Stabilization mechanism of limaprost in solid dosage form

Yamamoto

et al. 2015

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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 F 2α (PGF 2α ) 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 PGF 2α and protons of both α-and β-CDs, suggesting that PGF 2α 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 -PGA 1 (11-deoxy-Δ 10 ) and 17S,20-dimethyl-trans-Δ 2 -8-iso-PGE 1 (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.Key words Limaprost alfadex; α-cyclodextrin; β-cyclodextrin; ternary inclusion complex; NMR spectroscopy; kinetics α-, β-and γ-Cyclodextrins (CDs) are cyclic oligosaccharides in which six, seven and eight D-glucose units, respectively, are linked by α-1,4 glycosidic bonds.

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confidence: 99%

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

Inoue

Yamamoto

et al. 2015

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“…And near infrared spectroscopic study and solid NMR study showed that molecular mobility of ingredients are different and that water mobility in each ingredient are different. 4) These were suggested to affect the stability of Limaprost in each formulation. In this report we studied the effect of inclusion complex formation with CyD on the stability of Limaprost.…”

Section: Resultsmentioning

confidence: 99%

Improved Stability of OPALMON Tablets under Humid Conditions IV: Effect of Polysaccharides and Disintegrants on the Stability and Dissolution Property of OPALMON Tablets

Nishiwaki

Nishiura

et al. 2008

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Opalmon tablet is the first oral drug containing prostaglandin E 1 (PGE 1 ) derivative as a pharmaceutical preparation for the circulatory system. Opalmon was approved and marketed for the adaptation disease of "confinement-related thromboangiitis ulcer, sharp pain and anaphrodisia and ischemia characteristics symptom" and "the improvement of subjective symptom and walking ability with postnatal lumbar spinal canal stenosis". Opalmon tablets contain the active pharmaceutical ingredient (API) Limaprost-alfadex, which is the inclusion complex of Limaprost, a PGE 1 derivative, with a-cyclodextrin (a-CyD). The main degradation product under high humidity is 17S,20-dimethyl-trans-D 2 -PGA 1 (11-deoxy-D 10 , Fig. 1). The aim of this study was to improve the chemical stability of unpackaged Limaprost-alfadex under high humidity. We found that the chemical stability of Limaprost-alfadex was significantly improved by adding dextran and dextrin to the tablet formulation.1,2) To supply improved Opalmon tablets containing the freeze-dried composite of Limaprost-alfadex with dextran for moisture resistance, the new formulation must satisfy the Japanese guidelines for bioequivalence studies for formulation changes in oral drugs.3) Furthermore, the dissolution property of the new formulation containing the freeze-dried Limaprost-alfadex and dextran has to be equivalent to that of the former lactose formulation containing freeze-dried Limaprost-alfadex and lactose. We herein report the effect of various tablet ingredients, including dextran, dextrin, lactose and some disintegrants, on the chemical stability, dissolution property, and stickiness of the tablet. Furthermore, we examined how these polysaccharides stabilize Limaprost in the tablets. ExperimentalMaterials Limaprost-alfadex is specified in the Japanese Pharmaceutical Codex 2002. All excipients used were purchased with the following specifications. Lactose, dextran 40, cornstarch, dextrin, silicon dioxide and stearic acid are specified in Japanese Pharmacopoeia 15 (JP15). Calboxymethylstarch sodium is specified in the Japanese Pharmaceutical Excipients. The glucose chemical equivalence of dextrin is 8.Opalmon Tablet Preparation To study the effect of dextran/dextrin on the chemical stability of Opalmon, tablets were prepared at different weight ratios as shown in Table 1. The freeze-dried composite (i.e. Limaprost-alfadex and dextran 40) was prepared as follows: Limaprost-alfadex and the appropriate excipient were dissolved in distilled water at a ratio of 1 : 7 (w/w), freeze-dried, (Triomaster, Kyowa Vacuum Engineering Ltd.) and then sieved. Dextrin, lactose and stearic acid were blended and compressed with a rotary tablet press (Virgo, Kikusui Seisakusyo Ltd.). Tablets of 100 mg/6.5 mm in diameter were prepared at 800 kg compression force. To test stability, ; 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. Received May 7, 2007; accepted October 28, 2007 We studied the effects of dextran, dextrin, and disintegrants on the chemical stability of Opalmon tablets contain...

“…Trehalose did not improve the chemical stability of Limaprost, probably because trehalose is reported to stabilize mainly thermal degradations, [16][17][18][19][20][21] but not water-catalyzed degradations, and its stabilizing ability decreases under higher humidity conditions, as demonstrated in the insulin/ trehalose system. 22) On the other hand, dextran improved the stability of Limaprost alfadex, [23][24][25][26][27] which is utilized for the new formulation of Opalmon ® tablets since 2006. The product specification for purity of this formulation is maintained for two months at 25°C, 75%R.H., but at a higher humidity (30°C, 75%R.H.…”

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confidence: 99%

Stabilizing Effect of β-Cyclodextrin on Limaprost, a PGE<sub>1</sub> Derivative, in Limaprost Alfadex Tablets (Opalmon®) in Highly Humid Conditions

Inoue

Katayama

et al. 2014

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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.