The Effect of Drug Formulation on in vitro Performance Indices for Metered-Dose Inhalers with Regards to Varying Mouth-Throat Models

Abstract

Specific Aims: To elucidate the effect of the use of three different inlet configurations, percent ethanol in formulation, and propellant used on the percent respirable drug and MMAD of aerosolized particles from MDIs that contained beclomethasone dipropionate (BDP). Methods: The inlet configurations assessed in this study were the United States Pharmacopeia (USP) throat, the Alberta idealized mouth-throat replica (biological throat), and a large volume spacer (globe). ACI analyses were conducted on four different MDI formulations with regards to each of the three inlet configurations in quadruplicate. The two hydrofluoroalkane propellants assessed were HFA-134 and HFA-227. All four solution formulations contained 0.3% (w/w) beclomethasone dipropionate (BDP), two of which contained 8% (w/w) ethanol (one each with HFA-134a and HFA-227) and two contained 20% (w/w) ethanol (one each with HFA-134a and HFA-227). All experiments were conducted at a flow rate of 28.3L/min using an actuator with an orifice diameter of 0.29mm and a 50μL metered-valve. After each ACI test, the drug collected on each stage of the impactor was rinsed with known volumes of diluent and quantified by high performance liquid chromatography (HPLC). The MMAD was determined by using DistFit to lognormally fit the ACI data. The resiprable fraction was calculated as the mass of the drug collected on stages 3 through filter of the ACI divided by the total mass of the drug aerosolized. The two-sided student's t-test was the statistical test utilized, with an a priori alpha-value of 0.05. Main Results: The USP and biological throats had significantly lower percent respirable drug compared to the globe regardless of concentration of ethanol or propellant (p<0.05). The MMADs were significantly lower for configurations with the USP and biological throats as compared to the globe (p<0.05). The only formulation with a significant percent respirable drug difference between the USP and biological throats regarding was the 20% ethanol/HFA-227 formulation (20.9+/-0.15 and 16.8+/-1.3 respectively, p=0.005), with the USP throat having the significantly greater percent respirable drug. The USP throat had significantly larger MMADs compared to the biological throat regardless of formulation (p<0.05). For both propellants, the 8% ethanol formulation had significantly greater percent respirable drug compared to the 20% formulation for all three inlets (p<0.05). The 20% ethanol formulations had significantly higher MMADs compared to the 8% ethanol formulations in both the USP throat and globe and with both propellants (p<0.05). Only the 20% ethanol formulations demonstrated a significant difference when varying propellant while keeping all else constant, with the HFA-134a formulations having higher percent respirable drug with all inlets as compared to HFA-227 (p<0.05). When propellant used was varied with all else kept constant, the HFA-227 formulations had significantly higher MMADs compared to the HFA-134a formulations (p<0.05). Conclusion: It was found that significant differences in percent respirable drug and particle size (MMAD) resulting from varying inlet configurations was a function of formulation parameters, most notably, ethanol concentration. The differences may be attributed to factors that increased the time necessary for the evaporation of atomized particles prior to deposition in the impactor, the initial atomized droplet diameter, and/or the likelihood of particle impaction with regards to the mouth-throat inlet utilized. Further assessment is needed to evaluate the correlation of this data with in vivo analyses.