Zulbeari Nadina, Hansen Signe Malig, Holm René
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Pharmaceutics. 2024 Nov 21;16(12):1495. doi: 10.3390/pharmaceutics16121495.
Co-delivering dual-drug systems have proven to be effective in, for example, anticancer therapy or HIV prophylaxis due to a higher target selectivity and therapeutic efficacy from compound synergism. However, various challenges regarding physical stability can arise during the formulation definition when multiple drug compounds are included in the same formulation. In this work, the focus was on aqueous suspensions, which could be applied as long-acting injectable formulations to release the drug compounds over weeks to months after administration. It was possible to gain insights into dual-drug nano- and microsuspensions containing two acidic compounds (indomethacin and naproxen) prepared by milling with dual centrifugation. Information regarding the physical stability of individual suspensions was subtracted and compared to dual-drug suspensions when prepared with the same milling conditions and stored at elevated temperatures of 40 °C. Distinct particle size profiles after milling were obtained dependent on the stabilizer used in both individual and dual-drug suspensions. Most notably, the combination of indomethacin and naproxen in one formulation resulted in smaller sizes of drug particles compared to individual suspensions under the presence of some stabilizers. The obtained particle size profiles further indicated that at least one of the model compounds needed to be sufficiently stabilized from a stabilizer to obtain physically stable dual-drug suspensions over 28 days when stored at 40 °C. Similarly, the particle size distribution was dependent on the individual distribution of the suspensions, which showed a monomodal distribution could be achieved for dual-drug suspensions when at least one of the individual suspensions demonstrated a monomodal distribution in the presence of the stabilizer alone. Over a 28-day period, the smallest particle size was obtained in dual-drug suspensions stabilized with a combination of polysorbate 85 and poloxamer 338 compared to dual-drug suspensions stabilized with only a single stabilizer during preparation, indicating tendencies towards stabilization synergism from a combination of stabilizers as well as the model compounds. Overall, the study showed insights into the preparation and physical stability of dual-drug suspensions containing indomethacin and naproxen.
由于具有更高的靶标选择性以及化合物协同作用带来的治疗效果，共递送双药系统已被证明在例如抗癌治疗或HIV预防方面是有效的。然而，当在同一制剂中包含多种药物化合物时，在制剂定义过程中可能会出现各种与物理稳定性相关的挑战。在这项工作中，重点是水性悬浮液，其可作为长效注射制剂应用，以便在给药后数周甚至数月内释放药物化合物。通过双离心研磨制备含有两种酸性化合物（吲哚美辛和萘普生）的双药纳米和微悬浮液，可以深入了解相关情况。在相同研磨条件下制备并在40℃高温下储存时，将单个悬浮液的物理稳定性信息进行提取并与双药悬浮液进行比较。根据在单个和双药悬浮液中使用的稳定剂不同，研磨后可获得不同的粒度分布。最值得注意的是，在某些稳定剂存在的情况下，与单个悬浮液相比，在一种制剂中同时使用吲哚美辛和萘普生会使药物颗粒尺寸更小。所获得的粒度分布进一步表明，当在40℃储存28天时，至少一种模型化合物需要从稳定剂中获得充分稳定，以获得物理稳定的双药悬浮液。同样，粒度分布取决于各个悬浮液的分布情况，这表明当至少一种单个悬浮液在仅存在稳定剂的情况下呈现单峰分布时，双药悬浮液也可实现单峰分布。在28天的时间里，与制备过程中仅使用单一稳定剂稳定的双药悬浮液相比，用聚山梨酯85和泊洛沙姆338组合稳定的双药悬浮液获得了最小的粒度，这表明稳定剂组合以及模型化合物存在稳定协同作用的趋势。总体而言，该研究揭示了含有吲哚美辛和萘普生的双药悬浮液的制备和物理稳定性情况。
