Context: Salbutamol sulphate is widely used as bronchodilator for the treatment of asthma. Its use is limited by the relatively short duration of action and hence sustained delivery of salbutamol sulphate offers potential benefits to patients.

Objective: This study explores the preparation of lipid microparticles (LMs) as biocompatible carrier for the prolonged release of salbutamol sulphate.

Materials and methods: The LMs were produced using different lipidic materials and surfactants, by classical melt emulsification-based methods (oil-in-water and water-in-oil-in-water emulsions) and the spray congealing technique.

Results: For the LMs obtained by melt emulsification a lack of release modulation was observed. On the other hand, the sustained release of salbutamol sulphate was achieved with glyceryl behenate microparticles prepared by spray congealing. These LMs were characterized by scanning electron microscopy, X-ray diffractometry and differential scanning calorimetry. The drug loading was 4.72% (w/w). The particle size distribution measured by laser diffraction and electrical zone sensing was represented by a volume median diameter (Dv50) of 51.7–71.4 µm. Increasing the atomization air pressure from 4 to 8 bar produced a decrease of the Dv50 to 12.7–17.5 µm.

Conclusions: Incorporation of the hydrophilic salbutamol sulphate into LMs with sustained release characteristics was achieved by spray congealing.

Treatment for tuberculosis (TB) using the standard oral antibiotic regimen is effective but inefficient, requiring high drug dosing and lengthy treatment times. Three concurrent first-line antibiotics recommended by the World Health Organization (WHO) guidelines are pyrazinamide, rifampicin and isoniazid. Combining these antibiotics in a novel formulation for dry powder inhalation (DPI) may facilitate rapid and efficient resolution of local and systemic infection. However, spray-dried individually, these antibiotics were found to be physically unstable. A solution of the three antibiotics, at the WHO-recommended ratio, was spray-dried. The collected powder was assessed by a series of in vitro methods to investigate aerosol performance, particle physico-chemical characteristics and dissolution profile. Particles obtained were spherical with a surface composed primarily of rifampicin, as identified by TOF-SIMS. A mass median aerodynamic diameter of 3.5±0.1μm and fine particle fraction (<5μm) of 45±3% indicated excellent aerosol performance. The combination powder was differentiated by the presence of rifampicin dihydrate and the delta polymorph of pyrazinamide. Quantitative analysis indicated individual particles contained the three antibiotics at the expected proportions (400:150:75 w/w). This excipient-free triple antibiotic DPI formulation could be used as a significant enhanced treatment for TB.

Background: In silico simulation and percolation theory are important tools in the study of physical and mechanical behavior of pharmaceutical compacts. The aim was to generate a new in silico simulation program that describes the mechanical structure of binary compacts formed from an excipient with excellent compactibility and a drug with null compactibility.

Materials and methods: Paracetamol and microcrystalline cellulose powders were compressed under different pressures. Values for the indentation hardness and tensile strength were measured and fitted to the Leuenberger’s model. On the other hand, compacts with different composition were in silico simulated. In each system, the biggest excipient cluster was identified and quantified using the Hoshen−Kopelman algorithm. Then, the size of the biggest in silico cluster was correlated with experimental compactibility values.

Results and discussion: The Leuenberger’s model resulted in good fit to the experimental data for all formulations over 40% of excipient load. Formulations with high drug load (≥0.8) had reduced range for forming compacts and gave low compactibility values. The excipient percolation threshold for the simulated system was 0.3395, indicating that over this excipient fraction, a compact with defined mechanical properties will be formed. The compactibility values presented a change in the range of 0.3–0.4 of excipient fraction load, just where the in silico excipient percolation threshold was found.

Conclusion: Physical measurements of the binary compacts showed good agreement with computational measurements. Subsequently, this in silico approach may be used for the optimization of pharmaceutical powder formulations used in tablet compression.

Read More: http://informahealthcare.com/doi/abs/10.3109/03639045.2012.683439

The aerosol performance of budesonide solution-based pMDIs (HFA 134a), with various amounts of ethanol (5-30%, w/w) as co-solvents, was evaluated using the impaction and the laser diffraction. With the increase of ethanol concentration in a formulation, the mass median aerodynamic diameter (MMAD) was increased and the fine particle fraction (FPF) showed a significant decline. Although data obtain from the laser diffraction oversized that of the impaction measurements, good correlations were established between the two sets of data. Particles emitted from all the five formulations in this study were amorphous, with two different types of morphology – the majority had a smooth surface with a solid core and the others were internally porous with coral-like surface morphology. The addition of ethanol in the formulation decreased the percentage of such irregular-shape particles from approximate 52% to 2.5% when the ethanol concentration was increased from 5% to 30%. A hypothesis regarding the possible particle formation mechanisms was also established. Due to the difference of droplet composition from the designed formulation during the atomization process, the two types of particle may have gone through distinct drying processes: both droplets will have a very short period of co-evaporation, droplets with less ethanol may be dried during such period; while the droplets containing more ethanol will undergo an extra condensation stage before the final particle formation.

The potential of excipient coating to enhance aerosol performance of micronized drugs in carrier excipient-drug blends, used in dry powder inhalers, was investigated. Both EC (ethyl cellulose) and PVP (polyvinylpyrrolidone) were used as coating agents. Carriers were prepared via sieve fractioning followed by spray drying, with and without polymer additive. Each uncoated and coated carrier salbutamol sulphate (SS) blended systems were evaluated for particle size, morphology, drug carrier adhesion and aerosolisation performance, after blending and storage for 24h. All carrier-based systems prepared had similar particle sizes and morphologies. The surface chemistries of the carriers were significantly different, as was drug-carrier adhesion and aerosolisation performance. Particle adhesion between SS and aerosol performance (fine particle fraction; FPF) followed the rank: PVP coated>un-coated>EC coated lactose. This rank order could be attributed to the surface energy measured by contact goniometry and related to the chemistry of lactose and each polymer. Storage did not significantly affect aerosol performance, however a rank increase in mean FPF value was observed for uncoated and EC coated lactose. Finally, the net electrostatic charge across the aerosol cloud indicated that the EC coated lactose transferred less charge to SS particles. The performance of each carrier system could be attributed to the carrier surface chemistry and, in general, by careful selection of the coating polymer, drug-carrier adhesion, electrostatic charge and aerosol performance could be controlled.

Purpose

Liposomal ciprofloxacin nanoparticles were developed to overcome the rapid clearance of antibiotics from the lungs. The formulation was evaluated for its release profile using an air interface Calu-3 cell model and further characterised for aerosol performance and antimicrobial activity.

Methods

Liposomal and free ciprofloxacin formulations were nebulised directly onto Calu-3 bronchial epithelial cells placed in an in vitro twin-stage impinger (TSI) to assess the kinetics of release. The aerosol performance of both the liposomal and free ciprofloxacin formulation was characterised using the next generation impactor. Minimum inhibitory and bactericidal concentrations (MICs and MBCs) were determined and compared between formulations to evaluate the antibacterial activity.

Results

The liposomal formulation successfully controlled the release of ciprofloxacin in the cell model and showed enhanced antibacterial activity against Pseudomonas aeruginosa. In addition, the formulation displayed a respirable aerosol fraction of 70.5 ± 2.03% of the emitted dose.

Conclusion

Results indicate that the in vitro TSI air interface Calu-3 model is capable of evaluating the fate of nebulised liposomal nanoparticle formulations and support the potential for inhaled liposomal ciprofloxacin to provide a promising treatment for respiratory infections.

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).

The aim of this study was to prepare lipid microparticles (LMs) loaded with the polar bronchodilator agent salbutamol, and designed for sustained release pulmonary delivery. The microparticles were produced by melt emulsification followed by a sonication step, using different biocompatible lipid carriers (tristearin, stearic acid and glyceryl behenate) and phosphatidylcholine as the surfactant. The use of salbutamol free base, rather than salbutamol sulphate, was necessary to obtain the incorporation of the drug in the lipid particle matrix. The prolonged release of salbutamol base was achieved only by the glyceryl behenate microparticles (40.9% of encapsulated drug being released after 8 h). The salbutamol loading was 4.2% ± 0.1 and the mass median diameter, determined by laser diffraction, ranged from 4.8 to 5.4 µm. The sustained release of LMs were formulated as a carrier-free dry powder for inhalation and exhibited a fine particle fraction of 17.3% ± 2.2, as measured by multi-stage liquid impinger.

Objectives: To evaluate physicochemical properties of two micronized drugs, salbutamol sulfate (SS) and beclomethasone dipropionate (BDP) prepared as dry powder inhalation physical blends. Methods: Five different blends of SS:BDP ratios of 0:100, 25:75, 50:50, 75:25, and 100:0 (w/w) were prepared. Aerosolization performance was evaluated using a multistage impinger and a Rotahaler® device. Results: The median SS particle diameter was larger than BDP (4.33 ± 0.37 µm compared to 2.99 ± 0.15 µm, respectively). The SS appeared to have a ribbon-like morphology, while BDP particles had plate-like shape with higher cohesion than SS. This was reflected in the aerosolization performance of the two drugs alone, where SS had a significantly higher fine particle fraction (FPF) than BDP (12.3%, 3.1% and 2.9%, 0.2%, respectively). The study of cohesion versus adhesion for a series of SS and BDP probes on SS and BDP substrates suggested both to be moderately adhesive, verified using scanning Raman microscopy, where a physical association between the two was observed. A plot of loaded versus emitted dose indicated that powder bed fluidization was significantly different when the drugs were tested individually. Furthermore, the FPF of the two drugs from the binary blends, at all three ratios, were similar. Conclusions: Such observations indicate that when these two drugs are formulated as a binary system, the resulting powder structure is altered and the aerosolization performance of each drug is not reflective of the individual drug performance. Such factors could have important implications and should be considered when developing combination dry powder inhalation systems.

Two combination dry powder inhalation formulations were engineered via spray drying and co-spray drying salbutamol base (SB) and beclomethasone dipropionate (BDP). The aerosol performances of the individual drugs, a physical mix and the co-spray-dried particle systems were investigated after blending with conventional lactose carrier, under realistic dose regimes. Furthermore, each system was evaluated in terms of the physicochemical properties and via high-throughput Raman microscopy (to study co-association and deposition patterns after in vitro aerosolisation studies). In general, analysis of the aerosol performance (measured using a next-generation impactor) of the single drug and physical mix formulations suggested that SB and BDP have significantly different stage-deposition profiles. Such observations were further substantiated by scanning electron microscopy, where SB–BDP agglomeration could be observed in the physical mix. Stage deposition from the SB–BDP co-spray-dried powders were different than that for the physical mix, wherein the amount of SB and BDP on each stage was equivalent; suggesting that the two drugs could be targeted and deposited at the same location on the lung epithelia. Raman microscopy of the physical mix and co-spray-dried formulations also confirmed the differences in stage deposition between formulations and co-localised deposition for the co-spray-dried formulation. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4267–4276, 2012

Purpose

Conditions such as lung cancer currently lack non-invasively targetable and controlled release topical inhalational therapies. Superparamagnetic iron-oxide nanoparticles (SPIONs) have shown promising results as a targetable therapy. We aimed to fabricate and test the in-vitro performance of particles with SPION and drug within a lipid matrix as a potentially targetable and thermo-sensitive inhalable drug-delivery system.

Methods

Budesonide and SPIONs were incorporated into lipid particles using oil-in-water emulsification. Particles size, chemical composition, responsiveness to magnetic field, thermosensitiveness and inhalation performance in-vitro were investigated.

Results

Particles of average diameter 2–4 μm with budesonide and SPIONs inside the lipid matrix responded to a magnetic field with 100% extraction at a distance of 5 mm. Formulations were shown to have accelerated rate of drug release at hyperthermic temperatures (45°C)—controlled release. The produced inhalation dry powder presented promising inhalation performance, with an inhalable fine particle fraction of 30%.

Conclusions

The lipid system presented thermo-sensitive characteristics, suitable for controlled delivery, the model drug and SPION loaded lipid system was magnetically active and movable using simple permanent magnets, and the system demonstrates promise as an effective drug vehicle in targeted and controlled inhalation therapy.

Background: Inhaled dry powder mannitol has established in vivo therapeutic efficacy for enhancing mucociliary function. However, a single dose necessitates multiple inhalations of a sizeable powder mass. Nebulization of mannitol by vibrating mesh devices has recently been shown in vitro to impart similar dosing in a comparable or lesser treatment time. Nevertheless, the limited solubility of mannitol restricted fluid concentrations to 150 mg/mL. The present study examines the feasibility of higher solubility polyols that presumably possess similar therapeutic properties to mannitol but deliverable at higher concentrations to shorten treatment time. A secondary aim is to compare delivery by two commercially available mesh nebulizers—the Aeroneb® Go and PARI eFlow Rapid.

Methods: A series of formulations containing three polyols (mannitol, sorbitol, and xylitol) of increasing concentration in 1% w/v sodium chloride were nebulized. Aerosol characteristics and treatment times were determined primarily by laser diffraction.

Results: Results indicate viscosity is the primary determinant of vibrating mesh nebulizer performance. For both nebulizers, xylitol 334 mg/mL exhibits the greatest osmolar output—double that of 150 mg/mL mannitol.

Conclusions: A nebulized xylitol solution has potential clinical application for promoting rapid mucociliary clearance. Both vibrating mesh nebulizers facilitate quick treatment times. Future in vivo studies would compare the efficacy of nebulized xylitol to commercial hyperosmolar agents and establish any potential polyol-associated antibacterial activity.

Abstract

Objectives  Over the past 20 years, the inhalation drug delivery industry has undergone a quiet revolution after the phasing out of the chlorofluorocarbon propellants used to formulate pressure-metered dose inhalers (pMDIs). This review looks back to the creative landscape of those 20 years through a study of patent application trends. To this end, an analysis of the hydrofluoroalkane pMDIs patent landscape was undertaken.

Methods  A statistical analysis demonstrates that 20 years after the introduction of hydrofluoroalkanes in the inhalation delivery field, the original patent applications are coming to the end of their legal life.

Key findings  Detailed analysis revealed that, from a total of 971 of the patents identified, up to 2.3% will expire within the next 5 years, rising to up to 7.3% in the next 10 years. The UK and USA were the main patent destinations and locations of inventive activity, as measured by patent filing location. Interestingly, the UK was the first destination and location of inventive activity in Europe, largely due to the activity of GlaxoSmithKline, followed by Italy, thanks to the work of Trinity-Chiesi. The analysis also showed that patent assignees are not always major pharmaceutical companies, with suppliers of propellants, as well as companies without major inhalation activity (such as Novadel), making substantial contributions to the landscape.

Conclusions  These developments may have a significant impact on innovation trends and key company activity around novel pMDI formulations, in particular for generics manufacturers.

Abstract

Objectives  The formulation of multi-drug pressurised metered dose inhalers (pMDIs) opens up exciting therapeutic opportunities for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We have investigated the formulation of a solution-based triple therapy pMDI containing ipratropium, formoterol, budesonide and ethanol as co-solvent.

Methods  This system was characterised for in-vitro performance and compared with marketed pMDIs (Atrovent and Symbicort).

Key findings  No significant difference was found in the stage deposition of each drug from the triple therapy formulation, suggesting that the droplets contained a fixed ratio of the three components used. Stage deposition of formoterol and budesonide from the suspension-based marketed Symbicort were significantly different, suggesting that the two drugs were deposited as separate entities. Calculation of the mass median aerodynamic diameter (MMAD) of each formulation suggested Atrovent (ipratropium, MMAD = 0.9 ± 0.0 µm) to have a small particle size, similar to the triple therapy formulation. Atrovent, like the triple therapy formulation was solution based and it contained ethanol as a co-solvent (triple therapy formulation, MMAD = 1.3 ± 0.0 µm).

Conclusions  This study demonstrated the feasibility of formulating a solution-based pMDI containing a triple therapy with identical deposition pattern for the treatment of several respiratory diseases where multi-drug cell targeting is required.

The deposition, dissolution and transport of salbutamol base (SB) and salbutamol sulfate (SS) inhalation powders were investigated using the Calu-3 air interface cell culture model and Franz diffusion cell. Drug uptake by cells was studied with respect to deposited dose, drug solubility and hydrophobicity. Furthermore, the role of active transport via organic cationic transporters (OCTs) was studied. SB and SS were processed to have similar diameters (3.09 ± 0.06 μm and 3.07 ± 0.03 μm, respectively) and were crystalline in nature. Analysis of drug wetting, dissolution and diffusion using a conventional in vitro Franz cell (incorporating a cell culture support Transwell polyester membrane) showed diffusion of SB to be slower than that of SS (98.57 ± 4.23 μg after 4 h for SB compared to 98.57 ± 4.01 μg after 15 min for SS). Such observations suggest dissolution to be the rate-limiting step. In comparison, the percentage transfer rate using the air interface Calu-3 cell model suggested SB transport to be significantly faster than SS transport (92.02 ± 4.47 μg of SB compared to 63.76 ± 8.84 μg of SS transported over 4 h), indicating that passive diffusion through the cell plays a role in transport. Furthermore, analysis of SB and SS transport, over a range of deposited doses, suggested the transport rate in the Franz diffusion cell to be limited by wetting of the particle and dissolution into the medium. However, for the cell monolayer, the cell membrane properties regulate the diffusion and transport rate. Analysis of the drug transport in the presence of triethylamine (TEA), a known inhibitor of OCTs, resulted in a significant decrease in drug transport, suggesting an active transport mechanism. The presence of OCTs in this cell line was further validated by Western blot analysis. Finally, the transport of SS from a commercial product (Ventolin Rotacaps) was studied and showed good agreement with the model SS system studied here.

Control of cell–matrix interactions plays a role in the regulation of stem cell function. In this study basic fibroblast growth factor (bFGF) linked to maltose-binding protein (MBP) was designed as a matrix for cell adhesion. MBP–FGF was immobilized on polystyrene (PS) surfaces by spontaneous adsorption. The amount of MBP–bFGF immobilized on the PS surface increased with increasing protein concentration, being 158 ng cm−2 at 10 μg ml−1 protein. Human adipose-derived stem cell (hASC) adhesion to MBP–bFGF immobilized on a PS surface (PS–MBP–bFGF) was inhibited by heparin. Integrin signaling and cell spreading of hASC on PS–MBP–bFGF were down-regulated compared with those on fibronectin-coated surfaces or tissue culture polystyrene (TCP). hASC differentiated into adipocytes, which stained positive for lipid vacuoles with Oil Red, more readily on PS–MBP–bFGF than on TCP. In contrast, hASC hardly differentiated into osteoblast on PS–MBP–bFGF or on TCP. These results suggest that the mechanism of hASC adhesion to MBP–bFGF immobilized on a PS substrate is mediated by a specific interaction between bFGF and heparin, and that the adhesion mechanism might provide an insight into the design of biomaterials to control the fate of stem cells.

This study investigates the use of Monte Carlo simulation for the determination of release properties from cubic inert matrices. Specifically, the study has focused on factors including porosity, surface area and tortuosity. The release platform was formed by simulating matrices with different ratios of drug and excipient, which undergo drug release in a uni-directional (two-face) or omni-directional (six-face) process. Upon completion of each simulation the matrix ‘carcass’ was examined and porosity and tortuosity of the medium evaluated. The tortuosity of the medium was evaluated directly by a blind random walk algorithm. These parameters as well as the release profile were then studied with respect to common mathematical models describing drug diffusion (the square-root, power and Weibull models). It was found that, depending on their composition, the matrices systems were either homogeneous or heterogeneous in nature. Furthermore, it was found that the physical parameters could be successfully fitted to the a and b constants of the Weibull model. This approach allows the prediction of drug release from an inert matrix system with the knowledge of a few physical parameters.

Computational Fluid Dynamics (CFD) and Discrete Element Modelling (DEM) studies relevant to inhaled drug delivery are reviewed. CFD is widely used in device design to determine airflow patterns and turbulence levels. CFD is also used to simulate particles and droplets, which are subjected to various forces, turbulence and wall interactions. These studies can now be performed routinely because of the availability of commercial software containing high quality turbulence and particle models.

DEM allows for the modelling of agglomerate break-up upon interaction with a wall or due to shear in the flow. However, the computational cost is high and the number of particles that can be simulated is minimal compared with the number present in typical inhaled formulations. Therefore DEM is currently limited to fundamental studies of break-up mechanisms.

With decreasing computational limitations, simulations combining CFD and DEM that can address outstanding issues in agglomerate break-up and dispersion will be possible.

Inverse gas chromatography (IGC) is a sensitive technique for the measurement of powder surface properties, especially surface energetics. Given the importance of these characteristics to the performance of dry powder inhaler formulations (DPIs), it is unsurprising that IGC has been applied to the study of these systems. Monitoring batch-to-batch variation and the effects of processing steps are established uses of IGC in this field and the relevant studies are discussed. A less established use of IGC is for the prediction of DPI performance. Although some groups have found a negative relationship between the dispersive surface energy of one formulation component and fine particle delivery, such studies often have a number of limitations. More complex approaches have failed to produce consistent results. Further, more carefully designed, studies are required in this area. In the final section of this article, some areas for on-going research are discussed, including the need to critically assess the best method for the calculation of the specific free energy of adsorption with pharmaceutical materials.