Spray-dried respirable powders containing bacteriophages for the treatment of pulmonary infections

Myoviridae bacteriophages were processed into a dry powder inhalable dosage form using a low‐temperature spray‐drying process. The phages were incorporated into microparticles consisting of trehalose, leucine, and optionally a third excipient (either a surfactant or casein sodium salt). The particles were designed to have high dispersibility and a respirable particle size, and to preserve the phages during processing. Bacteriophages KS4‐ M, KS14, and cocktails of phages ΦKZ/D3 and ΦKZ/D3/KS4‐M were spray‐dried with a processing loss ranging from 0.4 to 0.8 log pfu. The aerosol performance of the resulting dry powders as delivered from an Aerolizer® dry powder inhaler (DPI) exceeded the performance of commercially available DPIs; the emitted mass and the in vitro total lung mass of the lead formulation were 82.7% and 69.7% of filled capsule mass, respectively. The total lung mass had a mass median aerodynamic diameter of 2.5–2.8 µm. The total in vitro lung doses of the phages, delivered from a single actuation of the inhaler, ranged from 10⁷ to 10⁸ pfu, levels that are expected to be efficacious in vivo. Spray drying of bacteriophages into a respirable dry powder was found to be feasible.     

Spray freeze drying for dry powder inhalation of nanoparticles

Formulating nanoparticles for delivery to the deep lung is complex and many techniques fail in terms of nanoparticle stability. Spray freeze drying (SFD) is suggested here for the production of inhalable nanocomposite microcarriers (NCM). Different nanostructures were prepared and characterized including polymeric and lipid nanoparticles. Nanoparticle suspensions were co-sprayed with a suitable cryoprotectant into a cooled, stainless steel spray tower, followed by freeze drying to form a dry powder while equivalent compositions were spray dried (SD) as controls. SFD-NCM possess larger specific surface areas (67–77 m²/g) and lower densities (0.02 g/cm³) than their corresponding SD-NCM. With the exception of NCM of lipid based nanocarriers, SFD produced NCM with a mass median aerodynamic diameter (MMAD) of 3.0 ± 0.5 μm and fine particle fraction (FPF ⩽ 5.2 μm) of 45 ± 1.6% with aerodynamic performances similar to SD-NCM. However, SFD was superior to SD in terms of maintaining the particle size of all the investigated polymeric and lipid nanocarriers following reconstitution (S_f/S_i ratio for SFD ≈ 1 versus >1.5 for SD). The SFD into cooled air proved to be an efficient technique to prepare NCM for pulmonary delivery while maintaining the stability of the nanoparticles.     

Inhalable tranexamic acid for haemoptysis treatment

PurposeAn inhalable dry powder formulation of tranexamic acid (TA) was developed and tested in a novel high-dose Orbital® multi-breath inhaler. The formulation was specifically intended for the treatment of pulmonary haemorrhage and wound healing associated with haemoptysis.MethodsInhalable TA particles were prepared by spray drying and the powder characterised using laser diffraction, electron microscopy, thermal analysis, moisture sorption and X-ray powder diffraction. The aerosol performance was evaluated using cascade impaction and inline laser diffraction and interaction with epithelia cells and wound healing capacity investigated using Calu-3 air interface model.ResultsThe spray dried TA particles were crystalline and spherical with a D_0.5 of 3.35 μm. The powders were stable and had limited moisture sorption (0.307% w/w at 90% RH). The Orbital device delivered ca. 38 mg powder per ‘inhalation’ at 60 l · min⁻¹ across four sequential shots with an overall fine particle fraction (⩽6.4 μm) of 59.3 ± 3.5% based on the emitted mass of ca. 150 mg. The TA particles were well tolerated by Calu-3 bronchial epithelia cells across a wide range of doses (from 1 nM to 10 nM) and no increase in inflammatory mediators was observed after deposition of the particles (a decrease in IL-1β, IL-8 and INFγ was observed). Time lapse microscopy of a damaged confluent epithelia indicated that wound closure was significantly greater in TA treated cells compared to control.ConclusionA stable, high performance aerosol of TA has been developed in a multi-breath DPI device that can be used for the treatment of pulmonary lesions and haemoptysis.     

Optimization of the aerosolization properties of an inhalation dry powder based on selection of excipients

The aim of this study was to investigate the influence of formulation excipients on physical characteristics of inhalation dry powders prepared by spray-drying. The excipients used were a series of amino acids (glycine, alanine, leucine, isoleucine), trehalose and dipalmitoylphosphatidylcholine (DPPC). The particle diameter and the powder density were assessed by laser diffraction and tap density measurements, respectively. The aerosol behaviour of the powders was studied in a Multi-Stage Liquid Impinger. The nature and the relative proportion of the excipients affected the aerosol performance of the powders, mainly by altering powder tap density and degree of particle aggregation. The alanine/trehalose/DPPC (30/10/60 w/w/w) formulation showed optimal aerodynamic behaviour with a mass median aerodynamic diameter of 4.7 μm, an emitted dose of 94% and a fine particle fraction of 54% at an airflow rate of 100 L/min using a Spinhaler inhaler device. The powder had a tap density of 0.10 g/cm³. The particles were spherical with a granular surface and had a 4 μm volume median diameter. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.     

Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections

Purpose

The potential of aerosol phage therapy for treating lung infections has been demonstrated in animal models and clinical studies. This work compared the performance of two dry powder formation techniques, spray freeze drying (SFD) and spray drying (SD), in producing inhalable phage powders.

Method

A Pseudomonas podoviridae phage, PEV2, was incorporated into multi-component formulation systems consisting of trehalose, mannitol and L-leucine (F1?=?60:20:20 and F2?=?40:40:20). The phage titer loss after the SFD and SD processes and in vitro aerosol performance of the produced powders were assessed.

Results

A significant titer loss (~2 log) was noted for droplet generation using an ultrasonic nozzle employed in the SFD method, but the conventional two-fluid nozzle used in the SD method was less destructive for the phage (~0.75 log loss). The phage were more vulnerable during the evaporative drying process (~0.75 log further loss) compared with the freeze drying step, which caused negligible phage loss. In vitro aerosol performance showed that the SFD powders (~80% phage recovery) provided better phage protection than the SD powders (~20% phage recovery) during the aerosolization process. Despite this, higher total lung doses were obtained for the SD formulations (SD-F1?=?13.1?±?1.7?×?10⁴ pfu and SD-F2?=?11.0?±?1.4?×?10⁴ pfu) than from their counterpart SFD formulations (SFD-F1?=?8.3?±?1.8?×?10⁴ pfu and SFD-F2?=?2.1?±?0.3?×?10⁴ pfu).

Conclusion

Overall, the SD method caused less phage reduction during the powder formation process and the resulted powders achieved better aerosol performance for PEV2.

     

Pulmonary delivery of pyrazinamide-loaded large porous particles

We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the different components occurring during the spray drying process and to obtain homogeneous LPPs, spray drying parameters were modified to decrease the drying speed. As a result, good aerodynamic properties for lung delivery were obtained with a fine particle fraction (FPF) of 40.1 ± 1.0%, an alveolar fraction (AF) of 29.6 ± 3.1%, a mass median aerodynamic diameter (MMAD_aer) of 4.1 ± 0.2 μm and a geometric standard deviation (GSD) of 2.16 ± 0.16. Plasma and epithelial lining fluid (ELF) concentrations of pyrazinamide were evaluated after intratracheal insufflation of PZA-LPPs (4.22 mg kg⁻¹) into rats and compared to intravenous administration (iv) of a pyrazinamide solution (5.82 mg kg⁻¹). The in vivo pharmacokinetic evaluation of PZA-LPPs in rats reveals that intratracheal insufflation of PZA-LPPs leads to a rapid absorption in plasma with an absolute bioavailability of 66%. This proves that PZA-LPPs dissolve fast upon deposition and that PZA crosses efficiently the lung barrier to reach the systemic circulation. PZA concentrations were 1.28-fold higher in ELF after intratracheal administration than after iv administration and the ratio of ELF concentrations over plasma concentrations was 2-fold greater. Although these improvements are moderate, lung delivery of PZA appears an interesting alternative to oral delivery of the molecule and should now be tested in an infected animal model to evaluate its efficacy against Mycobacterium tuberculosis.     

Spray drying of fenofibrate loaded nanostructured lipid carriers

The conversion of aqueous dispersion of nanostructured lipid carriers (NLCs) into dry powder by spray drying could be a useful approach to render NLCs with better physical chemical stability than the aqueous dispersion. In this study, aqueous NLC dispersion containing fenofibrate was converted into dry, easily reconstitutable powder using spray drying. A central composite face centered design (CCFD) was used to investigate the influence of the ratio of lipid to protectant (mannitol and trehalose) and crystallinity of spray-dried powder on the particle size, yield and residual moisture content of the dried powder. A linear relationship (R² = 0.9915) was established between the crystalline content of the spray-dried powders against the ratio of mannitol to trehalose from 3:7 to 10:0 (w/w). Spray drying of NLC aqueous dispersion using a mannitol and trehalose mixture resulted in an increase in particle size of the NLCs after reconstitution in water as compared to that in the initial aqueous dispersion. The decrease in crystallinity of the dry powder by reducing the ratio of mannitol to trehalose could improve the reconstitution of the NLCs in water. However the yield and residual moisture content of dry powder decreased with an increase in the ratio of mannitol to trehalose. Lipid nanoparticles were able to retain the drug incorporation and the prolonged drug release profile after spray drying. The experimental model was robust, and suggested that spray drying is a viable technique for the conversion of NLCs into dry powder.     

Mechanism of Protein Stabilization by Trehalose During Freeze-Drying Analyzed by In Situ Micro-Raman Spectroscopy

Raman investigations were performed in situ during freeze-drying of two model proteins, lysozyme and chymotrypsinogen. The structures of proteins dissolved in 0–30 wt % solutions of trehalose in D₂O were monitored with the fingerprint (800–1800 cm^? 1) spectrum, simultaneously with freezing, ice sublimation, and water desorption analyzed in the O-D stretching (2200–2700 cm^? 1) region. In the absence of trehalose, the main changes were detected at the end of primary drying, and correspond to distortion and disordering of secondary structures. A stabilizing effect of trehalose was evidenced in primary and secondary drying stages. Raman images were calculated after freezing and primary drying, providing the distributions of trehalose, water, and protein which occur during the first two stages of the lyophilization cycle. Raman images show a slight heterogeneity in the degree of protein denaturation at the end of primary drying, in relation with the structure of the frozen product observed during freezing. The ability of trehalose to make the protein more rigid was determined as responsible for the protein stabilization during a lyophilization cycle. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2484–2494, 2013     

Formulation of pH responsive peptides as inhalable dry powders for pulmonary delivery of nucleic acids

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease, but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells with the latter remaining effective even in the presence of lung surfactant containing bronchoalveolar lavage fluid (BALF), making this class of peptides attractive candidates for delivering nucleic acids to lung tissues. To further assess the suitability of pH responsive peptides for pulmonary delivery by inhalation, dry powder formulations of pH responsive peptides and plasmid DNA, with mannitol as carrier, were produced by either spray drying (SD) or spray freeze drying (SFD). The properties of the two types of powders were characterised and compared using scanning electron microscopy (SEM), next generation impactor (NGI), gel retardation and in vitro transfection via a twin stage impinger (TSI) following aerosolisation by a dry powder inhaler (Osmohaler™). Although the aerodynamic performance and transfection efficacy of both powders were good, the overall performance revealed SD powders to have a number of advantages over SFD powders and are the more effective formulation with potential for efficient nucleic acid delivery through inhalation.     

Preparation and Evaluation of Controlled Release Microparticles for Respiratory Protein Therapy

A series of microparticle formulations, designed for controlled release pulmonary therapy, were evaluated in terms of their physical properties, aerosol performance, lung epithelial cell toxicity, and controlled release profile. A protein, bovine serum albumin (BSA) was chosen as a model macromolecule active ingredient which was coprocessed, using spray drying, with varying concentrations of the release modifier, polyvinyl alcohol (PVA). The spray dried microparticles were tested for their physico-chemical characteristics (e.g., size distribution, morphology and density), in vitro aerosolisation performance using a 5-stage Marple Miller Impactor (MMI) and in vitro release profiles by a custom-built diffusion cell (in 100 mL phosphate buffer pH 7.4). The toxicity of PVA on lung epithelial cells was investigated using a human alveolar basal epithelium A549 cell line. Analysis of the particle size data indicated that all the spray dried BSA/PVA samples had similar size distributions with a median particle diameter (d_0.5) across all samples of 2.79 ± 0.11 µm. All formulations had relatively good aerosolisation performance when compared to conventional dry powder inhalation (DPI) formulations although increasing PVA percentage had a negative effect on the aerosol performance in vitro. Analysis of the difference and similarity factors for the release profiles indicated significant differences with respect to PVA concentration. Furthermore, cell toxicity analysis indicated PVA to have limited effect on cell viability after 24 h exposure. A series of protein-based inhalation formulations have been developed and tested, and shown to be suitable for controlled release in the respiratory tract. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2709–2717, 2009     

Local and systemic delivery of high-molecular weight drugs by powder inhalation

The pulmonary route has recently attracted attention as a noninvasive administration route for peptide and protein drugs, and an insulin powder for inhalation was approved by authorities in Europe and the USA. The present study examined usefulness of insulin and gene powders for systemic and local inhalation therapy. We prepared several dry insulin powders by spray drying to examine the effect of additives on insulin absorption. Citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder. However, in the powder with citric acid (MIC0.2 SD) insulin was unstable compared with the other powders examined. To improve insulin stability, a combination of insulin powder and citric acid powder was prepared (MIC Mix). MIC Mix showed hypoglycemic activity comparable to MIC0.2 SD while the insulin stability was much better than that of MIC SD. Next, dry insulin powders with mannitol were prepared with supercritical carbon dioxide (SCF); the powder thus prepared reduced blood glucose level rapidly and was more effective than that prepared by spray drying. Chitosan-pDNA complex powders as a pulmonary gene delivery system were also prepared with SCF and their in vivo activity was evaluated. The addition of chitosan suppressed the degradation of pCMV-Luc during preparation and increased the storage stability. The luciferase activity in mouse lung was evaluated after pulmonary administration of the powders. The chitosan-pDNA powder with an N/P ratio=5 increased the luciferase activity to 27 times that of the pCMV-Luc solution. These results suggest that gene powder with chitosan is a useful pulmonary gene delivery system.     

Single step bottom-up process to generate solid phospholipid nano-particles

Abstract

Context: The particularity of the Nano Spray Dryer B-90 is the nozzle containing a mesh vibrating at ultrasonic frequency.

Objective: To study process parameters and processability of crude phospholipid dispersions, in particular the effect of concentration and mesh aperture on both particle size of the dry solid phospholipid nano-particles and on the re-dispersed powder.

Materials and methods: Phospholipid dispersions containing trehalose as a stabilizer were spray dried. Particle size distributions of dry powders were evaluated by SEM micrographs and by PCS and cryo-TEM for the re-dispersed particles.

Results: Spray drying of crude liposome dispersions revealed solid phospholipid nano-particles. Aperture of nozzle mesh and concentration of the dispersions, respectively, both increased the size of solid phospholipid nano-particles. For crude dispersions, an upper limit with respect to processability was found close to below 10% (m/m) even if the crude dispersion was passed along the mesh several times; however, more effective dispersing methods such as pre-sonication can push the limit of processability to higher values.

Discussion and conclusion: The nano spray dryer is capable of spray drying crude dispersions of phospholipids in concentrations below 10% (m/m) generating solid phospholipid nano-particles relevant for pulmonary delivery. Re-dispersion of spray dried powder reveals liposomes.     

Inhalable oridonin-loaded poly(lactic-co-glycolic)acid large porous microparticles for in situ treatment of primary non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Traditional chemotherapy for this disease leads to serious side effects. Here we prepared an inhalable oridonin-loaded poly(lactic-co-glycolic)acid (PLGA) large porous microparticle (LPMP) for in situ treatment of NSCLC with the emulsion/solvent evaporation/freeze-drying method. The LPMPs were smooth spheres with many internal pores. Despite a geometric diameter of ~10 µm, the aerodynamic diameter of the spheres was only 2.72 µm, leading to highly efficient lung deposition. In vitro studies showed that most of oridonin was released after 1 h, whereas the alveolar macrophage uptake of LPMPs occurred after 8 h, so that most of oridonin would enter the surroundings without undergoing phagocytosis. Rat primary NSCLC models were built and administered with saline, oridonin powder, gemcitabine, and oridonin-loaded LPMPs via airway, respectively. The LPMPs showed strong anticancer effects. Oridonin showed strong angiogenesis inhibition and apoptosis. Relevant mechanisms are thought to include oridonin-induced mitochondrial dysfunction accompanied by low mitochondrial membrane potentials, downregulation of BCL-2 expressions, upregulation of expressions of BAX, caspase-3 and caspase-9. The oridonin-loaded PLGA LPMPs showed high anti-NSCLC effects after pulmonary delivery. In conclusion, LPMPs are promising dry powder inhalations for in situ treatment of lung cancer.     

Preparation and characterisation of novel spray-dried nano-structured para-aminosalicylic acid particulates for pulmonary delivery: impact of ammonium carbonate on morphology, chemical composition and solid state

Objectives The objective of this work was to spray dry p‐aminosalicylic acid (PAS) and its ammonium salt and to investigate the impact of the pore‐forming agent, ammonium carbonate (AC), on the morphological, aerodynamic and physicochemical properties of the resulting powders. Methods Microparticles were prepared by spray drying from ethanol/water solvent systems. Their solid‐state properties were evaluated by scanning electron microscopy, powder X‐ray diffraction, differential scanning calorimetry, thermogravimetric analysis and in‐vitro deposition, using the twin impinger. Key Findings The physicochemical properties of PAS were altered on spray drying with AC and a new solid state was produced. The solution composition impacted on the morphology of the resulting powders, which ranged from irregular crystal agglomerates to spherical crystal clusters and porous microparticles. The chemical composition, structure and morphology were dependent on process inlet temperature, low inlet temperatures resulting in a novel solid of stoichiometry; PAS : ammonia : water, 2 : 1 : 0.5. At higher temperatures pure PAS was obtained. In‐vitro deposition studies showed an increase in emitted dose from spray dried drug, relative to the micronised PAS. Conclusions Under appropriate process conditions AC interacts with the acidic PAS, resulting in the formation of a novel solid‐state drug phase. Spray‐dried PAS powders have potential for pulmonary delivery.     

Mucoadhesive microparticles as potential carriers in inhalation delivery of doxycycline hyclate: a comparative study

The present work compares and evaluates the suitability of different polymer-based microparticles for inhalation delivery of doxycycline hyclate. Mucoadhesive polymers, such as sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, starch, and carbopol were selected as carriers for inhalation delivery. Microparticles were prepared by spray drying and evaluated in terms of yield, moisture content, morphology, tapped density, encapsulation efficiency, in vitro mucoadhesion, thermal properties and in vitro aerosolization performance. Additionally, the cytotoxicity of the microparticles on H1299 human alveolar cell line was examined. Smooth spherical to collapsed doughnut shaped particles were formed. They exhibited tap densities of 0.202–0.502 g/cm³ and mass median aerodynamic diameter of 3.74–6.54 μm. Mucoadhesion was highest in case of carbopol-based microparticles. Drug release from these microparticles exhibited biphasic Fickian type of diffusion. Only at the highest concentration of microparticles (1 mg/mL) less than 90% cell viability was seen in DX loaded sodium alginate microparticles (DXSA, 87.2%), starch microparticles (DXST, 85.1%) and carbopol microparticles (DXCP, 82.7%) preparations after 48 h of exposure to alveolar cells. The results clearly indicate that sodium carboxymethyl cellulose-based microparticles may serve as an ideal carrier for inhalation delivery of doxycycline hyclate.     

A Novel Inhalable Form of Rifapentine

Recent murine studies found that rifapentine, dosed daily, at least halved tuberculosis treatment times compared with standard rifampicin and isoniazid-containing regimens. However, in humans, an inhalable form of rifapentine may be necessary to considerably shorten treatment duration because of the physiological barriers associated with oral therapy. The current study compares two inhalable rifapentine dry powders—a novel pure crystalline form and an amorphous form—by a series of in vitro tests. The crystalline and amorphous powders had a mass median aerodynamic size of 1.68 ± 0.03 and 1.92 ± 0.01 μm, respectively, associated with a fine particle fraction of 83.2 ± 1.2% and 68.8 ± 2.1%, respectively. A quinone degradation product was identified in the amorphous powder stored for 1 month, whereas the crystalline form remained chemically stable after storage at both 0% and 60% relative humidity, 25°C, for at least 3 months. Solubilized rifapentine was well tolerated by pulmonary tissue and macrophage cells up to approximately 50 μM. The accumulation of rifapentine within alveolar macrophage cells was significantly higher than for rifampicin, indicating enhanced delivery to infected macrophages. The novel inhalable crystalline form of rifapentine is suitable for targeted treatment of tuberculosis infection and may radically shorten treatment duration. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

Dry Powder Aerosols Generated by Standardized Entrainment Tubes From Drug Blends With Lactose Monohydrate: 1. Albuterol Sulfate and Disodium Cromoglycate

The major objective of this study was: discriminatory assessment of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs. Drug/lactose interactive physical mixtures (2%w/w) were prepared. Their properties were measured: solid-state characterization of phase behavior and molecular interactions by differential scanning calorimetry and X-ray powder diffraction; particle morphology and size by scanning electron microscopy and laser diffraction; aerosol generation by SETs and characterization by twin-stage liquid impinger and Andersen cascade impactor operated at 60 L/min. The fine particle fraction (FPF) was correlated with SET shear stress (τ_s), using a novel powder aerosol deaggregation equation (PADE). Drug particles were < 5 μm in volume diameter with narrow unimodal distribution (Span < 1). The lowest shear SET (τ_s = 0.624 N/m²) gave a higher emitted dose (ED ~ 84–93%) and lower FPF (FPF_6.4 ~ 7–25%). In contrast, the highest shear SET (τ_s = 13.143 N/m²) gave a lower ED (ED ~ 75–89%) and higher FPF (FPF_6.4 ~ 15–46%). The performance of disodium cromoglycate was superior to albuterol sulfate at given τ_s, as was milled with respect to sieved lactose monohydrate. Excellent correlation was observed (R² ~ 0.9804–0.9998) when pulmonary drug particle release from the surface of lactose carriers was interpreted by PADE linear regression for dry powder formulation evaluation and performance prediction.     

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1–34 for the treatment of osteoporosis

Osteoporosis treatment with PTH 1–34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1–34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1–34 nasal spray formulation bioactivity. The chemically synthesised PTH 1–34 had an EC₅₀ of 0.76 nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol^® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1–34 within an in vitro cell culture model (p > 0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol^® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1–34 into the blood via intranasal delivery produced a Cmax of 2.1 ± 0.5 ng/ml compared to 13.7 ± 1.6 ng/ml with Solutol^® HS15 enhancer (p = 0.016) and a Cmax14.8 ± 8 ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol^® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol^® HS15 formulation therefore demonstrated potential as a PTH 1–34 nasal spray formulation for the treatment of osteoporosis.     

Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung

Targeted aerosol delivery to specific regions of the lung may improve therapeutic efficiency and minimise unwanted side effects. Targeted delivery could potentially be achieved with porous microparticles loaded with superparamagnetic iron oxide nanoparticles (SPIONs)—in combination with a target-directed magnetic gradient field. The aim of this study was to formulate and evaluate the aerodynamic properties of SPIONs-loaded Trojan microparticles after delivery from a dry powder inhaler. Microparticles made of SPIONs, PEG and hydroxypropyl-β-cyclodextrin (HPβCD) were formulated by spray drying and characterised by various physicochemical methods. Aerodynamic properties were evaluated using a next generation cascade impactor (NGI), with or without a magnet positioned at stage 2. Mixing appropriate proportions of SPIONs, PEG and HPβCD allowed Trojan microparticle to be formulated. These particles had a median geometric diameter of 2.8 ± 0.3 μm and were shown to be sensitive to the magnetic field induced by a magnet having a maximum energy product of 413.8 kJ/m³. However, these particles, characterised by a mass median aerodynamic diameter (MMAD) of 10.2 ± 2.0 μm, were considered to be not inhalable. The poor aerodynamic properties resulted from aggregation of the particles. The addition of (NH₄)₂CO₃ and magnesium stearate (MgST) to the formulation improved the aerodynamic properties of the Trojan particles and resulted in a MMAD of 2.2 ± 0.8 μm. In the presence of a magnetic field on stage 2 of the NGI, the amount of particles deposited at this stage increased 4-fold from 4.8 ± 0.7% to 19.5 ± 3.3%. These Trojan particles appeared highly sensitive to the magnetic field and their deposition on most of the stages of the NGI was changed in the presence compared to the absence of the magnet. If loaded with a pharmaceutical active ingredient, these particles may be useful for treating localised lung disease such as cancer nodules or bacterial infectious foci.     

Investigation into the effect of varying l-leucine concentration on the product characteristics of spray-dried liposome powders

Objectives Spray-dried formulations offer an attractive delivery system for administration of drug encapsulated into liposomes to the lung, but can suffer from low encapsulation efficiency and poor aerodynamic properties. In this paper the effect of the concentration of the anti-adherent l-leucine was investigated in tandem with the protectants sucrose and trehalose. Methods Two manufacturing methods were compared in terms of their ability to offer small liposomal size, low polydispersity and high encapsulation of the drug indometacin. Key findings Unexpectedly sucrose offered the best protection to the liposomes during the spray drying process, although formulations containing trehalose formed products with the best powder characteristics for pulmonary delivery; high glass transition values, fine powder fraction and yield. It was also found that l-leucine contributed positively to the characteristics of the powders, but that it should be used with care as above the optimum concentration of 0.5% (w/w) the size and polydispersity index increased significantly for both disaccharide formulations. Conclusions The method of liposome preparation had no effect on the stability or encapsulation efficiency of spray-dried powders containing optimal protectant and anti-adherent. Using l-leucine at concentrations higher than the optimum level caused instability in the reconstituted liposomes.