首页 > 资讯 > 速释固体口服制剂溶出度检测新观点

出自识林

2015-08-02

FDA日前发布了一份名为《含有BCS I类与III类药物的速释口服固体制剂的溶出度试验与质量标准》的指南草案，这与稍早前同样针对速释口服固体制剂所发布的有关生物等效性试验豁免的指南草案不无联系。

BCS I类与III类是基于药品在生理pH范围内有较高的溶解度而定义的，如果设计成传统的速释剂型（主要是片剂和胶囊），能较快的释放，则也可能适用于生物等效性试验豁免——只要按照生物等效性豁免指南中详细阐述的条件，证明该药品达到易溶的标准即可。而这份新的指南草案，介绍了常规的溶出度试验，即所谓的“QC放行用”溶出度检测。

该指南草案以定义“适用的药品”作开头，指出定义为“适用的药品”需考虑满足下列六条规则：

• 必须是口服（吞咽）的速释剂型，须注意咀嚼片与口崩片不在此指南考虑范围内。
• 原料药若满足“高溶解”定义，必须满足在250毫升或更少的液体介质中，在从pH为1到pH为6.8的范围下，足以溶出单位制剂的最高剂量。该原料药还需在此化学环境下稳定存在至少24小时。
• 该指南并不适用于窄治疗指数（narrow therapeutic index，NTI）药物。在2012年12月所发布的法华林钠生物等效性指南中，对于窄治疗窗这一例外作了一定的介绍。GDUFA以后，OGD从350人增加到1300余人，应该专门就NTI起草一份技术指南，而不是在单个药品的生物等效性指南里逐一解释。
• 如果“达到最大血药浓度的时间”是药品达到预期用途所需考虑的关键因素，则该指南并不适用。这样看来，指南所圈定的范围可能不是所有的BCS I类与III类，而是几乎排除了传统可吞咽速释片剂之外的所有剂型，总之略显保守。
• 在药品的生产、检验包括稳定性研究期间，均需证明此产品满足溶出度标准。
• 辅料必须“与速释制剂的设计相适应”，须有“与药品标签上注明的功能相适应的正常用量”，“某些特殊辅料，如矫味剂与表面活性剂的大量使用，可能造成问题”。由于我们已经确定药品是含有高溶解性原料药的可吞咽剂型，上述假设似乎并不会构成问题。

如果药品及其剂型满足上述条件，给出了以下两种推荐的溶出度试验以供选择

• USP1型溶出仪，100转每分钟，500毫升0.01摩尔每升盐酸，37±0.5°C，无表面活性剂
• USP2型溶出仪，75转每分钟，500毫升0.01摩尔每升盐酸，37±0.5°C，无表面活性剂

这似乎是相当合理的条件。选择这些转速可以减少在转篮或桨的正下方无法搅动的“死区”形成锥形堆积。即使定义已要求原料药在250毫升的体积内（与生物等效性试验一杯水的体积相仿）可达到较高的溶解性，500毫升依然是保证溶出仪正常工作的最低容量。相应的质量标准如下

• BCS I类药品，30分钟时单点测试，Q值为80%
• BCS III类药品，15分钟时单点测试，Q值为80%

如我们在分析生物等效性豁免指南草案时所说，针对BCS III类药品设有更严格的标准。或许FDA也难以确定BCS III类药品在各种情况下能否生物等效，足以豁免相关试验。但无论如何，这并不影响本指南提出上述溶出度试验条件。

最后一点，该指南草案还允许以崩解试验替代溶出度试验。该试验应使用USP崩解仪，0.01摩尔每升盐酸，片剂应在五分钟内崩解完全。指南指出应选择溶出度试验作为首选方法，而崩解试验可作为替代方法。与溶出度试验相比，崩解试验如用于日常产品放行检验，可以更快的得到结果，甚至可能在中间过程中就能完成。

总之，这是一份有所建树的指南草案，提出了相对灵敏而简单的溶出度试验条件，并为日常产品放行检验提供崩解试验作备选。

作者：识林-Pepper
编译：识林-葳
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Original Version
FDA has released a draft Guidance titled “Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs”. This is a companion to the recently issued draft guidance on Biowaivers for these same dosage forms.

BCS Class 1 & 3 drugs are highly soluble across the physiological pH range and so are eligible for biowaiver in conventional IR dosage forms (mainly tablets and capsules) provided the dosage form rapidly releases these highly soluble drugs. The solubility characteristics of the dosage form must be demonstrated as detailed in the biowaiver guidance. This new draft guidance addresses routine dissolution testing, that is the so-called “QC Test” for dissolution.

The draft guidance begins by defining “eligible products”. There are 6 criteria that must be met for a dosage form to be considered “eligible”. These are:

• It must be an orally administered (swallowed) IR dosage form. Note that chewable and orally disintegrating dosage forms are not covered by this guidance.
• The drug substance must meet the “highly soluble” criteria of the highest dosage strength dissolving in 250 mL or less of aqueous media over the pH range 1 to 6.8. The drug substance must also be chemically stable for 24 hours under these conditions
• This guidance does not apply to narrow therapeutic index drugs. As an interesting aside it states that NTI classification is described in the Warfarin Sodium bioequivalence guidance issued December 2012. You would think with over 1300 people someone could get that into an NTI guidance.
• If the “time to maximum plasma concentration” is critical to the intended use then this guidance does not apply. I guess BCS 1 & 3 is not necessarily BCS 1 & 3. They have already excluded everything except a standard swallowed IR tablet, how special can it be?
• The manufacturing and testing history, including stability, should demonstrate that the product will meet dissolution specifications.
• Excipients should be “consistent with the design of IR drug products”. Excipients should be in “normal quantities that are consistent with the product’s labeled function”. “Large quantities of excipients, such as sweeteners and surfactants, may be problematic”. Since we have already established that these dosage forms are swallowed and contain highly soluble drug substances, this shouldn’t be a problem.

If the drug and its dosage form meet these conditions, then the dissolution test is defined as one of two possibilities.

• USP Apparatus 1, 100 rpm, 500 mL, 0.01 M HCL, 37±0.5°C (No Surfactant)
  
• USP Apparatus 2, 75 rpm, 500 mL, 0.01M HCl, 37±0.5°C (No Surfactant)
  

These seem very reasonable methods to use. The stirring speeds are chosen to minimize artifacts such as cone formation in the unstirred “dead space” directly under the basket or paddle. Although the volume of media used to determine that the drug substance is highly soluble is 250 mL (related to the glass of water used in biostudies), 500 mL is the minimum volume that allows normal functioning of the dissolution apparatus.

The specifications to be used are as follows.

• For BCS 1 products, a single point of Q=80% in 30 minutes
• For BCS 3 products, a single point of Q=80% in 15 minutes

As was foreshadowed in the biowaiver draft guidance, the tighter criteria is required for BCS 3 products because FDA is not certain that all BCS 3 situations will be bioequivalent and therefore qualify for the biowaiver. In any case it should not be a problem with the dissolution tests given in this guidance.

Finally the draft guidance allows the replacement of the dissolution test with a disintegration test. The test would use the USP disintegration apparatus and 0.01 M HCl and the dosage form should disintegrate completely in 5 minutes. The dissolution test must be retained as the primary method with the disintegration test as an alternate method. This will allow much quicker testing than the dissolution test for routine product release testing, it could even be done in-process.

Overall a positive draft guidance which proposes sensible and simple dissolution tests and has an added gift of a disintegration test option for routine finished product testing.

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