Engineered mannitol as an alternative carrier to enhance deep lung penetration of salbutamol sulphate from dry powder inhaler.

In this research mannitol particles were prepared by recrystallisation using non-solvent precipitation technique to investigate the effect of engineered carrier particles on their physicochemical properties and the in vitro deposition profiles of a model drug (salbutamol sulphate (SS)) from a dry powder inhaler (DPI). To this end, mannitol aqueous solution (15%, w/v) was added to different ratios of ethanol:water (100:0, 95:5, 90:10 and 85:15) to obtain mannitol particles. These crystallised mannitol particles were analysed in terms of micromeritic properties, morphology, DSC, FT-IR, and in vitro fine particle fraction (FPF) and emitted dose (ED) of SS. The results showed that the elongation ratio of all the recrystallised mannitol batches was higher than the original material giving them a needle-shaped morphology. Salbutamol sulphate deposition profiles from DPI formulation containing recrystallised needle-shaped mannitol showed enhanced performance and better delivery to the lower MSLI stages. The FPF increased from 15.4+/-1.1 to 45.8+/-0.7% when the commercial mannitol was replaced by mannitol crystallised from ethanol:water (90:10). This improvement could be due to the presence of elongated mannitol crystals in formulation blends. Solid state characterisation of engineered mannitol showed that the commercial mannitol was beta-form, mannitol recrystallised from ethanol:water (85:15) was alpha-form and that samples recrystallised in presence of pure ethanol or other ratios of ethanol:water (95:5 and 90:10) were the mixtures of alpha-, beta- and delta-forms. Multi-solvent recrystallisation technique was proved to have potential to produce mannitol crystals suitable for enhanced aerosolisation efficiency. Comparing different crystallised mannitol formulations showed that the final form (the type of polymorph) of the crystallised mannitol does not have a substantial effect on salbutamol sulphate aerosolisation performance.

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

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.

Factors affecting the release of nifedipine from a swellable elementary osmotic pump.

Oral osmotic devices including an elementary osmotic pump (EOP) are efficient systems for the delivery of drugs with high/moderately water-solubility. In this study we designed a new type of EOP for the efficient delivery of poorly water-soluble and practically insoluble drugs. In this system, called swellable elementary osmotic pump (SEOP), drug is released from the delivery orifice in the form of a very fine dispersion of drug in gel which is ready for dissolution and absorption. Factors affecting the release of drug from the SEOP containing a poorly water-soluble drug, nifedipine, were explored extensively. To this end, effect of swelling and wetting agents, orifice size, concentration of osmotic agent, and hydrophobic plasticizer were investigated. Interestingly, in the absence or low concentration of a hydrophobic plasticizer (caster oil), the osmotic devices did not retain their integrity in dissolution media. Caster oil in concentration of > 1% was necessary for tablets to retain their integrity during dissolution process. A zero-order release kinetics for nifedipine was achieved following the effective optimization of the concentrations of swelling agent, osmotic agent, wetting agent, and also size of orifice and membrane thickness in SEOP. The zero-order release lasted for 10 hr at pH 6.8 dissolution medium. The designed SEOP is suggested as an efficient controlled delivery system for oral delivery of a poorly water soluble drug such as nifedipine.