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Development of novel montelukast sodium-loaded oral solution and suspension

Title
Development of novel montelukast sodium-loaded oral solution and suspension
Author
김영훈
Alternative Author(s)
Young Hun Kim
Advisor(s)
최한곤
Issue Date
2015-08
Publisher
한양대학교
Degree
Doctor
Abstract
Development of novel montelukast sodium-loaded oral solution and suspension Part I : Novel montelukast sodium–loaded clear oral solution with enhanced stability and bioequivalence to commercial granules in rats To develop a montelukast sodium–loaded clear oral solution with enhanced stability that was bioequivalent to commercial granules in rats for the treatment of asthma, various montelukast sodium–loaded solutions were prepared with various amounts of solubilizers and stabilizer, and their solubility and stability were investigated. Furthermore, the dissolution and pharmacokinetic studies were carried out in rats with the optimised formulation and the commercial montelukast sodium–loaded granules.Among the solubilizers tested in this study, HP-β-CD (hydroxypropyl-β-cyclodextrin) was selected because it greatly improved the drug solubility and stability. Furthermore, EDTA sodium was used as a stabilizer because it gave excellent stability. In particular, the montelukast-loaded oral solution, an aqueous clear solution containing montelukast sodium, HP-β-CD, methylparaben sodium, propylparaben sodium and EDTA sodium at w/v percentages of 0.104/15.6/0.18/0.02/0.1, gave similar dissolution to the commercial granules in 0.5%(w/v) sodium lauryl sulphate in water, FDA regulated dissolution medium, even if it had different dissolution patterns from the commercial granule in water, pH 1.2, pH4.0 and pH 6.8. This oral solution gave similar plasma concentrations and pharmacokinetic parameters to the commercial granules, suggesting that it was bioequivalent to the commercial granules in rats. Moreover, this oral solution which did not produce oral mucosa irritation in the rat stomach was physically and chemically stable at 25oC/60% RH and 40oC/75% RH for at least 12 months.Thus, this oral solution is strongly recommended as an alternative to the oral montelukast-loaded product for the treatment of asthma. Part II : Novel montelukast sodium–loaded stable oral suspension bioequivalent to the commercial granules in rats To develop a montelukast sodium–loaded stable oral suspension bioequivalent to the commercial granules in rats, several montelukast sodium–loaded suspensions were prepared with a suspending agent, stabilizers and anti-aggregation agents, and their stabilities were investigated by visually observing the sedimentation phenomenon and determining concentration of the degradation product. Moreover, the dissolution and pharmacokinetic studies of the optimised formulation were examined in rats compared to the commercial montelukast sodium–loaded granules. Avicel RC-591, a suspending agent, prevented the sedimentation of these suspensions at >2.496 (w/v) percent composition. Amongst the stabilizers tested, fumaric acid furnished the lowest concentration of montelukast sulphoxide (a degradation product) in these suspensions at 40oC, proposing its excellent stability. Furthermore, as an anti-aggregation agent, glycerin gave lower amounts of degradation product compared to those with poloxamer 407 and Tween 80. In particular, the montelukast-loaded oral suspension, an aqueous suspension containing montelukast sodium, Avicel, fumaric acid and glycerin in the percentage composition of 0.312/2.496/0.0156/0.0624 (w/v), and the commercial granules exhibited similar dissolution profiles in 0.5% (w/v) aqueous solution of sodium lauryl sulphate. Moreover, pharmacokinetics in rats furnished by this suspension was comparable to that of the commercial granules, suggesting that they were bioequivalent. In addition, it was physically and chemically stable at 40oC for at least 6 months. Thus, this montelukast sodium-loaded oral suspension, with bioequivalence to the commercial granule and excellent stability, could be a prospective remedy for the treatment of asthma.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/128079http://hanyang.dcollection.net/common/orgView/200000426977
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > PHARMACY(약학과) > Theses (Ph.D.)
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