Design of a depot formulation for disulfiram
Drug addiction and abuse, specifically relating to alcohol, is a globally calamitous mental illness. An important facet of treating this destructive health issue is pharmacological intervention. The current treatment options and their limitations were reviewed as well as the advances that have been made in drug delivery technologies for combating addiction and abuse. The current treatment of addiction, and alcohol abuse in particular, is a large scale concern. Whilst treatment is available in the form of disulfiram, naltrexone and acamprosate; these too possess many short-comings. The greatest of which is poor compliance which results in relapse. This can be successfully averted by the utilisation of a feasible depot system to deliver the medication. Incorporation of disulfiram, an FDA-approved active with promising clinical potential, into a modified depot system comprising a dual delivery system yields a prospective solution to the drawbacks of current treatment regimes. The dual system is made up of nanomicelles dispersed within a thermosensitive gel. Immediate and sustained release is controlled by free disulfiram released into the gel and then the tissue and encapsulated disulfiram released from the nanomicelles into the gel and then the tissue, respectively. The thermosensitive gel is a carrier for the disulfiram-loaded nanomicelles and the free disulfiram. It also serves as a vehicle which allows ease of administration by maintaining a liquid state prior to intramuscular injection and thereafter solidifying into a solid gel-depot inside the muscle tissue. Polymers were selected based on the suitability to the desired outcome as well as compatibility with disulfiram. d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was used for nanomicelle formulation whilst Pluronic F127 (PF127) and high acyl gellan gum (HAGG) was chosen for the thermosensitive gel. A Face-Centred Central Composite Design was utilised for statistical optimization of the nanomicelles. The design consisted of two variables, 1) stirring time of the formulation (hours) and 2) the amount of TPGS used (mg), both of which were crucial to the success of the formation of the nanomicelles. Response surface and contour plots were generated for the variable effects on selected responses (i.e. drug entrapment efficiency, drug loading efficiency and drug release). Statistical optimization computed a single optimized formulation composed of 500mg TPGS and 1 hour of stirring. The optimized nanomicelles were then incorporated into the rheologically selected PF127-HAGG gel. The final nano-enclatherated-gel-composite (NEGC) underwent in vitro release testing, physicochemical characterization and physicomechanical characterization. Results displayed sustained release over 28 days with positive physicochemical and physicomechanical outcomes. Ex vivo results confirmed the release of disulfiram from the NEGC into the tissue as well as established the safety of the system through myotoxicity analysis. Administration of the NEGC to the Sprague-Dawley rat model determined the effectiveness and safety of the delivery system in vivo. Ultra Performance Liquid Chromatography was carried out on plasma to ascertain the level of disulfiram in the plasma. The NEGC yielded a maximum plasma level of 27.33g/mL which is above values previously reported. Ultrasound imaging confirmed the presence of the NEGC within the muscle over 28 days. Myotoxicity studies disclosed an increase in Creatine Kinase after administration with a return to normal levels within 24 hours indicating that permanent muscle damage did not occur. Histopathological lesions were symptomatic of injury and repair of tissue due to intramuscular needle insertion and the decline in lesion severity is indicative of mild, acute toxicity and repairable injury. The results obtained in this study revealed the therapeutic potential of the NEGC to treat not only alcohol addiction but perhaps other conditions as well due to the versatility of this dual delivery system.
A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Pharmacy Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, South Africa Johannesburg, 2016