Preclinical Characterization of Novel Formulation for Sustained Testosterone Delivery

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SUMMARY Several testosterone formulations have been approved for testosterone replacement therapy (TRT) of hypogonadal men, including injectable testosterone esters, transdermal patches, transdermal gels, buccal adhesive tablets, intranasal testosterone, and testosterone pellets; however, each formulation has significant drawbacks. Testosterone gels are currently the dominant products, but they are expensive, require daily application, can lead to transfer to women and children, and are associated with substantial variation in testosterone levels, and high discontinuation rates. Intramuscular testosterone esters provide greater bioavailability than transdermal formulations, and are gaining market share, but their administration is associated with peaks and valleys in testosterone levels that are associated with fluctuations in mood and sex drive. Thus, there is an unmet clinical need for improved products for testosterone replacement therapy (TRT). Advances in testosterone encapsulation methods in polymeric particles by FPT scientists have resulted in a highly tunable polymeric platform to achieve precise and reproducible nanoparticle production with high entrapment efficiency (97.6% – 99.6%), enabling delivery of a larger drug dose in a small volume and minimizing early burst. Based upon its innovative patent-protected (USPTO -US940291 8B2) dual core-shell nano-encapsulation technology, the FPT team has developed a novel micro/nanoparticle formulation - nanoTconsign (nTc) - using FDA approved polymeric materials to provide uniform testosterone delivery over 4- weeks without the early burst; this nTc formulation can be administered in an aqueous medium avoiding the oil injection-related adverse effects. The overall goals of this project are to further characterize and optimize the prototype nTc formulations in vivo in preclinical animal models, and to advance the nTc development towards IND filing to enable human studies. In Aim 1, the selected prototype nTc formulations will be tested in orchiectomized male rats over 4-weeks. These in vivo data on the testosterone pharmacokinetic profile will provide us with a key metric to further optimize the nTc formulations in Aim 1b by modifying the particle size distribution, polymeric composition, and testosterone loading to achieve the desired in vivo kinetics. The leading optimized formulations will be further characterized in multi-dose pharmacokinetic and ADE (absorption, distribution and excretion) studies in orchiectomized rats (Aim 2). In Aim 3, we will examine the repeat dose toxicity on physical function, reproductive behavior and liver/kidney function. The novel nTc formulation has the potential to offer superior pharmacokinetics and uniform delivery of testosterone for up to 4 weeks, which will improve adherence and treatment outcomes for patients seeking TRT. The innovative patent-protected, dual core-shell based nano- encapsulation methodology, the promising preliminary in vitro release data on the prototype nTc formulations, and an interdisciplinary team assembled by FPT, that includes scientific, and regulatory expertise, should facilitate the accomplishment of the proposed aims towards the ultimate goal of developing a product that will fill an unmet clinical need in testosterone replacement therapy.