Effect of the Moisture Content in Aerosol on the Spray Performance of Stmerin D HFA Preparations

Abstract

The pressurized metered dose inhaler (MDI) is a convenient and promising technology for drug delivery to the respiratory tract. For example, steroid MDIs have been applied to the topical therapy instead of oral administration which causes severe systemic side effects such as notable suppression of the hypothalamic-pituitary-adrenal axis, nephrosis, gastric ulcer, moon face and so on. As the topical therapy with MDI improves the therapeutic index by about 10 to 50 times, i.e., increase the local concentration and decrease the systemic content, the patients can reduce the dose or stop oral intake. 1-3)However, these MDIs contain chlorofluorocarbons (CFCs) as a propellant, which are known to contribute to ozone layer depletion.4) Therefore, many aerosol products using non-CFC propellants have been developed. 5) As a propellant for pharmaceutical use, two candidates named hydrofluoroalkanes (HFAs), HFA-134a and HFA-227, are available at this moment.Meanwhile, Stmerin ® D (Astellas Pharma Inc., Tokyo, Japan) was a MDI for the treatment of asthma, which contained isoproterenol sulfate (bronchodilator, b-adrenergic stimulant), atropinemethylbromide (bronchodilator, anticholinergic agent) and dexamethasone (anti-inflammatory drug). This commercial product also contained mixed CFCs (CFC-11/CFC-12/CFC-114) as propellants. So the CFC replacement was carried out due to the environmental problem. Generally the CFC replacement is considered to be very difficult because of the physicochemical differences between CFCs and HFAs.6,7) One of the main reasons is CFC-11, which has been used as a solvent in the aerosol formulations, is able to dissolve many suspending agents or surfactants and is also easily mixed with other CFCs, but the HFAs hardly dissolve such suspending agents. This makes it difficult to disperse the drugs in HFAs.From screening of large amount of suspending agents, we have recently found out that middle chain fatty acid triglyceride (MCT) has potential to suspend the drugs in HFAs. Two preparations with HFA-134a and HFA-227 were prepared.The objective of this study is to evaluate the stability of suspension type aerosol preparations with HFAs as propellants. For such kinds of aerosol preparations, the moisture content in the canister is known to influence the stability of spray performance.8) So the relationship between the moisture content in the canisters and spray performance is also discussed. ExperimentalMaterials Isoproterenol sulfate (Boehringer Ingelheim, Germany) and atropine-methylbromide (Boehringer Ingelheim, Germany) are used after pulverized using the jet mill. Dexamethasone micronised is purchased from Roussel uclaf (Paris, France). These active ingredients are of pharmaceutical grade and used without further purification.HFA-134a (1,1,1,2-tetrafluoroethane, Mistui Dupont Fluoro Chemicals, Japan) and 1,1,2,3,3, Solvey, Germany) are used as a propellant. Middle chain fatty acid triglyceride (MCT, Miglyol 812, Mitsuba, Japan) is used and functions as both a suspending agent and a lubricant for th...

Effect of the Moisture Content in Aerosol on the Spray Performance of Stmerin^® D Hydrofluoroalkane Preparations (2)

“…2). These results are consistent with our previous study, 3) which demonstrated that the moisture penetration of the MDI during storage influenced the spray performance, and that the FPD drastically decreased and dose content uniformity was inconsistent when moisture content exceeded 300 ppm. There are some reports on the influences of the moisture uptake into the MDIs on the product stabilities, 6,7) i.e., i) crystal growth might be occurred when solubility of the drug substance in the propellants would be increased or decreased, ii) chemical degradation might be occurred when the drug substances are easy to be hydrated and degradable to the water.…”

“…2) Our previous study demonstrated that the spray performance of a suspension MDI using hydrofluoroalkanes (HFA134a and HFA-227) was sensitive to moisture content, and that moisture could penetrate the canister under accelerated stress conditions at 40°C and 75% relative humidity (RH). 3) This study found that increased moisture content significantly reduced the uniformity of the aerosol delivered dose due to an increase in drug aggregation in the liquid HFA and a reduction of the suspension homogeneity. Further, the moisture strongly affects the particle size distribution after actuation because moisture reduces the propellant evaporation rate and increases the apparent particle size.…”

“…3) Regular Article * To whom correspondence should be addressed. e-mail: saburo.murata@astellas.com Micronised active ingredients, IPS (D 50 : 3.3 mcm), DEX (D 50 : 2.2 mcm), and AMB (D 50 : 3.0 mcm) were homogenized with MCT and pipetted into an aerosol canister.…”

Effect of moisture on the electrostatic charge properties of metered dose inhaler aerosols

“…The United States Pharmacopeia (1995) also reported its use on slow-flowing propellant gas streams fed into the reagent at 100 mL/min. Although the technique has been applied to MDI formulations (Kim et al, 1992;Kulphaisal et al, 2002;Murata et al, 2006;Williams III & Chengjiu, 2000;Williams III & Hu, 2000;Williams III et al, 1997), its accuracy for rapidly evaporating boli of pressurised gas is not satisfactorily reported hitherto. The aerosol might bubble too fast through the liquid reagent and vaporise into the titration cell headspace without sufficient mixing.…”

“…Since HFAs are more polar and more hygroscopic than CFCs (Williams, 1999;Williams III, Jie, & Koleng, 1997) water ingress is more significant in HFA MDIs. Ambient moisture diffuses into MDIs through the valve gaskets (Miller, 1990;Reynolds & McNamara, 1996;Williams, 1999) and adversely affect the physical stability of MDI formulations by promoting drug particle growth and aggregation (Murata, Ito, Izumi, & Chikushi, 2006;Williams III & Hu, 2000).…”