RESUMEN

Soluplus is a polymer that has been explored to prepare nanocomposites for pulmonary drug delivery and is non-toxic. However, its aerosolization attributes when spray-dried have not been investigated. Hence, this work aimed to investigate the aerosol performance of soluplus-based spray-dried powders. In addition, the potential use of leucine to improve the aerosolization of such particles was also investigated by including leucine at 10 or 20% w/w. 4% w/w salbutamol was used as a model drug in all the formulations primarily to aid quantification during aerosolization evaluation and for assessing the interaction between the drug and soluplus using infrared spectroscopy with the multivariate analysis approach of principal component analysis (PCA). Three formulations (4% salbutamol/96% soluplus, 4% salbutamol/86% soluplus/10% leucine, 4% salbutamol/76% soluplus/20% leucine) were prepared. The formulations were characterized in terms of solid-state, water content, particle size/morphology, and aerosolization. Similarly, two additional formulations (14% salbutamol/86% soluplus and 24% salbutamol/76% soluplus) were prepared to assess potential non-covalent interactions between salbutamol and soluplus. The formulations with only salbutamol and soluplus were amorphous, as evident from X-ray diffraction. Leucine was crystalline in the formulations. All the spray-dried formulations were irregular spheres with surface corrugation. The 96% soluplus powder showed an emitted fraction (EF) and fine particles fraction (FPF) of 91.9 and 49.8%, respectively. The inclusion of leucine at 10% did not increase the EF; however, an increase in FPF (69.7%) was achieved with 20% leucine. PCA of the infrared spectra suggested potential non-covalent interactions between salbutamol and soluplus. It hinted at the potential involvement of ketone groups of the excipient. This study concludes that soluplus-based spray-dried powder with or without leucine can potentially be utilized for pulmonary drug delivery. In addition, PCA can effectively be utilized in assessing interactions and overcoming limitations associated with visual assessment of the spectra of such formulations.

RESUMEN

High dose inhaled powders have received increased attention for treating lung infections. These powders can be prepared using techniques such as spray drying, spray-freeze drying, crystallization, and milling. The selected preparation technique is known to influence the solid state of the powders, which in turn can potentially modulate aerosolization and aerosolization stability. This review focuses on how and to what extent the change in solid state of high dose powders can influence aerosolization. It also discusses the commonly used solid state characterization techniques and the application of potential strategies to improve the physical and chemical stability of the amorphous powders for high dose delivery.

Asunto(s)

Inhaladores de Polvo Seco , Administración por Inhalación , Aerosoles , Humanos , Tamaño de la Partícula , Polvos

RESUMEN

INTRODUCTION: High dose powder inhalation is evolving as an important approach to to treat lung infections. It is important to its identify applications, consider the factors affecting high dose powder delivery, and assess the effect of high dose drugs in patients. AREA COVERED: Both current and pipeline high dose inhalers and their applications have been summarized. Challenges and opportunities to high dose delivery have been highlighted after reviewing formulation techniques in the context of factors affecting aerosolization, devices, and patient factors. EXPERT OPINION: High dose inhaled delivery of antimicrobials is an innovative way to increase treatment efficacy of respiratory infections, tackle drug resistance, and the scarcity of new antimicrobials. The high dose inhaled technology also has potential for systemic action; however, innovations in formulation strategies and devices are required to realize its full potential. Advances in formulation strategies include the use of excipients or the engineering of particles to decrease the cohesive property of microparticles and their packing density. Similarly, selection of a synergistic drug instead of an excipient can be considered to increase aerosolization and stability. Device development focused on improving dispersion and loading capacity is also important, and modification of existing devices for high dose delivery can also be considered.

Asunto(s)

Inhaladores de Polvo Seco , Testimonio de Experto , Administración por Inhalación , Aerosoles , Inhaladores de Polvo Seco/métodos , Excipientes , Humanos , Pulmón , Tamaño de la Partícula , Preparaciones Farmacéuticas , Polvos

RESUMEN

Pseudomonas aeruginosa infection is common in cystic fibrosis as well as non-cystic fibrosis bronchiectasis. The pathogen presents challenges for treatment due to its adaptive antibiotic-resistance, mainly pertaining to its biofilm-forming ability, as well as limitations associated with conventional drug delivery in achieving desired therapeutic concentration in the infection site. Hence, therapeutic approach has shifted towards the inhalation of antibiotics. Ceftazidime is a potent antibiotic against the pathogen; however, it is currently only available as a parenteral formulation. Here, spray dryer was employed to generate inhalable high dose ceftazidime microparticles. In addition, the use of amino acids (valine, leucine, methionine, phenylalanine, and tryptophan) to improve aerosolization as well as chemical stability of amorphous ceftazidime was explored. The particles were characterized using X-ray diffraction, infrared (IR) spectroscopy, calorimetry, electron microscopy, particle size analyzer, and next generation impactor. The chemical stability at 25 °C/<15% was assessed using chromatography. All co-spray dried formulations were confirmed as monophasic amorphous systems using calorimetry. In addition, principal component analysis of the IR spectra suggested potential interaction between tryptophan and ceftazidime in the co-amorphous matrix. Inclusion of amino acids improved aerosolization and chemical stability in all cases. Increase in surface asperity was clear with the use of amino acids which likely contributed to the improved aerosol performance, and potential interaction between amino acids and ceftazidime was plausibly the reason for improved chemical stability. Leucine offered the best aerosolization enhancement with a fine particle fraction of 78% and tryptophan showed stabilizing superiority by reducing chemical degradation by 51% over 10 weeks in 1:1 M ratio. The protection against ceftazidime degradation varied with the nature of amino acids. Additionally, there was a linear relationship between degradation protection and molar mass of amino acids or percentage weight of amino acids in the formulations. None of the amino acids were successful in completely inhibiting degradation of ceftazidime in amorphous spray-dried powder to prepare a commercially viable product with desired shelf-life. All the amino acids and ceftazidime were non-toxic to A549 alveolar cell line.

Asunto(s)

Inhaladores de Polvo Seco , Infecciones por Pseudomonas , Administración por Inhalación , Aerosoles/química , Aminoácidos/química , Antibacterianos , Ceftazidima , Inhaladores de Polvo Seco/métodos , Humanos , Leucina/química , Pulmón , Tamaño de la Partícula , Polvos/química , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa , Triptófano

RESUMEN

Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C/15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.

RESUMEN

Different formulation techniques have been investigated to prepare highly aerosolizable dry powders to deliver a high dose of antibiotics to the lung for treating local infections. In this study, we investigated the influence of the co-amorphization of a model drug, kanamycin, with selected amino acids (valine, methionine, phenylalanine, and tryptophan) by co-spray drying on its aerosolization. The co-amorphicity was confirmed by thermal technique. The physical stability was monitored using low-frequency Raman spectroscopy coupled with principal component analysis. Except for the kanamycin-valine formulation, all the formulations offered improved fine particle fraction (FPF) with the highest FPF of 84% achieved for the kanamycin-methionine formulation. All the co-amorphous formulations were physically stable for 28 days at low relative humidity (25 °C/<15% RH) and exhibited stable aerosolization. At higher RH (53%), even though methionine transformed into its crystalline counterpart, the kanamycin-methionine formulation offered the best aerosolization stability without any decrease in FPF. While further studies are warranted to reveal the underlying mechanism, this study reports that the co-amorphization of kanamycin with amino acids, especially with methionine, has the potential to be developed as a high dose kanamycin dry powder formulation.