Polymer coating of carrier excipients modify aerosol performance of adhered drugs used in dry powder inhalation therapy.

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.

Preparation and evaluation of single and co-engineered combination inhalation carrier formulations for the treatment of asthma.

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.

Co-deposition of a triple therapy drug formulation for the treatment of chronic obstructive pulmonary disease using solution-based pressurised metered dose inhalers.

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.

Co-spray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease.

The aim of this study was to assess the potential of delivering a combination therapy, containing mannitol (a sugar alcohol with osmotic characteristics), and ciprofloxacin hydrochloride (an antibacterial fluoroquinolone), as a dry powder inhaler (DPI) formulation for inhalation. Single and combination powders were produced by spray drying ciprofloxacin and mannitol, from aqueous solution, at different ratios and under controlled conditions, as to obtain similar particle size distributions. Each formulation was characterised using laser diffraction, scanning electron microscopy, differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and colloidal force microscopy. The in vitro aerosol performance of each formulation was studied using an Aerolizer DPI device and a multi-stage liquid impinger (analysed using high performance liquid chromatography). In addition, a disk diffusion test was performed to assess the in vitro antimicrobial activity of each formulation and starting materials. All formulations had similar particle size distributions, however, the morphology, thermal properties and moisture sorption was dependent on the relative percentages of each component. In general, the combination formulation containing 50% (w/w) mannitol appeared to have the best aerosol performance, good stability and lowest particle cohesion (as measured by colloid probe microscopy). Furthermore, of the formulations tested, mannitol did not appear to alter the effectiveness of the ciprofloxacin antimicrobial activity to Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes. The combination of co-spray-dried mannitol and ciprofloxacin from a DPI is an attractive approach to promote mucous clearance in the respiratory tract while simultaneously treating local chronic infection, such as chronic obstructive pulmonary disease and cystic fibrosis.

Can low-dose combination products for inhalation be formulated in single crystalline particles?

This study aims to produce and test the performance of novel crystalline respirable particles containing two low-dose active ingredients and mannitol. This technique overcomes the usual requirement of blending with lactose carriers in formulating combination inhalation products. Ternary powders were produced by co-spray drying solutions containing an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and mannitol as a crystalline excipient. Two formulations comprising widely used ICS and LABA were studied: budesonide/formoterol fumarate dihydrate/mannitol (B/F/M-SD) and fluticasone propionate/salmeterol xinafoate/mannitol (F/S/M-SD). Various physicochemical properties of the powders were analyzed. Aerosol performance was evaluated by dispersing each powder from an Aerolizer at 60 and 100 L/min into a Next Generation Impactor. We obtained partially hollow spherical particles (volume median diameters of 2 microm) with drug-enriched surfaces. Both formulations contained alpha-mannitol, and the ICSs were crystalline. The content of each drug component in the powder was found to conform to the theoretical dose. The ternary powders generated high fine particle fractions (>50% of the loaded dose), with concomitant drug deposition on the impactor stages. The aerosol performance of B/F/M-SD was maintained after storage over silica gel at 22 degrees C for 11 weeks. In conclusion, co-spray dried particles of ICS/LABA/M-SD were largely crystalline, stable and showed excellent aerosol performance. They may provide an attractive alternative strategy to develop combination products without lactose blends.

A novel method for the production of crystalline micronised particles.

The aim of this study was to develop a method for converting an amorphous drug to a crystalline form to enhance its stability and inhalation performance. Spray-dried amorphous salbutamol sulphate powder was conditioned with supercritical carbon dioxide (scCO(2)) modified with menthol. The effect of menthol concentration, pressure, temperature and time on the characteristics of the resulting salbutamol sulphate powder was investigated. Pure scCO(2) had no effect on the physical properties of amorphous salbutamol sulphate; however, scCO(2) modified with menthol at 150bar and 50 degrees C was efficient in converting amorphous drug to crystalline form after 12h of conditioning. The average particle size of powders decreased slightly after the conditioning process because of reducing agglomeration between particles by increasing surface roughness. Emitted dose measured by the fine particle fraction (FPF(emitted)) of amorphous salbutamol sulphate was enhanced from 32% to 43% after conditioning with scCO(2)+menthol and its water uptake was significantly decreased. This study demonstrates the potential of scCO(2)+menthol for converting amorphous forms of powders to crystalline, while preserving the particle size.

Does electrostatic charge affect powder aerosolisation?

To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelectric charging theories, based on the work function values from literature and electron transfer tendencies from measurement of contact angle. The latter generated a parameter, gamma(-)/gamma+, which is a measure of the electron-donating capacity relative to the electron-accepting tendency of material. Lowering the work function value or increasing the gamma(-)/gamma+ ratio of the container material resulted in mannitol being more negatively charged, and vice versa. After charging, the powder was dispersed from an Aerolizer(R), at 30 and 60 L/min, to study the aerosol performance. Irrespective of the charge level, the powder showed similar fine particle fraction, emitted dose and device retention at a given flow rate, indicating that charge induced by different containers during tumbling does not play a significant role in mannitol powder aerosolisation.

Controlled release antibiotics for dry powder lung delivery.

INTRODUCTION: Two controlled release (CR) antibiotics intended for inhalation therapy were evaluated. MATERIAL AND METHODS: Ciprofloxacin and doxycycline (both hydrochlorides) were selected as model drugs. Microparticles containing 90:10 ratio of polyvinyl alcohol (PVA) and single antibiotics or combinations were obtained via spray drying. The microparticles were evaluated in terms of particle size, morphology, thermal properties, aerosol performance, and in vitro release. RESULTS AND DISCUSSION: Analysis of the microparticle morphology indicated comparable size distributions (2.04 ± 0.06, 2.15 ± 0.01, and 2.21 ± 0.01 µm for ciprofloxacin, doxycycline, and co-spray-dried antibiotic formulations, respectively). Thermal analysis of the microparticles suggested similar responses, which were dominated by the endothermic peaks observed for PVA alone. Analysis of the aerosol performance suggested that the individual antibiotic formulations had different aerosol profiles that were dependent on the antibiotic used. In comparison, the combination CR antibiotics had identical aerosol profiles, suggesting that the microparticles were homogeneous. The release of antibiotics from the CR microparticles showed that ≤ 50% was released over a 6-hour period in comparison to ≥ 90% being released in the first hour for microparticles containing no PVA. CONCLUSIONS: The potential for antibiotic therapy, and specifically CR antibiotic therapy using dry powder inhalers, provides a promising route for the treatment of pulmonary infection.

Pulmonary spray dried powders of tobramycin containing sodium stearate to improve aerosolization efficiency.

PURPOSE: Tobramycin microparticulate powders containing the hydrophobic adjunct sodium stearate were studied for their use as pulmonary formulations in dry powder inhalers. METHODS: Spray-dried powders were characterized in terms of particle size distribution, morphology, crystallinity, drug dissolution rate, toxicity on epithelial lung cells and aerosol efficiency. RESULTS: The presence of the sodium stearate had a direct influence on the aerosol performance of tobramycin spray-dried powders. Powders containing 1% w/w sodium stearate had fine particle fraction FPF of 84.3 +/- 2.0% compared to 27.1 +/- 1.9% for powders containing no adjunct. This was attributed to the accumulation of sodium stearate at the particle surface. Powders with higher sodium stearate concentrations (2% w/w) showed significantly lower FPF (66.4 +/- 0.9%) and less accumulation of sodium stearate at the particle surface. This was attributed to the formation of adjunct micelles, which remained internalised in the particle structure due to their reduced tropism toward the drying drop surface and molecular mobility. Preliminary analysis of the toxicity effect of sodium stearate on A549 cell lines showed that the adjunct, in the concentration used, had no effect on cell viability over a 24-h period compared to particles of pure tobramycin. CONCLUSIONS: Tobramycin pulmonary powders with low level of sodium stearate, presenting high respiration performances and no overt toxicity on lung cells, could be used to improve therapeutic outcomes of patient with Cystic Fibrosis (CF).

Lactose composite carriers for respiratory delivery.

PURPOSE: Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug-carrier adhesion, variability in drug-carrier forces and influence on drug aerosol performance from carrier-drug blends. METHODS: Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 microm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63-90 microm carriers. The carriers were evaluated in terms of size (laser diffraction) morphology (electron microscopy and atomic force microscopy), crystallinity and drug adhesion (colloid probe microscopy). In addition, blends containing drug and carrier were prepared and evaluated in terms of drug aerosol performance. RESULTS: The surface morphology and physico-chemical properties of the composite carriers were significantly different. Depending on the initial primary lactose size, the composite particles could be prepared with different surface roughness. Variation in composite roughness could be related to the change in drug adhesion (via modification in contact geometry) and thus drug aerosol performance from drug-lactose blends. CONCLUSION: Composite based carriers are a potential route to control drug-carrier adhesion forces and variability thus allowing more precise control of formulation performance.

Scanning white-light interferometry as a novel technique to quantify the surface roughness of micron-sized particles for inhalation.

A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and alpha-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four samples of BSA) or decantation (two samples of lactose). Particle size distributions were characterized by laser diffraction, and particles were imaged by scanning electron microscopy (SEM). Surface roughness of the BSA and lactose particles was quantified by white-light optical profilometry using vertical scanning interferometry (VSI) at full resolution using a 50x objective lens with 2.0x and 0.5x fields of view for BSA and lactose, respectively. Data were analyzed using Vision software (version 32, WYKO), and surface roughness values are expressed as root-mean-square roughness ( Rrms). Furthermore, data were compared to topographical measurements made using conventional atomic force microscopy. Analysis of the optical profilometry data showed significant variation in BSA roughness ranging from 18.58 +/- 3.80 nm to 110.90 +/- 13.16 nm for the smoothest and roughest BSA particles, respectively, and from 81.20 +/- 15.90 nm to 229.20 +/- 68.20 nm for decanted and normal lactose, respectively. The Rrms values were in good agreement with the AFM-derived values. The particle morphology was similar to SEM and AFM images. In conclusion, scanning white-light interferometry provides a useful complementary tool for rapid evaluation of surface morphology and roughness in particles used for dry powder inhalation formulation.

Micro-particle corrugation, adhesion and inhalation aerosol efficiency.

Atomic force microscopy (AFM) was used to evaluate the particle adhesion and surface morphology of engineered particles for dry powder inhaler (DPI) respiratory therapy to gain a greater understanding of interparticle forces and the aerosolisation process. A series of spherical model drug particles of bovine serum albumin (BSA) was prepared with different degrees of surface corrugation. The particles were evaluated in terms of particle size (laser diffraction) and microscopic morphology (scanning electron microscopy). Conventional tapping mode AFM was used to evaluate the nanoscopic morphology and derive specific roughness parameters, while AFM colloid probe microscopy was used to directly measure the interaction of functionalised probes. The physical characterisation and AFM measurements were evaluated in terms of in vitro aerosolisation performance, using a conventional Rotahaler((R)) DPI and multistage liquid impinger. A direct relationship between the root mean square roughness, particle adhesion and in vitro aerosol performance (measured as fine particle fraction, FPF) was observed suggesting that as the degree of corrugation increased, particle adhesion was reduced which, resulted in a concomitant increase in FPF. This study demonstrates that AFM may be used to predict the aerosolisation performance micron sized particles for inhalation based on their morphological properties.

Cospray dried antibiotics for dry powder lung delivery.

The aim of this study was to assess the potential of delivering a combination antibiotic therapy, containing doxycycline and ciprofloxacin (both hydrochloride) as a dry powder (DPI) formulation for inhalation. Single and combination antibiotics were produced by spray drying. Particle size distributions were characterized by laser diffraction and imaging conducted by scanning electron microscopy. Solid-state characterisation of the antibiotics was carried out using differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and differential scanning calorimetry. Using the Aerolizer device, the aerosol performance was measured using multistage liquid impinger and analysed using high performance liquid chromatography (R(2) = 1.0, CV = 0.4-1.0%). Furthermore, a disk diffusion test was performed for the assessment of the in vitro antimicrobial activity of the raw and spray dried antibiotics against bacteria. Results showed that cospray drying of the ciprofloxacin and doxycycline produced an antibiotic formulation (in a 1:1 ratio) suitable for inhalation that showed to be physically more stable then the analogous single spray dried antibiotic. The cospray dried powder has improved dispersion over the less stable single spray dried ciprofloxacin. The spray dried antibiotics were observed to have similar antimicrobial activity to the original antibiotics for Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyrogenes, suggesting the spray drying process does not affect the anti-bacterial activity of the drug. Cospray dried antibiotics from a DPI is thus feasible and can potentially be an attractive delivery alternative to the more conventional systemic delivery route.

Role of agglomeration in the dispersion of salmeterol xinafoate from mixtures for inhalation with differing drug to fine lactose ratios.

The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (SX) dispersion from mixtures for inhalation by varying the SX concentration and the proportion of fine lactose (FL). SX concentrations and SX:FL ratios ranged from 1.0% to 5.0% (w/w) and from 1:0 to 1:8, respectively. The in vitro deposition of SX was measured using a twin stage impinger (TSI). The aerosol was characterized by particulate capture in the TSI stages and subsequent imaging by scanning electron microscopy and by real-time particle sizing. The presence of coarse lactose reduced SX dispersion compared with SX alone, and the dispersion was independent of SX concentration. SX dispersion in binary mixtures of SX and FL was independent of SX:FL ratio and was similar to that of carrier-based mixtures with high particulate loads. Increased concentrations of SX and proportions of FL in carrier-based mixtures resulted in increased SX dispersion. Agglomerate formation coincided with increased dispersion. The study demonstrated that agglomeration is one of the important factors in SX dispersion from carrier-based mixtures at high particulate loads.

The influence of drug morphology on aerosolisation efficiency of dry powder inhaler formulations.

The physicochemical properties of two forms of spray dried bovine serum albumin (BSA) have been investigated using particle sizing, surface energy measurement, atomic force microscopy (AFM) and colloid probe microscopy. The BSA powder had similar particle size distributions and surface energy but significantly different morphologies and roughness, classified as smooth and corrugated BSA. Adhesion forces between the corrugated BSA and alpha-lactose monohydrate indicated median adhesion forces were significantly less than for smooth/carrier interaction forces. These observations correlated well with aerosolisation from BSA/carrier blends, where the corrugated BSA particles gave a higher fine particle fraction than the smooth BSA, suggesting reduced BSA/carrier adhesion and increased drug liberation. The use of corrugated drug particle morphology in drug carrier DPI systems may lead to improved aerosol performance through reduced drug carrier contact area.

Adhesion and redistribution of salmeterol xinafoate particles in sugar-based mixtures for inhalation.

The aim of this study was to evaluate coarse and fine sugars as potential alternative excipients in dry powder inhalation formulations and to develop a greater understanding of the key interactions between the particulate species in these mixtures. Interactive mixtures composed of salmeterol xinafoate (SX) and different type of sugars (lactose, glucose, mannitol and sorbitol) were prepared using validated laboratory scale mixing. The sugars and SX were characterised by laser diffraction, scanning electron microscopy, atomic force microscopy and loss on drying method. Deposition of SX was measured using a twin-stage impinger and analysed using validated HPLC method (r(2)=1.0, CV=0.4-1.0%). Good correlation existed between the fine particle fraction (FPF) of SX and both the adhesion force and the moisture content. The addition of 10% fine sugars to produce ternary mixtures (i.e. SX, coarse and fine sugars) generally increased dispersion, with the addition of fine glucose>fine mannitol>fine lactose>fine sorbitol. The dispersion of SX showed a reciprocal relationship with the moisture content of the sugars with glucose showing the greatest and sorbitol showing the lowest extent of SX dispersion. The study clearly demonstrated that strong SX adhesion to coarse sugars reduced the extent of dispersion and that surface detachment of the SX and fine sugar from the coarse sugar carrier was important in the dispersion process.

Agglomerate strength and dispersion of salmeterol xinafoate from powder mixtures for inhalation.

PURPOSE: The study investigated the role of agglomeration and the effect of fine lactose size on the dispersion of salmeterol xinafoate (SX) from SX-lactose mixtures for inhalation. METHODS: Particle size distributions were characterised by Malvern Mastersizer S, Aerosizer and Spraytec, and imaging conducted by scanning electron microscopy (SEM). Inter-particulate adhesion was quantified by atomic force microscopy. Deposition of SX was measured using a twin stage impinger. SX was analysed using validated high-performance liquid chromatography method (r(2)=1.0, CV=0.4-1.0%). RESULTS: Addition of fine lactose with a volume median diameter (VMD) of 7.9 microm to a SX-lactose carrier and carrier-free mixture resulted in significantly better dispersion (16.8% for 20% added fine lactose) than fractions with VMD of 3.0, 17.7 and 33.3 microm (less than 9.1% for 20% fine lactose). Using the carrier-free mixtures, particle sizing of the aerosol cloud using the Spraytec, coupled with the application of the Aerosizer using differing dispersion energies and SEMs of the samples, indicated that an open packed, agglomerate structure improved SX dispersion. The highest extent of SX dispersion occurred when SX and fine lactose were detached from the surface, usually in the form of loose agglomerates. CONCLUSIONS: The outcomes of this research demonstrated how agglomerate structure influenced dispersion and the key role of fine lactose particle size in SX dispersion from mixtures for inhalation.