Vertzoni Maria, Fotaki Nikoletta, Kostewicz Edmund, Stippler Erika, Leuner Christian, Nicolaides Eleftheria, Dressman Jennifer, Reppas Christos
Laboratory of Biopharmaceutics and Pharmacokinetics, University of Athens, Athens, Greece.
J Pharm Pharmacol. 2004 Apr;56(4):453-62. doi: 10.1211/0022357022935.
The objective of this study was to test various aspects of dissolution media simulating the intralumenal composition of the small intestine, including the suitability of the osmolality-adjusting agents and of the buffers, the substitution of crude sodium taurocholate (from ox bile) for pure sodium taurocholate and the substitution of partially hydrolysed soybean phosphatidylcholine for egg phosphatidylcholine. It was concluded that biorelevant media should contain sodium as the major cation species to better reflect the physiology. However, the use of non-physiologically relevant buffers is inevitable, especially for simulation of the fed state in the small intestine. The buffers used may affect the solubility product of weakly basic compounds with pK(a)(s) higher than about 5, the solubility of extremely highly lipophilic compounds due to salting in/out properties of the anion of the buffer and the stability of the dissolving compound. It is prudent in relevant situations to run an additional dissolution test in a modified fed state simulated intestinal fluid (FeSSIF) (or fasted state simulated intestinal fluid (FaSSIF), where applicable) containing alternative buffer species. Although a mixture of bile salts is physiologically more relevant than pure sodium taurocholate, this issue seems to be of practical importance in only a few cases. Adequate simulations in these cases will probably require the use of a number of pure substances and could substantially increase the cost of the test. Finally, unless the drug is extremely lipophilic (ca. logP> 5), egg phosphatidylcholine can be substituted by partially hydrolysed soybean phosphatidylcholine.
本研究的目的是测试模拟小肠肠腔内成分的溶出介质的各个方面，包括渗透压调节剂和缓冲剂的适用性、用粗制牛磺胆酸钠（来自牛胆汁）替代纯牛磺胆酸钠以及用部分水解的大豆磷脂酰胆碱替代鸡蛋磷脂酰胆碱。得出的结论是，生物相关介质应以钠作为主要阳离子物种，以更好地反映生理情况。然而，使用非生理相关的缓冲剂是不可避免的，尤其是在模拟小肠的进食状态时。所使用的缓冲剂可能会影响pK(a)高于约5的弱碱性化合物的溶度积、由于缓冲剂阴离子的盐析/盐溶性质而对极高度亲脂性化合物的溶解度以及溶解化合物的稳定性。在相关情况下，谨慎的做法是在含有替代缓冲剂种类的改良进食状态模拟肠液（FeSSIF）（或适用时的禁食状态模拟肠液（FaSSIF））中进行额外的溶出试验。虽然胆盐混合物在生理上比纯牛磺胆酸钠更相关，但这个问题似乎仅在少数情况下具有实际重要性。在这些情况下进行充分的模拟可能需要使用多种纯物质，并且可能会大幅增加测试成本。最后，除非药物具有极高的亲脂性（约logP>5），鸡蛋磷脂酰胆碱可以用部分水解的大豆磷脂酰胆碱替代。
