The enhanced aerosol performance of salbutamol from dry powders containing engineered mannitol as excipient

Abstract

The aim of the present study was to investigate the effect of crystallising mannitol from different binary mixtures of acetone/water on the resultant physical properties and to determine the effects of any changes on in vitro aerosolisation performance, when the different mannitol crystals were used as a carrier in dry powder inhaler formulations containing salbutamol sulphate. Mannitol particles were crystallised under controlled conditions by dissolving the sugar in water and precipitating the sugar using binary mixtures of acetone/water in different percentages as anti-solvent media. For comparison purposes the physical properties and deposition behaviour of commercially available mannitol were also studied. SEM showed that all crystallised mannitol particles were more elongated than the commercial mannitol. Solid state studies revealed that commercial mannitol and mannitol crystallised using acetone in the presence of 10-25% v/v water as anti-solvent was beta-polymorphic form whereas mannitol crystallised in the presence of a small amount of water (0-7.5%) was the alpha-form. All the crystallised mannitol samples showed poor flowability. Nevertheless, the powdered crystallised mannitol and commercial samples were blended with salbutamol in the ratio 67.5:1. The aerosolisation performance of the formulations containing the engineered mannitol (evaluated using Multi Stage Liquid Impinger) was considerably better than that of the commercial mannitol formulation (the fine particle fraction was increased from 15.42% to 33.07-43.99%, for the formulations containing crystallised mannitol). Generally, carriers having a high tapped density and high fraction of fine carrier particles produced a high FPF. The improvement in the DPI performance could be attributed to the presence of elongated carrier particles with smooth surfaces since these are believed to have less adhesive forces between carrier and the drug resulting in easier detachment of the drug during the inhalation.

The Role of Carrier in Dry Powder Inhaler

“…Its potential use as a carrier for aerosol delivery has been reported (Tee et al, 2000;. Mannitol does not have a reducing sugar function, is less hygroscopic than lactose (Saint-Lorant et al, 2007)and gives a suitable sweet after-taste which has a benefit to patients confirming them that a dose has been properly administered (Kaialy et al, 2010).Mannitol proved to be the most promising candidate for this application than the more hygroscopic sugar alcohols such as sorbitol, xylitol and maltitol. D-mannitol is currently marketed in some countries as a pulmonary diagnostic dry powder inhalation aerosol (Aridol TM ) and as a therapeutic dry powder inhalation aerosol for the treatment of cystic fibrosis and chronic bronchitis (Bronchitol TM ) which are recently approved by US food and drug administration office and a European regulatory committee, respectively (Mansour et al, 2010).Spherical mannitol particles used in Aridol TM were produced by spray drying (Tang et al, 2009).A DPI formulation for inhalation of ciprofloxacin hydrochloride (an antibacterial fluoroquinolone) was prepared by its co-spray drying with different percentages of mannitol.…”

“…It was also indicated that mannitol particles crystallized from either acetone or ethanol (α-mannitol) showed the best aerosolisation performance while poorest aerosolisation performance was obtained from grounded mannitol (β-mannitol) (Kaialya et al, 2011).The same research group in another study again reported the better inhalation performance of salbutamol sulfate from elongated mannitol. In this study mannitol was crystallized from different binary mixtures of acetone/water and its carrier role in DPI formulations of salbutamol sulfate was investigated (Kaialy et al, 2010).Mannitol particles, produced by spray drying, have been used commercially (Aridol TM ) in bronchial provocation test (mannitol particle itself as an active ingredient not as a carrier). In a study, a confined liquid impinging jets (CLIJs) followed by jet milling was applied and introduced as an alternative method for spray drying.…”

Influence of mannitol concentration on the physicochemical, mechanical and pharmaceutical properties of lyophilised mannitol

“…In contrast to jet-milling, particles with precisely engineered physical properties were, for instance, engineered using antisolvent crystallization (Kaialy et al, 2014(Kaialy et al, , 2010, batch cooling crystallization (Kaialy et al, 2012), spray drying (Vehring, 2008), spray-freeze drying (Rogers et al, 2003), etc. Freeze-drying (lyophilisation) is a technical procedure that involves the removal of frozen water by sublimation.…”

Development of Dry Salbutamol Sulfate Powder with High Inhalation Performance Independent of Inhalation Patterns

“…[14][15][16][17] From the stand point of particle shape, the shape with a smaller surface contact area generally results in a higher dispersibility.…”

“…[14][15][16][17] From the stand point of particle shape, the shape with a smaller surface contact area generally results in a higher dispersibility. 18) The particles prepared by the supercritical fluid antisolvent method presented various shapes as a function of materials and preparation conditions.…”