Zulbeari Nadina, Mustafova Sibel Selyatinova, Simonsen Adam Cohen, Lund Frederik Wendelboe, Holm René
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
Int J Pharm. 2024 Nov 15;665:124726. doi: 10.1016/j.ijpharm.2024.124726. Epub 2024 Sep 16.
Aqueous suspensions of poorly soluble, crystalline drug particles in the sub-micron range hold the ability to regulate the drug release for a defined period of time after e.g., intramuscular, or subcutaneous administration, working as an eminent formulation strategy for the preparation of long-acting injectables. Aqueous suspensions are typically prepared by top-down approaches, e.g., wet bead media milling or high-pressure homogenization, containing the active pharmaceutical compound and surfactants and/or polymers for stabilization purposes. Currently, the screening of proper stabilizers and adequate stabilizer concentration during formulation investigations is based on a trial-and-error approach with variations in combinations, concentrations, and/or ratios. To obtain a more efficient methodology during formulation screening, the present study investigated the correlation between the surface activity of two different surfactants, i.e., poloxamer 188 and polysorbate 20, by drop profile tensiometry and Langmuir trough monolayer, and the obtained sizes of cinnarizine particles as a tool to predict the optimal surfactant concentration to prepare physical stable nano- and microsuspensions. The obtained results demonstrated that the molecular area determined as the area per surfactant molecule measured in the Langmuir trough combined with the specific surface area of the prepared suspensions could be used to predict the suitable concentration of the surfactant based upon short-term stress stability data. The results further showed that higher concentrations of poloxamer 188 were necessary to stabilize the suspensions when compared to the needed concentration of polysorbate 20. In addition, it was observed that there was a need for a slightly higher surfactant concentration when the suspensions were milled with the smallest bead size of 0.5 mm instead of larger sizes of bead (0.8 and 1.0 mm), which could not be accounted for by differences in specific surface area.
亚微米级难溶性结晶药物颗粒的水悬浮液能够在肌内或皮下给药等方式后，在规定时间内调节药物释放，是制备长效注射剂的一种重要制剂策略。水悬浮液通常通过自上而下的方法制备，例如湿珠介质研磨或高压均质化，其中含有活性药物化合物以及用于稳定化目的的表面活性剂和/或聚合物。目前，在制剂研究过程中筛选合适的稳定剂和适当的稳定剂浓度是基于一种反复试验的方法，涉及组合、浓度和/或比例的变化。为了在制剂筛选过程中获得更有效的方法，本研究通过滴外形张力测定法和朗缪尔槽单分子层研究了两种不同表面活性剂泊洛沙姆188和聚山梨酯20的表面活性之间的相关性，以及获得的桂利嗪颗粒尺寸，以此作为预测制备物理稳定的纳米和微悬浮液的最佳表面活性剂浓度的工具。所得结果表明，在朗缪尔槽中测得的每个表面活性剂分子的面积即分子面积与所制备悬浮液的比表面积相结合，可用于根据短期应力稳定性数据预测表面活性剂的合适浓度。结果还表明，与聚山梨酯20所需浓度相比，需要更高浓度的泊洛沙姆188来稳定悬浮液。此外，观察到当用最小珠径为0.5毫米的珠子而不是更大尺寸（0.8和1.0毫米）的珠子研磨悬浮液时，需要略高的表面活性剂浓度，这不能用比表面积的差异来解释。
