The enhanced aerosol performance of salbutamol from dry powders containing engineered mannitol as excipient (original) (raw)
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Colloids and Surfaces B-biointerfaces, 2010
In this research mannitol particles were prepared by recrystallisation using non-solvent precipitation technique to investigate the effect of engineered carrier particles on their physico-chemical 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 crystallized from ethanol: water (90:10). This improvement could be due to the presence of elongated mannitol crystals in formulation blends. Solid state characterization of engineered mannitol showed that the commercial mannitol was β-form, mannitol recrystallized from ethanol: water (85:15) was α -form and that samples recrystallized in presence of pure ethanol or other ratios of ethanol: water (95:5, 90:10) were the mixtures of α, β and δ-form. 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 AAPS journal, 2013
The aim of this study was to evaluate the influence of novel engineered fine mannitol particles (4.7%, w/w) on the performance of lactose–salbutamol sulphate dry powder inhaler (DPI) formulations to obtain promising aerosolisation properties. The results showed that the more elongated the fine mannitol particles, the weaker the drug–carrier adhesion, the better the drug content homogeneity, the higher the amount of drug expected to be delivered to the lower airways and the higher the total DPI formulation desirability. Linear relationships were established showing that mannitol particles with a more elongated shape generated powders with broader size distributions and that were less uniform in shape. The weaker the drug–carrier adhesion, the higher the fine particle fraction of the drug is upon aerosolisation. It is believed that more elongated fine mannitol particles reduce the number of drug–carrier and drug–drug physical contact points and increase the ability of the drug particles to travel into the lower airways. Additionally, a lower drug–carrier contact area, lower drug–carrier press-on forces and easier drug–carrier detachment are suggested in the case of formulations containing more elongated fine mannitol particles. Ternary ‘drug-coarse carrier-elongated fine ternary component’ DPI formulations were more favourable than both ‘drug-coarse carrier’ and ‘drug-elongated coarse carrier’ binary formulations. This study provides a comprehensive approach for formulators to overcome the undesirable properties of dry powder inhalers, as both improved aerosolisation performance and reasonable flow characteristics were obtained using only a small amount of elongated engineered fine mannitol particles.
International journal of pharmaceutics, 2009
Mannitol particles, produced by spray drying (SD), have been used commercially (Aridol) in bronchial provocation test. In this study, we propose an alternative method to produce inhalable mannitol powders. The elongated mannitol particles (number median length 4.0microm, and axial ratio of 3.5) were prepared using a confined liquid impinging jets (CLIJs) followed by jet milling (JM). Spray dried and jet milled raw mannitol particles were compared in an attempt to assess the performance of the particles produced by the new method. Aerosol performance of the three different powders (CLIJ, SD, and JM) was relatively poor (fine particle fraction or FPF(loaded) below 15%) when dispersed by the Rotahaler. Dispersion through the Aeroliser led to better aerosol performance of the CLIJ mannitol (FPF(loaded) 20.3%), which is worse than the JM (FPF(loaded) 30.3%) and SD mannitol particles (FPF(loaded) 45.7%) at 60 L/min, but comparable (FPF(loaded) 40.0%) with those of the JM (FPF(loaded) 40.7...
Mannitol Polymorphs as Carrier in DPIs Formulations: Isolation Characterization and Performance
Pharmaceutics, 2021
The search for best performing carriers for dry powder inhalers is getting a great deal of interest to overcome the limitations posed by lactose. The aerosolization of adhesive mixtures between a carrier and a micronized drug is strongly influenced by the carrier solid-state properties. This work aimed at crystallizing kinetically stable D-mannitol polymorphs and at investigating their aerosolization performance when used in adhesive mixtures with two model drugs (salbutamol sulphate, SS, and budesonide, BUD) using a median and median/high resistance inhaler. A further goal was to assess in vitro the cytocompatibility of the produced polymer-doped mannitol polymorphs toward two lung epithelial cell lines. Kinetically stable (up to 12 months under accelerate conditions) α, and δ mannitol forms were crystallized in the presence of 2% w/w PVA and 1% w/w PVP respectively. These solid phases were compared with the β form and lactose as references. The solid-state properties of crystalliz...
The Effect of Engineered Mannitol-Lactose Mixture on Dry Powder Inhaler Performance
Pharmaceutical research, 2012
Purpose To obtain crystals with favourable morphological features suitable for use as carriers in formulations for dry powder inhalers (DPIs) using simultaneous engineering of lactose-mannitol mixtures. Methods Mannitol and lactose individually and the two sugars with three different ratios were crystallised/co-crystallised using anti-solvent precipitation technique. The obtained crystals were sieved to separate 63-90 µm size fractions and then characterised in terms of size, shape, density and in vitro aerosolisation performance. Solid state of the crystallized samples was studied using FT-IR, XRPD and DSC. Results At unequal ratios of mannitol to lactose, the elongated shape dominated in the crystallisation process. However, lactose exerted an opposite effect to that of mannitol by reducing the elongation ratio, and increasing the width and thickness of the crystals. Crystallised β-lactose showed different anomer compared to commercial lactose (α-lactose-monohydrate). Also crystallised α-mannitol showed different polymorphic form compared to the commercial mannitol (β-mannitol). Crystallised mannitol:lactose showed up to 5 transitions corresponding to α-mannitol, α-lactose-monohydrate, β-lactose, 5α-/3β-lactose and 4α-/1β-lactose. In vitro deposition assessments showed that crystallised carriers produced more efficient delivery of salbutamol sulphate in comparison to formulations containing commercial. Conclusion The simultaneous crystallization of lactose-mannitol can be used as a new approach to improve the performance of DPI formulations.