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Dry powder inhaler formulation of high-payload antibiotic nanoparticle complex intended for bronchiectasis therapy: Spray drying versus spray freeze drying preparation

Yu H, Teo J, Chew JW, Hadinoto K

Abstract

Inhaled nano-antibiotics have recently emerged as the promising bronchiectasis treatment attributed to the higher and more localized antibiotic exposure generated compared to native antibiotics. Antibiotic nanoparticle complex (or nanoplex in short) prepared by self-assembly complexation with polysaccharides addresses the major drawbacks of existing nano-antibiotics by virtue of its high payload and cost-effective preparation. Herein we developed carrier-free dry powder inhaler (DPI) formulations of ciprofloxacin nanoplex by spray drying (SD) and spray freeze drying (SFD). d-Mannitol and l-leucine were used as the drying adjuvant and aerosol dispersion enhancer, respectively. The DPI formulations were evaluated in vitro in terms of the (1) aerosolization efficiency, (2) aqueous reconstitution, (3) antibiotic release, and (4) antimicrobial activity against respiratory pathogen Pseudomonas aeruginosa. The SFD powders exhibited superior aerosolization efficiency to their SD counterparts in terms of emitted dose (92% versus 66%), fine particle fraction (29% versus 23%), and mass median aerodynamic diameter (3μm versus 6μm). The superior aerosolization efficiency of the SFD powders was attributed to their large and porous morphology and higher l-leucine content. While the SFD powders exhibited poorer aqueous reconstitution that might jeopardize their mucus penetrating ability, their antibiotic release profile and antimicrobial activity were not adversely affected.

KEYWORDS:

Antibiotic nanoparticles, Chronic lung infection, Cystic fibrosis, Dry powder inhaler, Pulmonary drug delivery, spray freeze drying

Spray Freeze-Drying as an Alternative to the Ionic Gelation Method to Produce Chitosan and Alginate Nano-Particles Targeted to the Colon

Gamboa A, Araujo V, Caro N, Gotteland M, Abugoch L, Tapia C

Abstract

Chitosan and alginate nano-composite (NP) carriers intended for colonic delivery containing prednisolone and inulin were obtained by two processes. Spray freeze-drying using chitosan (SFDC) or alginate (SFDA) was proposed as an alternative to the traditional chitosan-tripolyphosphate platform (CTPP). NPs were fully characterised and assessed for their yield of particles; level of prednisolone and inulin release in phosphate and Krebs buffers; and sensitivity to degradation by lysozyme, bacteria and faecal slurry. NPs based on chitosan showed similar properties (size, structure, viscoelastic behaviour), but those based on SFDC showed a higher mean release of both active ingredients, with similar efficiency of encapsulation and loading capacity for prednisolone but lower for inulin. SFDC was less degraded in the presence of lysozyme and E. coli and was degraded by B. thetaiotaomicron but not by faecal slurry. The results obtained with SFDA were promising because this NP showed good encapsulation parameters for both active ingredients and biological degradability by E. coli and faecal slurry. However, it will be necessary to use alginate derivatives to reduce its solubility and improve its mechanical behaviour.

KEYWORDS:

alginate; biodegradable polymers; chitosan; colonic drug delivery; nanoparticles; spray freeze-drying

Mass production of graphene nanoscrolls and their application in high rate performance supercapacitors

Bingna Zheng, Zhen Xu and Chao Gao

The output of graphene nanoscrolls (GNSs) has been greatly enhanced to the gram-level by using an improved spray-freeze-drying method without damaging the high transforming efficiency (>92%). The lowest bulk density of GNS foam reaches 0.10 mg cm⁻³. Due to the unique morphology and high specific surface area (386.4 m² g⁻¹), the specific capacitances of the GNSs (90–100 F g⁻¹ at 1 A g⁻¹) are all superior to those of multiwalled carbon nanotubes meanwhile maintaining excellent rate capabilities (60–80% retention at 50 A g⁻¹). For the first time, all-graphene-based films (AGFs) are fabricated via the intercalation of GNSs into graphene layers. The AGF exhibits a capacitance of 166.8 F g⁻¹ at 1 A g⁻¹ and rate capability (83.9% retention at 50 A g⁻¹) better than those of pure reduced graphene oxide (RGO) films and carbon nanotubes/graphene hybrid films (CGFs).

Graphical abstract: Mass production of graphene nanoscrolls and their application in high rate performance supercapacitors

Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections

Leung SS, Parumasivam T, Gao FG, Carrigy NB, Vehring R, Finlay WH, Morales S, Britton WJ, Kutter E, Chan HK

Abstract

PURPOSE:

The potential of aerosol phage therapy for treating lung infections has been demonstrated in animal models and clinical studies. This work compared the performance of two dry powder formation techniques, spray freeze drying (SFD) and spray drying (SD), in producing inhalable phage powders.

METHOD:

A Pseudomonas podoviridae phage, PEV2, was incorporated into multi-component formulation systems consisting of trehalose, mannitol and L-leucine (F1 = 60:20:20 and F2 = 40:40:20). The phage titer loss after the SFD and SD processes and in vitro aerosol performance of the produced powders were assessed.

RESULTS:

A significant titer loss (~2 log) was noted for droplet generation using an ultrasonic nozzle employed in the SFD method, but the conventional two-fluid nozzle used in the SD method was less destructive for the phage (~0.75 log loss). The phage were more vulnerable during the evaporative drying process (~0.75 log further loss) compared with the freeze drying step, which caused negligible phage loss. In vitro aerosol performance showed that the SFD powders (~80% phage recovery) provided better phage protection than the SD powders (~20% phage recovery) during the aerosolization process. Despite this, higher total lung doses were obtained for the SD formulations (SD-F1 = 13.1 ± 1.7 × 10⁴ pfu and SD-F2 = 11.0 ± 1.4 × 10⁴ pfu) than from their counterpart SFD formulations (SFD-F1 = 8.3 ± 1.8 × 10⁴ pfu and SFD-F2 = 2.1 ± 0.3 × 10⁴ pfu).

CONCLUSION:

Overall, the SD method caused less phage reduction during the powder formation process and the resulted powders achieved better aerosol performance for PEV2.

KEYWORDS:

aerosols; antibiotic-resistant bacteria; phage therapy; pulmonary infections

Solidification of nanosuspensions for the production of solid oral dosage forms and inhalable dry powders

Maria Malamatari, Satyanarayana Somavarapu, Kevin M.G. Taylor & Graham Buckton

Abstract

Introduction: Nanosuspensions combine the advantages of nanotherapeutics (e.g. increased dissolution rate and saturation solubility) with ease of commercialisation. Transformation of nanosuspensions to solid oral and inhalable dosage forms minimises the physical instability associated with their liquid state, enhances patient compliance and enables targeted oral and pulmonary drug delivery.

Areas covered: This review outlines solidification methods for nanosuspensions. It includes spray and freeze drying as the most widely used techniques. Fluidised-bed coating, granulation and pelletisation are also discussed as they yield nanocrystalline formulations with more straightforward downstream processing to tablets or capsules. Spray-freeze drying, aerosol flow reactor and printing of nanosuspensions are also presented as promising alternative solidification techniques. Results regarding the solid state, in vitro dissolution and/or aerosolisation efficiency of the nanocrystalline formulations are given and combined with available in vivo data. Focus is placed on the redispersibility of the solid nanocrystalline formulations, which is a prerequisite for their clinical application.

Expert opinion: A few solidified nanocrystalline products are already on the market and many more are in development. Oral and inhalable nanoparticle formulations are expected to have great potential especially in the areas of personalised medicine and delivery of high drug doses (e.g. antibiotics) to the lungs, respectively.

Keywords

dry powder for inhalation, matrix former, nanosuspension, redispersibility, solidification, solid oral dosage forms, spray-freeze drying

Inhalable nanocomposite microparticles: Preparation, characterization and factors affecting formulation

Elsayed I, AbouGhaly MH

Abstract

INTRODUCTION:

Nanocomposite microparticles are intelligent carriers utilised for pulmonary drug delivery. These carriers are composed of drug-encapsulated nanoparticles dispersed in microstructures of polysaccharides. Upon administration, the inhaled microparticles can penetrate and be deposited deeply in the lung due to their adjusted aerodynamic particle size. Subsequently, the nanoparticles are released into the lung and are retained there for a prolonged time due to their resistance to immunological opsonisation, engulfment and digestion.

AREA COVERED:

Nanocomposite microparticles may be prepared by spray drying, spray freeze drying, spray drying fluidised bed granulation or dry coating techniques. The selection of the included excipients, preparation technique and optimisation of the operational parameter play a significant role in the determination of the aerodynamic particle size, redispersibility of the nanoparticles, morphology, yield, moisture content, flowability and in vitro drug release. Moreover, the in vivo behaviour of this novel carrier may be optimised and traced by studying the lung deposition of the inhaled particles and the biological activity of the encapsulated drug.

EXPERT OPINION:

Nanocomposite microparticles have been found to be superior to both nanoparticles and microparticles and may represent a promising carrier for pulmonary drug delivery.

KEYWORDS:

aerodynamic particle size, lung deposition, nanocomposite microparticles, spray freeze drying.

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Nanoembedded Microparticles for Stabilization and Delivery of Drug-Loaded Nanoparticles

Bohr A, Water J, Beck-Broichsitter M, Yang M

Abstract

Nanoparticle-based pharmaceutical products are currently finding their way onto the market as a popular strategy to improve the therapeutic efficacy of numerous drugs, hereunder medications for a targeted treatment of severe diseases (e.g., cancer). Drug-loaded polymer and lipid nanoparticles are typically produced via solventbased methods and result in colloidal suspensions, which often suffer from physical and chemical instability (e.g., formation of aggregates) resulting in loss of functionality. There are various ways to stabilize such nanoparticlebased formulations including addition of ionic materials to provide electrostatic repulsion or polymer materials forming a steric barrier between the particles. However, for long-term stability often water needs to be removed to obtain a dry product. For this purpose atomization-based techniques such as spray-drying and spray freeze-drying are frequently used to remove water from the nanoparticle suspensions and to form tailored powder products (e.g., nanoembedded microparticles (NEMs)). NEMs provide an excellent vehicle for both stabilization of nanoparticles and delivery of the nanoparticles to their intended site of action. Excipients such as sugars and biocompatible polymers are used to prepare the surrounding, stabilizing matrix. Further, these “Trojan” vehicles are compatible with a wide range of therapeutic molecules, nanocarriers and applications for different routes of administration. The preparation, properties and stability of these NEMs are described in this review and their application and future development are discussed.

Keywords: Nanoembedded microparticles, drug delivery, spray freeze drying, nanomedicine, nanoparticles, spray drying

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Spark plasma sintering of zirconia/nano-nickel composites

Carlos F. Gutierrez-Gonzalez, Nestor W. Solis Pinargote, Said Agouram,
Pavel Y. Peretyagin, Sonia Lopez-Esteban and Ramon Torrecillas

Abstract

This work describes a whole processing route for obtaining dense and nanostructured zirconia-nickel composites with low contents of metallic phase (1–3.5 vol%). For the processing route, a combinationof spray-freezing and lyophilization has been proposed. After the calcination and reduction of the resultingpowders an X-ray and HRTEM characterization has been performed. This showed the formation of pure zirconia and nickel, well dispersed and homogeneously distributed, nanostructured phases. The obtainedpowders were subsequently sintered by Spark Plasma Sintering (SPS). As a result, dense ZrO2 Ni composites were obtained, revealing that the sizes of the metal particles were kept in the nanometer rangeand appear homogeneously and well dispersed into the ceramic matrix. The mechanical behavior of these materials was evaluated by means of the Vickers hardness, showing and increment of about 25% with respect to pure zirconia with only a Ni concentration of 1 vol%.

Keywords

Spark plasma sintering, nanomaterials, nanocomposites, nanoceramics, powder materials, zirconia-nickel composites, mechanical properties.

Inhalable Spray-Freeze-Dried Powder with L-Leucine that Delivers Particles Independent of Inspiratory Flow Pattern and Inhalation Device

Otake H, Okuda T, Hira D, Kojima H, Shimada Y, Okamoto H

Abstract

PURPOSE:

The purpose of this study was to develop inhalable particles that can reach deep into the lungs efficiently independent of inhalation patterns of patients and inhalation devices. We prepared porous particles including L-leucine (Leu), a dispersive agent, by a spray-freeze-drying (SFD) method and examined the influence of inspiratory flow patterns and inhalation devices with various inhalation resistances.

METHODS:

Four types of SFD powder with different Leu contents (0-10%) were prepared. Scanning electron microscopy and laser diffraction were used to measure the morphology and size distribution of the powders. In-vitro inhalation characteristics were determined using a twin-stage liquid impinger equipped with an inspiratory flow pattern simulator. The effects of Leu on the adhesion force and electrostatic property of the particles were evaluated.

RESULTS:

The inhalation performance of the powders was improved by the addition of Leu. The powders with Leu showed a high inhalation performance regardless of inspiratory flow patterns and devices. The addition of Leu decreased the adhesion force and increased the surface potential of the powders.

CONCLUSIONS:

The SFD particles with Leu showed high inhalation performance regardless of the inhalation patterns and devices, which was attributed to the decreased adhesion force between particles and increased dispersibility.

KEYWORDS:

L-leucine (Leu), dry powder inhaler (DPI), inhalation device, inspiratory flow pattern, spray-freeze-drying (SFD).

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Fabrication and optical studies of transparent Tm, Ho:YAG ceramics

Agata Sidorowicz^,Magdalena Nakielska, Anna Wajler, Helena Węglarz, Katarzyna Jach, Andrzej Olszyna

Abstract

The aim of this work has been to obtain transparent Tm, Ho:YAG ceramics (thulium doping range: 2–6 at.%, holmium doping range: 0.1–1.0 at.%) by reaction sintering using commercial powders. It has been proved that the particle size, purity and degree of agglomeration of the powders used are crucial from the point of view of the optical quality of ceramics. The spectroscopic measurements of Tm, Ho:YAG ceramics with different concentration of active ions (including transmission and emission spectra measurements) have been presented and discussed. As has been found, both concentration of holmium and thulium separately as well as the balance between them are of great importance. Energy transfer between Tm and Ho ions has been demonstrated.

Yttrium aluminum garnet, Transparent ceramic, Tm, Ho:YAG, Freeze Granulation, Reactive sintering.

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