Merck
  • Home
  • Search Results
  • Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (2015-07-30)
Sha Liu, Alan B Watts, Ju Du, Amanda Bui, Soraya Hengsawas, Jay I Peters, Robert O Williams
ABSTRACT

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product. In this study, BMP fixed dose combinations of SX and MF with or without stabilizing excipients (lactose, mannitol, glycine and trehalose) were prepared and characterized with respect to their thermal properties, morphology, aerodynamic performance and physical stability. BMP combination formulations of SX and MF exhibited improved aerodynamic properties when delivered by dry powder inhalation as compared to the micronized blends of the same substances. Aerodynamic evaluation was carried out by next generation pharmaceutical impactor (NGI) with a marketed DPI device. Results demonstrated that co-deposition occurred when SX and MF were formulated together as composite particles in a BMP, while physical blends resulted in inconsistent deposition and dose uniformity. As a result of the bottom-up particle engineering approach, combination BMP formulations allow for dual API composite formulations to be dispersed as aerosolized particles. Aerosolized BMP combination formulations resulted in delivered dose uniformity and co-deposition of each API. Further, an excipient-free formulation, BMP SXMF, delivered approximately 50% of the loaded dose in the respirable range and demonstrated stability at ambient conditions for 6months. Single dose 24-h pharmacokinetic studies in rats demonstrated that lung tissue deposition and blood circulation (AUC0-24h) of two APIs were higher for the BMP combination group exhibiting a significantly higher lung concentration of drugs than for the crystalline physical blend. While high system drug levels are generally undesirable in lung targeted therapies, high blood levels in this rodent study could be indicative of increased pulmonary tissue exposure using BMP formulations.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sigma-Aldrich
Methanol, Absolute - Acetone free
Sigma-Aldrich
Methanol, ACS spectrophotometric grade, ≥99.9%
Sigma-Aldrich
Methanol, Laboratory Reagent, ≥99.6%
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sigma-Aldrich
Methanol, BioReagent, ≥99.93%
Sigma-Aldrich
Methanol, ACS reagent, ≥99.8%
Sigma-Aldrich
Methanol, NMR reference standard
Sigma-Aldrich
Glycine, ACS reagent, ≥98.5%
Sigma-Aldrich
Methanol, anhydrous, 99.8%
Sigma-Aldrich
Glycine, 99%, FCC
Sigma-Aldrich
D-Mannitol, ACS reagent
Sigma-Aldrich
D-Mannitol, BioXtra, ≥98% (HPLC)
Sigma-Aldrich
D-Mannitol, suitable for plant cell culture
Sigma-Aldrich
D-Mannitol, ≥98%
Sigma-Aldrich
D-Mannitol, meets EP, FCC, USP testing specifications
Sigma-Aldrich
α-Lactose monohydrate, BioXtra, ≥99% total lactose basis (GC)
Sigma-Aldrich
α-Lactose monohydrate, ≥99% total lactose basis (GC)
Sigma-Aldrich
Glycine, ReagentPlus®, ≥99% (HPLC)
Sigma-Aldrich
Glycine, from non-animal source, meets EP, JP, USP testing specifications, suitable for cell culture, ≥98.5%
Sigma-Aldrich
Glycine, BioXtra, ≥99% (titration)
Sigma-Aldrich
Glycine, suitable for electrophoresis, ≥99%
Sigma-Aldrich
α-Lactose monohydrate, suitable for cell culture, BioReagent
Sigma-Aldrich
Glycine, puriss. p.a., reag. Ph. Eur., buffer substance, 99.7-101% (calc. to the dried substance)
Sigma-Aldrich
D-Mannitol, BioUltra, ≥99.0% (sum of enantiomers, HPLC)
Sigma-Aldrich
Glycine, meets analytical specification of Ph. Eur., BP, USP, 99-101% (based on anhydrous substance)
SAFC
Glycine
Sigma-Aldrich
Glycine, BioUltra, for molecular biology, ≥99.0% (NT)
Sigma-Aldrich
Formic acid, ≥95%, FCC, FG
Sigma-Aldrich
Acetonitrile, for DNA synthesis