASE

“…This was performed by plotting three standard curves, each constructed by the five different hormone concentrations of the work solutions (i.e., 14,17,20,23, and 26 µg mL −1 for T in T emuls ; 35, 42.5, 50, 57.5, and 65 µg mL −1 for P in P emuls ; 14, 17, 20, 23, and 26 µg mL −1 for E2 in E emuls , and Biest; 56, 68, 80, 92, and 104 µg mL −1 for E3 in Biest). For this purpose, the data for each concentration range after fitting by the ordinary least-squares method were statistically evaluated; this method accounted for homoscedasticity (Cochran's test), residues' normality (Shapiro-Wilk test), and the lack of fit test (analysis of variance, ANOVA).…”

“…The validated methods were then employed for in vitro drug release tests, where biorelevant media were prepared according to the procedure described by Baert et al 14 To select the most suitable medium for each product/emulsion, the following compositions were used: 0.01 M phosphate buffered saline, pH 7.4 (NaCl-138.0 mM; KCl-2.7 mM; KH 2 PO 4 -1.43 mM; Na 2 HPO 4 -8.57 mM); artificial human sweat (NaCl-49.96 mM; CaCl 2 -0.15 mM; MgSO 4 -1.0 mM; KH 2 PO 4 -7.5 mM); simulated body fluid (NaCl-136.8 mM; KCl-3.0 mM; CaCl 2 -2.5 mM; MgCl 2 -1.5 mM; Na 2 SO 4 -0.5 mM; NaHCO 3 -4.2 mM; KH 2 PO 4 -1.0 mM). The solubility of these compositions was also determined with additional measurements using bovine serum albumin (BSA) or hydroxypropyl-β-cyclodextrin (HPBCD) as the medium, resulting in a total of nine different media samples.…”

“…However, in practice, their use was not feasible as they were not biocompatible with the receptor medium for establishing an in vitro-in vivo relationship. 14 As a concentration of 50 g L −1 is quite often accepted as the mean albumin concentrations in human serum, 19 5% of BSA was added in all biorelevant media. As an alternative, 0.5% of HPBCD was also added.…”

GREEN TEA IN TRANSDERMAL FORMULATION: HPLC METHOD FOR QUALITY CONTROL ANDIN VITRODRUG RELEASE ASSAYS

“…The preparation of the receptor media were according to Baert et al (2010) 17 and the exact compositions of the same (aqueous solutions) are described in Table 1.…”

“…In order to develop a new formulation, it is necessary to assess the quality of the bio-active molecules. Among the specific tests conducted for the quality assessment of transdermal emulsions, 17 the in vitro drug release carried out in Franz-type diffusion cell is widely used. Such a test can estimate the release of drugs from semisolid systems into synthetic skin and predict the percutaneous systemic absorption of topically applied active compounds.…”