<br>用于口腔结核治疗的德拉马尼纳米颗粒的乳化配制和放大,Molecular Pharmaceutics

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用于口腔结核治疗的德拉马尼纳米颗粒的乳化配制和放大
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2023-08-14 , DOI: 10.1021/acs.molpharmaceut.3c00240
Nicholas J Caggiano ₁ , Madeleine S Armstrong ₁ , Joanna S Georgiou ₁ , Aditya Rawal ₂ , Brian K Wilson ₁ , Claire E White _{3,

4} , Rodney D Priestley _{1,

5} , Robert K Prud'homme ₁

Affiliation

Delamanid (DLM) 是一种疏水性小分子治疗剂，用于治疗耐药结核病 (DR-TB)。由于其疏水性和由此导致的水溶性差，人们研究了无定形固体分散体（ASD）等制剂策略，以增强其水溶解动力学，从而提高口服生物利用度。然而，ASD 制剂在结核病高发地区通常遇到的恶劣储存条件下容易受到温度和湿度引起的相分离和重结晶的影响。纳米封装代表了一种替代配方策略，可增加水溶解动力学，同时在高温和湿度下保持稳定。包覆纳米颗粒药物核心的稳定剂层限制了储存期间扩散导致的大药物域的形成，这与 ASD 相比具有优势。最初尝试通过沉淀驱动的自组装形成负载 DLM 的纳米粒子，但没有成功，因为 DLM 上存在的三氟甲基和硝基官能团被认为会干扰表面稳定剂的附着。因此，在这项工作中，我们研究了通过乳化对 DLM 进行纳米胶囊化，避免形成固体药物核心，而是在纳米颗粒形成过程中保持 DLM 溶解在二氯甲烷分散相中。通过探针超声法筛选初始乳液配方表明，质量比为 1:1 的卵磷脂和 HPMC 稳定剂形成了 250 nm 尺寸稳定的乳液液滴，负载量为 40% DLM。进行了放大研究，使用高压均质化（一种连续且工业规模化的技术）在更大范围内产生几乎相同的液滴尺寸分布。将所得乳液喷雾干燥形成干燥粉末，体外溶出研究表明，由于 DLM 的比表面积增加和部分无定形特性，与原样结晶 DLM 和微粉化结晶 DLM 相比，溶出动力学显着增强-负载纳米粒子。固态核磁共振和溶出研究表明，在加速稳定性测试（50 °C/75% RH，开瓶）期间，乳液粉末具有良好的物理稳定性。

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Formulation and Scale-up of Delamanid Nanoparticles via Emulsification for Oral Tuberculosis Treatment

Delamanid (DLM) is a hydrophobic small molecule therapeutic used to treat drug-resistant tuberculosis (DR-TB). Due to its hydrophobicity and resulting poor aqueous solubility, formulation strategies such as amorphous solid dispersions (ASDs) have been investigated to enhance its aqueous dissolution kinetics and thereby improve oral bioavailability. However, ASD formulations are susceptible to temperature- and humidity-induced phase separation and recrystallization under harsh storage conditions typically encountered in areas with high tuberculosis incidence. Nanoencapsulation represents an alternative formulation strategy to increase aqueous dissolution kinetics while remaining stable at elevated temperature and humidity. The stabilizer layer coating the nanoparticle drug core limits the formation of large drug domains by diffusion during storage, representing an advantage over ASDs. Initial attempts to form DLM-loaded nanoparticles via precipitation-driven self-assembly were unsuccessful, as the trifluoromethyl and nitro functional groups present on DLM were thought to interfere with surface stabilizer attachment. Therefore, in this work, we investigated the nanoencapsulation of DLM via emulsification, avoiding the formation of a solid drug core and instead keeping DLM dissolved in a dichloromethane dispersed phase during nanoparticle formation. Initial emulsion formulation screening by probe-tip ultrasonication revealed that a 1:1 mass ratio of lecithin and HPMC stabilizers formed 250 nm size-stable emulsion droplets with 40% DLM loading. Scale-up studies were performed to produce nearly identical droplet size distribution at larger scale using high-pressure homogenization, a continuous and industrially scalable technique. The resulting emulsions were spray-dried to form a dried powder, and in vitro dissolution studies showed dramatically enhanced dissolution kinetics compared to both as-received crystalline DLM and micronized crystalline DLM, owing to the increased specific surface area and partially amorphous character of the DLM-loaded nanoparticles. Solid-state NMR and dissolution studies showed good physical stability of the emulsion powders during accelerated stability testing (50 °C/75% RH, open vial).

更新日期：2023-08-14

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