Noboru Sekiya

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.

Effects of novel cathepsin K inhibitor ONO-5334 on bone resorption markers: a study of four sustained release formulations with different pharmacokinetic patterns

The purpose of the study was clarify the effect of the cathepsin K inhibitor ONO-5334 on bone resortion markers using sustained release (SR) formulations with different pharmacokinetic (PK) patterns, and identify the optimal SR formulation. The PK profiles and pharmacodynamic effect on bone resorption markers of 4 SR candidates formulations were evaluated in healthy postmenopausal women within a randomized, 2-part, open-label crossover study. In Part A, subject received a single dose of each formulation orally in the fed state. In Part B, two selected formulations were evaluated in the fasted state. From the results from Part A, Cmax was reduced and plasma concentrations of ONO-5334 were sustained with all SR formulations compared with an immediate release tablet. In pharmacodynamics, the level of C-terminal telopeptide of type I collagen (CTX) in serum and urine were inhibited with SR tablets rather than with granules. Cmax and area under the concentration–time curve from time 0 to the last measurable time point (AUC0−t) of SR tablets were higher than those of granules. From Part B, Cmax in the fasted condition was lower than that in the fed condition with two SR tablets. In contrast, C24 h in the fasted condition was slightly higher than that in the fed condition, but AUC0−t was similar. The inhibitory effect on CTX in serum and urine may depend on the PK pattern of ONO-5334. The SR tablets was well tolerated in postmenopausal women and has the optimal SR profiles on pharmacodynamics effect on bone resortion markers and PK profile. These results suggest that SR tablets of ONO-5334 are an excellent drug candidate for osteoporosis.

Formation of the Ternary Inclusion Complex of Limaprost with α- and β-Cyclodextrins in Aqueous Solution

The inclusion mode of Limaprost in the presence of α- and β-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of β-CD in the solid state. The inclusion sites of α- and β-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of α- and β-CDs, displacements in (13)C chemical shifts of prostaglandin F2α (PGF2α) were observed in the ω-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both α- and β-CDs. In two-dimensional (2D) (1)H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF2α and protons of both α- and β-CDs, suggesting that PGF2α interacts with α- and β-CDs to form a ternary complex by including the ω-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Δ(2)-PGA1 (11-deoxy-Δ(10)) and 17S,20-dimethyl-trans-Δ(2)-8-iso-PGE1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ(10), while β-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both α- and β-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/α-CD/β-CD complex.