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1.  Combined Inhaled Salbutamol and Mannitol Therapy for Mucus Hyper-secretion in Pulmonary Diseases 
The AAPS Journal  2014;16(2):269-280.
This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10−6 and MA 10−3 M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-014-9560-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3933573  PMID: 24431080
cilia responce; epithelia transport; lung delivery; mannitol; salbutamol; smooth muscle responce
2.  Modification of Disodium Cromoglycate Passage Across Lung Epithelium In Vitro Via Incorporation into Polymeric Microparticles 
The AAPS Journal  2011;14(1):79-86.
Two microparticle systems containing disodium cromoglycate (DSCG) alone or with polyvinyl alcohol (DSCG/PVA) were produced via spray drying and compared in terms of their physicochemical characteristics, aerosol performance and drug uptake across a pulmonary epithelial cell line (Calu-3), cultured under air interface conditions. The particle size distribution of DSCG and DSCG/PVA were similar, of spherical geometry, amorphous and suitable for inhalation purposes. Aerosolisation studies using a modified twin-stage impinger showed the DSCG/PVA to have greater aerosol performance than that of DSCG alone. Aerosol particles of DSCG and DSCG/PVA were deposited onto the surface of the Calu-3 air interface epithelium monolayer and the drug uptake from apical to basal directions measured over time. Drug uptake was measured across a range of doses to allow comparison of equivalent drug and powder mass deposition. Analysis of the data indicated that the percentage cumulative drug uptake was independent of the mass of powder deposited, but dependent on the formulation. Specifically, with the formulation containing DSCG, the diffusion rate was observed to change with respect to time (indicative of a concentration-dependent diffusion process), whilst DSCG/PVA showed a time-independent drug uptake (suggesting a zero-order depot release).
PMCID: PMC3291191  PMID: 22203523
Calu-3; controlled release; disodium cromoglycate; dry powder inhaler; DSCG
3.  Solid Lipid Budesonide Microparticles for Controlled Release Inhalation Therapy 
The AAPS Journal  2009;11(4):771-778.
A solid lipid microparticle system containing budesonide was prepared by oil in water emulsification followed by spray drying. The solid lipid system was studied in terms of morphology, particle size distribution, crystallinity, thermal properties, aerosol performance, and dissolution/diffusion release. The microparticle system was also compared to conventional spray-dried crystalline and amorphous budesonide samples. The particle size distributions of the crystalline, amorphous, and solid lipid microparticles, measured by laser diffraction, were similar; however, the microparticle morphology was more irregular than the spray-dried drug samples. The thermal response of the solid lipid microparticles suggested polymorphic transition and melting of the lipid, glycerol behenate (at ~48°C and ~72°C). No budesonide melting or crystallisation peaks were observed, suggesting that the budesonide was integrated into the matrix. X-ray powder diffraction patterns of the crystalline and amorphous budesonide were consistent with previous studies while the solid lipid microparticles showed two peaks, at approximately 21.3 and 23.5 2θ suggesting the metastable sub-α and primarily β′ form. Analysis of the in vitro diffusion/dissolution of the formulations was studied using a flow through model and curves analysed using difference/similarity factors and fitted using the Higuchi model. Regression analysis of this data set indicated differences in the t0.5, where values of 49.7, 35.3, and 136.9 min were observed for crystalline, amorphous, and the solid lipid microparticles, respectively. The aerosol performance (<5 μm), measured by multistage liquid impinger, was 29.5%, 27.3%, and 21.1 ± 0.6% for the crystalline, amorphous, and the solid lipid microparticles, respectively. This study has shown that solid lipid microparticles may provide a useful approach to controlled release respiratory therapy.
PMCID: PMC2782082  PMID: 19908147
controlled release; dry powder inhalation; solid lipid microparticles
4.  Development of an In Vivo Ovine Dry Powder Inhalation Model for the Evaluation of Conventional and Controlled Release Microparticles 
The AAPS Journal  2009;11(3):465-468.
PMCID: PMC2758118  PMID: 19568940
controlled release; dry powder inhalation; in vivo; ovine model; pharmacokinetics
5.  Microstructural Analysis of Porous Composite Materials: Dynamic Imaging of Drug Dissolution and Diffusion Through Porous Matrices 
The AAPS Journal  2008;10(4):560-564.
PMCID: PMC2628213  PMID: 19009357
dissolution and diffusion; microstructure; porous matrix; X-ray computerised microtomography
6.  Surface Energy of Microcrystalline Cellulose Determined by Capillary Intrusion and Inverse Gas Chromatography 
The AAPS Journal  2008;10(3):494-503.
Surface energy data for samples of microcrystalline cellulose have been obtained using two techniques: capillary intrusion and inverse gas chromatography. Ten microcrystalline cellulose materials, studied using capillary intrusion, showed significant differences in the measured surface energetics (in terms of total surface energy and the acid–base characteristics of the cellulose surface), with variations noted between the seven different manufacturers who produced the microcrystalline cellulose samples. The surface energy data from capillary intrusion was similar to data obtained using inverse gas chromatography with the column maintained at 44% relative humidity for the three samples of microcrystalline cellulose studied. This suggests that capillary intrusion may be a suitable method to study the surface energy of pharmaceutical samples.
PMCID: PMC2761700  PMID: 18841480
capillary intrusion; dynamic contact angle; excipient; inverse gas chromatography; microcrystalline cellulose; surface energy
7.  The potential use of raman mapping to investigate in vitro deposition of combination pressurized metered-dose inhalers 
The AAPS Journal  2004;6(4):41-44.
Scanning near-infrared Raman microscopy has been used to map aerosol particulate deposits produced from pressurized metered-dose inhalers (pMDI). A commercially available combination asthma therapy pMDI (Ventide, Allen and Hanbury, UK), containing salbutamol and beclometasone dipropionate, was analyzed by conventional in vitro quantitative analysis and scanning Raman microscopy. Raman maps, taken from Andersen cascade impactor plate stages 3 and 5 (over 100 × 100 μm areas) suggested good correlation with chemical analysis of the respective stages. Scanning Raman microscopy allows visual differentiation between formulation components (not possible using conventional imaging techniques), while potentially allowing chemical quantification.
PMCID: PMC2751228  PMID: 15760097
pMDIs; combination therapy; Raman mapping; SEM; Andersen Cascade Impactor

Results 1-7 (7)