Dissolution Methods for Topical Ocular Emulsions

摘要： 目前，外用眼用乳剂还没有专门的溶出度测定方法。 配方。眼球前引流、含泪配方的稀释以及眨眼对 该制剂的流变性影响眼科外用疗效 乳剂。乳剂体系中的药物可以以不同的相存在(溶解形式、胶束形式和 乳剂形式)。用相同的成分和浓度配制的非专利产品 品牌产品可能具有不同的物理化学性质，从而改变治疗效果，因为 制造过程中的差异。因此，开发适当的溶出度测试是至关重要的 可以区分产品和配方变量，还可以预测仿制药的生物等效性 产品处于活体条件下。这样的质量控制测试不仅有助于产品开发过程， 而且还方便了产品审批。 到目前为止，市场上只有三种FDA批准的眼用乳剂(Restasis； Durezol和Reresh Endua)。FDA要求仿制药必须含有相同的有效成分 相同浓度，根据FDA标准生产，但非活性成分允许不同。 然而，眼部组织(角膜或房水)的生物等效性或与该品牌的疗效不是必需的。 眼科非专利药。因此，很少进行临床研究，因此安全性和有效性都很高。 关于仿制药的信息缺乏。Durezol？(双氟泼尼特的外用乳剂)用于治疗 术后炎症与疼痛及其专利权将于2018年到期。敌敌畏(DFBA)不溶于 水及其系统吸收显示非常有限。因此，很难在体内建立这种病毒 DFBA未来仿制制剂的生物等效性。因此，发展体外检测技术至关重要。 DFBA的生物等效性方法和体外试验应能区分药物产品 并能预测该产品的临床疗效。 在本研究中，含有相同成分的DFBA乳剂(Q1)和含有相同成分的乳剂 原料(Q2)的浓度将在不同的工艺条件下制备。物理化学 将测试Q1和Q2配方的性质，以及可能影响 该产品的生物利用度将得到确认。 最初，将使用不同的溶出度测试来确定乳剂的溶出度。 理化性质差异较大的制剂(预计会影响生物利用度) 将被选作溶出度研究。这些方法的优点和局限性以及这些方法的能力 方法在检测过程差异和预测体内性能，并将稳健性 评估过了。上述选定配方的渗透性将使用人角膜上皮细胞进行测试 培养(HEC-2)模型。理化性质和体外释放数据将符合眼科模块 Gastro Plus软件及其在生物等效性预测中的使用将得到验证。选定的测试配方 根据物理化学和释放速率特性(这些特性差异最大的那些)将 在新西兰白兔身上进行体内疗效测试。来自溶出度研究的药物释放数据将 与体内生物利用度数据相关(体外-体内相关性)。一项全面的分析 溶出法的优缺点及检测能力 将进行制造差异和体内性能预测。 这项建议的具体目标是： 1.在不同生产条件下配制Q1/Q2眼科外用乳剂 2.使用各种体外释放方法对制备的制剂进行溶出度研究 3.确定可区分不同眼用乳剂配方的溶出度方法 该项目的预期结果是局部眼用乳剂的体外溶出度测定。我们 设想这项研究的结果将有助于FDA制定建议以确定 普通外用眼用乳剂制剂的生物等效性。

SUMMARY: Currently there is no specific compendial assay for dissolution for topical ophthalmic emulsion formulations. Precorneal drainage, dilution of the formulations with tears and the effect of blinking on rheological properties of the formulation affect the efficacy of the topical Therapeutic efficacy of the ophthalmic emulsions. The drug in the emulsion system may exist in different phases (solubilized form, micelle form and emulsion form). Generic products prepared with the same ingredients & their concentration as that of the brand product may have different physicochemical properties and thereby altered therapeutic efficacy because of the differences in manufacturing process. It is therefore critical to develop appropriate dissolution test that can discriminate the product and formulation variables and also predict the bioequivalency of the generic products in in vivo conditions. Such quality control tests would not only help the product development process, but also facilitates the product approval. To date there are only three FDA approved ophthalmic emulsions are in the market (Restasis¿; Durezol¿ and Refresh Endura¿). The FDA requires the generics to have the same active ingredient at the same concentration, manufactured according to FDA standards, but inactive ingredients are allowed to differ. However bioequivalency in the eye tissue (cornea or aqueous humor) or efficacy to the brand are not required for ophthalmic generics. Hence clinical studies are rarely conducted and therefore safety and efficacy information on the generics is lacking. Durezol¿ (topical emulsion of Difluprednate) is used for the treatment of postoperative inflammation & pain and its patent rights expire in 2018. Difluprednate (DFBA) is insoluble in water and its systemic absorption was shown to be very limited. Hence it will be difficult establishing in vivo bioequivalence of the future generic formulations of DFBA. It is therefore critical to develop in vitro testing methods of bioequivalence for DFBA, and the in vitro tests should be able to discriminate the drug products and be able predict the clinical efficacy of the product. In the present study, DFBA emulsions with same ingredients (Q1) and the emulsions with same concentration of the ingredients (Q2) will be prepared under different process conditions. Physicochemical properties of the Q1 and Q2 formulations will be tested and the Critical Quality Attributes (CQA) that may affect the bioavailability of the product will be identified. Initially different dissolution tests will be employed to determine the dissolution rate from the emulsions. Formulations with large differences in physicochemical properties (that are expected to affect bioavailability) will be chosen for dissolution studies. Advantages and limitations of these methods and the capability of these methods in detecting the process differences and predicting the in vivo performance, and robustness will be assessed. Permeability of the above selected formulation will be tested using human corneal epithelial cell culture (HEC-2) model. Physicochemical properties and in vitro release data will be fit into Ocular Module of the Gastro Plus software and its use in predicting bioequivalence will be validated. Test formulations selected from physicochemical and release rate characteristics (those with largest differences in these properties) will be tested for in vivo efficacy in New Zealand white rabbits. The drug release data from dissolution studies will be correlated with in vivo bioavailability data (in vitro-in vivo correlation). A comprehensive analysis of the dissolution methods in terms of their advantages and disadvantages and the capability of detecting manufacturing differences and predicting in vivo performance will be performed. Specific aims for the proposal are: 1. To formulate Q1/Q2 topical ophthalmic emulsions under different manufacturing conditions 2. To conduct dissolution studies with the prepared formulations using various in vitro release methods 3. To identify a dissolution method that can discriminate different ophthalmic emulsion formulations The expected outcome of the project is an in vitro dissolution assay for topical ophthalmic emulsions. We envision that the results from the study will help FDA in developing recommendations to determine bioequivalence of generic topical ophthalmic emulsion dosage forms.