轉(zhuǎn)自：Best Media 以及醫(yī)藥領(lǐng)袖

馬博士，您好,！聽(tīng)了您的講座受益良多,，有幾個(gè)問(wèn)題向您請(qǐng)教：

1、在日本12年公布的《含量不同的口服固體制劑生物等效性試驗(yàn)指導(dǎo)原則》中提到 “附件2溶出曲線校正方法：當(dāng)藥物溶出有滯后現(xiàn)象時(shí),，通常將溶出率達(dá)標(biāo)示量的5%時(shí)所需的時(shí)間稱為“延遲時(shí)間”,。延遲時(shí)間可根據(jù)各自的溶出數(shù)據(jù)、采用內(nèi)差法求得,。當(dāng)參比制劑與試驗(yàn)制劑的溶出有滯后現(xiàn)象時(shí),，應(yīng)扣除參比制劑與試驗(yàn)制劑每條溶出曲線的延遲時(shí)間，求得各自的平均溶出曲線,，再進(jìn)行溶出曲線相似性的比較”,，您對(duì)這個(gè)“延遲時(shí)間”怎么解讀，在一致性評(píng)價(jià)過(guò)程中能否使用,？

答：這是日本12年公布的《含量不同的口服固體制劑生物等效性試驗(yàn)指導(dǎo)原則》中提出的當(dāng)溶出有滯后現(xiàn)象時(shí),采用延遲時(shí)間對(duì)溶出曲線予以校正的方法,。雖然其他類似指導(dǎo)原則中沒(méi)有看到有關(guān)說(shuō)明，個(gè)人認(rèn)為是合理的,，在一致性評(píng)價(jià)過(guò)程中遇到類似情況可以通過(guò)詳細(xì)說(shuō)明予以使用,。

2、如何進(jìn)行BCS分類的查詢 

答： 可以查閱文獻(xiàn),。一些文章列出了大量藥物的BCS分類資料,。下面是一個(gè)例子。

3,、一個(gè)藥品在PH1.2中15分鐘85%以上,，pH4.5 30分鐘-60分鐘內(nèi)達(dá)到90%,，在水中和pH6.8中溶出很低且RSD高，這種情況是這樣算是一個(gè)比較的結(jié)果呢,，還是需要改變?nèi)艹鼋橘|(zhì)（添加SDS）或選取其他介質(zhì)進(jìn)行研究,。 

答：可以試試改變?nèi)艹鼋橘|(zhì)（添加SDS）或選取其他介質(zhì)進(jìn)行研究。如果結(jié)果不理想,，則可能與配方中某種受pH值影響大的輔料含量有關(guān),。需要改進(jìn)配方。

4,、一個(gè)軟膠囊品種,，原研歐洲和亞洲上市,，F(xiàn)DA網(wǎng)站上有公布其溶出度測(cè)定的方法,，我們買到三批不同批號(hào)的原研產(chǎn)品，參照FDA的方法做發(fā)現(xiàn)兩個(gè)問(wèn)題：

1） 原研制劑三批差異較大,；

2）批內(nèi)12片溶出10min,、15min、20min甚至30min的RSD過(guò)大的現(xiàn)象,?？紤]到劑型的特殊性，我們參照FDA公布的其他軟膠囊的溶出方法,，我們將取樣時(shí)間調(diào)整為20,，30，45,，60和90min,，并采用了多種方式優(yōu)化溶出度測(cè)定方法如改變測(cè)定方法、提高轉(zhuǎn)速,、加入胰酶,，甚至提高表面活性劑（LDAO）的用量，優(yōu)化溶出度測(cè)定方法,，均難以降低RSD,，難以采用相似因子f2比較參比制劑和自制制劑溶出曲線的相似性。對(duì)于這種批內(nèi)溶出差異高的制劑老師有什么建議,？ 

答：溶出結(jié)果的RSD確實(shí)在溶出度試驗(yàn)中很重要,。有二大因素將導(dǎo)致溶出結(jié)果的變化。一個(gè)是制造工藝,，另一個(gè)是溶出過(guò)程,。實(shí)際上，很難確定哪一個(gè)因素起的作用大,?？梢詮娜艹銮€對(duì)產(chǎn)品制造工藝和溶出方法進(jìn)行評(píng)價(jià),。例如，如果早期溶出結(jié)果RSD較大,，說(shuō)明方法因素影響較大,，如介質(zhì)，攪拌速度的影響等,。如果軟明膠膠囊2小時(shí)后溶出結(jié)果RSD大于20%,，3小時(shí)后溶出結(jié)果RSD 降為0.5%，說(shuō)明膠囊內(nèi)顆粒的溶出是主要因素,。在膠囊殼開(kāi)口后,，膠囊內(nèi)顆粒溶出變化較大。而3小時(shí)后溶解速度減小,，藥物釋放降低,。因此，膠囊內(nèi)顆粒溶出對(duì)RSD影響減小,。你的情況可能還是要從方法上下功夫,。 象介質(zhì)，攪拌速度,，取樣,，過(guò)濾等都會(huì)影響測(cè)定結(jié)果。

5,、在《普通口服固體制劑溶出曲線測(cè)定與比較指導(dǎo)原則》其他項(xiàng)下提到“當(dāng)溶出曲線不能采用相似因子（f2）法比較時(shí),，可采用其他適宜的比較法，但在使用時(shí)應(yīng)給予充分論證,?！保镀胀诜腆w制劑溶出度試驗(yàn)技術(shù)指導(dǎo)原則》中也提到的溶出批內(nèi)差異較大時(shí)可采用非模型依賴多變量置信區(qū)間法進(jìn)行溶出比較,，想向您請(qǐng)教下這種方法的可行性,？能否舉例說(shuō)明如何具體操作？

答：“普通口服固體制劑溶出度試驗(yàn)技術(shù)指導(dǎo)原則”中有關(guān)非模型依賴多變量置信區(qū)間法 對(duì)于批內(nèi)溶出量相對(duì)標(biāo)準(zhǔn)偏差大于15%的產(chǎn)品,， 可能更適于采用非模型依賴多變量置信區(qū)間方法進(jìn)行溶出曲線比較,。建議按照下列步驟進(jìn)行：

（1）測(cè)定參比樣品溶出量的批間差異，然后以此為依據(jù)確定多變量統(tǒng)計(jì)矩（Multivariate statistical distance,，MSD）的相似性限度,。 

（2）確定受試和參比樣品平均溶出量的多變量統(tǒng)計(jì)矩。 

（3）確定受試和參比樣品實(shí)測(cè)溶出量多變量統(tǒng)計(jì)矩的90%置信區(qū)間,。 

（4）如果受試樣品的置信區(qū)間上限小于或等于參比樣品的相似性限度,，可認(rèn)為兩個(gè)批次的樣品具有相似性。

比較復(fù)雜,。找到一篇文章,。你自己去讀,。

Model Independent Approaches One such model is the independent multivariate confidence region procedure (Bootstrap approach) method. Bootstrap allows for the use of f2, not as a point estimator but as a confidence interval, thus overcoming concerns encountered when f2 is used solely as a point estimate. Computation of the bias corrected and accelerated (BCA) confidence intervals is suggested. The bootstrap method simulates the distribution of f2 values to determine whether or not two profiles exhibit comparable in vitro behavior. (6,9) This can include the following steps: 

1. Generate N bootstrap samples (e.g., N = 1000) by resampling independently with replacement from dissolution data for the test and reference groups. 

2. Calculate f2 values from N bootstrap samples. 

3. Calculate the bias correction statistic to correct for the potential skewed distribution of f2 derived from the bootstrap samples. This can be achieved by calculating the acceleration statistic (i.e., the rate of change of the standard error of the estimate of the sample statistic) by obtaining n jackknife samples (e.g., n = 24) derived from original dissolution data

4. Calculate lower and upper bounds of the confidence interval using type 1 error, f2 values of N bootstrap samples, bias correction, and acceleration statistics.

To declare similarity between test and reference dissolution profiles, the lower bound of the confidence interval must equal 50 or more. To illustrate, the bootstrap method was applied by the FDA when they evaluated the reformulated 400 mg mesalamine delayed-release (MDR) (DelzicolTM) against the original 400 mg mesalamine modified-release tablets (10). The newly marketed MDR capsule and discontinued tablet (Asacol?) formulations have a pH-dependent release mechanism designed to delay release until the formulation reaches the distal gastrointestinal (GI) tract (pH~6.5), thus, increasing the level of exposure to the colon in patients with ulcerative colitis. The dissolution characteristics and pharmacokinetics of these MDR capsules and tablets are highly variable. As part of the reformulation program to market the capsule formulation, the similarity of dissolution profiles to the original MDR tablet formulation were needed across various pH values to provide the necessary assurance of comparable product performance (10). For modified-release oral dosage forms such as DelzicolTM that are developed for targeted local drug delivery within the GI tract, the dissolution profiles must contain at least three timepoints (11). As stated in the SUPAC MR 1997 guidance, “Adequate sampling should be performed, for example, at 1, 2, and 4 h and every two hours thereafter until either 80% of the drug from the drug product is released or an asymptote is reached.” (12) (Fig. 1).

Fig. 1 Modified-release dissolution time points A multipoint dissolution profile comparison was generated between the mesalamine capsules and tablets over a range of pH values (pH 4.5, 6.0, 6.5, 6.8, 7.2, and 7.5). The similarity factors (f2) values were calculated and provided for each dissolution media. Figure 2 displays the dissolution profiles before and after the formulation change at pH at 7.2, for which the f2 value was calculated to be 55.5 by the applicant. The variability (%RSD) in the dissolution data was very high at the 15- (170.1%), 30- (80.9%) and 45- (33.4%) min time points. Because of this, the f2 test could not be used and the FDA applied the model independent bootstrap approach.

Example: bootstrap versus original method for f2 determination results

Fig. 2 Example: bootstrap versus original method for f2 determination results The bootstrap lower confidence interval with a bias correction was equal to 49.8. The FDA accepted this value in demonstrating similarity of the two products. The bootstrap method should not be used to improve an f2 but rather it should be used as a mechanism for dealing with the issue of data variability. It is noted that there is an open software available for the bootstrap calculation (13).