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Micro-fluidic Spray Freeze Dried Ciprofloxacin Hydrochloride-Embedded Dry Powder for Inhalation
Abstract
Active pharmaceutical ingredient (API)-embedded dry powder for inhalation (AeDPI) is highly desirable for pulmonary delivery of high-dose drug. Herein, a series of spray freeze-dried (SFD) ciprofloxacin hydrochloride (CH)-embedded dry powders were fabricated via a self-designed micro-fluidic spray freeze tower (MFSFT) capable of tuning freezing temperature of cooling air as the refrigerant medium. The effects of total solid content (TSC), mass ratio of CH to L-leucine (Leu) as the aerosol dispersion enhancer, and the freezing temperature on particle morphology, size, density, moisture content, crystal properties, flowability, and aerodynamic performance were investigated. It was found that the Leu content and freezing temperature had considerable influence on the fine particle fraction (FPF) of the SFD microparticles. The optimal formulation (CH/Leu = 7:3, TSC = 2%w/w) prepared at - 40°C exhibited remarkable effective drug deposition (~ 33.38%), good aerodynamic performance (~ 47.69% FPF), and excellent storage stability with ultralow hygroscopicity (~ 1.93%). This work demonstrated the promising feasibility of using the MFSFT instead of conventional liquid nitrogen assisted method in the research and development of high-dose AeDPI.
... This combination showed minimally hygroscopic particles with prolonged storage stability, excellent therapeutic ingredient deposition, and remarkable aerodynamic performance. This study showed that MFSFD might replace the liquid nitrogen-aided approach in high-dose AeDPI investigations [135]. ...
Respirable particles are integral to effective inhalable therapeutic ingredient delivery, demanding precise engineering for optimal lung deposition and therapeutic efficacy. This review describes different physicochemical properties and their role in determining the aerodynamic performance and therapeutic efficacy of dry powder formulations. Furthermore, advances in top-down and bottom-up techniques in particle preparation, highlighting their roles in tailoring particle properties and optimizing therapeutic outcomes, are also presented. Practices adopted for particle engineering during the past 100 years indicate a significant transition in research and commercial interest in the strategies used, with several innovative concepts coming into play in the past decade. Accordingly, this article highlights futuristic particle engineering approaches such as electrospraying, inkjet printing, thin film freeze drying, and supercritical processes, including their prospects and associated challenges. With such technologies, it is possible to reshape inhaled therapeutic ingredient delivery, optimizing therapeutic benefits and improving the quality of life for patients with respiratory diseases and beyond.
... SF-40D-N20L8D2T1 (Fig. 3g). It could be ascribed that hydrophobic leucine was inclined to occupy the surface of atomized droplets, with their hydrophobic isobutyl group pointing toward the air and their hydrophilic amino group and carboxyl group oriented toward the water [41,42]. And the leucine would quickly precipitate and remain on the microparticle surface during freezing process, thus inhibiting the growth and diffusion of the ice crystals [43,44], ultimately obtaining intact SFD microparticles. ...
Based on the drug repositioning strategy, niclosamide (NCL) has shown potential applications for treating COVID-19. However, the development of new formulations for effective NCL delivery is still challenging. Herein, NCL-embedded dry powder for inhalation (NeDPI) was fabricated by a novel spray freeze drying technology. The addition of Tween-80 together with 1,2-Distearoyl-sn-glycero-3-phosphocholine showed the synergistic effects on improving both the dispersibility of primary NCL nanocrystals suspended in the feed liquid and the spherical structure integrity of the spray freeze dried (SFD) microparticle. The SFD microparticle size, morphology, crystal properties, flowability and aerosol performance were systematically investigated by regulating the feed liquid composition and freezing temperature. The addition of leucine as the aerosol enhancer promoted the microparticle sphericity with greatly improved flowability. The optimal sample (SF-80D-N20L2D2T1) showed the highest fine particle fraction of ~47.83%, equivalently over 3.8 mg NCL that could reach the deep lung when inhaling 10 mg dry powders.
... The high SSA of SFD powders is reported to lead to faster reconstitution times and the subambient drying temperatures make SFD suitable to process thermolabile materials [12,20,28,31,32]. Although to the best of our knowledge, there are still no commercial products produced by SFD, its potential for the production of dry powders of biopharmaceuticals for different delivery routes has already been demonstrated [17,19,33,34]. ...
Biopharmaceuticals have established an indisputable presence in the pharmaceutical pipeline, enabling highly specific new therapies. However, manufacturing, isolating, and delivering these highly complex molecules to patients present multiple challenges, including the short shelf-life of biologically derived products. Administration of biopharmaceuticals through inhalation has been gaining attention as an alternative to overcome the burdens associated with intravenous administration. Although most of the inhaled biopharmaceuticals in clinical trials are being administered through nebulization, dry powder inhalers (DPIs) are considered a viable alternative to liquid solutions due to enhanced stability. While freeze drying (FD) and spray drying (SD) are currently seen as the most viable solutions for drying biopharmaceuticals, spray freeze drying (SFD) has recently started gaining attention as an alternative to these technologies as it enables unique powder properties which favor this family of drug products. The present review focus on the application of SFD to produce dry powders of biopharmaceuticals, with special focus on inhalation delivery. Thus, it provides an overview of the critical quality attributes (CQAs) of these dry powders. Then, a detailed explanation of the SFD fundamental principles as well as the different existing variants is presented, together with a discussion regarding the opportunities and challenges of SFD as an enabling technology for inhalation-based biopharmaceuticals. Finally, a review of the main formulation strategies and their impact on the stability and performance of inhalable biopharmaceuticals produced via SDF is performed. Overall, this review presents a comprehensive assessment of the current and future applications of SFD in biopharmaceuticals for inhalation delivery.
In the case of dry powder inhalation systems (DPIs), the development of carrier-free formulations has gained increased attention. Thereby, spray-drying is a promising technology and is widely used to produce carrier-free DPIs. Numerous works have been published about the co-spray-drying of active ingredients with various solid excipients and their effect on the physicochemical characteristics and aerodynamic properties of the formulations. However, only a few studies have been reported about the role of the solvents used in the stock solutions of spray-dried formulations. In the present work, DPI microcomposites containing ciprofloxacin hydrochloride were prepared by spray-drying in the presence of different ethanol concentrations. The work expresses the roughness, depth and width of the dimples for particle size as a novel calculation possibility, and as a correlation between the MMAD/D0.5 ratio and correlating it with cohesion work, these new terms and correlations have not been published – to the best of our knowledge –, which has resulted in gap-filling findings. As a result, different proportions of solvent mixtures could be interpreted and placed in a new perspective, in which the influence of different concentrations of ethanol on the habit of the DPI formulations, and thus on in vitro aerodynamic results. Based on these, it became clear why we obtained the best in vitro aerodynamic results for DPI formulation containing 30% ethanol in the stock solution.
Although dry powder inhalers (DPIs) have attracted great interest compared to nebulizers and metered-dose inhalers (MDIs), drug deposition in the deep lung is still insufficient to enhance therapeutic activity. Indeed, it is estimated that only 10–15% of the drug reaches the deep lung while 20% of the drug is lost in the oropharyngeal sphere and 65% is not released from the carrier. The potentiality of the powders to disperse in the air during the patient’s inhalation, the aerosolization, should be optimized. To do so, new strategies, in addition to classical lactose-carrier, have emerged. The lung deposition of carrier-free particles, mainly produced by spray drying, is higher due to non-interparticulate forces between the carrier and drug, as well as better powder uniformity and aerosolization. Moreover, the association of two or three active ingredients within the same powder seems easier. This review is focused on a new type of carrier-free particles which are characterized by a sugar-based core encompassed by a corrugated shell layer produced by spray drying. All excipients used to produce such particles are dissected and their physico-chemical properties (Péclet number, glass transition temperature) are put in relation with the lung deposition ability of powders. The importance of spray-drying parameters on powders’ properties and behaviors is also evaluated. Special attention is given to the relation between the morphology (characterized by a corrugated surface) and lung deposition performance. The understanding of the closed relation between particle material composition and spray-drying process parameters, impacting the final powder properties, could help in the development of promising DPI systems suitable for local or systemic drug delivery.
Background:
Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, is a triple fixed-dose combination in late-stage clinical development for chronic obstructive pulmonary disease (COPD).
Methods:
We conducted two studies to characterize the pharmacokinetic (PK) profile of BGF MDI in patients with COPD: (i) a phase I, open-label, single and chronic (7-day) dosing study (NCT03250182) with one treatment arm (BGF MDI 320/18/9.6 μg); and (ii) a PK sub-study of KRONOS (NCT02497001), a phase III, randomized, double-blind study in which patients received 24 weeks' treatment with BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 320/9 μg. PK parameters in both studies included maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 12h (AUC0-12).
Results:
In the phase I PK study (30 patients), budesonide and glycopyrronium Cmax were comparable after single and chronic dosing of BGF MDI (accumulation ratio [RAC] 95% and 107%, respectively) whereas Cmax for formoterol was slightly higher after chronic dosing (RAC 116%). AUC0-12 for budesonide, glycopyrronium, and formoterol were higher following chronic versus single dosing, with an RAC of 126%, 179%, and 143%, respectively. After 7 days' dosing, AUC0-12 and Cmax for all three components of BGF MDI were similar to those in the KRONOS PK sub-study (202 patients) at Week 24. In the latter sub-study, Cmax and AUC0-12 at Week 24 were generally comparable across treatments for budesonide (geometric mean ratios [GMR] of 96%-109% for BGF MDI vs BFF MDI or BUD/FORM DPI), glycopyrronium (GMR of 88%-100% for BGF MDI vs GFF MDI), and formoterol (GMR of 80%-113% for BGF MDI vs GFF MDI or BFF MDI).
Conclusions:
Steady-state PK parameters of budesonide, glycopyrronium, and formoterol were similar after 7 days' dosing in the phase I PK study and after 24 weeks in the KRONOS PK sub-study. Systemic exposure to budesonide, glycopyrronium, and formoterol was generally comparable across treatments in the KRONOS PK sub-study, suggesting no meaningful drug-drug or within-formulation PK interactions.
Developing strategies for the production of porous particles with controllable structures using a spray-drying method has attracted attention of researchers for decades. Although many papers have reported their successful production of porous particles using this method, information on how to create and control the porous structures as well as what parameters involving and what formation mechanism occurring during the synthesis process are still not clear. To meet these demands, the present review covers strategies in the spray-drying developments for the fabrication of porous particles with controllable structure. This information is important for optimizing the production of porous particles with desirable properties. Regulation of process conditions and precursor formulations are also explained, including composition, type, and physicochemical properties of droplet and raw components used (i.e., host component, template, and solvent). The electrostatic interactions between the individual components and the droplets are also presented, while this information tends to be neglected in the conventional spray-drying process. To clarify how the porous particles are designed, current experimental results completed with illustrations for the proposal particle formation mechanism are presented. The review also completed with the opportunities and potential roles of the changing porous structures in practical uses. This review would provide information on how to produce porous particles that can be used for advanced functional materials, such as catalysts, adsorbents, and sensors.
Pulmonary route is extensively studied for the diagnosis and treatment of pulmonary and extra pulmonary disease conditions such as asthma, tuberculosis, emphysema, and bronchitis. Formulation design, inhalation device and particle size play key role in determining the aerosol performance. The lack of desired clinical outcome along with the problem regarding efficacy or any adverse drug effect may arise due to improper training and education in use of the device to control the actuation and aerosol inhalation. This review summarizes the difference in the mechanistic features of current marketed aerosol delivery devices with respect to mechanism of aerosol generation with possible advancements in the aerosol design. The delivery options in the pulmonary route and its merits together with the limitations are also discussed. An update is provided regarding the current research and clinical outcome of the use of inhalational technology.
In spray freeze-drying (SFD), the solution is typically dispersed into a gaseous cold environment producing frozen microparticles that are subsequently dried via sublimation. This technology can potentially manufacture bulk lyophilized drugs at higher rates compared with conventional freeze-drying in trays and vials because small frozen particles provide larger surface area available for sublimation. Although drying in SFD still has to meet the material collapse temperature requirements, the final characteristics of the respective products are mainly controlled by the spray-freezing dynamics. In this context, the main goal of this work is to present a single droplet spray-freezing model and validate it with previously published simulations and experimental data. For the investigated conditions, the droplet temperature evolutions predicted by the model agree with experiments within an error of ±10%. The proposed engineering-level modeling framework is intended to assist future development of efficient SFD processes and support scale up from laboratory to commercial scale equipment.
In this study, ciprofloxacin hydrochloride (CIP)-loaded poly-ε-caprolactone (PCL) nanoparticles were prepared for pulmonary administration. CIP-loaded PCL nanoparticles were prepared by solid-in-oil-in-water (s/o/w) emulsion solvent evaporation method and the effects of various formulation parameters on the physicochemical properties of the nanoparticles were investigated. PCL nanoparticles showed spherical shapes with particle sizes around 143-489 nm. Encapsulation efficiency was found to be very low because of water-solubility properties of CIP. However, surface modification of nanoparticles with chitosan caused an increase in the encapsulation efficiency of nanoparticles. At drug release study, CIP-loaded PCL nanoparticles showed initial burst effect for 4 h and then continuously released for 72 h. Nanocomposite microparticles containing CIP-loaded PCL nanoparticles were prepared freeze-drying method and mannitol was used as carrier material. Tapped density and MMADt results show that nanocomposite microparticles have suitable aerodynamic properties for pulmonary administration. Antimicrobial efficacy investigations showed that CIP-encapsulated PCL nanoparticles and nanocomposite microparticles inhibited the growth of bacteria. Also when the antimicrobial activity of the nanoparticles at the beginning and at the sixth month was examined, it was found that the structure of the particulate system was still preserved. These results indicated that nanocomposite microparticles containing CIP-loaded PCL nanoparticles can be used for pulmonary delivery.
Ciprofloxacin (CF) is one of the topmost selling antibiotics and it is available at a cheap cost which is used to treat many bacterial infections. Many research scientists are working on this drug for various applications on different drug delivery systems. The main objective of this paper is to enlighten about the details of pure drug CF and its delivery systems along with current research on this drug. This review focused on history, pharmacokinetics, mechanism of action, types of dosage form available in the market with their cost, current research going on this drug with their applications and methods development for estimation of CF. It also highlighted the possible interactions and adverse drug reactions of CF and patents available. The present review revealed that the only analytical method for estimation of CF was developed in the first decade, few drug delivery systems (DDS) of CF were developed in the second decade and more research work on the development of novel DDS of CF founded in the last decade.
Chronic obstructive pulmonary disease (COPD) is characterized by chronic respiratory symptoms and airflow limitation, resulting from abnormalities in the airway and/or damage to the alveoli. Primary care physicians manage the healthcare of a large proportion of patients with COPD. In addition to determining the most appropriate medication regimen, which usually includes inhaled bronchodilators with or without inhaled corticosteroids, physicians are charged with optimizing inhalation device selection to facilitate effective drug delivery and patient adherence. The large variety of inhalation devices currently available present numerous challenges for physicians that include: (1) gaining knowledge of and proficiency with operating different device classes; (2) identifying the most appropriate inhalation device for the patient; and (3) providing the necessary education and training for patients on device use. This review provides an overview of the inhalation device types currently available in the United States for delivery of COPD medications, including information on their successful operation and respective advantages and disadvantages, factors to consider in matching a device to an individual patient, the need for device training for patients and physicians, and guidance for improving treatment adherence. Finally, the review will discuss established and novel tools and technology that may aid physicians in improving education and promoting better adherence to therapy.
The aim of this study was to investigate the ability of L-leucine (LL) in preventing moisture-induced deterioration in the in vitro aerosolization performance of spray-dried (SD) salbutamol sulfate (SS). Increasing mass fraction of LL (5–80%) were co-spray dried with SS, and the physicochemical properties of the powders were characterized by laser diffraction, X-ray powder diffraction (XRD) and dynamic vapour sorption (DVS). Furthermore, the surface morphology and chemistry of fine particles was analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The in vitro aerosolization performance of powders stored at different relative humidity (RH) was evaluated by a next generation impactor (NGI). The SD SS powders were moderately hygroscopic and amorphous, of which the uptake of moisture upon storage caused a drop in the aerosolization performance. The results showed that 40% (w/w) LL was sufficient to eliminate the effect of moisture on the aerosolization performance at 60% RH. The formulation containing 40% (w/w) LL also maximized the aerosolization performance of SD SS powders (stored in desiccator) with the emitted fraction being 90.0 ± 1.8%, and the fine particle fraction based on the recovered dose (FPFrecovered) and emitted dose (FPFemitted) being 78.0 ± 3.7% and 86.6 ± 2.9%, respectively. The underlying mechanisms were that the crystalline LL increased the degree of particle surface corrugation, and reduced particle fusion and cohesiveness to facilitate dispersion. However, there is still a great challenge to prevent the moisture-induced deterioration in the aerosolization performance at 75% RH due to the recrystallization of SD SS. In conclusion, LL is a potential excipient for reducing moisture-induced deterioration in the aerosolization performance of SD amorphous powders, but still has drawbacks in preventing the recrystallization-induced deterioration.
The hydrogen bond is an important intermolecular interaction in chemical, biological, and materials systems. A proper understanding of noncovalent interactions, notably hydrogen bonds between molecules in supramolecular aggregates, is essential for the design of crystalline materials and new supramolecular systems with desired physical and chemical properties. The International Union of Pure and Applied Chemistry provided a broadly acceptable and yet fairly precise definition of the hydrogen bond in 2011. Knowledge of weak intermolecular interactions and hydrogen bonding has immediate applications in the discovery of new medicines and in the development of novel and biocompatible pharmaceutical products and implants for the next wave of innovations. In this article, we summarize a tutorial background of the hydrogen-bond interaction and then present examples of molecular crystals sustained by this interaction and the role of hydrogen bonding in directing the structural organization. The examples are meant to illustrate the different facets of hydrogen bonding in crystal structures, their design, and properties. We close with some of the new techniques for structure determination for very small or weakly diffracting crystals, as is often the case for supramolecular materials and pharmaceutical products.
Abstract: A Dry powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. DPIs are commonly used to treat respiratory diseases such as asthma, bronchitis and COPD. Interest in DPI as an efficient and environmentally friendly way of delivering drugs to the lung has accelerated in recent years. Dry powder inhaler can meet these goals only with a suitable powder formulation, an efficient metering system, and a carefully selected device. It is mainly classified into three classes; Nebulizer, pMDI, DPI. DPIs are an alternative to pMDI that delivers medication to the lungs in the form of a dry powder. Particle Size of API must be present in size range about 1-10 μm which also guarantee that the patient gets the same dose every time at different airflow rate. DPI are formulated using four types of formulation strategies such as; Carrier free, Drug carrier, Drug additive, Drug carrier additive. Lung deposition study is completed by ‘Twin Stage Impingner’. The inward breath gadget is imperative in accomplishing satisfactory conveyance of breathed in medication to lung which basically grouped in view of measurements sort into single-unit and multi-dosage stores.
This work is aimed to study the effects of component size and solubility on the surface composition of spray dried (SD) uniform two-component particles fabricated by micro-fluidic spray dryer. Various precursor liquid consisting of small molecular of methionine (Met, 33 g/L) or lysine (Lys, 739 g/L) and large-sized silica (12 nm) were prepared by adjusting the mass ratio of components. X-ray energy dispersive results showed that the respective enrichment degree (De) of Met and Lys on the surface of SD-M1S9 and -L1S9 prepared at 150 °C were 182 ± 9% and 125 ± 14%. The De of hydrophobic Met for SD-M1S1 and -M9S1 were 46 ± 9% and 4 ± 2%, respectively, whereas relative hydrophilic Lys mainly distributed internal of the particle meanwhile the De of silica on the surface for SD-L1S1 and -L9S1 were 17 ± 4% and 12 ± 1%, respectively. Drying temperature (120 and 180 °C) showed more apparent effect on the De of amino acid for the particles of less amino acid. The possible formation mechanism of surface composition and the surface composition impact on the wettability of particles were explored. These results provide new guidance for manufacturing functional SD powders with various components.
Spray drying is a constructive single-step manufacturing technique used to produce dry powder. Spray drying plays a remarkable role in producing inhalable powder formulations due to its ability to engineer particles with optimized characteristics for inhalation. However, the complexity of drying kinetics and particle formation process coupled with the specificity of the targeted physicochemical characteristics of inhalable particles makes it a very interesting area of research. This review will discuss various aspects of spray drying such as configurations and functions, drying kinetics, component distribution and particle solidification. Furthermore, the review will focus on the functionality and behavior of excipients during drying. Finally, characterization techniques used to investigate components distribution within dried particles will be highlighted with research thrust in this area.
Drying is an indispensable operation in the preparation of pharmaceutical powders and always
remained one of the energetic tasks in the pharmaceutical industry. Improving the stability,
solubility, and dissolution of pharmaceutical products are being prime objectives of the drying
process, intending to produce the products loving the dry state. Though there are voluminous
literatures available concerning drying operations, there is scant information available regarding
the applicability of drying in drug delivery and process scale-up. The current communication
embodies the different particle engineering technologies of drying viz. spray, freeze, and sprayfreeze drying. In addition, potential uses of drying in the taste masking, and the development of
inhalable powders presented briefly. Recent advancements in the drying of novel drug delivery
systems is the major focus of the present review. In our opinion, the commercial aspects,
regulatory guidelines, and scale-up strategies presented herein provide an opportunity to readers,
researchers, and industrialists to ruin the critical issues during drying operations and aid in
developing quality pharmaceutical technologies.
The particle formation of L-leucine, a dispersibility-enhancing amino acid used in the spray drying of inhalable pharmaceutical aerosols, was extensively studied using three experimental methods, and the results were interpreted with the aid of theory. A comparative-kinetics electrodynamic balance was used to study the shell formation behavior in single evaporating microdroplets containing leucine and trehalose. Different concentration thresholds of solidification and shell formation were determined for trehalose and leucine, which were then used in the particle formation model to predict the properties of spray-dried particles. Furthermore, a droplet chain instrument was used to study the particle morphologies and particle densities that were not accessible in the single particle experiments. Lab-scale spray drying was also used to produce powders typical for actual pharmaceutical applications. Raman spectroscopy confirmed that a glass former, such as trehalose, can inhibit the crystallization of leucine. The surface compositions of these spray-dried powders were analyzed via time-of-flight secondary ion mass spectrometry. The leucine surface coverage in a polydisperse powder was determined to be a function of the particle size or the initial droplet diameter of each respective particle. This observation confirms the important role of leucine crystallization kinetics in its shell-forming capabilities. A critical supersaturation ratio of 3.5 was also calculated for leucine, at which it is assumed to instantaneously nucleate out of solution. This ratio was used as the threshold for the initiation of crystallization. Crystallinity predictions for the leucine-trehalose particles based on this supersaturation ratio were in good agreement with the solid-state characterizations obtained by Raman spectroscopy. This study improves the fundamental understanding of the particle formation process of leucine-containing formulations, which can apply to other crystallizing systems and potentially facilitate the rational design of such formulations with reduced experimental effort.
Microparticulate formulations of intranasal drug administration, i.e. nasal powder, have aroused widespread interest in academia and industry. However, low drug bioavailability due to poor hydrophilicity and rapid clearance of nasal mucosa remains an important challenge. Herein, with resveratrol as poorly water-soluble model drug, hydroxypropyl-β-cyclodextrin as complexation agent and excipient, chitosan as mucoadhesive enhancer, a series of uniform microparticles were fabricated using a self-designed microfluidic spray granulation platform. The effects of feed solution composition and process technique on particle size, morphology, density and flowability were investigated. The obtained powder presented the significantly enhanced resveratrol dissolubility over 1800 times pure resveratrol and the excellent antioxidant activity with Net AUC value exceeding 60. Chitosan played an important role in adjusting resveratrol release behavior and improving particle mucoadhesive property. This study shows promise for facile and scalable production of high-quality nasal powder using combined complexation method with spray drying and spray freeze drying technique.
Previous studies have shown that combining colistin (Col), a cationic polypeptide antibiotic, with ivacaftor (Iva), a cystic fibrosis (CF) drug, could achieve synergistic antibacterial effects against Pseudomonas aeruginosa. The purpose of this study was to develop dry powder inhaler formulations for co-delivery of Col and Iva, aiming to treat CF and lung infection simultaneously. In order to improve solubility and dissolution for the water-insoluble Iva, Iva was encapsulated into bovine serum albumin (BSA) nanoparticles (Iva-BSA-NPs). Inhalable composite microparticles of Iva-BSA-NPs were produced by spray-freeze-drying using water-soluble Col as the matrix material and l-leucine as an aerosol enhancer. The optimal formulation showed an irregularly shaped morphology with fine particle fraction (FPF) values of 73.8 ± 5.2% for Col and 80.9 ± 4.1% for Iva. Correlations between "
D
×
ρ
tapped
" and FPF were established for both Iva and Col. The amorphous solubility of Iva is 66 times higher than the crystalline solubility in the buffer. Iva-BSA-NPs were amorphous and remained in the amorphous state after spray-freeze-drying, as examined by powder X-ray diffraction. In vitro dissolution profiles of the selected DPI formulation indicated that Col and Iva were almost completely released within 3 h, which was substantially faster regarding Iva release than the jet-milled physical mixture of the two drugs. In summary, this study developed a novel inhalable nanocomposite microparticle using a synergistic water-soluble drug as the matrix material, which achieved reduced use of excipients for high-dose medications, improved dissolution rate for the water-insoluble drug, and superior aerosol performance.
Spray-freeze-drying (SFD) is a process in which a solution is dispersed into a freezing medium and dried by sublimation, resulting in lyophilized powders with spherical particles. This study aims at screening and evaluating the impact of the excipient choice and spray solution characteristics in SFD on the physico-chemical characteristics of lyospheres and rate their suitability for producing pulmonary applicable powders using a novel SFD method. A monodisperse droplet-stream was injected into a vortex of cold gas for the production of inhalable, uniform spherical lyophilisates with a narrow particle size distribution. Model solutions containing graded contents (0.3 %, 1.0 %, and 3.0 % w/v) of common bulk-forming excipients like mannitol, lactose, poylvinylpyrrolidone (PVP), maltodextrin or hydroyxpropyl methylcellulose (HPMC) and their blends were dispersed using a single 20 μm pinhole diaphragm. Powders were analyzed regarding their geometric particle size, apparent density, mechanical stability and aerodynamic performance. The diameter of the frozen droplets partially correlated with the Ohnesorge number of the spray solutions. The lyosphere powders had median geometric particle diameters ranging from 20 µm to 81 µm. Some powders showed signs of particle shrinkage during the drying step and diameters were reduced down to 30 % of their initial size. The apparent particle densities ranged from 0.009 g/cm³ to 0.087 g/cm³. The mechanical stability of the lyospheres depended on the constituents and concentration of the initial spray solution. Mannitol/maltodextrin formulations yielded large porous particles with promising performance in the Next-Generation-Impactor, emitted fractions between 92 – 98 % (w/w) and fine-particle-fractions of over 55 % (w/w). According to our first steps towards formulations for free-flowing inhalable spray freeze-dried powders the impact of excipient choice on the SFD process is significant and based on the current findings we consider mannitol or mannitol/maltodextrin as best performing formulations.
Levodopa inhalation powder (Inbrija®) is approved for the intermittent treatment of OFF episodes in patients with Parkinson’s disease (PD) treated with levodopa/dopa-decarboxylase inhibitor (LD-DCI) in the EU and specifically with carbidopa/levodopa in the USA. The approved dosage is 84 mg taken as needed up to five times a day. Administered via a breath-actuated inhaler, this formulation enables levodopa to bypass the gastrointestinal (GI) tract and, instead, rapidly enter the bloodstream through the pulmonary system. In the 12-week, double-blind, placebo-controlled, phase III SPAN-PD trial, as-needed levodopa inhalation powder 84 mg improved motor symptoms during OFF periods in PD patients (aged 30–86 years) treated with levodopa and carbidopa or benserazide. The likelihood of achieving an ON state 60 min postdose was significantly higher in the levodopa inhalation powder than the placebo group, with most patients in the levodopa inhalation powder group experiencing improvements in PD symptoms. Findings from longer-term, 52-week phase III studies were consistent with those from the SPAN-PD trial with regards to the treatment of OFF episodes. Levodopa inhalation powder was generally well tolerated and did not noticeably affect pulmonary function in PD patients. Providing a nonintrusive, convenient treatment method, levodopa inhalation powder is a promising option for the intermittent treatment of OFF episodes in patients with PD treated with a LD-DCI.
A novel pure insulin spray-dried powder for DPI product (Ins_SD) was studied with respect to physico-chemical stability, in vitro respirability, bioavailability, activity and tolerability.
Ins_SD powder exhibited a very high in vitro respirability, independently of the DPI product preparation (manual or semi-automatic). Physico-chemical characteristics of Ins_SD powder remained within the pharmacopoeia limits during 6 months of storage at room temperature.
PK/PD profiles were measured in rats that received the pulmonary powders by intratracheal insufflation and compared with Afrezza inhalation insulin. Due to the low drug powder mass to deliver, both insulin powders were diluted with mannitol. Insulin from Ins_SD was promptly absorbed (tmax 15 min and Cmaxx4.9 ± 1.5 mU/ml). Afrezza had a slower absorption (tmax 30 min and Cmax of 1.8 ± 0.37 mU/ml). After glucose injection, Ins_SD determined a rapid reduction of glucose level, similar to Afrezza. As reference, insulin subcutaneous injection showed a long-lasting hypoglycemic effect due to the slow absorption that prolonged insulin plasma level.
In summary, Ins_SD product is suitable for post-prandial glucose control, providing a convenient and compliant product, in particular in the event of using a disposable device.
Albeit the product has to be stored in fridge, its stability at room temperature allows the diabetic individual to carry the daily dose in normal conditions.
Ciprofloxacin hydrochloride (CIP) is a common fluoroquinolone antibiotic agent, and in the marketed product the compound exists as the hydrate phase (1.43 hydrate). Upon heating, the stable hydrate phase dehydrates and converts to a new anhydrous form 1 (AH1). Further heating results in a phase transformation that gives another new anhydrous form 2 (AH2). The crystal structures of CIP 1.43 hydrate and AH2 were solved from single crystal X-ray structure analysis. However, the single crystal of CIP AH1 could not be obtained, thus the crystal structure of CIP AH1 was determined directly from powder X-ray diffraction data using synchrotron technique. The crystal structure of AH1 is partly related to the hydrate as they both show similar one-dimensional (1D) chain and two-dimensional sheet structure. In the AH2, it is only the 1D chain that is retained after phase transformation. The mechanism of dehydration and the phase transformation is determined by correlating structural differences of AH1 and AH2. Each crystalline phase of CIP shows different physical stability, dissolution rate, and colour which can be derived from structural difference among the phases.
Introduction: Dry powder inhalers (DPIs) are popular for pulmonary drug delivery. Various techniques have been employed to produce inhalation drug particles and improve the delivery efficiency of DPI formulations. Physical stability of these DPI formulations is critical to ensure the delivery of a reproducible dose to the airways over the shelf-life.
Areas covered: This review focuses on the impact of solid-state stability on aerosolization performance of DPI drug particles manufactured by powder production approaches and particle engineering techniques. It also highlights the different analytical tools that can be used to characterize the physical instability originating from production and storage.
Expert opinion: A majority of the DPI literature focuses on the effects of physico-chemical properties such as size, morphology and density on aerosolization. While little has been reported on the physical stability, particularly the stability of engineered drug particles for use in DPIs. Literature data have shown that different particle engineering methods and storage conditions may cause physical instability of dry powders for inhalation and can significantly change the aerosol performance. A systematic examination of physical instability mechanisms in DPI formulations is necessary during formulation development in order to select the optimum formulation with satisfactory stability. In addition, the use of appropriate characterization tools are critical to detect and understand physical instability during the development of DPI formulations.
Spray freeze drying is relatively a recent drying technique involving heterogeneous set of steps which includes droplet formation, freezing, and sublimation. It has proven benefits over other drying methods in terms of producing products with improved structural integrity, superior quality, and better shelf stability. With such merits, spray freeze drying has found numerous applications in the field of drug delivery. Spray freeze drying yields particles of sizes and densities that show higher stability in the lungs, nasal mucosa, intestine, and skin, as compared to other drying technologies. These particles also possess the vital trait of sustained release and specificity through various delivery routes as compared to conventional drying techniques. This drives the market for commercialization of spray freeze dried drugs. The focus of this paper is on manufacturing approaches of spray freeze dried powders, with emphasis on its application in drug delivery systems. An overview of other applications of spray freeze drying is also presented.
Droplet vitrification is one of the most attractive tools for cells cryopreservation due to its ultra-rapid cooling rate. However, this method has its own limitation because of the Leidenfrost phenomenon. In this work, the infrared imaging technology was utilized to investigate the effects of cryoprotective agents (CPA) concentrations and volumes on levitating velocities and durations of CPA droplets on liquid nitrogen (LN2), and the model of non-isothermal crystallization kinetics was also adopted here for theoretical analysis of the temperature distributions and degree of crystallization inside the droplets. The experimental results showed that the movements of droplets on LN2 became slower when increasing the CPA concentrations, but they were independent on the volumes except for higher CPA concentration cases (i.e., 50% glycerol and VS55). And the Leidenfrost effect time (i.e. the levitation time on the liquid nitrogen) became longer as increasing both the CPA concentrations and volumes. The theoretical results indicated that the final crystallinity inside droplets reached 1 for both water and 20% glycerol cases, a magnitude of 1 × 10⁻⁶ for 50% glycerol and 1 × 10⁻¹³ for VS55, respectively. Furthermore, the motion of droplets was strongly related to the crystallinity rates and cooling rates inside the droplets.
Intranasal vaccination using dry powder vaccine formulation represents an attractive, non-invasive vaccination modality with better storage stability and added protection at the mucosal surfaces. Herein we report that it is feasible to induce specific mucosal and systemic antibody responses by intranasal immunization with a dry powder vaccine adjuvanted with an insoluble aluminum salt. The dry powder vaccine was prepared by thin-film freeze-drying of a model antigen, ovalbumin, adsorbed on aluminum (oxy)hydroxide as an adjuvant. Special emphasis was placed on the characterization of the dry powder vaccine formulation that can be realistically used in humans by a nasal dry powder delivery device. The vaccine powder was found to have “passable” to “good” flow properties, and the vaccine was uniformly distributed in the dry powder. An in vitro nasal deposition study using nasal casts of adult humans showed that around 90% of the powder was deposited in the nasal cavity. Intranasal immunization of rats with the dry powder vaccine elicited a specific serum antibody response as well as specific IgA responses in the nose and lung secretions of the rats. This study demonstrates the generation of systemic and mucosal immune responses by intranasal immunization using a dry powder vaccine adjuvanted with an aluminum salt.
The growing interest on polymeric delivery systems for pulmonary administration of drugs anticipates a more direct and efficient treatment of diseases such as tuberculosis (TB) that uses the pulmonary route as the natural route of infection. Polymeric microparticles or nano-in-microparticles offer target delivery of drugs to the lungs and the potential to control and sustain drug release within TB infected macrophages improving the efficiency of the anti-TB treatment and reducing side effects. In a dry powder form these inhalable delivery systems have increased stability and prolonged storage time without requiring refrigeration, besides being cost-effective and patient convenient.
Thus, this review aims to compile the recent innovations of inhalable polymeric dry powder systems for the delivery of anti-TB drugs exploring the methods of production, aerodynamic characterization and the efficacy of targeted drug delivery systems using in vitro and in vivo models of the disease. Advanced knowledge and promising outcomes of these systems are anticipated to simplify and revolutionize the pulmonary drug delivery and to contribute towards more effective anti-TB treatments.
Carrier based dry powder inhalers (DPIs) are common vehicles for pulmonary delivery of active pharmaceutical ingredients (APIs), thus powder properties of carrier would generate a pronounced impact on the two dominant delivery stages of the DPIs. In our previous study, a novel modified carrier, the nanoporous mannitol carriers (NPMCs) was prepared to achieve satisfactory aerosolization performance. While the aerosolization performance enhancement mechanism of NPMCs based DPI was still uncovered. The purpose of this study was to explore the relationship between the powder property of NPMCs and the aerosolization performance of their corresponding DPI formulations. Particle size analysis of NPMCs was assessed by Sympatec® dynamic laser diffraction. Powder property of NPMCs was performed by FT4 powder rheometer. Aerosolization performance was evaluated by the next generation impactor to simulate the deposition profile of NPMCs based DPI formulations in respiratory tract. Similar particle size distribution was observed among the NPMCs formulations (p > 0.05), which were appropriate for DPIs. And NPMCs exhibited superior flowability, aeration and permeability behaviors in FT4 tests, meanwhile higher fine particle fraction (FPF) values in NGI test comparing to the nonporous mannitol. Further, two positive correlations between the basic flow energy (BFE) and ρb (R² = 0.901), specific energy and ρb values (R² = 0.912) were obtained in NPMC systems, respectively. The relationship between BFE and FPF was explored quantitatively as well, and it revealed an inverse correlation (R² = 0.934). Therefore, the aerosolization performance enhancement of NPMCs based DPI could be reasonably explained by powder property of carriers quantified by the FT4 powder rheometer, which was a promising tool for the design of DPI carrier.
Ciprofloxacin is a broad-spectrum antibiotic for treatment of pulmonary diseases such as chronic obstructive pulmonary disease and cystic fibrosis. The purpose of this work was to rationally study the spray drying of ciprofloxacin in order to identify the formulation and operating conditions that lead to a product with aerodynamic properties appropriate for dry powder inhalation. A 24 − 1 fractional factorial design was applied to investigate the effect of selected variables (i.e., ciprofloxacin hydrochloride (CIP) concentration, drying air inlet temperature, feed flow rate, and atomization air flow rate) on several product and process parameters (i.e., particle size, aerodynamic diameter, moisture content, densities, porosity, powder flowability, outlet temperature, and process yield) and to determine an optimal condition. The studied factors had a significant effect on the evaluated responses (higher p value 0.0017), except for the moisture content (p value > 0.05). The optimal formulation and operating conditions were as follows: CIP concentration 10 mg/mL, drying air inlet temperature 110°C, feed volumetric flow rate 3.0 mL/min, and atomization air volumetric flow rate 473 L/h. The product obtained under this set had a particle size that guarantees access to the lung, a moisture content acceptable for dry powder inhalation, fair flowability, and high process yield. The PDRX and SEM analysis of the optimal product showed a crystalline structure and round and dimpled particles. Moreover, the product was obtained by a simple and green spray drying method.
Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders.
The aim of this study is to investigate the influence of excipients on physical and aerosolization stability of spray dried Ciprofloxacin dry powder inhaler formulations. The model drug, Ciprofloxacin hydrochloride, was co-spray dried with excipients such as disaccharides (sucrose, lactose, trehalose), mannitol and L-leucine. The spray dried samples were stored at two different relative humidity (RH) conditions of: (1) 20% and (2) 55% RH at 20°C. Ciprofloxacin co-spray dried with disaccharides and L-leucine in the mass ratio of 1:1 demonstrated an increase in fine particle fraction (FPF) as compared with the spray dried Ciprofloxacin alone when stored at 20% RH. However, deterioration in FPF of Ciprofloxacin co-spray dried with disaccharide and mannitol was observed upon storage at 55% RH as compared to the corresponding formulations stored at 20% RH due to particle agglomeration. Whereas, 10% and 50% w/w L-leucine in the formulation showed no change in aerosol performance (FPF of 71.1 ± 3.5%. and 79.5 ± 3.1%, respectively) when stored at 55% RH for 10 days as compared to 20% RH (FPF of 68.1 ± 0.3% and 73.6 ± 7.1%, respectively). L-leucine demonstrated short-term aerosolization stability by alleviating crystallization of Ciprofloxacin to some extent and preventing significant change in particle morphology. L-leucine is well-recognized as aerosolization enhancer; our study has shown L-leucine is also a physical and aerosolization stabilizer for spray dried Ciprofloxacin DPI formulations. Such stability enhancing activities were attributed to the enrichment of L-leucine on the particle surface as confirmed by XPS data, and intermolecular interactions between L-leucine and Ciprofloxacin as measured by FT-IR.
Enzyme-immobilized particles with high enzymatic activities are fundamentally and practically important for many areas, such as pharmaceuticals, medicine, and biocatalysis. In this study, by selecting trypsin and trehalose as the representative enzyme and excipient, two techniques, spray drying (SD) and spray freeze drying (SFD), have been utilized to generate enzyme-immobilized particles and comparatively studied. In both methods, uniform enzyme-immobilized microparticles are successfully obtained by using a micro-fluidic aerosol nozzle (MFAN) as the monodisperse droplet generator. The particle morphology, size and inner structure are distinctly different between the SD- and SFD-derived trypsin/trehalose composite microparticles. The former shows crumpled morphology, smaller sizes and dense inner structure while the latter shows spherical and open porous morphology with larger particle sizes. The particle formation processes in both methods are discussed. The more surface-active and large-sized trypsin molecules tend to be accumulated at the air-liquid interface of drying droplets, leading to particle buckling in SD and the formation of thin surface trypsin-enriched layer in SFD. The trypsin enzymatic activity is highly related to the presence of trehalose and the processing method. For the pure trypsin microparticles, SFD leads to a better activity preservation than SD does due to the much higher temperature adopted in SD. The presence of trehalose can significantly protect the enzymatic activity of trypsin, reaching 97.7 ± 2.6% and 97.3 ± 1.6% activity preservation with the optimal trypsin/trehalose mass ratio of 1:1 for both the SD- and SFD-derived microparticles, respectively. The protection of the enzymatic activity originates from the hydrogen bonding formation between trypsin and trehalose and the formation of highly amorphous glass matrices, which decrease enzyme unfolding and aggregation. In terms of process operability, SD offers a rather simple and economic means to produce enzymatic microparticles of high activity with the appropriate dosage of trehalose.
Antibiotic delivery in form of dry powder inhalation has been studied for possible clinical treatment of respiratory tract infection in the recent years. Dry powder inhalation of ciprofloxacin hydrochloride (CIP) assures local antibacterial activity and comfort of easy application. The aim of this work was to test the stability of co-spray-dried CIP in carrier free system. Since the microparticles in the dry powder system are amorphous and do not contain any stabilizer, the effects of temperature and relative humidity (RH) on the physicochemical properties and aerosolization behavior are very important. Therefore investigation of the role of excipients (such as polyvinyl alcohol (PVA), l-leucine (LEU) and hydroxypropyl-beta-cyclodextrin (CD)) on physicochemical stability and aerosolization performance is essential element prior designing the final dosage form. Stability tests (stress and accelerated) were performed at 40±2°C and 75±5% RH during 6 months. Particle characterization and size measurement - as the most important parameters in aerodynamic behavior - were done by the laser diffraction method, the surface morphology of microparticles was evaluated by scanning electron microscopy (SEM). The physiochemical properties of microparticles were investigated by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The resulting aerodynamic behavior of microparticles was studied by Andersen cascade impactor. The overall stability results (against RH and temperature) showed that microparticles containing CIP and LEU alone and in combination with the other excipients were more stable than those containing PVA or CD alone. In relation to fine particle fraction and mass median aerodynamic diameter (determining the aerosolization parameters), it was found that the particle size and particle shape did not show significant changes after the storage. Among the excipients LEU was found to have many advantages, including relatively simple formulation, enhanced aerosolization behaviour, convenient portability and inherently improved stability. Such a composition may serve as an innovative drug delivery system for the local treatment of respiratory tract infection and cystic fibrosis.
Introduction:
Early dry powder inhalers (DPIs) were designed to deliver low drug doses in asthma and COPD therapy. Nearly all concepts contained carrier-based formulations and lacked efficient dispersion principles. Therefore, particle engineering and powder processing are increasingly applied today as repair actions for the poor design choices to achieve acceptable lung deposition with these inhalers.
Areas covered:
The consequences of the choices made for early DPI development are discussed with respect of efficacy, production costs and safety. The tremendous amount of energy put into understanding and controlling the dispersion performance of adhesive mixtures is reviewed. Newly developed particle manufacturing and powder formulation processes are presented and challenges, objectives, and new tools available for future DPI design are discussed.
Expert opinion:
Improved inhaler design is desired to make dry powder inhalation for future applications cost-effective and safe. With an increasing interest in high dose drug delivery, vaccination and systemic delivery via the respiratory tract, innovative formulation technologies alone may not be sufficient. Safety is served by increasing patient adherence to the therapy, minimising the use of unnecessary excipients and making simple and self-intuitive inhalers, which give good feedback to the patient about the inhalation manoeuvre. For some applications, like vaccination and delivery of hygroscopic formulations, disposable inhalers may be preferred.
While the therapeutic benefits of curcumin delivery to the lung to treat various pulmonary disorders have been established, development of inhaled curcumin formulation that can address its inherently low aqueous solubility remains lacking. Although curcumin nanocapsules prepared by conventional encapsulation methods can improve the dissolution rate, their intricate preparation makes them less attractive for widespread implementation. Recently, our group developed a new class of curcumin nanoparticles in the form of curcumin-chitosan nanoparticle complex (or curcumin nanoplex in short) by a simple, cost-effective, and highly efficient method based on self-assembly drug-polysaccharide complexation. Owing to its nanosize and amorphous state, the curcumin nanoplex possessed high supersaturation generation capability upon dissolution that in turn produced high apparent solubility of curcumin.
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 (3 μm versus 6 μm). 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.
Spray-freeze-drying (SFD) is a unique powderization technique to produce highly porous dry powders with a low density. The characteristic morphology can markedly contribute to the superior inhalation performances of SFD powders. Due to the increased specific surface area of the powders, however, moisture adsorption may readily occur, subsequently leading to losses of their inhalation potentials. In this study, hydrophobic amino acids were newly applied as pharmaceutical excipients to obtain SFD powders with both a favorable inhalation performance and antihygroscopic property.SFD powders composed of several hydrophobic amino acids were prepared. The morphology, particle size distribution, and crystallinity of the prepared powders were evaluated by scanning electron micrography, laser diffraction, and X-ray powder diffraction, respectively. The inhalation characteristics of the SFD powders were examined using a twin-stage liquid impinger equipped with an inspiratory pattern simulator and devices. To investigate their antihygroscopicity, moreover, the SFD powders were stored under a humidified condition to assess the morphology, crystallinity, and inhalation performance as described above.It was demonstrated that a SFD powder composed of L-leucine, L-isoleucine, or L-phenylalanine showed a superior inhalation performance, which was sufficiently maintained after storage under the humidified condition, strongly indicating their antihygroscopicity. These results indicated that the hygroscopicity of SFD powders can be effectively improved by the application of hydrophobic amino acids as excipients.
The formation of heterogeneous particle structure in skim milk powder has been investigated in a post-crystallization facility using experimental and a mathematical model. Various processing conditions were used to produce these heterogeneous structures. The experimental process parameters were used as initial and boundary conditions for the model. The modelled data agreed well with the experimental data. The experimental and modelling results show that the powder processed at high water activity (aw = 0.7) with low initial moisture content ( = 0.01 kg/kg) developed a crystalline surface layer while the core of the particle remained amorphous. This structure is referred to as an egg-shell structure. The powder that was processed at low water activity (aw = 0.1) with high initial moisture content ( = 0.2 kg/kg) developed a crystalline core while the surface of the particle remained amorphous. This structure is referred to as an egg-yolk structure. Understanding the dependency of particle microstructures on the processing conditions could be useful when developing procedures to control the drying equipment because the particle microstructure affects the physicochemical properties of the powder and potential applications and behaviour of the powder.
Thin film freezing (TFF) was employed to produce brittle matrix powders, capable of forming into respirable low-density particles upon aerosolization. The objective of this study is to investigate the impact of processing parameters in the TFF process on the physicochemical and aerodynamic properties of the resulting formulations. TFF formulation produced at the higher freezing rate (cryogenic surface temperature: -140°C) showed greater specific surface area, higher porosity and lower density, compared to the TFF formulation prepared at the intermediate freezing rate (cryogenic surface temperature: -50°C) and slow freezing rate (slow freezing on the shelf of -40°C). All of these enhanced properties induced by faster freezing rate further contributed to an increased fine particle fraction (FPF) of the obtained formulations. Moreover, an increasing trend of FPF was observed for these TFF powders when the initial solid concentration was reduced, probably due to the enhanced brittleness. The variation of the freezing rate and initial solid loading in the TFF process enabled the production of formulations with tailored physicochemical properties and brittleness, leading to improved aerodynamic performance.
The viscosity concept is introduced to granular powders after the analogous temperature is defined consistently with thermodynamics, and the corresponding viscosity equation is obtained with the aid of Eyring's rate process theory and free volume concept. The popular empirical powder flowability criteria scaled with the Hausner ratio or Carr index are theoretically found only to work at special conditions and more universal criteria correlated with shearing conditions and particle physical properties are presented. Our results resolve a long time controversial mystery related to those two empirical indexes on powder flowability, and has a broad impact in many industrial areas. The work presented in this article may lay a foundation to scale powder flowability in a more fundamental and consistent manner.
Pharmaceutical spray-freeze drying (SFD) includes a heterogeneous set of technologies with primary applications in apparent solubility enhancement, pulmonary drug delivery, intradermal ballistic administration and delivery of vaccines to the nasal mucosa. The methods comprise of three steps: droplet generation, freezing and sublimation drying, which can be matched to the requirements given by the dosage form and route of administration. The objectives, various methods and physicochemical and pharmacological outcomes have been reviewed with a scope including related fields of science and technology.
Copyright © 2015. Published by Elsevier B.V.
Respiratory infections represent a major global health problem. They are often treated by parenteral administrations of antimicrobials. Unfortunately, systemic therapies of high-dose antimicrobials can lead to severe adverse effects and this calls for a need to develop inhaled formulations that enable targeted drug delivery to the airways with minimal systemic drug exposure. Recent technological advances facilitate the development of inhaled anti-microbial therapies. The newer mesh nebulisers have achieved minimal drug residue, higher aerosolisation efficiencies and rapid administration compared to traditional jet nebulisers. Novel particle engineering and intelligent device design also make dry powder inhalers appealing for the delivery of high-dose antibiotics. In view of the fact that no new antibiotic entities against multi-drug resistant bacteria have come close to commercialisation, advanced formulation strategies are in high demand for combating respiratory 'super bugs'.
Copyright © 2014 Elsevier B.V. All rights reserved.
Spray-freeze-drying (SFD) is an unconventional freeze drying technique that produces uniquely powdered products whilst still including the benefits of conventionally freeze dried products. SFD has potential applications in high value products due to its edge over other drying techniques in terms of product structure, quality, and the retention of volatiles and bioactive compounds. In cases where other drying techniques cannot provide these product attributes, SFD stands out despite the costs and complexities involved. This paper outlines the principles, methods, significant process parameters, particle morphology and quality aspects of SFD. Recent developments in this technique are reviewed including ultrasonic spray-freeze-drying, the application of computational fluid dynamics and mathematical modelling, and the incorporation of new technologies to improve product quality. In addition, the advantages, limitations and future scope for research in the field of SFD are discussed.
Inhaled antibiotics dramatically improve targeting of drug to the site of respiratory infections, while simultaneously minimizing systemic exposure and associated toxicity. The high local concentrations of antibiotic may enable more effective treatment of multi-drug resistant pathogens. This review explores barriers to effective treatment with inhaled antibiotics. In addition, potential opportunities for improvements in treatment are reviewed.