Johnson Coleman, Chen Beibei, Bhalla Aanya, Crowell Eric, Zhang Feng
University of Texas at Austin, College of Pharmacy, Division of Molecular Pharmaceutics and Drug Delivery, Austin, TX, USA.
University of Texas at Austin, Dell Medical School, Department of Ophthalmology, Austin, TX, USA.
Int J Pharm. 2025 Aug 20;681:125822. doi: 10.1016/j.ijpharm.2025.125822. Epub 2025 Jun 6.
Drug delivery products based on poly(lactic-co-glycolic acid) (PLGA) often have multiphasic drug release profiles with slow "lag phase(s)" and rapid "burst phase(s)," which can limit therapeutic efficacy. The purpose of this study was to develop voriconazole (VCZ)/PLGA intravitreal implants with steady drug release profiles, i.e., without lag and burst phases. This study was performed by manufacturing several implant formulations by melt extrusion and testing these formulations for in-vitro drug release. Prototype implants containing only VCZ and PLGA (Resomer® RG 502H) displayed triphasic release profiles with long lag phases and large burst phases, attributed to drug release occurring by autocatalytic PLGA erosion. Better drug release profiles were attained by incorporating water-soluble polymeric excipients into the VCZ/PLGA implants. Incorporation of poly(ethylene glycol) (PEG) resulted in extended first-order release via dissolution and diffusion of VCZ through an interconnected porous network within the implant's PLGA matrix. Incorporation of poly(vinyl pyrrolidone) (PVP) resulted in pseudo zeroth-order release by creating a viscous gel within an interconnected porous network, with the gel functioning as a barrier to diffusion of drug and PVP. Importantly, the formation of these interconnected porous networks depended on the implants being phase-separated suspensions of crystalline drug and soluble excipient in the implant's PLGA matrix. To ensure this phase state, the solubility/temperature phase diagram of VCZ/PLGA was determined using melting point depression measurements and Flory-Huggins modeling, and extrusion temperatures were selected at which VCZ is insoluble in PLGA and would not dissolve into the molten PLGA during extrusion. The miscibilities of PEG/PLGA and PVP/PLGA were also considered in the extrusion process design.
基于聚乳酸-乙醇酸共聚物（PLGA）的药物递送产品通常具有多相药物释放曲线，包括缓慢的“滞后相”和快速的“突释相”，这可能会限制治疗效果。本研究的目的是开发具有稳定药物释放曲线（即无滞后相和突释相）的伏立康唑（VCZ）/PLGA玻璃体内植入物。本研究通过熔融挤出制备几种植入物制剂，并对这些制剂进行体外药物释放测试。仅含有VCZ和PLGA（Resomer®RG 502H）的原型植入物显示出三相释放曲线，具有长滞后相和大突释相，这归因于通过自催化PLGA侵蚀发生的药物释放。通过将水溶性聚合物辅料掺入VCZ/PLGA植入物中可获得更好的药物释放曲线。掺入聚乙二醇（PEG）导致通过VCZ在植入物的PLGA基质内相互连接的多孔网络中的溶解和扩散实现延长的一级释放。掺入聚乙烯吡咯烷酮（PVP）通过在相互连接的多孔网络内形成粘性凝胶导致伪零级释放，该凝胶起到药物和PVP扩散屏障的作用。重要的是，这些相互连接的多孔网络的形成取决于植入物是晶体药物和可溶性辅料在植入物的PLGA基质中的相分离悬浮液。为确保这种相态，使用熔点降低测量和Flory-Huggins模型确定VCZ/PLGA的溶解度/温度相图，并选择挤出温度，在该温度下VCZ不溶于PLGA且在挤出过程中不会溶解到熔融的PLGA中。在挤出工艺设计中还考虑了PEG/PLGA和PVP/PLGA的混溶性。
