Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE₁ Derivative, in Limaprost Alfadex Tablets (Opalmon®) in Highly Humid Conditions

Abstract

Stabilization against humidity of Limaprost (a prostaglandin E 1 derivative), which is currently marketed as Opalmon ® , was undertaken using β-cyclodextrin (β-CD). Aqueous solutions of Limaprost alfadex/dextran 40 were lyophilized with and without β-CD. Limaprost alfadex lyophilized with β-CD was more chemically stable in humid conditions than that without β-CD. Moreover, the addition of β-CD as an excipient to tablets of these lyophilized composites remarkably improved the stability of Limaprost, and Limaprost in this moisture-resistant formulation was chemically stable for 19 weeks at 30°C, 75% relative humidity (R.H.). Chemical analysis of Limaprost and its degradation products indicated that degradation proceeded in the inclusion form (i.e., within the CD cavity). Solid 2 H-NMR spectroscopic studies showed that β-CD constrained the molecular mobility of water in the solid state. These results suggested that the stabilization of Limaprost by β-CD was at least partly due to the restricted molecular mobility of water, which acted as a catalytic species for the degradation, and also to the protection of the five-membered ring of Limaprost from water catalytic dehydration through inclusion complex formation with β-CD.

Ternary inclusion complex formation and stabilization of limaprost, a prostaglandin E 1 derivative, in the presence of α- and β-cyclodextrins in the solid state

“…The ternary inclusion complex was prepared by freeze-drying the limaprost/CDs solution at a ratio of limaprost:a-CD:b-CD = 1:3.5:3.5. In previous papers (Moribe et al, 2007;Inoue at al., 2014b), we reported that the molar ratio of limaprost: a-or b-CD did not significantly affect the degradation of the drug in the range of 1:3.5-1:12. Therefore, the lowest molar ratio of 1:3.5 was selected from viewpoints of the solubilization of the drug by CDs and the detection limit of solid state NMR peaks described later.…”

“…Therefore, it is important to ensure drug stability under humid conditions, especially in the case of one-dose packages from which tablets or capsules are removed and placed in a non-waterproof paper bag. In previous papers, we reported that the stability of limaprost alfadex (lyophilized composite) containing dextran was improved by the addition of b-CD (Inoue et al, 2014b). The stability of limaprost alfadex in the dextran/b-CD composite was further improved by the addition of b-CD as an external excipient in tablets.…”

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients

“…It is a commercially available tablet containing the α-CyD complex, namely limaprost alfadex. 23,24) The tablet form ensures its dose uniformity and increases the aqueous solubility of limaprost. Limaprost alfadex tablet (Opalmon) is chemically stable for 3 or more years under airtight conditions.…”

“…24) Therefore, it is vital to warrant its stability under humid conditions, particularly in the case of single-dose packages from which tablets are removed and placed in a non-waterproof paper bag. Thus far, Inoue et al 23) reported that the stability of limaprost alfadex including dextran was increased by addition of β-CyD. Also, the stability of limaprost alfadex in the dextran/β-CyD composite was further increased by addition of β-CyD as an external excipient in tablets.…”

Characterization of α-Glucosidase Inhibitor/Cyclodextrin Complex Prepared by Freeze-Drying

“…For example, formulation of an inclusion complex made of itraconazole, a sparingly soluble antifungal agent, and hydroxypropyl- β CD [4] increased the solubilization of the drug. Additionally, formulation of an inclusion complex made of limaprost, a prostaglandin E 1 derivative that is unstable to moisture, and α -cyclodextrin [5] increased the drug's stability. Further, masking a drug with cyclodextrin decreased the bitter taste of the drug [6].…”