RESUMO
PURPOSE: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device. METHODS: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies. RESULTS: APSD testing alone might not be able to explain differences reported elsewhere in in vivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products. CONCLUSIONS: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing in vitro tools that are able to provide a bridge between material attributes or process parameters and in vivo performance.
RESUMO
To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 µg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 µm for MF-I and 5.50 µm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.
Assuntos
Sprays Nasais , Humanos , Disponibilidade Biológica , Furoato de Mometasona/farmacocinética , Tamanho da Partícula , Equivalência Terapêutica , Método Duplo-Cego , Estudos Cross-OverRESUMO
Micronization of crystalline active pharmaceutical ingredients can lead to formation of a thermodynamically unstable material with surface disorder. This material undergoes structural stabilization and particle-level changes over time that, in turn, alters the surface properties and interparticle interactions of the micronized drug. The unstable nature of the micronized drug can lead to variability in the performance of dry powder inhaler drug products. To improve the physicochemical stability of the micronized drug, an annealing step is often introduced. However, there is limited understanding of changes in the micronized drug under different annealing conditions. In this study, we examine the molecular- and particle-level changes occurring in a micronized drug during annealing under varying temperature and humidity conditions using orthogonal techniques. We demonstrate the use of surface free energy (SFE) measured by inverse gas chromatography (IGC) to monitor surface-specific changes. Micronization led to an increase in SFE, which progressively reduced during annealing. SFE trends correlated with the molecular-level surface disorder patterns measured by relative humidity perfusion microcalorimetry. The interparticle interactions tracked using IGC and atomic force microscopy show that as the micronized drug stabilized, there was a transition from dominant drug-drug cohesive forces to drug-lactose adhesive forces. For the nonhygroscopic model compound, combined high temperature-high humidity conditions showed fastest annealing kinetics. Further, the SFE descriptor enabled us to differentiate the extent of mechanical activation of the neat micronized drug and co-micronized drug-magnesium stearate blends. The study identifies tools for characterizing postmicronization material changes that can help develop materials with consistent quality.
Assuntos
Composição de Medicamentos , Lactose/química , Preparações Farmacêuticas/química , Pós/química , Aerossóis , Química Farmacêutica , Umidade , Propriedades de Superfície , TemperaturaRESUMO
This study investigated the structural relaxation of micronized fluticasone propionate (FP) under different lagering conditions and its influence on aerodynamic particle size distribution (APSD) of binary and tertiary carrier-based dry powder inhaler (DPI) formulations. Micronized FP was lagered under low humidity (LH 25 C, 33% RH [relative humidity]), high humidity (HH 25°C, 75% RH) for 30, 60, and 90 days, respectively, and high temperature (HT 60°C, 44% RH) for 14 days. Physicochemical, surface interfacial properties via cohesive-adhesive balance (CAB) measurements and amorphous disorder levels of the FP samples were characterized. Particle size, surface area, and rugosity suggested minimal morphological changes of the lagered FP samples, with the exception of the 90-day HH (HH90) sample. HH90 FP samples appeared to undergo surface reconstruction with a reduction in surface rugosity. LH and HH lagering reduced the levels of amorphous content over 90-day exposure, which influenced the CAB measurements with lactose monohydrate and salmeterol xinafoate (SX). CAB analysis suggested that LH and HH lagering led to different interfacial interactions with lactose monohydrate but an increasing adhesive affinity with SX. HT lagering led to no detectable levels of the amorphous disorder, resulting in an increase in the adhesive interaction with lactose monohydrate. APSD analysis suggested that the fine particle mass of FP and SX was affected by the lagering of the FP. In conclusion, environmental conditions during the lagering of FP may have a profound effect on physicochemical and interfacial properties as well as product performance of binary and tertiary carrier-based DPI formulations.
Assuntos
Broncodilatadores/química , Fluticasona/química , Administração por Inalação , Química Farmacêutica/métodos , Inaladores de Pó Seco/métodos , Lactose/química , Tamanho da Partícula , Pós/química , Xinafoato de Salmeterol/química , Propriedades de SuperfícieRESUMO
The study aimed to establish a function-based relationship between the physical and bulk properties of pre-blended mixtures of fine and coarse lactose grades with the in vitro performance of an adhesive active pharmaceutical ingredient (API). Different grades of micronised and milled lactose (Lactohale (LH) LH300, LH230, LH210 and Sorbolac 400) were pre-blended with coarse grades of lactose (LH100, LH206 and Respitose SV010) at concentrations of 2.5, 5, 10 and 20 wt.%. The bulk and rheological properties and particle size distributions were characterised. The pre-blends were formulated with micronised budesonide and in vitro performance in a Cyclohaler device tested using a next-generation impactor (NGI) at 90 l/min. Correlations between the lactose properties and in vitro performance were established using linear regression and artificial neural network (ANN) analyses. The addition of milled and micronised lactose fines with the coarse lactose had a significant influence on physical and rheological properties of the bulk lactose. Formulations of the different pre-blends with budesonide directly influenced in vitro performance attributes including fine particle fraction, mass median aerodynamic diameter and pre-separator deposition. While linear regression suggested a number of physical and bulk properties may influence in vitro performance, ANN analysis suggested the critical parameters in describing in vitro deposition patterns were the relative concentrations of lactose fines % < 4.5 µm and % < 15 µm. These data suggest that, for an adhesive API, the proportion of fine particles below % < 4.5 µm and % < 15 µm could be used in rational dry powder inhaler formulation design.
Assuntos
Lactose/química , Pós/química , Administração por Inalação , Aerossóis/química , Budesonida/química , Química Farmacêutica/métodos , Portadores de Fármacos/química , Inaladores de Pó Seco/métodos , Nebulizadores e Vaporizadores , Redes Neurais de Computação , Tamanho da Partícula , Reologia/métodosRESUMO
The effect of milled and micronized lactose fines on the fluidization and in vitro aerosolization properties of dry powder inhaler (DPI) formulations was investigated, and the suitability of static and dynamic methods for characterizing general powder flow properties of these blends was assessed. Lactose carrier pre-blends were prepared by adding different lactose fines (Lactohale® (LH) 300, 230 and 210) with coarse carrier lactose (Lactohale100) at 2.5, 5, 10 and 20 wt% concentrations. Powder flow properties of lactose pre-blends were characterized using the Freeman Technology FT4 and Schulze RST-XS ring shear tester. A strong correlation was found between the basic flow energy (BFENorm) measured using the Freeman FT4 Rheometer and the flowability number (ffc) measured on Schulze RST-XS. These data indicate that both static and dynamic methods are suitable for characterizing general powder flow properties of lactose carriers. Increasing concentration of fines corresponded with an increase in the normalized fluidization energy (FENorm). The inclusion of fine particles of lactose resulted in a significant (p < 0.05) increase in fine particle delivery of budesonide and correlated with FENorm. This trend was strongest for lactose containing up to 10 wt% LH300. A similar trend was found for the milled lactose grades LH230 and LH210. However, the increase in FENorm upon addition of milled fines only corresponded to a very slight improvement in the performance. These data suggest that whilst the fluidization energy correlated with fine particle delivery, this relationship is specific to lactose grades of similar particle size.
Assuntos
Química Farmacêutica/métodos , Portadores de Fármacos/química , Inaladores de Pó Seco/métodos , Lactose/química , Pós/química , Administração por Inalação , Budesonida/química , Sistemas de Liberação de Medicamentos/métodos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
PURPOSE: To investigate the influence of primary crystallization conditions on the mechanical properties and secondary processing behaviour of fluticasone propionate (FP) for carrier based dry powder inhaler (DPI) formulations. METHODS: Young's modulus of FP crystals produced using different anti-solvents was determined using nanoindentation. Physicochemical and surface interfacial properties via the cohesive-adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) of air-jet micronised FP crystals were investigated. These data were correlated to in vitro aerosolization performance of binary and combination DPI formulations containing salmeterol xinafoate (SX). RESULTS: Young's modulus of FP crystals produced using different anti-solvents ranged from 0.6-12.4 GPa. Crystals with low Young's modulus required multiple passes in the microniser to reduce the particle size to less than 5 µm, whilst those with the highest Young's modulus required a single pass. CAB of micronized FP samples was similar with respect to lactose, however, their adhesive affinity to SX varied. Samples of FP with greatest adhesion to SX produced greater fine particle delivery of SX in combination DPI formulations. CONCLUSIONS: Crystallisation conditions may affect the mechanical properties of FP, and therefore secondary processing of the material and their interfacial properties and product performance in carrier based DPI formulations.
Assuntos
Androstadienos/química , Inaladores de Pó Seco/métodos , Adesividade , Química Farmacêutica , Cristalização/métodos , Módulo de Elasticidade , Excipientes/química , Fluticasona , Fenômenos Mecânicos , Microscopia de Força Atômica/métodos , Microscopia Eletrônica de Varredura/métodos , Nanotecnologia/métodos , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Demonstrating bioequivalence (BE) of nasal suspension sprays is a challenging task. Analytical tools are required to determine the particle size of the active pharmaceutical ingredient (API) and the structure of a relatively complex formulation. This study investigated the utility of the morphologically-directed Raman spectroscopy (MDRS) method to investigate the particle size distribution (PSD) of nasal suspensions. Dissolution was also investigated as an orthogonal technique. Nasal suspension formulations containing different PSD of mometasone furoate monohydrate (MFM) were manufactured. The PSD of the MFM batches was characterized before formulation manufacture using laser diffraction and automated imaging. Upon formulation manufacture, the droplet size, single actuation content, spray pattern, plume geometry, the API dissolution rate, and the API PSD by MDRS were determined. A systematic approach was utilized to develop a robust method for the analysis of the PSD of MFM in Nasonex® and four test formulations containing the MFM API with different particle size specifications. Although the PSD between distinct techniques cannot be directly compared due to inherent differences between these methodologies, the same trend is observed for three out of the four batches. Dissolution analysis confirmed the trend observed by MDRS in terms of PSD. For suspension-based nasal products, MDRS allows the measurement of API PSD which is critical for BE assessment. This approach has been approved for use in lieu of a comparative clinical endpoint BE study [1]. The correlation observed between PSD and dissolution rate extends the use of dissolution as a critical analytical tool demonstrating BE between test and reference products.
Assuntos
Furoato de Mometasona/farmacocinética , Administração Intranasal , Furoato de Mometasona/administração & dosagem , Furoato de Mometasona/química , Tamanho da Partícula , Análise Espectral Raman , Suspensões , Equivalência TerapêuticaRESUMO
In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.8, and C-3.7), differing only in type and composition of lactose fines, exhibited median mass aerodynamic diameter (MMAD) of 4.5 µm (A-4.5), 3.8 µm (B-3.8), and 3.7 µm (C-3.7) and varied in dissolution rates (A-4.5 slower than B-3.8 and C-3.7). In vitro total lung dose (TLDin vitro) was determined as the average dose passing through three anatomical mouth-throat (MT) models and yielded dose normalization factors (DNF) for each DPI formulation X (DNFx = TLDin vitro,x/TLDin vitro,A-4.5). The DNF was 1.00 for A-4.5, 1.32 for B-3.8, and 1.21 for C-3.7. Systemic PK after inhalation of 500 µg FP was assessed in a randomized, double-blind, four-way crossover study in 24 healthy volunteers. Peak concentrations (Cmax) of A-4.5 relative to those of B-3.8 or C-3.7 lacked bioequivalence without or with dose normalization. The area under the curve (AUC0-Inf) was bio-IN-equivalent before dose normalization and bioequivalent after dose normalization. Thus, PK could detect differences in pulmonary available dose (AUC0-Inf) and residence time (dose-normalized Cmax). The differences in dose-normalized Cmax could not be explained by differences in in vitro dissolution. This might suggest that Cmax differences may indicate differences in regional lung deposition. Overall this study supports the use of PK studies to provide relevant information on the pulmonary performance characteristics (i.e., available dose, residence time, and regional lung deposition).
Assuntos
Broncodilatadores/farmacocinética , Medicamentos Genéricos/farmacocinética , Fluticasona/farmacocinética , Administração por Inalação , Adolescente , Adulto , Aerossóis , Área Sob a Curva , Broncodilatadores/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Liberação Controlada de Fármacos , Medicamentos Genéricos/administração & dosagem , Inaladores de Pó Seco , Feminino , Fluticasona/administração & dosagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pós , Equivalência Terapêutica , Adulto JovemRESUMO
This study used statistical simulations to investigate the performance of the population bioequivalence test applied to image-based particle size measurements (such as morphologically directed Raman spectroscopy) and methods for designing in vitro bioequivalence trials using prior information. Simulations of in vitro population bioequivalence trials were conducted across a range of representative D50 (number-weighted median particle diameter from a log-normal particle size distribution) and span (which is defined as [Formula: see text] where D90 and D10 are the number-weighted 90th and 10th percentiles in particle diameters sampled from a log-normal particle size distribution) values respectively. The performance of the population bioequivalence test in the simulations was driven by an interplay between overall test variability and the widening or narrowing of the bioequivalence region due to variance terms in the test statistic definition. These findings were dependent upon differences in the variability of D50 and span and may generalise to a wider range of in vitro metrics. Trial design optimisation using power and assurance approaches followed patterns consistent with these findings. As more novel scientific methods are applied to the development of complex generic drug products, the procedures outlined in this study may be used at the inception stage of future in vitro bioequivalence trials to reduce the risk of conducting costly trials with low probabilities of success.
Assuntos
Estudos de Equivalência como Asunto , Projetos de Pesquisa , Equivalência Terapêutica , Simulação por Computador , Humanos , Modelos Biológicos , Tamanho da PartículaRESUMO
The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.
Assuntos
Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Administração por Inalação , Corticosteroides/química , Agonistas de Receptores Adrenérgicos beta 2/química , Aerossóis , Combinação de Medicamentos , Composição de Medicamentos , Liberação Controlada de Fármacos , Inaladores de Pó Seco , Cinética , Inaladores Dosimetrados , Solubilidade , Equivalência TerapêuticaRESUMO
PURPOSE: Engineering of inhalation particles incorporating, in each individual particle, a combination of a long-acting beta-agonist and a glucocorticosteroid in a pre-determined and constant ratio for delivery via a dry powder inhaler (DPI). METHODS: Individual crystalline particles containing both the glucocorticosteroid fluticasone propionate (FP) and long-acting beta-agonist salmeterol (SX) were prepared, in a ratio of 10:1, using the solution atomization and crystallization by sonication (SAX) process. Combination drug particles were characterized by particle size, morphology, crystallinity and aerosolisation efficiency using inertial impaction. RESULTS: Combination drug particles were spherical and crystalline, with a median diameter of 4.68 +/- 0.01 microm. Aerosolisation of formulations containing combination drug particles resulted in greater uniformity in delivery ratios of both actives across all stages of the impactor before and after storage. CONCLUSIONS: Actives in a pre-determined dose ratio can be crystallised in a single particle using the SAX process.
Assuntos
Corticosteroides/química , Agonistas Adrenérgicos beta/química , Albuterol/análogos & derivados , Androstadienos/química , Engenharia de Proteínas , Administração por Inalação , Albuterol/química , Broncodilatadores/química , Varredura Diferencial de Calorimetria , Combinação de Medicamentos , Armazenamento de Medicamentos , Fluticasona , Inalação , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Pós , Xinafoato de SalmeterolRESUMO
The inclusion of different carrier materials in a dry powder inhaler (DPI) system can alter formulation performance, which might be attributable to variation in the adhesion between drug and carrier particles. The aim of this study was, therefore, to further examine the relationship between drug-carrier adhesion and performance, by comparing data relating to many different drug-carrier combinations. Four drugs and four carriers were employed, giving a total of 16 combinations. The relative magnitude of the drug-carrier adhesion for each combination was quantified using the cohesion-adhesion balance (CAB) approach to colloidal probe atomic force microscopy. The in vitro inhalation performance of the 16 formulations (1.5% w/w drug) was investigated and found to vary significantly. Plots of fine particle dose against drug-carrier CAB ratio revealed that performance was optimised when the drug-carrier CAB ratio was slightly cohesive. This trend was found to fit with those from similar previous studies, although due to the smaller number of formulations investigated previously, the full extent of this relationship had not been revealed. It was concluded, therefore, that when developing a carrier-based DPI, the selection of a drug-carrier combination with a slightly cohesive CAB ratio might result in optimal performance.
Assuntos
Portadores de Fármacos , Pós , Adesividade , Administração por Inalação , Albuterol/administração & dosagem , Albuterol/análogos & derivados , Albuterol/química , Androstadienos/administração & dosagem , Androstadienos/química , Antialérgicos/administração & dosagem , Antialérgicos/química , Cápsulas , Química Farmacêutica , Cristalização , Excipientes , Fluticasona , Lactose/química , Microscopia de Força Atômica , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Xinafoato de Salmeterol , Difração de Raios XRESUMO
Patent literature describes "conditioning" techniques which employ organic vapours to recrystallise amorphous regions in micronised particles, with the aim of improving their processability and physico-chemical stability. This report describes a preliminary study investigating the efficacy of PhaseImaging atomic force microscopy (AFM) for the investigation of such processes. AFM phase images demonstrated variation in mechanical properties across the surface of milled budesonide particles, which diminished upon exposure to ethanol vapour. No variation was seen in phase images of unmilled budesonide. Dynamic vapour sorption confirmed the presence amorphous material in the milled sample and its subsequent recrystallisation following exposure to ethanol vapour under the same conditions as those used in the AFM experiment. It was therefore hypothesised that variation in the phase images indicated the presence of amorphous regions which were subsequently conditioned. PhaseImaging AFM may therefore be a useful method for the study of conditioning techniques, enabling the efficacy and kinetics of the process to be observed.
Assuntos
Broncodilatadores/química , Budesonida/química , Cristalização , Composição de Medicamentos , Microscopia de Força AtômicaRESUMO
The successful manufacture of a regulatory approved dry powder inhaler (DPI) product is only achievable by applying robust control systems to all aspects of analytical, engineering, and material based processes. Whilst many aspects of DPI drug product manufacturing can be adequately controlled, it is often the control of materials, that is, drug substance and excipients, which can lead to variation in the quality of the final drug product. This article gives an overview of DPI excipients and highlights the challenges of defining and, importantly, understanding the relationships between quality and functionality for excipient components in DPI formulations.
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Excipientes/química , Nebulizadores e Vaporizadores , Pós/química , Excipientes/normasRESUMO
Unfractionated heparin is an anti-inflammatory mucoactive agent, with the potential to treat the inflamed and mucus-obstructed airways in patients with cystic fibrosis. In this study, unfractionated heparin has been spray-dried to produce spherical micronized particles in the size range 1-5 microm, which is suitable for delivery by dry-powder inhalation. Spray drying parameters have been optimized using a 2(4) factorial experimental design. The feed concentration and atomization spray flow rate have the greatest effects on recovery (typically 60%) and particle size.
Assuntos
Aerossóis , Heparina/administração & dosagem , Administração por Inalação , Varredura Diferencial de Calorimetria , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Microscopia Eletrônica de Varredura , Tamanho da Partícula , PósRESUMO
The aim of this investigation was to study the influence of crystalline habit of active pharmaceutical ingredients on the cohesive-adhesive force balance within model dry powder inhaler (DPI) formulations and the corresponding affect on DPI formulation performance. The cohesive-adhesive balance (CAB) approach to colloid probe atomic force microscopy (AFM) was employed to determine the cohesive and adhesive interactions of micronized budesonide particles against the {102} and {002} faces of budesonide single crystals and crystalline substrates of different sugars (cyclodextrin, lactose, trehalose, raffinose, and xylitol), respectively. These data were used to measure the relative level of cohesion and adhesion via CAB and the possible influence on in vitro performance of a carrier-based DPI formulation. Varying the crystal habit of the drug had a significant effect on the cohesive measurement of micronized budesonide probes, with the cohesive values on the {102} faces being approximately twice that on the {002} crystal faces. However, although different CAB values were measured with the sugars with respect to the crystal faces chosen for the cohesive-based measurement, the overall influence on the rank order of the CAB values was not directly influenced. For these data sets, the CAB gradient indicated that a decrease in the dominance of the adhesive forces led to a concomitant increase in fine particle delivery, reaching a plateau as the cohesive forces became dominant. The study suggested that crystal habit of the primary drug crystals influences the cohesive interactions and the resulting force balance measurements of colloid probe CAB analysis.
Assuntos
Budesonida/química , Nebulizadores e Vaporizadores , Pós/química , Adesividade , Budesonida/administração & dosagem , Química Farmacêutica , Cristalização , Microscopia de Força Atômica , Modelos MolecularesRESUMO
The airways of most people with cystic fibrosis are colonized with biofilms of the Gram-negative, opportunistic pathogen Pseudomonas aeruginosa. Delivery of antibiotics directly to the lung in the form of dry powder aerosols offers the potential to achieve high local concentrations directly to the biofilms. Unfortunately, current aerosolised antibiotic regimes are unable to efficiently eradicate these biofilms from the airways. We investigated the ability of the innate antimicrobial, lactoferrin, to enhance the activity of two aminoglycoside antibiotics (tobramycin and gentamicin) against biofilms of P. aeruginosa strain PAO1. Biofilms were prepared in 96 well polystyrene plates. Combinations of the antibiotics and various lactoferrin preparations were spray dried. The bacterial cell viability of the various spray dried combinations was determined. Iron-free lactoferrin (apo lactoferrin) induced a 3-log reduction in the killing of planktonic cell by the aminoglycoside antibiotics (p<0.01) and also reduced both the formation and persistence of P. aeruginosa biofilms (p<0.01). Combinations of lactoferrin and an aminoglycoside displays potential as an effective new therapeutic strategy in the treatment of P. aeruginosa biofilms infections such as those typical of the CF lungs.
Assuntos
Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacologia , Gentamicinas/farmacologia , Lactoferrina/administração & dosagem , Lactoferrina/farmacologia , Tobramicina/farmacologia , Anti-Infecciosos/química , Apoproteínas/administração & dosagem , Apoproteínas/química , Apoproteínas/farmacologia , Biofilmes/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Sinergismo Farmacológico , Lactoferrina/química , Pós , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
Recent years have seen a marked diversification of excipient based formulation strategies used for the development and commercialisation of dry powder inhaler (DPI) products. These innovative approaches not only provide benefits to patients and health care professionals through the availability of a wider range of therapeutic DPI products, but, importantly, also allow formulators to exploit the potential opportunities that excipients provide for the development of DPIs. Whilst many DPI products have, and continue to be developed using a single formulation excipient, the commercialisation of DPI products which contain the two excipients lactose monohydrate and magnesium stearate, namely the 'dual excipient platform' has recently been achieved. This article provides an overview of the background and current status of the development of such 'dual excipient platform' based DPI products.