DRUG DELIVERY THROUGH INTACT AND ABLATED SKIN
While transdermal drug delivery offers numerous advantages, the morphology of skin limits its scope to a narrow range of drugs (potent, log P between 1-3, with a molecular weight <500 Da) that can be delivered at therapeutically relevant flux. Cosmetic techniques such as non-ablative fractional lasers, microdermabrasion and microneedle treatment can intervene to reversibly compromise the integrity of the skin making skin more permeable to hydrophilic compounds that have otherwise limited dermal diffusion. The first half of our aims focus on the novel use of these cosmetic techniques to enhance the transdermal permeation of small molecular drugs. All in vitro permeation studies were performed using vertical Franz diffusion cell which essentially consists of donor compartment where the drug formulation is added, a receptor compartment that holds phosphate buffer saline, and human dermatomed skin clamped between the two compartments. High Performance Liquid Chromatography was used to quantitate all drugs analyzes in our work. The average cumulative amount of drug that permeated through untreated skin (control/passive) resulted in transdermal delivery of 72.61 ± 50.35 μg/cm2 and 22.80 ± 0.64 μg/cm2 of diclofenac sodium and sumatriptan succinate, respectively. Laser pre-treatment of skin significantly increased (p<0.005) delivery of diclofenac sodium to 575.66 ± 207.18 μg/cm2 and sumatriptan succinate to 498.32 ± 97.54 μg/cm2. In case of microdermabrasion and microneedle pretreatment studies, the transdermal delivery of sumatriptan succinate increased from 6.45 ± 0.17 μg/sq.cm and 21.16 ± 2.90 μg/sq.cm to 116.08 ± 70.88 μg/sq.cm and 512.07 ± 89.76μg/sq.cm in 24 hours, respectively. Results of our studies demonstrate significant enhancement of in vitro transdermal permeation of small molecular weight drugs over human dermatomed skin when pre-treated with the cosmetic technique (non-ablative fractional laser, microdermabrasion and microneedle) in comparison to passive (without application of any cosmetic technique) permeation. Visual characterization studies (histological staining, dye binding studies, proscope imaging, scanning electron microscopy) of skin validate the mechanisms underlying the techniques. The second half of our studies focused on the development of transdermal gel formulation and drug-in-adhesive matrix type patch of 4-benzylpiperidine for cocaine use disorder and attention deficit hyperactivity disorder. 4-benzylpiperidine is a substitute agonist for cocaine use disorder with a short duration of action and hence can benefit from sustaining its duration of action and this can be achieved by a transdermal formulation. Our studies incorporated the drug into a transdermal hydroxy propyl cellulose based gel formulation and provided sustained release of the drug over 24 hours. Gels were formulated with varying amount of gelling agent and subjected to rheological analysis. Franz cells were used to investigate the in vitro permeation and high performance liquid chromatography was used to quantitate the drug. Transdermal permeation of 4-benzylpiperidine from propylene glycol solution (1, 10, 20 and 50 mg/ml) corresponded to 16% to 31% delivery (49.45 11.60, 258.47 48.50, 600.26 74.18, 1945.20 405.59 g/cm2). The average cumulative amount of drug delivered from gel formulation was 1824.90 ± 425.12 µg/cm2. Thixotropic test demonstrated 2% hydroxyl propyl cellulose based gel to have the highest structure recovery ratio. The calculated theoretical permeability coefficient and theoretical flux value (32.637 ug/cm2/h) predicted high percutaneous absorption. This was further validated by the experimentally determined permeability coefficients and flux values (62.73 ± 12.14 ug/cm2/h), demonstrating proficient transdermal delivery of 4-benzylpiperidine. Literature demonstrates correlation between cocaine use disorder treatment and pharmacotherapy of attention deficit hyperactivity disorder. While gels can provide sustained release of the drug, drug release from a patch can be controlled better and it is harder to extract drug from a patch for abuse. Hence, further studies aimed at developing a drug-in-adhesive matrix type patch of 4-benzylpiperdine to treat attention deficit hyperactivity disorder. Several common adhesives, backing membranes and release liner were analyzed to develop patches. Among the patches developed, polyisobutylene adhesive based patch with higher drug concentration exhibited superior transdermal permeation (1608.5 53.4 µg/cm2 over 48 hrs). In the last aim, we evaluated the deactivation efficiency of an activated carbon based drug disposal system. Food and Drug Administration has protocols in place for drug disposal but these protocols do not deactivate the drug and therefore the drug can pose a risk to contaminate water systems or can be abused by extraction. The deactivation efficiency of a disposal system was analyzed by employing an immediate release (meperidine HCl) and controlled release (oxycodone HCl) opioid drug dosage forms of high abuse potential. The deactivation efficiency of the system was tested by collecting samples at different time points up to 28 days. High performance liquid chromatography was used to quantitate the drugs. At the end of the 28-day study, 100 % of both the drugs were deactivated. In the desorption study, no drug leached out from the activated carbon in larger volume of water and less than 1.4 % leached out on extraction with ethanol.
Ganti, Sindhu Sunkara