Moriyama Kei, Takami Yoichiro, Uozumi Natsuki, Okuda Akiko, Yamashita Mayumi, Yokomizo Rie, Shimada Kenichi, Egawa Takashi, Kamei Takehito, Takayanagi Kazunobu
Shujitsu University, School of Pharmacy, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516 Japan.
Department of Pharmacy, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602 Japan.
J Pharm Health Care Sci. 2016 Feb 10;2:4. doi: 10.1186/s40780-016-0038-7. eCollection 2016.
Atropine sulfate is an anticholinergic agent for treatment of hypertrophic pyloric stenosis and is orally administrated as a triturate with lactose hydrate. Because of the low safety margin of atropine sulfate, triturate uniformity is a key safety factor. In this study, we assessed the uniformity of atropine sulfate in 1000-fold triturates prepared by wet mixing and dry mixing methods and discussed the cause of the difference in uniformity between two preparation methods.
A 1000-fold triturate of atropine sulfate with lactose hydrate was prepared by two different methods: wet mixing and dry mixing. The wet mixing was performed according to Kurashiki Central Hospital protocol and the dry mixing was a simple physical mixing by a rocking mixer. The uniformity of atropine sulfate content in aliquots of a 1000-fold triturate with lactate hydrate was assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantification. Solid-state analyses of the triturates by Raman chemical imaging and X-ray powder diffraction (XRPD) were performed to investigate the difference in uniformity.
The LC-MS/MS quantification showed that the uniformity of atropine sulfate in the 1000-fold triturate was excellent for wet mixing but was significantly variable for dry mixing. On the basis of the Raman chemical imaging and XRPD analyses, it was indicated that an amorphous thin film of atropine sulfate coated the surfaces of the lactose hydrate particles during wet mixing and contributed to the uniformity of the triturate. In contrast, clusters of the crystalline atropine sulfate were found in the dry mixing samples.
The results showed that better atropine sulfate triturate uniformity was achieved using the wet mixing method rather than the dry method and the cause of the uniformity difference between two mixing methods was indicated by the multilateral assessment.
硫酸阿托品是一种用于治疗肥厚性幽门狭窄的抗胆碱能药物，以与水合乳糖的研磨剂形式口服给药。由于硫酸阿托品的安全范围较窄，研磨剂的均匀性是一个关键的安全因素。在本研究中，我们评估了通过湿法制粒和干法制粒方法制备的1000倍研磨剂中硫酸阿托品的均匀性，并探讨了两种制备方法之间均匀性差异的原因。
通过两种不同的方法制备硫酸阿托品与水合乳糖的1000倍研磨剂：湿法制粒和干法制粒。湿法制粒按照仓敷中央医院的方案进行，干法制粒是通过摇摆混合器进行的简单物理混合。通过液相色谱-串联质谱（LC-MS/MS）定量法评估1000倍含乳酸水合物研磨剂等分试样中硫酸阿托品含量的均匀性。通过拉曼化学成像和X射线粉末衍射（XRPD）对研磨剂进行固态分析，以研究均匀性的差异。
LC-MS/MS定量分析表明，1000倍研磨剂中硫酸阿托品的均匀性在湿法制粒时极佳，但在干法制粒时差异显著。基于拉曼化学成像和XRPD分析，表明在湿法制粒过程中，硫酸阿托品的无定形薄膜覆盖在水合乳糖颗粒表面，有助于研磨剂的均匀性。相比之下，在干法制粒样品中发现了结晶硫酸阿托品的聚集体。
结果表明，使用湿法制粒方法比干法制粒方法能获得更好的硫酸阿托品研磨剂均匀性，并且通过多方面评估指出了两种混合方法之间均匀性差异的原因。
