How Much Surface Coating of Hydrophobic Azithromycin Is Sufficient to Prevent Moisture-Induced Decrease in Aerosolisation of Hygroscopic Amorphous Colistin Powder?

Aerosolisation performance of hygroscopic particles of colistin could be compromised at elevated humidity due to increased capillary forces. Co-spray drying colistin with a hydrophobic drug is known to provide a protective coating on the composite particle surfaces against moisture-induced reduction in aerosolisation performance; however, the effects of component ratio on surface coating quality and powder aerosolisation at elevated relative humidities are unknown. In this study, we have systematically examined the effects of mass ratio of hydrophobic azithromycin on surface coating quality and aerosolisation performance of the co-spray dried composite particles. Four combination formulations with varying drug ratios were prepared by co-spray drying drug solutions. Both of the drugs in each combination formulation had similar in vitro deposition profiles, suggesting that each composite particle comprises two drugs in the designed mass ratio, which is supported by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) data. XPS and ToF-SIMS measurements also revealed that 50% by weight (or 35% by molecular fraction) of azithromycin in the formulation provided a near complete coating of 96.5% (molar fraction) on the composite particle surface, which is sufficient to prevent moisture-induced reduction in fine particle fraction (FPF)recovered and FPFemitted. Higher azithromycin content did not increase coating coverage, while contents of azithromycin lower than 20% w/w did not totally prevent the negative effects of humidity on aerosolisation performance. This study has highlighted that a critical amount of azithromycin is required to sufficiently coat the colistin particles for short-term protection against moisture.     

Preparation and characterisation of controlled release co-spray dried drug-polymer microparticles for inhalation 2: Evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols.

Three in vitro methodologies were evaluated as models for the analysis of drug release from controlled release (CR) microparticulates for inhalation. USP Apparatus 2 (dissolution model), USP Apparatus 4 (flow through model) and a modified Franz cell (diffusion model), were investigated using identical sink volumes and temperatures (1000ml and 37 degrees C). Microparticulates containing DSCG and different percentages of PVA (0%, 30%, 50%, 70% and 90%) were used as model CR formulations. Evaluation of the release profiles of DSCG from the modified PVA formulations, suggested that all data fitted a Weibull distribution model with R(2)0.942. Statistical analysis of the t(d) (time for 63.2% drug release) indicated that all methodologies could distinguish between microparticles that did or did not contain PVA (Students t-test, p<0.05). However, only the diffusion model could differentiate between samples containing different PVA percentages. Similar results were observed when analysing the data using similarity and difference factors. Furthermore, analysis of the release kinetic profiles for all samples suggested the data fitted the Higuchi diffusion model (R(2)0.862 for the diffusion methodology data set). Due to the relatively low water content in the respiratory tract and the lack of differentiation between formulations for USP Apparatus 2 and 4, it is concluded that the diffusion model is more applicable for the evaluation of CR inhalation medicines.     

Evaluation of HPβCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery

For therapeutic peptides, the lung represents an attractive, noninvasive route into the bloodstream. To achieve optimal bioavailability and control their fast rate of absorption, peptides can be protected by coprocessing with polymers such as polyethylene glycol (PEG). Here, we formulated and characterized salmon calcitonin (sCT)-loaded microparticles using linear or branched PEG (L-PEG or B-PEG) and hydroxypropyl-beta-cyclodextrin (HPβCD) for pulmonary administration. Mixtures of sCT, L-PEG or B-PEG and HPβCD were co-spray dried. Based on the particle properties, the best PEG:HPβCD ratio was 1:1 w:w for both PEGs. In the sCT-loaded particles, the L-PEG was more crystalline than B-PEG. Thus, L-PEG-based particles had lower surface free energy and better aerodynamic behavior than B-PEG-based particles. However, B-PEG-based particles provided better protection against chemical degradation of sCT. A decrease in sCT permeability, measured across Calu-3 bronchial epithelial monolayers, occurred when the PEG and HPβCD concentrations were both 1.6 wt %. This was attributed to an increase in buffer viscosity, caused by the two excipients. sCT pharmacokinetic profiles in Wistar rats were evaluated using a 2-compartment model after iv injection or lung insufflation. The maximal sCT plasma concentration was reached within 3 min following nebulization of sCT solution. L-PEG and B-PEG-based microparticles were able to increase T(max) to 20 ± 1 min and 18 ± 8 min, respectively. Furthermore, sCT absolute bioavailability after L-PEG-based microparticle aerosolization at 100 μg/kg was 2.3 times greater than for the nebulized sCT solution.     

Characterization and in vivo evaluation of ocular minitablets prepared with different bioadhesive Carbopol-starch components.

The purpose of this study was to evaluate different bioadhesive ocular formulations based on drum dried waxy maize starch (DDWM), Amioca starch and Carbopol 974P. The concentrations of Carbopol 974P in the mixtures varied between 5 and 25% (w/w). The rheological properties of the non-sterilized and gamma-irradiated physical blends of Carbopol 974P with either DDWM or Amioca were compared to those of the corresponding co-spray dried Amioca starch/Carbopol powders. Higher viscosity or consistency values were measured for sterilized co-spray dried powder mixtures containing an amount of Carbopol 974P equal or above 15% (w/w) compared to the physical blends. Sustained release minitablets (2 mm, 6 mg), consisting of sodium fluorescein as model drug and the bioadhesive powders, were manufactured at a compression force of 1.25 kN. Afterwards, the tablets were sterilized with gamma-irradiation. The amount of Carbopol in the co-spray dried powder mixtures on the one hand and gamma-irradiation on the other hand had no significant influence on the crushing strength and friability of the minitablets evaluated. However, these two factors affected the in vitro release properties of the minitablets. The slowest release was obtained with tablets containing 25% Carbopol 974P, which unfortunately possess mucosal irritating properties. By using co-spray dried Amioca with 15% (w/w) Carbopol 974P, a slower release can be achieved compared to the physical mixtures of DDWM or Amioca starch with Carbopol 974P. Moreover, this ocular formulation is very promising and is preferred, as it did not cause any mucosal irritation and released the model drug for at least 12 h, after application in the fornix.     

Long-term controlled release of PLGA microparticles containing antidepressant mirtazapine

The aim of the study was to prepare PLGA microparticles for prolonged release of mirtazapine by o/w solvent evaporation method and to evaluate effects of PVA concentration and organic solvent choice on microparticles characteristics (encapsulation efficiency, drug loading, burst effect, microparticle morphology). Also in vitro drug release tests were performed and the results were correlated with kinetic model equations to approximate drug release mechanism. It was found that dichloromethane provided microparticles with better qualities (encapsulation efficiency 64.2%, yield 79.7%). Interaction between organic solvent effect and effect of PVA concentration was revealed. The prepared samples released the drug for 5 days with kinetics very close to that of zero order (R^2?=?0.9549 – 0.9816). According to the correlations, the drug was probably released by a combination of diffusion and surface erosion, enhanced by polymer swelling and chain relaxation.     

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     

Effect of maltodextrin and superdisintegrant in directly compressible powder mixtures prepared via co-spray drying.

The effect of maltodextrins and superdisintegrants on the tablet properties was evaluated in directly compressible powders coprocessed via spray drying. Powder mixtures containing acetaminophen, mannitol, erythritol and different maltodextrin types were prepared via co-spray drying and physically mixed with crospovidone (6% w/w, Kollidon CL) in order to evaluate the influence of maltodextrin grade (amylose/amylopectin ratio) on powder hygroscopicity, flowability, density and compactability. In addition, different superdisintegrant types and grades (6% w/w) were co-spray dried to evaluate their effect on tablet disintegration time. Tablet disintegration was affected by the amylose/amylopectin ratio of the maltodextrins. Tablets containing Glucidex 2 (1-5% amylose) had a longer disintegration time compared to Glucidex 9 (20% amylose) (11.8min versus 5.7min) and Unipure DC (50-70% amylose) (1min). The disintegration time of tablets containing a coprocessed superdisintegrant was long due to loss of superdisintegrant during processing (preferential depositing on the spray dryer wall) and was in the following order: Kollidon CL相似文献   

Fabrication of drug-loaded biodegradable microcapsules for controlled release by combination of solvent evaporation and layer-by-layer self-assembly

The initial burst release of drug from polymer microparticles remains an unsolved problem. Here, we deposited polysaccharides on drug-loaded microspheres using layer-by-layer self-assembly to produce core-shell microparticles for sustained drug release. The ibuprofen (IBU)-loaded poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microparticles were fabricated by conventional solvent evaporation. The processing parameters, such as pH of water phase, drug/polymer ratio, polymer type, and emulsifier concentration, were optimized according to the encapsulation efficiency and drug loading as pH 4.0, drug/polymer ratio=10/50 (wt), HV in PHBV=6wt.%, and PVA concentration=1% (w/v). The multilayer shells of chitosan (CHI)/sodium alginate (ALG) and poly(diallyldimethylammonium chloride) (PD)/sodium poly(styrenesulfonate) (PSS) were formed on the IBU-loaded PHBV microparticles using layer-by-layer self-assembly. The in vitro release experiments revealed that, as for the microparticles with three CHI/ALG bilayer shells, the initial burst release of IBU from the microparticles was significantly suppressed and the half release time was prolonged to 62h from 1h for the microparticles without coverage. The compact CHI/ALG multilayer film was observed with an atomic force microscopy (AFM) due to the matched distance of charges along the CHI chain and those along the ALG chains. The present combination for encapsulating drug-loaded microparticles demonstrates an effective way to prolong the drug release with reduced initial burst.     

Excipient-free nanoporous microparticles of budesonide for pulmonary delivery

The aim of this study was to investigate the application of a spray-drying process for the production of nanoporous microparticles (NPMPs) to budesonide, and to characterise the particles produced in terms of their suitability for pulmonary delivery.Budesonide was spray dried with and without ammonium carbonate from ethanol/water or methanol/water solutions. The solid-state characteristics and micromeritic (particle size, density, surface area) properties of spray dried powders were assessed. In vitro deposition studies were performed to assess aerosol performance.The densities of the NPMPs were significantly lower and the surface areas significantly higher than for non-porous spray dried or micronised material. NPMPs of budesonide demonstrated improved aerosolisation properties compared to spray dried non-porous, micronised material and two budesonide commercial products. All spray dried materials were amorphous in nature. The glass transition temperature (90 °C) was sufficiently high to suggest good physical stability at room temperature. When stored at 25 °C/60% RH NPMPs showed a reduced tendency to recrystallise compared to the equivalent non-porous spray dried powder. The physical stability and amorphous nature of NPMPs was retained, under these storage conditions for at least one year and the in vitro aerosolisation properties were not affected by the storage conditions.Excipient-free porous microparticles, prepared by the novel process described, show good potential for drug delivery by oral inhalation with improved in vitro deposition properties compared to non-porous particles.     

Modification of Disodium Cromoglycate Passage Across Lung Epithelium In Vitro Via Incorporation into Polymeric Microparticles

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).     

Enhancement of immune response of HBsAg loaded poly (L-lactic acid) microspheres against hepatitis B through incorporation of alum and chitosan

PURPOSE: Poly (L-lactic acid) (PLA) microparticles encapsulating Hepatitis B surface antigen (HBsAg) with alum and chitosan were investigated for their potential as a vaccine delivery system. METHODS: The microparticles, prepared using a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation method with polyvinyl alcohol (PVA) or chitosan as the external phase stabilising agent showed a significant increase in the encapsulation efficiency of the antigen. RESULTS: PLA-Alum and PLA-chitosan microparticles induced HBsAg serum specific IgG antibody responses significantly higher than PLA only microparticles and free antigen following subcutaneous administration. Chitosan not only imparted a positive charge to the surface of the microparticles but was also able to increase the serum specific IgG antibody responses significantly. CONCLUSIONS: The cytokine assays showed that the serum IgG antibody response induced is different according to the formulation, indicated by the differential levels of interleukin 4 (IL-4), interleukin 6 (IL-6) and interferon gamma (IFN-gamma). The microparticles eliciting the highest IgG antibody response did not necessarily elicit the highest levels of the cytokines IL-4, IL-6 and IFN-gamma.     

Spray drying of budesonide, formoterol fumarate and their composites-II. Statistical factorial design and in vitro deposition properties

The aim of this study was to investigate the effect of changing spray drying parameters on the production of a budesonide/formoterol fumarate 100:6 (w/w) composite. The systems were spray dried as solutions from 95% ethanol/5% water (v/v) using a Büchi 191-Mini Spray Dryer. A 2(5-1) factorial design study was undertaken to assess the consequence of altering spray drying processing variables on particle characteristics. The processing parameters that were studied were inlet temperature, spray drier airflow rate, pump rate, aspirator setting and feed concentration. Each batch of the resulting powder was characterised in terms of thermal and micromeritic properties as well as an in vitro deposition by twin impinger analysis. Overall, the parameter that had the greatest influence on each response investigated was production yield - airflow (higher airflow giving greater yields), median particle size - airflow (higher airflow giving smaller particle sizes) and Carr's compressibility index - feed concentration (lower feed concentration giving smaller Carr's indices). A six- to seven-fold difference in respirable fraction can be observed by changing the spray drying process parameters. The co-spray dried composite system which displayed best in vitro deposition characteristics, showed a 2.6-fold increase in respirable fraction in the twin impinger experiments and better dose uniformity compared with the physical mix of micronised powders.     

The effect of vehicle on physical properties and aerosolisation behaviour of disodium cromoglycate microparticles spray dried alone or with L-leucine

The aim of this study was to improve the aerosolisation behaviour of disodium cromogycate (DSCG), using spray drying technique. The effect of vehicle on the drug particle properties was investigated. L-leucine was selected as a natural antiadherent amino acid to improve the deagglomeration of DSCG particles. Spray dried samples of DSCG alone or with L-leucine were prepared from water and ethanol under the same conditions. The powder properties of the samples were examined by laser diffraction, helium densitometer, X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. The in vitro deposition was determined, using an Andersen cascade impactor with a Spinhaler at a flow rate of 60 l/min. An amorphous form of the drug was obtained when water was used. However, crystal transformation of original DSCG in the presence of ethanol during spray drying resulted in production of elongated particles. These particles exhibited improved aerodynamic properties, compared to the amorphous and commercial materials. Significant differences in fine particle fraction were observed using the two vehicles. Co-spray drying of DSCG and L-leucine improved the deposition profiles of the drug. These results indicated that the change in crystal structure of DSCG during spray drying process was susceptible to the nature of the vehicle. A crystalline form of DSCG with good aerodynamic properties was achieved during spray drying process. In addition, the processing of DSCG with L-leucine in a single step using ethanol resulted in an improvement in dispersion properties of the drug particles.     

The influence of humidity on the aerosolisation of micronised and SEDS produced salbutamol sulphate.

The influence of storage humidity on the aerosolisation efficiency of micronised and supercritical fluid salbutamol sulphate formulations (containing a lactose carrier) were investigated using the twin stage impinger (TSI). Storage humidity had a significant effect on the aerosolisation efficiency of both micronised and solution enhanced dispersion by supercritical fluids (SEDS) salbutamol sulphate (ANOVA P <0.05), suggesting capillary interactions to be an important factor when considering formulation performance. Furthermore, significant differences between the aerosolisation performance of micronised and SEDS salbutamol sulphate were observed at elevated humidities (>63% RH) (Fishers pairwise P <0.05). It is suggested that such variations may be due to differences in physical stability of the micronised and SEDS produced material. Dynamic vapor sorption, and atomic force microscopy (AFM) phase imaging suggested the micronised material to contain amorphous content that was most likely present on the micronised particulate surfaces. Thus, at high humidity, surface amorphous regions may have the ability to re-crystallize and effectively 'fuse' to the lactose carrier surface. This would potentially reduce the ability for the micronised material to be aerosolized and thus result in a greater decrease in FPF when compared to SEDS produced material at equivalent RH.     

High drug load,stable, manufacturable and bioavailable fenofibrate formulations in mesoporous silica: a comparison of spray drying versus solvent impregnation methods

Encapsulation of drugs in mesoporous silica using co-spray drying process has been recently explored as potential industrial method. However, the impact of spray drying on manufacturability, physiochemical stability and bioavailability in relation to conventional drug load processes are yet to be fully investigated. Using a 2³ factorial design, this study aims to investigate the effect of drug-loading process (co-spray drying and solvent impregnation), mesoporous silica pore size (SBA-15, 6.5 nm and MCM-41, 2.5 nm) and percentage drug load (30% w/w and 50% w/w) on material properties, crystallinity, physicochemical stability, release profiles and bioavailability of fenofibrate (FEN) loaded into mesoporous silica. From the scanning electronic microscopy (SEM) images, powder X-ray diffraction and Differential scanning calorimetry measurements, it is indicated that the co-spray drying process was able to load up to 50% (w/w) FEN in amorphous form onto the mesoporous silica as compared to the 30% (w/w) for solvent impregnation. The in vitro dissolution rate of the co-spray dried formulations was also significantly (p?=?0.044) better than solvent impregnated formulations at the same drug loading. Six-month accelerated stability test at 40?°C/75% RH in open dish indicated excellent physical and chemical stability of formulations prepared by both methods. The amorphous state of FEN and the enhanced dissolution profiles were well preserved, and very low levels of degradation were detected after storage. The dog data for the three selected co-spray-dried formulations revealed multiple fold increment in FEN bioavailability compared to the reference crystalline FEN. These results validate the viability of co-spray-dried mesoporous silica formulations with high amorphous drug load as potential drug delivery systems for poorly water soluble drugs.     

Ciclosporin-loaded poly(lactide) microparticles: effect of TPGS

The properties of spray dried PLA microparticles were affected by the choice of solvents, amount of ciclosporin and TPGS added. Ethyl acetate formed microparticle with smooth surface when compared to those produced by dichloromethane. The results of FTIR have not shown chemical interaction amongst PLA, ciclosporin and TPGS while thermal analysis showed physical interactions amongst these components. TPGS was found to lower Tg value of PLA by exerting a plasticizing effect while ciclosporin reverted this effect. When the content of TPGS increased from 2% (w/w) to 10% (w/w), the microparticles tended to agglomerate due to the lowering of the polymer Tg values at the employed spray drying temperature. In addition, a lesser amount of ciclosporin was found at the surface of the microparticle and resulted in smaller initial release of ciclosporin. When 2% (w/w) TPGS was used, the initial release of ciclosporin was enhanced and the microparticles formed were not agglomerated.     

Enhancement of immune response of HBsAg loaded poly (L-lactic acid) microspheres against Hepatitis B through incorporation of alum and chitosan

Purpose: Poly (L-lactic acid) (PLA) microparticles encapsulating Hepatitis B surface antigen (HBsAg) with alum and chitosan were investigated for their potential as a vaccine delivery system.

Methods: The microparticles, prepared using a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation method with polyvinyl alcohol (PVA) or chitosan as the external phase stabilising agent showed a significant increase in the encapsulation efficiency of the antigen.

Results: PLA-Alum and PLA-chitosan microparticles induced HBsAg serum specific IgG antibody responses significantly higher than PLA only microparticles and free antigen following subcutaneous administration. Chitosan not only imparted a positive charge to the surface of the microparticles but was also able to increase the serum specific IgG antibody responses significantly.

Conclusions: The cytokine assays showed that the serum IgG antibody response induced is different according to the formulation, indicated by the differential levels of interleukin 4 (IL-4), interleukin 6 (IL-6) and interferon gamma (IFN-γ). The microparticles eliciting the highest IgG antibody response did not necessarily elicit the highest levels of the cytokines IL-4, IL-6 and IFN-γ.     

The effect of homogenization method on the properties of carbamazepine microparticles prepared by spray congealing

Abstract

The aim of this study was to investigate the influence of ultrasound and high-shear mixing on the properties of microparticles obtained by spray congealing. Dispersions containing 10% carbamazepine and 90% carrier Gelucire® 50/13 (w/w) were prepared using magnetic stirring, high-shear mixing, or ultrasound. Each preparation was made using hot-melt mixing spray congealing to obtain the microparticles. All microparticles presented a spherical shape with high encapsulation efficiency (>99%). High-shear mixing and ultrasound promoted a decrease in the size of microparticles (D₉₀) to 62.8?±?4.1?μm and 64.9?±?3.3?μm, respectively, while magnetic stirring produced microparticles with a size of 84.1?±?1.4?µm. The use of ultrasound led to microparticles with increased moisture content as identified through sorption isotherm studies. In addition, rheograms showed distinct rheological behaviour among different dispersion preparations. Therefore, the technique used to prepare dispersions for spray congealing can affect specific characteristics of the microparticles and should be controlled during the preparation.     

Effect of Lipidic Excipients on the Particle Properties and Aerosol Performance of High Drug Load Spray Dried Particles for Inhalation

High drug load inhalable particles were prepared by co-spray drying a hydrophobic, crystalline, small molecule drug with various lipid or phospholipid excipients at a 9:1 molar ratio to understand the primary drivers of aerosol performance. The effect of excipient structure on solid-state, surface characteristics, and aerodynamic performance of the co-spray dried particles was studied while keeping the spray drying parameters constant. Spray drying of the drug with lipids produced crystalline drug particles, whereas phospholipids produced partially amorphous drug particles. All of the co-spray dried particles were nearly spherical with a smooth surface, except for the spray dried drug particles without excipients – which showed the presence of rough crystals on the surface. All co-spray dried particles showed surface enrichment of the excipient. The surface enrichment of the phospholipids was higher compared to the lipids. Co-spray dried particles that showed higher surface enrichment of excipients showed improved aerosol performance. In comparing all the excipients studied, distearyolphosphatidylcholine (DSPC) showed maximum enrichment on the particle surface and thereby significantly improved aerosol performance. This study demonstrated that the addition of small amounts of lipid excipients during spray drying can change surface morphology, composition, and cohesion, impacting aerosol performance of drugs.     

Effects of Surface Composition on the Aerosolisation and Dissolution of Inhaled Antibiotic Combination Powders Consisting of Colistin and Rifampicin

Colistin is often the only effective antibiotic against the respiratory infections caused by multidrug-resistant Gram-negative bacteria. However, colistin-resistant multidrug-resistant isolates have been increasingly reported and combination therapy is preferred to combat resistance. In this study, five combination formulations containing colistin (COL) and rifampicin (RIF) were prepared by spray drying. The lowest minimum inhibitory concentration (MIC) value against Pseudomonas aeruginosa PAO1 was measured for the formulation of COL/RIF?=?4:1 with relatively high emitted doses (over 80%) and satisfactory fine particle fractions (over 60%). Data from X-ray photoelectron spectroscopy (XPS) and nano-time-of-flight secondary ion mass spectrometry (ToF-SIMS) showed the surfaces of particles were mainly covered by rifampicin even for the formulation with a mass ratio of COL/RIF?=?4:1. Because colistin is hygroscopic and rifampicin is hydrophobic, moisture absorption of combination formulations was significantly lower than the pure colistin formulation in the dynamic vapour sorption results. To investigate the dissolution characteristics, four dissolution test methods (diffusion Franz cell, modified Franz cell, flow-through and beaker methods) were employed and compared. The modified Franz cell method was selected to test the dissolution behaviour of aerosolised powder formulations to eliminate the effect of membrane on dissolution. The results showed that surface enrichment of hydrophobic rifampicin neither affected aerosolisation nor retarded dissolution rate of colistin in the combination formulations. For the first time, advanced surface characterisation techniques of XPS and ToF-SIMS have shown their capability to understand the effect of surface composition on the aerosolisation and dissolution of combination powders.