Mechanisms of chemical and physical transdermal penetration enhancement

The underlying theme of this thesis is one of exploring the processes involved in the enhancement of percutaneous absorption. The development of an attenuated total reflectance Fourier-Transform infrared (ATR-FTIR) spectroscopic method to analyse diffusion of suitable topically applied compounds in membrane is described. Diffusion coefficients (D/h2) and membrane solubility (AO) for topically applied compounds were determined using a solution to Fick's second law of diffusion. This method was employed to determine the diffusional characteristics of a model permeant, 4-cyanophenol (CP), across silicone membrane as a function of formulation applied and permeant physicochemical properties. The formulations applied were able to either affect CP diffusivity and/or its membrane solubility in the membrane; such parameters partially correlated with permeant physicochemical properties in each formulation. The interplay during the diffusion process between drug, enhancer and vehicle in stratum corneum (SC) was examined. When enhancers were added to the applied formulations, CP diffusivity and solubility were significantly enhanced when compared to the neat propylene glycol (PG) application. Enhancers did not affect PG diffusivity in SC but enhancers did affect PG solubility in SC. PG diffusion closely resembled that of CP, implying that the respective transport processes were inter-related. Additionally, a synergistic effect, which increases CP diffusivity and membrane solubility in SC, was found to occur between PG and water. Using 12-azidooleic acid (AOA) as an IR active probe for oleic acid, the simultaneous penetration of CP, AOA and PG into human stratum corneum was determined. It was found that the diffusion profiles for all three permeants were similar. This indicated that the diffusion of each species through SC was closely related and most likely occurred via the same route or SC microenvironment.

Development and formulation of wax-based transdermal drug delivery systems

Topical and transdermal formulations are promising platforms for the delivery of drugs. A unit dose topical or transdermal drug delivery system that optimises the solubility of drugs within the vehicle provides a novel dosage form for efficacious delivery that also offers a simple manufacture technique is desirable. This study used Witepsol® H15 wax as a abase for the delivery system. One aspect of this project involved determination of the solubility of ibuprofen, flurbiprofen and naproxen in the was using microscopy, Higuchi release kinetics, HyperDSC and mathematical modelling techniques. Correlations between the results obtained via these techniques were noted with additional merits such as provision of valuable information on drug release kinetics and possible interactions between the drug and excipients. A second aspect of this project involved the incorporation of additional excipients: Tween 20 (T), Carbopol®971 (C) and menthol (M) to the wax formulation. On in vitro permeation through porcine skin, the preferred formulations were: ibuprofen (5% w/w) within Witepsol®H15 + 1% w/w T; flurbiprofen (10% w/w) within Witepsol®H15 + 1% w/w T; naproxen (5% w/w) within Witepsol®H15 + 1% w/w T + 1% C and sodium diclofenac (10% w/w) within Witepsol®H15 + 1% w/w T + 1% w/w T + 1% w/w C + 5% w/w M. Unit dose transdermal tablets containing ibuprofen and diclofenac were produced with improved flux compared to marketed products; Voltarol Emugel® demonstrated flux of 1.68x10-3 cm/h compared to 123 x 10-3 cm/h for the optimised product as detailed above; Ibugel Forte® demonstrated a permeation coefficient value of 7.65 x 10-3 cm/h compared to 8.69 x 10-3 cm/h for the optimised product as described above.

An in-vitro-in-vivo model for the transdermal delivery of cholecalciferol for the purposes of rodent management

The natural selection of anticoagulant resistant rats has resulted in a need for an alternative to anticoagulant rodenticides which differs in both active ingredient and in the method of dosing. Cholecalciferol toxicity to rodents using the dermal route is demonstrated using a variety of penetration enhancing formulations in two in-vitro models and finally in-vivo. A 1 ml dose of 50/50 (v/v) DMSO/ethanol containing 15% (v/v) PEG 200 and 20% (w/v) cholecalciferol was judged as 'sufficiently effective' in line with the European Union's Biocidal Products Regulation (No. 528/2012) during in-vivo studies. This dose was found to cause 100% mortality in a rat population in 64.4 h (±22 h).