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Low-Molecular-Weight Heparin-Coated and Montelukast-Filled Inhalable Particles: A Dual-Drug Delivery System for Combination Therapy in Asthma.
- Source :
-
Journal of pharmaceutical sciences [J Pharm Sci] 2017 Apr; Vol. 106 (4), pp. 1124-1135. Date of Electronic Publication: 2017 Jan 03. - Publication Year :
- 2017
-
Abstract
- Montelukast, a cysteinyl leukotriene type 1 receptor antagonist, exhibits secondary anti-inflammatory properties when used at higher concentrations. Low-molecular-weight heparin (LMWH) evokes pronounced anti-inflammatory effects by interrupting leukocyte adhesion and migration. We hypothesized that inhalable particles containing montelukast plus LMWH release both drugs in a sustained fashion and protect the lungs against allergen-induced inflammation. Large porous particles of montelukast and LMWH were prepared using a double-emulsion-solvent-evaporation method. Montelukast was first encapsulated in copolymer-based particles using polyethylenimine as a porosigen; the resulting particles were then coated with LMWH. The particles were evaluated for physicochemical properties, respirability, and release profiles. The anti-inflammatory effect of the optimized formulation was studied in ovalbumin-sensitized asthmatic Sprague Dawley rats. The optimized large porous particles had a diameter of 10.3 ± 0.7 μm, exhibited numerous surface indentations and pores, showed acceptable drug entrapment efficiency (66.8% ± 0.4% for montelukast; 91.7% ± 0.8% adsorption efficiency for LMWH), demonstrated biphasic release patterns, and escaped the uptake by the rat alveolar macrophages. The number of infiltrating inflammatory cells in asthmatic rat lungs, treated with dual-drug particles, was >74% fewer than in untreated asthmatic rat lungs. Similarly, the airway walls of asthmatic animals treated with dual-drug particles were 3-fold thinner than those of untreated asthmatic animals (p < 0.001). The optimized formulation protects lungs against methacholine-induced airway hyper-reactivity. Overall, this study demonstrates the feasibility of loading 2 drugs, montelukast and LMWH, into an inhalable particulate system and establishes that this novel combination therapy produces sustained drug release and elicits a robust anti-inflammatory response in the lungs.<br /> (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Acetates metabolism
Administration, Inhalation
Animals
Anti-Asthmatic Agents administration & dosage
Anti-Asthmatic Agents metabolism
Anticoagulants administration & dosage
Anticoagulants metabolism
Asthma metabolism
Cyclopropanes
Dose-Response Relationship, Drug
Drug Therapy, Combination
Heparin, Low-Molecular-Weight metabolism
Inflammation Mediators antagonists & inhibitors
Inflammation Mediators metabolism
Male
Particle Size
Polyesters administration & dosage
Polyesters metabolism
Polyethylene Glycols administration & dosage
Polyethylene Glycols metabolism
Quinolines metabolism
Rats
Rats, Sprague-Dawley
Sulfides
Acetates administration & dosage
Asthma drug therapy
Drug Delivery Systems methods
Heparin, Low-Molecular-Weight administration & dosage
Microspheres
Quinolines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1520-6017
- Volume :
- 106
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of pharmaceutical sciences
- Publication Type :
- Academic Journal
- Accession number :
- 28057540
- Full Text :
- https://doi.org/10.1016/j.xphs.2016.12.025