Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada.
Department of Pharmaceutical Sciences, Universidade Federal de Pernambuco, Avenida Professor Arthur de Sá, SN - Cidade Universitária, Recife, PE 50740-521, Brazil.
Int J Pharm. 2020 May 15;581:119292. doi: 10.1016/j.ijpharm.2020.119292. Epub 2020 Mar 31.
The use of water-insoluble carriers for amorphous solid dispersions (ASDs) has attracted more recent interest as the kinetic solubility profiles (KSP) from these systems can achieve a more sustained level of supersaturation when compared with ASDs based on water-soluble polymers. However, the effect of swelling capacity of water-insoluble carriers on the resulting KSP of ASDs has not been fully explored in terms of their achievable degree and extent of drug supersaturation. Thus, the objective of this study is to compare kinetic solubility profiles of ASDs based on commercially available water-insoluble carriers in order to bridge this knowledge gap and provide fundamental information important to the design of ASDs based on water-insoluble carriers. This was achieved by comparing the KSP from non-sink dissolution studies of ASDs of two model poorly-water soluble drugs, indomethacin (IND) and posaconazole (PCZ) based on commercially available water-insoluble carriers with different equilibrium water swelling such as fully hydrolyzed (physically crosslinked) poly (vinyl alcohol) (PVA), Eudragit RS PO, as well as chemically crosslinked PHEMA hydrogels . Our results show that the higher the swelling capacity of the water-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to drug precipitation. The interplay of particle size, total dose and the swelling capacity was also shown to be an essential aspect when tailoring the supersaturation generation from water-insoluble polymer-based ASDs. The importance of the swelling feature was confirmed using firstly different polymer carriers (PVA, Eudragit RS PO, and PHEMA) and then polymer samples of identical composition and drug loading but with different swelling capacities (e.g., PVA, physically crosslinked to different degrees). Furthermore, a large drug partitioning value between the polymer carrier and dissolution medium was found to limit the extent of drug release or supersaturation buildup from these ASDs. Finally, the existence of electrostatic polymer-drug interactions realized from our molecular dynamic simulations supports the observed impact of the large partitioning of the model drug IND between the polymer ED RS PO and the dissolution medium, thereby leading to a lower degree of supersaturation generation (or slower drug release) from this ASD.
水不溶性载体在无定形固体分散体（ASD）中的应用引起了人们的兴趣，因为与基于水溶性聚合物的 ASD 相比，这些系统的动力学溶解度谱（KSP）可以实现更持续的过饱和度水平。然而，水不溶性载体的溶胀能力对 ASD 的 KSP 的影响，就其可实现的药物过饱和度程度和范围而言，尚未得到充分探索。因此，本研究的目的是比较基于市售水不溶性载体的 ASD 的动力学溶解度谱，以弥补这一知识空白，并为基于水不溶性载体的 ASD 的设计提供重要的基础信息。这是通过比较两种模型疏水性药物（吲哚美辛（IND）和泊沙康唑（PCZ））基于市售水不溶性载体的 ASD 在非溶出研究中的 KSP 来实现的，这些载体具有不同的平衡水溶胀能力，例如完全水解（物理交联）的聚乙烯醇（PVA）、Eudragit RS PO 以及化学交联的 PHEMA 水凝胶。我们的结果表明，水不溶性载体的溶胀能力越高，过饱和度产生的速度越快，药物沉淀导致持续过饱和度的时间越短。还表明，当调整基于水不溶性聚合物的 ASD 中过饱和度的产生时，粒径、总剂量和溶胀能力的相互作用也是一个重要方面。通过首先使用不同的聚合物载体（PVA、Eudragit RS PO 和 PHEMA），然后使用相同组成和药物负载但具有不同溶胀能力的聚合物样品（例如，物理交联程度不同的 PVA），证实了溶胀特性的重要性。此外，发现聚合物载体和溶解介质之间的大药物分配值限制了这些 ASD 中药物释放或过饱和度的建立程度。最后，我们的分子动力学模拟实现的静电聚合物-药物相互作用支持了模型药物 IND 在聚合物 ED RS PO 和溶解介质之间的大分配的观察到的影响，从而导致该 ASD 中过饱和度的产生程度较低（或药物释放较慢）。
