Development of hydrogel-based in vitro dissolution apparatus for microparticle formulations

项目摘要 药物制剂的开发是为了给患者带来最大的益处。最大 当药物以预定的方式正确释放以维持药物的释放时， 最低有效浓度和最高毒性浓度之间的剂量， 治疗剂量 范围.使用药物溶出特性进行质量控制的基本假设是， 预期制剂具有相同的体内药物吸收性质 动力学是一样的。然而，对于通用制剂，类似的体外溶出特性不 确保它们具有相同的体内吸收特性。这仅仅是因为体外 溶解性质取决于所用的溶解方法。体外溶出度使用中的问题 因为比较不同制剂的方法对于非口服制剂变得复杂 缓释（SR）肠胃外贮库制剂。在许多肠胃外贮库制剂中， 微粒制剂是最常用的并且是本研究的焦点。 本项目的目标是设计和开发新的体外溶出装置， 体内性质，即，制剂在肠胃外给药后可能遇到的条件。有 三个具体目标。这三个目标将同时进行，因为它们是相互依存的。第一 具体目标是设计和开发用于测试胃肠外SR的新的体外溶出装置 制剂。这些装置将被设计为并入现有的USP装置类型4，以便于 与现有的测试设备相适应。第二个具体目标是配制SR曲普瑞林 使用微制造方法制备微粒，并将其与目前现有的临床产品进行比较。 比较将是Akina的新的基于水凝胶模板的微加工方法和 传统的复乳技术，以及与Trelstar？，这是一种市售的曲普瑞林 在另一个实施方案中，制备了用于用作对照制剂的微粒。第三个具体目标是进行体外溶出 研究制备的制剂，并确定最灵敏的溶出方法。的制剂 将通过作为第一个目标的一部分开发的方法进行测试，以确定 区分SR制剂之间差异的溶出方法。 区分SR制剂中的差异的能力是重要的，因为其理化性质是重要的。 与制剂相关的差异可能影响药物的生物利用度。圆满完成 该项目预计将生产一种新的溶出仪，可以帮助区分配方 在不同的生产条件下生产。该溶出度测定将通过以下方式帮助整体公众健康： 提高确保所有可注射SR制剂具有适当生物利用度的能力， 持续治疗剂量的释放曲线。

PROJECT SUMMARY Drug formulations are developed to deliver drugs for the maximum benefit to patients. The maximum benefit to the patients occurs when the drug is released correctly in a predetermined manner to maintain the dose between the minimum effective concentration and upper level toxic concentration, the therapeutic dose range. The underlying assumption of using the drug dissolution property for quality control is that different formulations are expected to have the same in vivo drug absorption property as long as the in vitro drug release kinetics are the same. For generic formulations, however, the similar in vitro dissolution property does not guarantee that they would have the same in vivo absorption properties. This is simply because the in vitro dissolution property depends on the dissolution method used. The issue of using in vitro dissolution property as a means to compare different formulations becomes complicated for non-oral formulations such as sustained release (SR) parenteral depot formulations. Of the many parenteral depot formulations, microparticle formulations have been most frequently used and are the focus of this study. The goal of this project is to design and develop new in vitro dissolution apparatus that can incorporate in vivo properties, i.e., conditions that a formulation may encounter after parenteral administration. There are three specific aims. The three aims will be conducted simultaneously, as they are interdependent. The first specific aim is to design and develop new in vitro dissolution apparatuses for testing parenteral SR formulations. These apparatus will be designed to incorporate into the existing USP apparatus type 4 for ease of adaptation with current testing equipment. The second specific aim is to formulate SR triptorelin microparticles using microfabrication method and compare these with the currently existing clinical product. The comparison will be between Akina's novel hydrogel-template based microfabrication method and conventional double emulsion technique as well as with Trelstar�, which is a commercially available triptorelin microparticle to be used as a control formulation. The third specific aim is to conduct in vitro dissolution studies of the prepared formulations and identify the most sensitive dissolution method. The formulations prepared in the second Aim will be tested by the methods developed as part of the first aim in order to identify a dissolution method which discriminates the differences between the SR formulations. The ability to distinguish differences in SR formulations is important as the physicochemical differences relevant to the formulation may affect the bioavailablity of the drug. The successful completion of this project is expected to produce a new dissolution apparatus which can aid in distinguishing formulations generated under different manufacturing conditions. This dissolution assay will aid overall public health by improving the capability to ensure that all injectable SR formulations have the appropriate bioavailability and release profiles for sustained therapeutic dose.