Preclinical Characterization of Novel Formulation for Sustained Testosterone Delivery

总结 几种睾酮制剂已被批准用于20岁以下儿童的睾酮替代疗法（TRT）。 性腺功能减退的男性，包括注射睾酮酯，透皮贴剂，透皮凝胶，口腔 粘性片剂、鼻内睾酮和睾酮丸;然而，每种制剂具有显著的 缺点. Tehran凝胶是目前的主导产品，但它们价格昂贵，需要每天 应用，可导致转移给妇女和儿童，并与重大变化， 睾酮水平和高停药率肌肉注射睾酮酯提供更大的 生物利用度比透皮制剂，并获得市场份额，但他们的管理， 与睾丸激素水平的高峰和低谷有关，睾丸激素水平与情绪和性的波动有关。 驱动因此，对于用于睾酮替代疗法（TRT）的改进产品存在未满足的临床需求。 FPT科学家在聚合物颗粒中的睾酮封装方法的进展导致了 高度可调聚合物平台，以实现精确和可再现的纳米颗粒生产， 包封率（97.6% - 99.6%），能够以小体积递送较大的药物剂量， 最小化早期爆发。基于其创新的专利保护（USPTO -US 940291 8B 2）双核壳 纳米封装技术，FPT团队已经开发出一种新的微/纳米颗粒配方- nanoTconsign（nTc）-使用FDA批准的聚合物材料，在4- 10天内提供均匀的睾酮递送。 无早期突释;该nTc制剂可在水性介质中给药，避免油 注射相关的不良反应。 本项目的总体目标是进一步表征和优化原型nTc制剂的体内 在临床前动物模型中，并推进nTc开发向IND申请，以实现人体研究。 在目标1中，将在睾丸切除的雄性大鼠中对选定的原型nTc制剂进行为期4周的试验。 这些关于睾酮药代动力学特征的体内数据将为我们提供进一步研究的关键指标。 通过修改粒度分布、聚合物组成和 睾酮负载以实现所需的体内动力学。领先的优化配方将进一步 在多剂量药代动力学和ADE（吸收、分布和排泄）研究中， 睾丸切除大鼠（Aim 2）。在目标3中，我们将检查重复给药对身体功能的毒性， 生殖行为和肝肾功能。新的nTc制剂具有提供上级 药代动力学和睾酮的均匀递送长达4周，这将改善依从性， 寻求TRT的患者的治疗结果。创新的专利保护，双核壳基纳米， 封装方法，原型nTc制剂有希望的初步体外释放数据， 由FPT组建的跨学科团队，包括科学和监管专业知识， 促进实现拟议目标，最终目标是开发一种产品， 填补了睾酮替代疗法中未满足的临床需求。

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.