title: Low-Molecular-Weight Heparin-Coated and Montelukast-Filled Inhalable Particles: A Dual-Drug Delivery System for Combination Therapy in Asthma.
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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas 79106.
authors.forename: Brijeshkumar
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas 79106.
authors.forename: Jahidur
authors.initials: J
authors.lastname: Rashid
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas 79106.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas 79106. Electronic address: fakhrul.ahsan@ttuhsc.edu.
authors.forename: Fakhrul
authors.initials: F
authors.lastname: Ahsan
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000378:metabolism; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004359:Drug Therapy, Combination; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008863:Microspheres; D010316:Particle Size; D011091:Polyesters / Q000008:administration & dosage / Q000378:metabolism; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides
chemical_list: D000085:Acetates; D018927:Anti-Asthmatic Agents; D000925:Anticoagulants; D003521:Cyclopropanes; D006495:Heparin, Low-Molecular-Weight; D018836:Inflammation Mediators; D011091:Polyesters; D011804:Quinolines; D013440:Sulfides; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; C093875:montelukast
keywords: asthma; combination therapy; low-molecular-weight heparin; microparticles; montelukast; pulmonary delivery