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1.
Int J Pharm ; 572: 118740, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31648015

RESUMEN

In respiratory and genetic disorders such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and cystic fibrosis (CF), the lungs produce excess mucus, resulting in a thickened mass, which clogs up the airways and reduces airflow. Consequently, breathing becomes more difficult. Medications that break down the structure of mucus will be especially useful in managing the early symptoms of these diseases and preventing their progression into the more severe forms. This work therefore seeks to develop an inhaled mucoactive dry powder formulation that is efficacious on multiple fronts. As an innovative step, sodium chloride was used to tailor the surface architecture of ambroxol hydrochloride particles, such that the resulting angular features on the surfaces contributed to the creation of corrugated particles with enhanced aerodynamicity. The optimized spray-dried powder particles were of respirable-size (d50 of 2.85 ±â€¯0.15 µm) and moderately corrugated. When the crystalline powder was dispersed via an Aerolizer® inhaler at 60 L/min, it gave a fine particle fraction (FPF) of ~31%, which was a ten-fold improvement over the unmodified species (i.e. ambroxol hydrochloride alone). Tests on artificial sputum medium (ASM) showed that the optimized formulation was potentially useful in liquefying the mucus, which favorably pointed towards the effectiveness of the formulation. In addition, the formulation was also stable to moisture ingress (up to ~60% RH) and had good flowability. Hence, the advent of angular adjuvant sodium chloride particles in a mucoactive formulation conferred a three-fold benefit to the product: (1) Improved aerodynamicity and flowability, (2) Enhanced moisture stability and (3) Synergistic mucolytic properties.


Asunto(s)
Ambroxol/química , Inhaladores de Polvo Seco , Expectorantes/química , Moco , Cloruro de Sodio/química , Administración por Inhalación , Aerosoles , Desecación , Tamaño de la Partícula , Polvos , Reología , Esputo , Resultado del Tratamiento
2.
J Pharm Sci ; 105(4): 1501-12, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27019964

RESUMEN

Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 µm-3.4 ± 0.1 µm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa.


Asunto(s)
Antibacterianos/administración & dosificación , Inhaladores de Polvo Seco , Administración por Inhalación , Aerosoles/administración & dosificación , Aerosoles/farmacología , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Humanos , Tamaño de la Partícula , Polvos
3.
Eur J Pharm Sci ; 70: 37-44, 2015 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-25612805

RESUMEN

Airway mucus hypersecretion is a common clinical feature of many severe respiratory diseases, and when complicated by a recalcitrant bacterial infection, the whole treatment regimen thereby becomes more challenging and protracted. The accumulation of thickened mucus secretions in the lower airways provides a nutrient-rich breeding ground for bacteria that promotes their growth and limits the ease of effective eradication. Unfortunately, no direct-inhaled dry powder formulation to treat these respiratory mucoid infections more effectively is available commercially. This work therefore seeks to develop a highly-efficacious ternary dry powder inhaler (DPI) formulation (ciprofloxacin hydrochloride (CIP), gatifloxacin hydrochloride (GAT) and ambroxol hydrochloride (AMB)) capable of delivering a novel multi-pronged attack (synergy, quorum quenching and mucociliary clearance) on Pseudomonas aeruginosa, a common respiratory bacteria found in mucoid infections. The powders were prepared via spray drying, evaluated on their aerosol performance via a multi-stage liquid impinger (MSLI) and tested for their efficacies in bacteria-spiked artificial sputum medium (ASM). The optimized particles were of respirable-size (d50 of ∼1.61±0.03µm) and slightly corrugated. When dispersed via an Aerolizer® inhaler at 60L/min, the powder showed concomitant in vitro deposition, minimal capsule, device and throat retention, and highly promising and uniform fine particle fractions (of the loaded dose) of ∼64-69%, which was a vast improvement over the singly-delivered actives. Favourably, when tested on bacteria-spiked ASM, the optimized ternary formulation (with AMB) was more effective at killing bacteria (i.e. faster rate of killing) than just the synergistic antibiotics alone (binary formulation; without AMB). In conclusion, a ternary antibiotic-(non-antibiotic) DPI formulation involving a unique multi-pronged attack mechanism was successfully pioneered and optimized for mucoid infections.


Asunto(s)
Antibacterianos/administración & dosificación , Infecciones Bacterianas , Inhaladores de Polvo Seco , Pseudomonas aeruginosa/efectos de los fármacos , Infecciones del Sistema Respiratorio , Administración por Inhalación , Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/metabolismo , Inhaladores de Polvo Seco/métodos , Humanos , Tamaño de la Partícula , Pseudomonas aeruginosa/metabolismo , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/metabolismo , Esputo/efectos de los fármacos , Esputo/microbiología , Difracción de Rayos X
4.
J Pharm Sci ; 103(4): 1115-25, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24510431

RESUMEN

Despite advances in vaccination and antimicrobial therapy, community-acquired pneumonia (CAP) remains as a leading cause of morbidity and mortality worldwide. As the severity of CAP has been linked to the extent of inflammation in the body, adjunctive therapeutic measures aimed at modulating the immune response have therefore become increasingly attractive in recent years. In particular, for CAP patients with underlying medical conditions such as chronic obstructive pulmonary disease (COPD), a steroid-antibiotic combination will no doubt be a useful and timely therapeutic intervention. Unfortunately, no combined steroid-antibiotic dry powder formulation is available commercially or has been reported in the academic literature. The aim of this work was hence to develop a novel steroid-antibiotic dry powder inhaler formulation [ciprofloxacin hydrochloride (CIP) and beclomethasone dipropionate (BP)] for inhaled anti-infective therapy. The spray-dried powder was of respirable size (d50 of ∼2.3 µm), partially crystalline and had BP preferentially deposited on the particle surface. Favorably, when formulated as a binary mix, both CIP and BP showed much higher drug release and fine particle fractions (of the loaded dose) over their singly delivered counterparts, and had robust activity against the respiratory tract infection-causing bacteria Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus.


Asunto(s)
Antibacterianos/administración & dosificación , Beclometasona/administración & dosificación , Ciprofloxacina/administración & dosificación , Glucocorticoides/administración & dosificación , Administración por Inhalación , Antibacterianos/química , Antibacterianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Beclometasona/química , Beclometasona/farmacología , Ciprofloxacina/química , Ciprofloxacina/farmacología , Inhaladores de Polvo Seco , Glucocorticoides/química , Glucocorticoides/farmacología , Humanos , Klebsiella pneumoniae/efectos de los fármacos , Neumonía/tratamiento farmacológico , Polvos , Pseudomonas aeruginosa/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos
5.
Int J Pharm ; 452(1-2): 194-200, 2013 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-23680726

RESUMEN

Dry powder inhalers (DPIs) are used predominantly for the treatment of pulmonary diseases by delivering drugs directly into the lungs. The drug delivery efficiency is typically low and there is significant drug retention inside the DPI. An innovative 'green' initiative aimed at minimizing drug wastage via channeling the residual drug into the useful inhaled therapeutic fraction was pioneered. Drug retention could be minimized via coating the drug capsule and delivery device with pharmaceutically acceptable force-control agents. This coating reduces the adhesion between the drug particles and the internal surfaces of the DPI, which in turn increases the fine particle dose by as much as 300%.


Asunto(s)
Sistemas de Liberación de Medicamentos/instrumentación , Inhaladores de Polvo Seco/instrumentación , Muramidasa/química , Aerosoles , Tamaño de la Partícula , Polvos
6.
Eur J Pharm Biopharm ; 83(2): 275-84, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23010564

RESUMEN

In combination antimicrobial therapy, the desired outcome is to broaden the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may also emerge from such combinations, leading to treatment failure with serious consequences. It is therefore imperative to screen the drug candidates for compatibility and possible antagonistic interactions. The aim of this work was to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary (ciprofloxacin hydrochloride and gatifloxacin hydrochloride, SD-CIP/GAT) and ternary (ciprofloxacin hydrochloride, gatifloxacin hydrochloride, and lysozyme, SD-CIP/GAT/LYS) combinations were prepared via spray-drying on a BUCHI® Nano Spray Dryer B-90. The powder morphologies were spherical with a slightly corrugated surface and all within the respirable size range. The powders yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® at 60 L/min. Time-kill studies carried out against the respiratory tract infection-causing bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia, and Acinetobacter baumannii at 1 × the minimum inhibitory concentration (MIC) over 24h revealed no antagonistic behavior for both the binary and ternary combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the dual combination (SD-CIP/GAT) when it was tested against P. aeruginosa bacteria.


Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Polvos/química , Polvos/farmacología , Administración por Inhalación , Infecciones Bacterianas/tratamiento farmacológico , Química Farmacéutica/métodos , Sinergismo Farmacológico , Inhaladores de Polvo Seco/métodos , Infecciones del Sistema Respiratorio/tratamiento farmacológico
7.
Expert Opin Drug Deliv ; 8(7): 965-72, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21675936

RESUMEN

INTRODUCTION: Spray drying is an extremely well-established technology for the production of micro-particulate powders suited for a variety of drug delivery applications. In recent years, the rise in nanomedicine has placed increased pressure on the existing systems to produce nanoparticles in good yield and with a narrow size distribution. However, the separation and collection of nanoparticles with conventional spray dryer set ups is extremely challenging due to their typical low collection efficiency for fine particles < 2 µm. Currently, nanoparticles have to be agglomerated into larger microparticles, via a two-step approach, in order to collect them in a sizeable amount. However, this method has to contend with the issue of adequate redispersibility of the primary particles to reap the full benefits of nanosizing. AREAS COVERED: An overview on the advances in spray drying technology is provided in this review with particular emphasis on the novel Buchi® Nano Spray Dryer B-90. Readers will appreciate the limitations of conventional spray drying technology, understand the mechanisms of the Buchi® Nano Spray Dryer B-90, and also learn about the strengths and shortcomings of the system. EXPERT OPINION: The Buchi® Nano Spray Dryer B-90 offers a new, simple and alternative approach for the production of nanoparticles suited for a variety of drug delivery applications.


Asunto(s)
Sistemas de Liberación de Medicamentos , Nanotecnología , Solventes , Electricidad Estática
8.
Int J Pharm ; 403(1-2): 192-200, 2011 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-20951781

RESUMEN

There has been an increasing interest in the development of protein nanotherapeutics for diseases such as cancer, diabetes and asthma. Spray drying with prior micro mixing is commonly used to obtain these powders. However, the separation and collection of protein nanoparticles with conventional spray dryer setups has been known to be extremely challenging due to its typical low collection efficiency for fine particles less than 2µm. To date, there has been no feasible approach to produce these protein nanoparticles in a single step and with high yield (>70%). In this study, we explored the feasibility of the novel Nano Spray Dryer B-90 (equipped with a vibrating mesh spray technology and an electrostatic particle collector) for the production of bovine serum albumin (BSA) nanoparticles. A statistical experimental design method (Taguchi method based on three levels, five variables L(18) orthogonal array robust design) was implemented to study the effect of and optimize the experimental conditions of: (1) spray mesh size, (2) BSA solution concentration, (3) surfactant concentration, (4) drying air flow rate and (5) inlet temperature on: (1) size and (2) morphology (axial ratio). Particle size and morphology were predominantly influenced by the spray mesh size and surfactant concentration, respectively. The drying air flow rate and inlet temperature had minimal impact. Optimized production of smooth spherical nanoparticles (median size: 460±10nm, axial ratio: 1.03±0.00, span 1.03±0.03, yield: 72±4%) was achieved using the 4µm spray mesh at BSA concentration of 0.1% (w/v), surfactant concentration of 0.05% (w/v), drying flow rate of 150L/min and inlet temperature of 120°C. The Nano Spray Dryer B-90 thus offers a new, simple and alternative approach for the production of protein nanoparticles suited for a variety of drug delivery applications.


Asunto(s)
Portadores de Fármacos/química , Nanomedicina/métodos , Nanopartículas/química , Proteínas , Tecnología Farmacéutica/métodos , Diseño de Equipo , Microscopía Electrónica de Rastreo , Nanomedicina/instrumentación , Nanopartículas/ultraestructura , Tamaño de la Partícula , Proteínas/administración & dosificación , Proteínas/química , Proteínas/uso terapéutico , Albúmina Sérica Bovina/administración & dosificación , Albúmina Sérica Bovina/química , Electricidad Estática , Propiedades de Superficie , Tecnología Farmacéutica/instrumentación
9.
Metab Eng ; 12(6): 526-36, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20826224

RESUMEN

Significant efforts have been made to improve the sialylation of recombinant glycoproteins with the aim of extending their in vivo circulation time. Here, we report a systematic functional analysis of 31 N-glycosylation-related genes on sialylation of recombinant EPO in six cell lines. BHK and CHO cells were found to sialylate recombinant EPO most effectively. None of the 31 genes, individually or in combination, was able to improve EPO sialylation in these cells. HEK293, Cos-7 and 3T3 cells showed intermediate sialylation capabilities, whereas NS0 cells sialylated recombinant EPO poorly. Overexpression of ST6GalI, ST3GalIII or ST3GalIV, but not ST3GalVI, was able to improve EPO sialylation in these four cell lines. qRT-PCR experiments revealed that ST3GalIII and ST3GalIV are indeed under expressed in HEK293, 3T3 and NS0 cells. Co-expression of upstream glycogenes failed to synergize with these sialyltransferases to further enhance sialylation, suggesting that the upstream glycogenes are all expressed at sufficient levels.


Asunto(s)
Eritropoyetina/metabolismo , Glicosilación , Silanos/metabolismo , Células 3T3/metabolismo , Animales , Células CHO , Células COS , Línea Celular , Chlorocebus aethiops , Cricetinae , Cricetulus , Glicoproteínas/química , Glicoproteínas/aislamiento & purificación , Células HEK293 , Humanos , Focalización Isoeléctrica , Lectinas/química , Ratones , Ácido N-Acetilneuramínico/química , Proteínas Recombinantes , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancias Reactivas al Ácido Tiobarbitúrico/química
10.
Eur J Pharm Sci ; 40(1): 16-24, 2010 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-20172026

RESUMEN

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.


Asunto(s)
Corticoesteroides/administración & dosificación , Agonistas Adrenérgicos beta/administración & dosificación , Cristalización/métodos , Administración por Inhalación , Corticoesteroides/química , Agonistas Adrenérgicos beta/química , Albuterol/administración & dosificación , Albuterol/análogos & derivados , Androstadienos/administración & dosificación , Budesonida/administración & dosificación , Budesonida/química , Rastreo Diferencial de Calorimetría , Química Farmacéutica/métodos , Combinación de Medicamentos , Etanolaminas/administración & dosificación , Etanolaminas/química , Combinación Fluticasona-Salmeterol , Fumarato de Formoterol , Humanos , Manitol/química , Microscopía de Fuerza Atómica , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Espectroscopía de Fotoelectrones , Propiedades de Superficie , Temperatura de Transición , Difracción de Rayos X
11.
Langmuir ; 24(14): 7538-44, 2008 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-18558778

RESUMEN

Advances in nanomedicine are expected to escalate in the coming years, particularly related to the availability and delivery of optimum dosage. It is crucial that the dissolution behavior of such novel dosage forms be adequately scrutinized to maximize their therapeutic benefits. In this work, the dissolution behavior of irregularly shaped nanoparticles was analyzed using a modified negative-two-thirds-root diffusion model (with shape factor, sigma, incorporated into the equation to describe shape evolution). The model was shown to be effective in describing the transition from peanut-shape nanoparticles (connected by bridges) to discrete spheres during the dissolution process. Due to the eventual aggregation of the discrete spheres in solution, description of the dissolution behavior was limited to the aggregate as a whole. Scanning electron microscopy, diffusion layer thickness calculations, and sonication studies provide information to show that, during dissolution, the bridges dissolve, yielding discrete spheres which then aggregate randomly in solution. Viscosity experiments reveal that the dissolution behavior was predominantly diffusion-controlled. The dissolution behavior of irregularly shaped nanoparticles in solution is described as going from bridged particles to discrete particles, to aggregates, and finally to full dissolution.


Asunto(s)
Cefuroxima/análogos & derivados , Modelos Biológicos , Nanopartículas/química , Cefuroxima/química , Difusión , Cinética , Microscopía Electrónica de Rastreo , Nanopartículas/ultraestructura , Soluciones
12.
Pharm Res ; 25(7): 1696-701, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18320295

RESUMEN

PURPOSE: Many existing and new drugs fail to be fully utilized because of their limited bioavailability due to poor solubility in aqueous media. Given the emerging importance of using nanoparticles as a promising way to enhance the dissolution rate of these drugs, a method must be developed to adequately reflect the rate-change due to size reduction. At present, there is little published work examining the suitability of different dissolution apparatus for nanoparticles. METHODS: Four commonly-used methods (the paddle, rotating basket and flow-through cell from the US Pharmacopia, and a dialysis method) were employed to measure the dissolution rates of cefuroxime axetil as a model for nanodrug particles. RESULTS: Experimental rate ratios between the nanoparticles and their unprocessed form were 6.95, 1.57 and 1.00 for the flow-through, basket and paddle apparatus respectively. In comparison, the model-predicted value was 7.97. Dissolution via dialysis was rate-limited by the membrane. CONCLUSIONS: The data showed the flow-through cell to be unequivocally the most robust dissolution method for the nanoparticulate system. Furthermore, the dissolution profiles conform closely to the classic Noyes-Whitney model, indicating that the increase in dissolution rate as particles become smaller results from the increase in surface area and solubility of the nanoparticles.


Asunto(s)
Nanopartículas/química , Preparaciones Farmacéuticas/química , Antibacterianos/administración & dosificación , Antibacterianos/química , Cefuroxima/administración & dosificación , Cefuroxima/análogos & derivados , Cefuroxima/química , Química Farmacéutica , Cristalización , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Preparaciones Farmacéuticas/administración & dosificación , Polvos , Solubilidad , Difracción de Rayos X
13.
Pharm Res ; 24(9): 1608-17, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17404810

RESUMEN

PURPOSE: The current study aimed to examine the pharmaceutical applications of the focused-ion-beam (FIB) in the inhalation aerosol field, particularly to particle porosity determination (i.e. percentage of particles having a porous interior). MATERIALS AND METHODS: The interior of various spray dried particles (bovine serum albumin (BSA) with different degrees of surface corrugation, mannitol, disodium cromoglycate and sodium chloride) was investigated via FIB milling at customized conditions, followed by viewing under a high resolution field-emission scanning electron microscope. Two sets of ten particles for each sample were examined. RESULTS: For the spray-dried BSA particles, a decrease in particle porosity (from 50 to 0%) was observed with increasing particle surface corrugation. Spray-dried mannitol, disodium cromoglycate and sodium chloride particles were determined to be 90-100%, 0-10% and 0% porous, respectively. The porosity in the BSA and mannitol particles thus should be considered for the aerodynamic behaviour of these particles. CONCLUSIONS: The FIB technology represents a novel approach useful for probing the interior of particles linking to the aerosol properties of the powder. Suitable milling protocols have been developed which can be adapted to study other similar particles.


Asunto(s)
Aerosoles/química , Microscopía Electrónica de Rastreo , Tecnología Farmacéutica , Administración por Inhalación , Cromolin Sódico/química , Manitol , Porosidad , Albúmina Sérica Bovina/ultraestructura
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