Transdermal drug delivery is an exciting and challenging area. There are numerous transdermal delivery systems currently available on the market. However, the transdermal market still remains limit...

Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skin's outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. Here, we present a clinical study of MN-enhanced delivery of a medication to humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications.

Attenuated-total-reflectance Fourier-transform-infrared spectroscopy has been used to rapidly and noninvasively quantify in vivo the uptake of a chemical into the outermost, and least permeable, layer of human skin (the stratum corneum). The objective of the experiment was to develop a general model to predict the rate and extent of chemical absorption for diverse exposure scenarios from simple, and safe, short-duration studies. Measurement of the concentration profile of the chemical in the stratum corneum, and analysis of the data using the unsteady-state diffusion equation, enabled estimation of the permeability coefficient and calculation of the time required to achieve maximal transdermal flux. Validation of the spectroscopic technique employed was established, and quantitation of chemical uptake into the stratum corneum was confirmed independently using trace amounts of radiolabeled chemical in conjunction with liquid scintillation counting and accelerator mass spectrometry. The results presented have pharmacological and toxicological implications, as the technology lends itself both to the prediction of transdermal drug delivery, and the feasibility of this route of administration, and to the assessment of risk after dermal contact with toxic chemicals.

Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.

Context: The nonpsychoactive cannabinoid, cannabidiol (CBD), has great potential for the treatment of chronic and ‘breakthrough’ pain that may occur in certain conditions like cancer. To fulfill this goal, suitable noninvasive drug delivery systems need to be developed for CBD. Chronic pain relief can be best achieved through the transdermal route, whereas ‘breakthrough’ pain can be best alleviated with intranasal (IN) delivery. Combining IN and transdermal delivery for CBD may serve to provide patient needs-driven treatment in the form of a nonaddictive nonopioid therapy. Objective: Herein we have evaluated the IN and transdermal delivery of CBD with and without permeation enhancers. Materials and Methods: In vivo studies in rats and guinea pigs were carried out to assess nasal and transdermal permeation, respectively. Results: CBD was absorbed intranasally within 10 minutes with a bioavailability of 34–46%, except with 100% polyethylene glycol formulation in rats. Bioavailability did not improve with enhancers. The steady-state plasma concentration of CBD in guinea pigs after transdermal gel application was 6.3 ± 2.1 ng/mL, which was attained at 15.5 ± 11.7 hours. The achievement of a significant steady-state plasma concentration indicates that CBD is useful for chronic pain treatment through this route of administration. The steady-state concentration increased by 3.7-fold in the presence of enhancer. A good in vitro and in vivo correlation existed for transdermal studies. Conclusion: The results of this study indicated that CBD could be successfully delivered through the IN and transdermal routes.