FDA IVPT资料 | 透皮外用制剂（IVPT）研究参考案例

There are two methodogies that are currently employed to asses skin integrity for IVPT studies.  However, there is not standardized criteria that are available to assess viable skin membranes for use in IVPT.

• The measured resistance is dependent on the device, ie., applied frequency, resulting current, ionic strength of the solution as well as the surface area of the skin sample. Actual readings, measured in kΩ, is difficult to correlate with the data that has been reported in various existing literature.

- 测得的电阻取决于设备，即应用频率、产生的电流、溶液的离子强度以及皮肤样本的表面积。实际读数以kΩ为单位，测量结果很难与各种现有文献中报告的数据相关联。

• It was determined that the skin sections that showed resistance values less than 3 times of baseline (without skin membrane, solution reading) had compromised barrier and rejected for the study. Alternatively, those skin section with resistance readings higher than 20 times of the baseline resistance, were with keratinized epithelium and also rejected from the study

经确定，显示电阻值低于基准值（无皮肤膜，溶液读数）3倍的皮肤部分具有受损屏障并被排除在研究之外。相反，那些电阻读数高于基准电阻的20倍的皮肤部分，则具有角化上皮层，也被排除在研究之外。

• Furthermore as the supporting data we measured the transepidermal water loss (TEWL) with a VapoMeter (Delfin Technologies Ltd., Finland), the standard limited value as suggested in various literatures <15 g m^-2 h^-1  was used.

- 此外，我们还使用经皮水分流失测量仪测量了经皮水分流失（TEWL），采用了各种文献建议的标准限值 <15 g m^-2 h^-1。

However the criteria that has been used for skin selection for the IVPT studies in many cases exhibited with quite different flux profiles within the same and different donors.

然而，目前在许多情况下用于IVPT研究的皮肤选择标准在同一供体和不同供体之间显示出相当不同的通量曲线。

More research is need to standardized skin integrity testing procedures in qualification of the viable skin membranes used IVPT studies.

需要进行更多的研究来标准化皮肤完整性测试程序，以确定可用于IVPT研究的活性皮肤膜。

皮肤电阻率仪——皮肤完整性检测仪器

离体皮肤电阻测试仪用于体外透皮试验(IVPT)中离体皮肤的屏障完整性评价(SIFT)，通过测量电阻进行离体皮肤的评估筛选，控制皮肤的质量，降低体外透皮试验的相对标准偏差。

2022年10月FDA发布的中表示，在使用皮肤进行IVPT实验前后需要测量皮肤的完整性，且皮肤电阻率测定法是推荐方法之一。

经皮水分流失测量仪——皮肤完整性检测仪器

• 通过测量TEWL值来反映皮肤屏障的完整性；用于体外透皮试验(IVPT)中离体皮肤的完整性评价(SIFT)；

• 可单独使用或与电脑连接一起使用；

• 便携，无电线，可轻松测量。

2022年10月FDA发布的中表示，在使用皮肤进行IVPT实验前后需要测量皮肤的完整性，且经皮水分流失测定法是推荐方法之一。

Advantages of complete volume removal/replacement

• Simplify flux calculation

• Close to In Vivo situation

• Help solubilize a hydrophobic analyte and maintain sink

• Avoiding the occurrence of negative flux values as sometimes occurs with slow/low penetrating compounds when aliquot sampling is used

全部取样/补液的优势：

• 简化通量计算

• 接近体内情况

• 有助于溶解亲脂性分析物并维持溶液

• 避免使用等分采样时，有时会出现负通量值的情况，特别是对于慢速/低渗透化合物

Adventives of partial volume removal/replacement

• Easy to handle sample collections during manual operation

• Giving opportunity to use automated diffusion cells systems

• Sink condition is maintain

• Cumulative amounts are detectable in low level drug presented at early time points samples

部分取样/补液的优势：

• 易于手动操作时处理样品收集

• 提供使用自动扩散池系统的机会

• 保持溶液状态

• 在早期时间点的样品中，可以检测到低水平药物的累积量

More research is required to compare skin absorption profiles obtained with complete and partial volume replacement in IVPT studies

需要进行更多研究来比较在IVPT研究中使用完整和部分体积取样/补液所获得的皮肤吸收曲线。

Fig1 Mean Flux (μg/cm²/hr) Results: Partial volume (0.5 mL) volume withdraw/ replacement at each time points.  Across Donor Summary Percutaneous Absorption of low permeable anaytethrough ex vivo Human Torso Skin over 48 hours from a Single Application.(Mean ±SD, n=6 Donors)

透皮扩散仪VDC 12Plus

透皮扩散仪器是用于外用制剂关键质量属性研究的重要仪器。VDC-12PLUS的设计满足USP<1724>、FDA、EMA、PMDA等法规和指导原则的标准。

一体化设计

一体化设计使得仪器整体尺寸更小，占用空间更少；同时优化管路设计，减少了管路死体积，让实验数据可靠性获得有效提升；

7×2设计

可以两侧设计不同的实验参数，如温度、转速、取样时间。同时每组6+1的设计满足法规要求；一台仪器相当于两台，可以同时完成两组不同实验；

空白位

满足法规要求的空白位设计，在进行IVPT实验时，更方便设计非给药对照组，可排除皮肤基质及其他潜在杂质的干扰。

For some of topical formulations we observed unconventional flux profiles when no maximum peak,  Jmax was identify across multiple subsequent time points even 72hrs or 98hrs IVPT duration.

对于一些局部制剂，我们观察到非常规通量曲线，即在多个连续时间点甚至在72小时或98小时的IVPT持续时间内，未发现最大峰值Jmax。

Fig2 The Percutaneous Absorption of low permeable analyte through ex vivo Human Torso Skin over 96 hours from a single application on individual donors.  Mean on of n=3 skin pieces for each donor is presented.  a) donor 1, with 5 mg/cm²; b) donor 1, with 15 mg/cm²; c) donor 2, with 5 mg/cm²;  d) donor 2, with 15 mg/cm²;

图2 透过体外人体躯干皮肤的低渗透分析物的经皮吸收，从单次应用开始到96小时，对各个供体进行了研究。每个供体的n=3 皮肤片的均值呈现。a）供体1，5 mg/cm²；b）供体1，15 mg/cm²；c）供体2，5 mg/cm²；d）供体2，15 mg/cm²；

There is a need to determine:

- How such profiles can be used in pharmacokinetic endpoints calculation

- If the dose duration method is applicable for such cases

有必要确定：

- 如何将这种曲线用于药代动力学终点的计算

原文在FDA网站搜索：“There are two methodogies that are currently employed to asses skin integrity for IVPT studies. However, there is  not standardized criteria that are available to assess viable skin membranes for use in IVPT”也可以找到原文。