A novel solubilization technique for poorly soluble drugs through the integration of nanocrystal and cocrystal technologies

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• 作者：Masatoshi Karashima ; ^{masatoshi.karashima@takeda.com" class="auth_mail" title="E-mail the corresponding author} ; Kouya Kimoto ; Katsuhiko Yamamoto ; Takashi Kojima ; Yukihiro Ikeda
• 关键词：ACT ; acetamide ; BCS ; biopharmaceutical classification system ; CAF ; caffeine ; CBZ ; carbamazepine ; CCF ; cocrystal former ; CYT ; cytosine ; DH ; dihydrate ; FSD ; furosemide ; GCDC ; glycochenodeoxycholate ; HPMC ; hydroxypropyl methylcellulose ; IMC ; indomethacin ; NIC ; nicotinamide ; PVDF ; polyvinylidene difluoride ; SAC ; saccharin ; SDS ; sodium dodecyl sulfate
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：107
• 期：Complete
• 页码：142-150
• 全文大小：1520 K

文摘

The aim of the present study was to develop a novel solubilization technique consisting of a nano-cocrystal suspension by integrating cocrystal and nanocrystal formulation technologies to maximize solubilization over current solubilizing technologies.

Monodisperse carbamazepine–saccharin, indomethacin–saccharin, and furosemide–caffeine nano-cocrystal suspensions, as well as a furosemide–cytosine nano-salt suspension, were successfully prepared with particle sizes of less than 300 nm by wet milling with the stabilizers hydroxypropyl methylcellulose and sodium dodecyl sulfate. Interestingly, the properties of resultant nano-cocrystal suspensions were dramatically changed depending on the physicochemical and structural properties of the cocrystals. In the formulation optimization, the concentration and ratio of the stabilizers also influenced the zeta potentials and particles sizes of the resultant nano-cocrystal suspensions. Raman spectroscopic analysis revealed that the crystalline structures of the cocrystals were maintained in the nanosuspensions, and were physically stable for at least one month. Furthermore, their dissolution profiles were significantly improved over current solubilization-enabling technologies, nanocrystals, and cocrystals.

In the present study, we demonstrated that nano-cocrystal formulations can be a new promising option for solubilization techniques to improve the absorption of poorly soluble drugs, and can expand the development potential of poorly soluble candidates in the pharmaceutical industry.