Purpose: Newly synthesized amphetamine analogues, which can selectively stimulate the release of dopamine and norepinephrine, have been explored for the treatment of attention deficit hyperactivity disorder, cocaine dependence and weight loss. However, such psychostimulants pose a high potential of misuse and abuse. Being tamper resistant, transdermal delivery of these agents via patches may prove beneficial. The aim of this study was to develop a transdermal patch for a liquid, volatile, amphetamine-like monoamine releaser, 3-fluoroamphetamine (3-FA), which also possesses physiochemical properties in favor of transdermal delivery.
Methods: The solubility of 3-FA in pressure sensitive adhesives, acrylate (DURO-TAK 9301 and 900A), polyisobutylene (PIB, DURO-TAK 6908), and silicone (BIO-PSA 7-4301) polymers, was tested.
Drug-in-adhesive transdermal patches were prepared by solvent casting method. Patches prepared using PIB and silicone adhesives contained 3-FA dispersed in each adhesive matrix by a pulsed shaking method, employing a bead ruptor, operated at 5 m/s with 6 cycles (10s shaking followed by 10s dwell time). The solvent in the casted film was allowed to evaporate by first air-drying at room temperature and then oven drying at higher temperature. The coat weight and drug content of the resultant patches were determined and stored in nitrogen-filled pouches for stability evaluation in terms of drug content, and globules distribution, if applicable, for two months. Stable patches were evaluated for their tack, peel and shear properties. In addition, placebo patches, with and without homogenization using bead ruptor, were prepared and analyzed to see the effect of homogenization on adhesive properties of the patch. Tack test was performed on a texture analyzer equipped with a 7 mm-diameter probe, with target force set at 250 and 500 g for acrylate and PIB patches, respectively, and hold time set for 10 s universally, in which absolute positive force, positive area and separation distance were recorded. The peel property was evaluated using a 180° peel adhesion tester, on which the force required to peel 1 inch (width: 1 inch) of patch off stainless steel (acrylate patch) or high-density polyethylene panel (PIB patch) at a speed of 6 inch/min, was determined. Shear test was conducted on a static shear tester by measuring the detachment time post the application of a 500 g weight to patches (length x width: 1 inch x ½ inch) adhered to the same panel type used for shear test.
In vitro permeation from the patches across heat separated human epidermis on vertical Franz diffusion cells were evaluated over 24 h. Phosphate buffered saline (10 mM, pH 7.4) was used to maintain the sink condition in the receptor compartment. At predetermined time points, 300 μL of sample was taken followed by the addition of the same amount of fresh phosphate buffered saline. The quantification of 3-FA was performed on high performance liquid chromatography coupled with UV detector, with matrix-matched calibration curves for permeation study and patch drug content determination, respectively.
Results: Over 20% w/w of 3-FA was soluble in acrylate adhesives, exceeding the calculated target drug loading of 10% w/w. DURO-TAK 9301 was further pursued for formulating a clear matrix-based patch. The solubility of 3-FA in PIB and silicone adhesives was observed to be lower than 0.1% w/w, and therefore micro-dispersion of 3-FA in these adhesives was explored. 3-FA, a fluorine-containing drug, may potentially bind to fluoropolymer-coated liners and hence, siliconized membrane Loparex 44916 was chosen as release liner. However, due to its incompatibility with silicone adhesives, silicone adhesives were not tested further. ScotchPak 9735 featured minimal moisture and oxygen transmission, hence was utilized as backing membrane for both adhesives.
The optimized clear acrylate patch showed drug content of 12.01±1.00 % with coat weight of 83.75±2.36 gsm. In the optimized micro-dispersion PIB patch, drug content of 10.91±0.48 % with coat weight of 98.55±7.72 gsm was observed. In vitro permeation studies revealed a cumulative amount of 948.71±135.26 and 797.79±32.90 µg/sq.cm of 3-FA in 24 hours for acrylate and PIB patches, respectively.
Both patches were found to be stable, without any drug loss over two months. No agglomeration of globules was observed under light microscope (20x magnification) in PIB patches during the 2-month duration. In addition, acceptable tack, peel and shear properties were observed for 3-FA containing patches, with no significant difference found in such properties for placebo patches with or without bead ruptor homogenization treatment.
Conclusion: Transdermal delivery systems of 3-FA including clear matrix-based acrylate patches and micro-dispersed drug-in-PIB adhesive patches were successfully developed, characterized, and tested for in vitro skin permeation.
Sonalika A. Bhattaccharjee– Graduate Student, Mercer University
Kevin Murnane– Assistant Professor of Pharmaceutical Sciences, Mercer University, Atlanta, Georgia
Bruce Blough– Senior Research Chemist, Research Triangle Institute, North Carolina
Ajay Banga– Professor and Department Chair, Mercer University, Atlanga, Georgia