Sustained Release of 2R,6R-Hydroxynorketamine by MacroPoSH Microneedle Patch for the Treatment of Post-Traumatic Stress Disorder and Pain

Sustained transdermal drug delivery by grooved microneedle arrays (MNA) can enhance patient compliance, reduce costs, and increase access to treatment. To date, the major obstacle in developing such delivery devices is the drug-loading capacity required to achieve clinically relevant doses. This proposal sets out a series of studies to develop and validate a novel wearable MNA Band-Aid-like patch that can carry a payload sufficient to deliver an effective dose. The Partnering Principal Investigator (PI), Dr. Sonkusale, has developed this state-of-the-art, low-cost technology in his laboratory. To demonstrate the advantages of MNA technology for drug delivery to treat disorders that have a high incidence in military Service Members and Veterans, ketamine and its metabolite 2R, 6R-hydroxynorketamine ((2R, 6R)-HNK) have been chosen as the test compounds of interest. The MNA patches will be evaluated in rats on behavioral endpoints that are relevant to post-traumatic stress disorder (PTSD) and chronic pain conditions. Targeting these endpoints to demonstrate the flexibility and functionality of the sustained delivery device will achieve the secondary goal of these studies. That is to provide preclinical evidence in support of developing (2R,6R)-HNK as a therapeutic for PTSD and chronic pain conditions.

Service Members are at increased risk of developing PTSD and chronic pain conditions due to combat exposure. Despite widespread availability of therapies to treat mental health disorders, as many as 40% of patients diagnosed PTSD are treatment resistant. Similarly, treatment options for chronic pain conditions are limited by an over-reliance on opioid analgesics. Accumulating evidence supports the use of subanesthetic doses of ketamine to treat pain and promote stress resilience. Ketamine has dramatically improved treatment outcomes for those suffering from PTSD and chronic pain conditions. Despite the potential of ketamine to be a transformative medicine for military medicine, ketamine is limited by its intravenous route of administration, aversive side effects, and potential abuse liability. (2R, 6R)-HNK produces many of ketamine's beneficial behavioral effects in preclinical studies, but unlike ketamine, it does not produce reward, dystaxia, or sedation.

We propose to use state-of-the-art technology to achieve minimally invasive MNA transdermal drug delivery. This device will provide programmable and accurate (2R,6R)-HNK release at a range of dosage rates that are required to treat several conditions. The MNA patches will be made using the cross-over-lines (COL) method invented by Dr. Sonkusale. To achieve clinically relevant doses for drug delivery, a separate large capacity drug reservoir will be combined with the MNA patch. Preclinical validation of this sustained delivery device will be conducted by the research team of the Initiating PI, Dr. Lucki. Three different (2R,6R)-HNK treatment strategies of varying duration and frequency will be screened for efficacy in attenuating cold and heat hypersensitivity. Subsequently, the optimal dosing regimen will be evaluated in a rodent model of neuropathic pain. Rats will be exposed to a paradigm that produces prolonged expression of contextual fear memory that increases over time. Using a clinically relevant dosing regimen (six MNA patch infusions of 10mg/kg/1 h separated by 48 intervals), the ability of (2R,6R)-HNK to reduce contextual fear memory, acoustic startle response and elevated plus maze reactivity. An additional series of studies will validate a wearable wireless sensor device, in a flexible Band-Aid-like format, used to measure heart rate variability (HRV) and electrodermal activity (EDA), two physiological biomarkers that can distinguish PTSD patients from healthy controls. We will validate the efficacy of transdermal delivery of (2R,6R)-HNK on the resolution of EDA and HRV profiles in rats that exhibit enhanced fear memory recall and generalized fear. The pharmacological effects of these varied (2R,6R)-HNK dosing regimens on pain and fear memory endpoints will be contrasted with the those obtained by reference standards and a known ketamine infusion strategy to obtain optimal behavioral effects in rats.

Ultimately, this device could be used to administered other prescription and non-prescription medications in general, and specifically allow for an alternative route of administration of (2R,6R)-HNK that can offer personalized treatment regimens for individuals suffering from intractable pain and PTSD. This technology and this medication could significantly improve combat casualty care treatment options and facilitate continued care of active-duty Service Members, Veterans, and their families.