Izutsu Ken-Ichi, Yoshida Hiroyuki, Abe Yasuhiro, Yamamoto Eiichi, Sato Yoji, Ando Daisuke
School of Pharmacy at Narita, International University of Health and Welfare, Kozunomori 4-3, Narita 286-8686, Japan.
Division of Drugs, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki 210-9501, Japan.
Pharmaceutics. 2024 Sep 30;16(10):1280. doi: 10.3390/pharmaceutics16101280.
The combination of multiple polymers is anticipated to serve as a means to diversify the physical properties and functionalities of dissolving microneedles. The mixing state of components is considered as a crucial factor in determining their suitability. The purpose of this study was to elucidate whether thermal analysis of frozen aqueous solutions can appropriately predict the miscibility of hyaluronic acid (HA) and other polymers used for dissolving microneedles prepared by a micromolding method. Aliquots of aqueous polymer solutions were applied for thermal analysis by heating the samples from -70 °C at 5 °C/min to obtain the transition temperature of amorphous polymers and/or the crystallization/melting peaks of polymers (e.g., polyethylene glycol (PEG)). Films and dissolving microneedles were prepared by air-drying of the aqueous polymer solutions to assess the polymer miscibility in the solids. The frozen aqueous single-solute HA solutions exhibited a clear T' (the glass transition temperature of maximally freeze-concentrated solutes) at approximately -20 °C. The combination of HA with several polymers (e.g., dextran FP40, DEAE-dextran, dextran sulfate, and gelatin) showed a single T' transition at temperatures that shifted according to their mass ratio, which strongly suggested the mixing of the freeze-concentrated solutes. By contrast, the observation of two T' transitions in a scan strongly suggested the separation of HA and polyvinylpyrrolidone (PVP) or HA and polyacrylic acid (PAA) into different freeze-concentrated phases, each of which was rich in an amorphous polymer. The combination of HA and PEG exhibited the individual physical changes of the polymers. The polymer combinations that showed phase separation in the frozen solution formed opaque films and microneedles upon their preparation by air-drying. Coacervation occurring in certain polymer combinations was also suggested as a factor contributing to the formation of cloudy films. Freezing aqueous polymer solutions creates a highly concentrated polymer environment that mimics the matrix of dissolving microneedles prepared through air drying. This study demonstrated that thermal analysis of the frozen solution offers insights into the mixing state of condensed polymers, which can be useful for predicting the physical properties of microneedles.
多种聚合物的组合有望成为使溶解微针的物理性质和功能多样化的一种手段。组分的混合状态被视为决定其适用性的关键因素。本研究的目的是阐明对冷冻水溶液进行热分析是否能够适当地预测透明质酸（HA）与通过微成型方法制备溶解微针所使用的其他聚合物的混溶性。通过以5℃/分钟的速率将样品从-70℃加热，对聚合物水溶液的等分试样进行热分析，以获得无定形聚合物的转变温度和/或聚合物（例如聚乙二醇（PEG））的结晶/熔融峰。通过将聚合物水溶液空气干燥制备薄膜和溶解微针，以评估固体中的聚合物混溶性。冷冻的单溶质HA水溶液在约-20℃处表现出明显的T'（最大冷冻浓缩溶质的玻璃化转变温度）。HA与几种聚合物（例如葡聚糖FP40、二乙氨基乙基葡聚糖、硫酸葡聚糖和明胶）的组合在根据其质量比而变化的温度下表现出单一的T'转变，这强烈表明冷冻浓缩溶质发生了混合。相比之下，在扫描中观察到两个T'转变强烈表明HA和聚乙烯吡咯烷酮（PVP）或HA和聚丙烯酸（PAA）分离成不同的冷冻浓缩相，每个相富含一种无定形聚合物。HA和PEG的组合表现出聚合物各自的物理变化。在冷冻溶液中表现出相分离的聚合物组合在通过空气干燥制备时形成不透明的薄膜和微针。某些聚合物组合中发生的凝聚也被认为是导致形成浑浊薄膜的一个因素。冷冻聚合物水溶液会产生一个高度浓缩的聚合物环境，该环境模拟通过空气干燥制备的溶解微针的基质。本研究表明，对冷冻溶液进行热分析可以深入了解凝聚聚合物的混合状态，这对于预测微针的物理性质可能是有用的。
