Purpose: Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Another prevalent public health concern is the illicit use of cocaine, which remains one of the most abused drugs worldwide. However, there is no FDA-approved pharmacotherapy for cocaine abuse. Chronic cocaine abuse has been associated with depletion of dopamine, and substitute agonists that function as substrate-based dopamine/norepinephrine releasers have shown promise. Similarly, dopamine depletion is characteristic to ADHD patients as well. 4-benzylpiperidine, a substrate-based dopamine/norepinephrine releasing substitute-agonist, has demonstrated preclinical efficacy in cocaine abuse, but has a rapid onset and short duration of action. Transdermal patches can provide the much needed slow and sustained delivery of 4-benzylpiperidine which can reduce abuse potential, promote abstinence and prolong its duration of action; further reducing the frequency of dosing, leading to better compliance. Further, transdermal patches can be abuse-deterrent as it is harder and more time consuming to extract drug from them as compared to conventional dosage forms. Considering the preclinical efficacy of 4-benzylpiperidine and the therapeutic benefits of transdermal drug delivery, the aim of our study was to develop a drug-in-adhesive matrix transdermal patch of 4-benzylpiperidine for cocaine-use disorder and ADHD. The transdermal matrix patch developed was then evaluated for in vitro drug permeation profile across dermatomed human skin, and characterized for adhesion-related properties.
Methods: Commonly used pressure sensitive adhesives (PSAs), acrylate (DURO-TAK 387-2287 and DURO-TAK 387-2516), silicone (BIO PSA 7-4301) and polyisobutylene (PIB) (DURO-TAK 87-6908), were explored to develop a matrix type transdermal patch of 4-benzylpiperidine. Slide crystallization studies were performed to test solubility and screen adhesives and other additives. Silicone PSA along with colloidal silicon dioxide as viscosity builder, fluoropolymer coated membranes as the release liner and polyester based membranes as backing, was chosen to develop a drug in silicone adhesive patch (S1). PIB based patches were developed with drug in adhesive, along with oleic acid and oleyl alcohol as permeation enhancers, polyester for the release liner and polyethylene as backing (P1 and P2). In vitro permeation studies of the patches through dermatomed human skin were performed using Franz cells. Phosphate buffer (pH 7.4) was used as the receptor. Sampling of receptor solution was performed over 48 h and analysis was done using HPLC. Statistics was performed using ANOVA and p<0.05 was considered to arbitrate significant differences between the groups. The patch with highest permeation was selected as the final patch and evaluated for coat weight, shear strength, tack and peel adhesion.
Results: Solubility and slide crystallization studies demonstrated incompatibility of acrylate PSA with the drug, hence, silicone and PIB PSAs were selected for further patch development. The use of oleic acid, oleyl alcohol and isopropyl myristate was found to be beneficial in increasing the loading of the drug in the patches, in addition to their role as permeation enhancers. Colloidal silicone dioxide was successfully incorporated in the silicone-based patches as a viscosity-building agent. The average cumulative amount of 4-benzylpiperidine that permeated across dermatomed human skin, over 48 hours, from S1 silicone adhesive patch, P1 drug-in-PIB adhesive patch and P2 drug-in-PIB adhesive patch were found to be 559.2 ± 79.4 µg/sq.cm, 748.1 ± 36.0 µg/sq.cm, and 1608.5 ± 53.4 µg/sq.cm respectively. Considering an application area of 50 sq.cm, 28.76 ± 4.54 mg, 37.40 ± 1.80 mg, and 80.43 ± 2.67 mg may be delivered from S1, P1 and P2, respectively. Higher delivery of drug from the two PIB based transdermal patches over the silicone-based transdermal patch was obtained, and the P2 PIB based PSA transdermal patch was selected as the final patch for further evaluation of adhesive properties. The final patch demonstrated uniformity in coat weight (4.1 ± 0.6 mg), peel adhesion (0.7 ± 0.2 g), tack test (average positive force of 80.4 ± 11.9 g) and shear strength (average time taken for the patch to drop from the test surface, under a weight of 500 g, was found to be 53.8 ± 7.9 seconds).
Conclusion: The development of a transdermal drug-in-adhesive patch of 4-benzylpiperidine was successful with silicone and PIB PSAs. PIB-based patch P2 showed the highest permeation, which can be attributed to the higher loading of 4-benzylpiperidine (15% w/w) as well as the addition of two permeation enhancers, oleic acid and oleyl alcohol.
Sindhu Ganti– Graduate student, Mercer University, Atlanta, Georgia
Sonalika Bhattaccharjee– Graduate student, Mercer University, Atlanta, Georgia
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
Sonalika Bhattaccharjee– Mercer University, Atlanta