Ternary inclusion complex formation and stabilization of limaprost, a prostaglandin E1 derivative, in the presence of α- and β-cyclodextrins in the solid state.
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-Δ(2)-prostaglandin A1 (referred as 11-deoxy-Δ(10)) 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-Δ(10) 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.
CMC Regulatory and Analytical R&D, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan. Electronic address: ya.inoue@ono.co.jp.
Yasuo
Y
Inoue
Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
Daisuke
D
Iohara
Pharmaceutical Development Laboratories, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
Noboru
N
Sekiya
CMC Strategy Development, Ono Pharmaceutical Co., Ltd., 8-2, Kyutaromachi 1-chome, Chuo-ku, Osaka 541-8564, Japan.
Masanobu
M
Yamamoto
Toray Research Center, Inc., 3-7 Sonoyama 3, Otsu, Shiga 520-8567, Japan.
Hiroyuki
H
Ishida
Toray Research Center, Inc., 3-7 Sonoyama 3, Otsu, Shiga 520-8567, Japan.
Yoko
Y
Sakiyama
Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
Fumitoshi
F
Hirayama
Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Hidetoshi
H
Arima
Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan.
Kaneto
K
Uekama
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization / Q000379:methods; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D019999:Pharmaceutical Solutions / Q000737:chemistry; D012995:Solubility; D047391:alpha-Cyclodextrins / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
D005079:Excipients; D019999:Pharmaceutical Solutions; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; D000527:Alprostadil; C059238:limaprost
Cyclodextrin; Limaprost; Solid state; Stability; Ternary inclusion complex