Ternary inclusion complex formation and stabilization of limaprost, a prostaglandin E1 derivative, in the presence of α- and β-cyclodextrins in the solid state

• Published in: International journal of pharmaceutics Vol. 509; no. 1-2; pp. 338 - 347
• Main Authors: Inoue, Yasuo, Iohara, Daisuke, Sekiya, Noboru, Yamamoto, Masanobu, Ishida, Hiroyuki, Sakiyama, Yoko, Hirayama, Fumitoshi, Arima, Hidetoshi, Uekama, Kaneto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25-07-2016
• Subjects: alpha-Cyclodextrins - chemistry; Alprostadil - analogs & derivatives; Alprostadil - chemistry; beta-Cyclodextrins - chemistry; Chemistry, Pharmaceutical - methods; Crystallization - methods; Cyclodextrin; Excipients - chemistry; Freeze Drying - methods; Limaprost; Magnetic Resonance Spectroscopy - methods; Pharmaceutical Solutions - chemistry; Solid state; Solubility; Stability; Ternary inclusion complex; Solid state; Cyclodextrin; Stability; Limaprost; Ternary inclusion complex
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2016.06.018

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Limaprost/α-cyclodextrin (CD)/β-CD ternary inclusion complex was prepared by freeze-drying a solution containing all three components. Under humid conditions, limaprost was more stable in the ternary α-/β-CD inclusion complex than in the binary α- or β-CD complex. Specifically, during storage at 30°C/75% relative humidity (R.H.) for 4 weeks, about 19% of limaprost degraded into 17S,20-dimethyl-trans-Δ2-prostaglandin A1 (referred as 11-deoxy-Δ10) in the β-CD complex, 8.1% degraded in the α-CD complex, and only 2.2% degraded in the α-/β-CD complex. The mechanism of limaprost stabilization in the presence of both CDs was investigated by Raman and solid-state NMR spectroscopy and powder X-ray diffractometry. The fast degradation of limaprost to 11-deoxy-Δ10 in the β-CD complex was due to the rapid crystallization of β-CD from the complex, liberating the free amorphous drug, which is susceptible to degradation. The dissociation and crystallization of β-CD from the inclusion complex were suppressed by freeze-drying limaprost in the presence of both α- and β-CDs. In addition, the interaction between limaprost and the two CDs was reinforced by inclusion of different moieties of limaprost: α-CD predominantly included the alkyl ω-chain, whereas β-CD included the five-membered ring. Thus, a stable ternary inclusion complex was formed that included limaprost, maintaining the amorphous state of the complex and dramatically stabilizing the drug under humid conditions.