"Assessing THC Pro-drugs in Transmucosal Patch Delivery Formulations for the Treatment of Neuropathological Conditions"

∆⁹-Tetrahydrocannabinol (THC) is the primary active ingredient of the plant Cannabis sativa (marijuana) and is responsible for the majority of the pharmacological effects of the plant.  Due to many positive biological activities of THC, marijuana has been advocated for its medicinal value.  To date, the most promising clinical applications approved by the FDA are for the control of nausea and vomiting associated with chemotherapy and for appetite stimulation for AIDS patients suffering from anorexia as a result of wasting syndrome.  THC, however, demonstrates other biological activities which lend themselves to possible additional therapeutic applications, particularly in the area of neuropathological conditions.  These include depression, migraine headaches, alcohol and other chemical dependence withdrawal symptoms, spasticity, anxiety/stress, epileptic seizures and pain.  Many of the pharmacologic properties of the marijuana plant or THC could be directed to provide specific therapeutic effects given the appropriate dosage form. Although a THC formulation currently under development is a pro-drug (THC hemisuccinate) formulated in a suppository base, it is significant to note that the only dosage form currently approved by the FDA is an oral, soft gelatin capsule.  This dosage form is expensive, results in inconsistent pharmacological effects and pharmacokinetic profiles, allows the drug to undergo extensive first-pass metabolism producing high levels of 11-OH-THC and thus exhibits undesirable side effects.  Therefore, for proper study of THC’s therapeutic activities, including behavioral assessments, one must shift the paradigm of THC research to appropriate delivery systems.  The overall goal of this research project is to screen, formulate, produce and determine the bioavailability of ∆⁹-THC pro-drugs via a hot-melt extruded “Transmucosal Matrix Patch” (TMP) delivery system in an animal model.  The THC pro-drugs will be incorporated into a bioadhesive drug delivery system that is applied to a subject’s buccal or labial oral mucosa.  The controlled release of these medicinal agents is delivered to the systemic circulation of the subject via a bio-erodable polymer matrix.  Our approach in Aim 1 is to screen and evaluate a series of THC pro-drugs to determine their thermal stability and physicochemical properties.  Aims 2 and 3 will include the formulation and production of preliminary TMP systems incorporated with pro-drugs that demonstrate acceptable pre-formulation profiles, including the testing and evaluation of the feasibility of the preliminary systems (in-vitro) to identify lead formulations.  Aim four will involve the hot-melt extrusion and die-cutting of the lead systems.  Specific Aim 5 will test, evaluate and finalize two optimized TMP systems for each THC pro-drug.  These final TMP formulations will be tested in an animal model in Aim 6 to determine pharmacokinetic profiles and bioavailability.  Successful incorporation of THC pro-drugs into a hot-melt extruded system as an alternate, more efficient method of delivery will have a tremendous impact on many chronically ill patients.  This novel drug delivery system for these pro-drugs may serve as a valuable mechanism for more efficient study of THC’s therapeutic potential for many neuropathological processes.