RTX is the most potent known agonist of the transient receptor potential cation channel subfamily V member 1 (TRPV1). It is a selective neurotoxin that can ablate TRPV1-bearing neural structures, most importantly, nociceptive (pain sensing) spinal nerve fibers, and has been unequivocally demonstrated by several laboratories to induce long-lasting analgesia (chronic pain relief). Why has RTX not be turned into a commercially available drug to date? We identified a trifecta of barriers to progress that guided our unpublished studies and led to the enclosed SBIR Phase I application. The first is the formulation as a drug, specifically toxic diluents relied upon such as Tween/polysorbate, a cause of life-threatening anaphylaxis, to solubilize RTX. The second is a lack of patent protection for any financial investment into the preclinical and clinical development process. The third is a lack of effective contenders in the commercial space. Preliminary data demonstrates that we have overcome the first barrier by developing a 2nd generation formulation of RTX using the FDA-approved cyclodextrin Captisol® as solubilizer, Cap®RTX; that we have overcome the second barrier by securing patent protection via licensing of Captisol® from Ligand Pharmaceuticals; and that we have validated the mechanism and analgesic efficacy of the new formulation in a large animal model of pain. Market research has identified interventional pain physicians and health insurance managers as primary customers and determined a first year (after FDA approval) sales revenue potential of $200M (at 1% market penetration). The proposed commercial product Cap®RTX translates the broad existing knowledge base on TRPV1- mediated neural ablation into a minimally toxic commercial product with the potential to engender a paradigm- shift in the treatment of hitherto intractable chronic locoregional pain. Hypothesis: Lyophilization preserves Cap®RTX permitting the production of single-dose vials, storage at room temperature, ease of reconstitution, and subsequent undiminished pharmacological activity in vivo. Aim 1. To test lyophilization of Cap®RTX by critical process parameter optimization. Prolonged shelf life and bedside-preparability would facilitate clinical testing of Cap®RTX and future marketing as a drug. This will be accomplished through the systematic development and testing of a lyophilized formulation. Aim 2. To test the minimal effective dose of Cap®RTX. Safety of RTX depends not only on its formulation but equally importantly on the selectivity of its delivery that will be optimized by determining minimum effective dose and volume delivered by the periganglionic-epidural route ung real-time image guidance. Aim 3. To produce a small-scale run of individual dose vials. 500 dose vials will be produced and tested for shelf life at 1d, 1w, and 1mo using a validated HPLC assay with detection by Mass Spectrometry. Impact and Future Directions: If successful, the proposed studies lead to the commercial development, a pre-IND meeting with the FDA, and formal toxicology studies to test Cap®RTX as a drug for intractable pain.
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