Study of pH Stability of R-Salbutamol Sulfate Aerosol Solution and Its Antiasthmatic Effects in Guinea Pigs

Biol Pharm Bull. 2017 Sep 1;40(9):1374-1380. doi: 10.1248/bpb.b17-00067. Epub 2017 Jun 24.

Abstract

Currently, all commercial available nebulized salbutamol in China is in its racemic form. It is known that only R-salbutamol (eutomer) has therapeutic effects, while S-salbutamol (distomer) may exacerbate asthma after chronic use. Therefore, it is an unmet clinical need to develop R-salbutamol as a nebulized product that is more convenient for young and old patients. In our study, a stable aerosol solution of R-salbutamol sulfate was established, and its antiasthmatic effects were confirmed. The decomposition rate and racemization effect of the R-salbutamol sulfate solution were evaluated over a pH range from 1 to 10 (except pH=7, 8) at 60°C. The aerodynamic particle size of the R-salbutamol sulfate solution and commercial RS-salbutamol sulfate solution were both tested in vitro by Next-Generation Impactor (NGI) in 5°C. Laser diffractometer was used to characterize the droplet-size distribution (DSD) of both solutions. We next conducted an in vivo animal study to document the antiasthmatic effect of R-salbutamol aerosol sulfate solution and determine the relationship to RS-salbutamol. The results showed that the R-salbutamol sulfate solution was more stable at pH 6. In vitro comparison studies indicated that there was no distribution difference between R-salbutamol sulfate solution and the commercial RS-salbutamol solution. The animal results showed that R-salbutamol was more potent than RS-salbutamol against the same dose of histamine challenge. Unlike commercial RS-salbutamol, which was acidified to a pH of 3.5 to extend bench life but may cause bronchoconstriction in asthmatic patients, the neutralized R-salbutamol solution was more suitable for clinic use.

Keywords: R-salbutamol sulfate; antiasthma effect; nebulization; pH stability; particle size.

MeSH terms

  • Aerosols
  • Albuterol / administration & dosage*
  • Albuterol / chemistry
  • Albuterol / therapeutic use
  • Animals
  • Anti-Asthmatic Agents / administration & dosage*
  • Anti-Asthmatic Agents / chemistry
  • Anti-Asthmatic Agents / therapeutic use
  • Asthma / drug therapy*
  • Bronchodilator Agents / administration & dosage*
  • Bronchodilator Agents / chemistry
  • Bronchodilator Agents / therapeutic use
  • Chemistry, Pharmaceutical
  • China
  • Female
  • Guinea Pigs
  • Hydrogen-Ion Concentration
  • Male
  • Sulfates / administration & dosage
  • Sulfates / chemistry
  • Sulfates / therapeutic use

Substances

  • Aerosols
  • Anti-Asthmatic Agents
  • Bronchodilator Agents
  • Sulfates
  • Albuterol