Dry Powder Inhalation System Research Articles

Pulmonary administration of cross-linked chitosan nanoparticles of genistein for regulating blood glucose

The research study focused on the development and characterization of sustained release formulation of genistein (GEN)-loaded chitosan (CS) nanoparticles to deliver in the form of dry powder inhaler (DPI) via pulmonary route to offer higher stability and anti-diabetic activity. The GEN-loaded nanoparticles were prepared by cross-linking reaction of CS and sodium hexametaphosphate (SHMP). The optimized formulation displayed particle size (PS) of 684.2 ± 26.5 nm, zeta potential (ZP) of 19.6 ± 4.50 mV, % entrapment efficiency (% EE) of 87.33 ± 8.46 % and drug release profile of 85.48 ± 5.50 % for 48 h. The in-vivo studies exhibited a superior sustained release formulation of GEN in the regulation of blood glucose levels (BGLs). The powder showed the emitted fraction (EF) of 86.76 % and effective inhalation index (EI) of 85.41 %. The reduction of BGLs (85 %) was observed in the diabetic group. This might be due to the inhibition of proliferation of pancreatic β-cells (growth factor inhibition targeting cAMP and ERK1/2 pathway), antioxidative activity, reducing insulin resistance, and the adipose tissue mass and alteration of the hepatic glucose metabolism. Hence, these results proved the delivery of GEN in the form of DPI system as a favorable route for treating type-1 diabetes mellitus with a longer duration of action.

Development of Paclitaxel Proliposomal Dry Powder Inhaler (PTX-PLM-DPI) by Freeze-Drying Method for Lung Cancer

Despite various efforts, a successful selective delivery system for chemotherapeutic agents for lung cancer is still lacking. Dry powder inhaler (DPI) systems based on proliposomes (PLMs) could be a potential system for the efficient delivery of paclitaxel to lungs. PLM-based DPI prepared with a freeze-drying method can therefore be an alternative. Paclitaxel-loaded PLM-based DPI (PTX-PLM-DPI) powders were prepared using the method of thin film deposition on a carrier followed by freeze drying. These were prepared using soya phosphatidylcholine (SPC) and cholesterol as the lipids and mannitol as the carrier. The reconstituted liposomes were evaluated in terms of size, morphology, drug entrapment, release and cytotoxicity. The DPI powders were evaluated for their flow property, surface topography, dose uniformity and in vitro lung deposition. Stable and free-flowing PTX-PLM-DPI powder was obtained that could be reconstituted into homogenous liposomal vesicles < 200 nm as confirmed by TEM and SEM studies. The liposomes showed drug entrapment of 92.64 ± 1.4% and diffusion-controlled release of up to 28% in 24 h. These liposomes showed better dose-dependent cytotoxicity in A549 cells in comparison to paclitaxel suspension with IC50 values of 46 ± 0.87 ng/mL and 154.9 ± 3.64 ng/mL, respectively. In vitro lung deposition studies of the PTX-PLM-DPI showed sufficient deposition with the fine particle fraction (FPF) of 50.86 ± 2.8% of particles with an aerodynamic diameter less than 5 µ. Hence, it canbe concluded that PLM-based DPI prepared by freeze drying can be a promising, stable, safe and free-flowing system for the enhanced lung delivery of paclitaxel.

Efficiency of a Lyophilizate for Dry Powder Inhalation System for Drug Delivery of Ghrelin in Monkeys

Background: A lyophilizate for dry powder inhalation (LDPI) system is unique in that its formulation, a lyophilized cake, is aerosolized just upon inhalation by convection flow of air. An LDPI system may be advantageous, especially for biopharmaceutics, such as proteins and peptides, because formulations can be manufactured without high temperature and shear stress. It was already reported that formulations of peptides used in an LDPI system showed high aerosoli-zation performance. However, it was not confirmed whether the LDPI system could deliver drugs efficiently enough for practical use. Objective: In this study, we compared the drug delivery efficiency of an LDPI system with intra-venous and subcutaneous injections. Methods: We administered LDPI formulations containing ghrelin as model formulations to monkeys and measured pharmacokinetic profiles. Results: As a result of pharmacokinetics testing in the monkeys, the bioavailability of an inhaled drug was 5-15%. Conclusion: It is expected that the LDPI system can deliver drugs efficiently enough for practical use even in the systemic application of bio-pharmaceutics.

Investigation of Physico-Chemical Stability and Aerodynamic Properties of Novel "Nano-in-Micro" Structured Dry Powder Inhaler System.

Pulmonary drug transport has numerous benefits. Large surface areas for absorption and limited drug degradation of the gastrointestinal system are provided through the respiratory tract. The administration is painless and easy for the patient. Due to their better stability when compared to liquid formulations, powders have gained popularity among pulmonary formulations. In the pharmaceutical sector, quality assurance and product stability have drawn a lot of attention. Due to this, it was decided to perform a long-term stability study on a previously developed, nanosized dry powder inhaler (DPI) formulation that contained meloxicam. Wet milling was implemented to reduce the particle size, and nano spray-drying was used to produce the extra-fine inhalable particles. The particle diameter was determined using dynamic light scattering and laser diffraction. Scanning electron microscopy was utilized to describe the morphology. X-ray powder diffraction and differential scanning calorimetry were applied to determine the crystallinity. In an artificial lung medium, the in vitro dissolution was studied. The Andersen Cascade Impactor was used to investigate the in vitro aerodynamic characteristics. The stability test results demonstrated that the DPI formulation maintained its essential qualities after 6 and 12 months of storage. Consequently, the product might be promising for further studies and development.

Comparison of HPMC Inhalation-Grade Capsules and Their Effect on Aerosol Performance Using Budesonide and Rifampicin DPI Formulations.

Despite the fact that capsules play an important role in many dry powder inhalation (DPI) systems, few studies have been conducted to investigate the capsules’ interactions with respirable powders. The effect of four commercially available hydroxypropyl methylcellulose (HPMC)inhalation-grade capsule types on the aerosol performance of two model DPI formulations (lactose carrier and a carrier-free formulation) at two different pressure drops was investigated in this study. There were no statistically significant differences in performance between capsules by using the carrier-based formulation. However, there were some differences between the capsules used for the carrier-free rifampicin formulation. At 2-kPa pressure drop conditions, Embocaps® VG capsules had a higher mean emitted fraction (EF) (89.86%) and a lower mean mass median aerodynamic diameter (MMAD) (4.19 µm) than Vcaps® (Capsugel) (85.54%, 5.10 µm) and Quali-V® I (Qualicaps) (85.01%, 5.09 µm), but no significant performance differences between Embocaps® and ACGcaps™ HI. Moreover, Embocaps® VG capsules exhibited a higher mean respirable fraction (RF)/fine particle fraction (FPF) with a 3-µm–sized cutoff (RF/FPF< 3 µm) (33.05%/35.36%) against Quali-V® I (28.16%/31.75%) (P < 0.05), and a higher RF/FPF with a 5-µm–sized cutoff (RF/FPF< 5 µm) (49.15%/52.57%) versus ACGcaps™ HI (38.88%/41.99%) (P < 0.01) at 4-kPa pressure drop condition. Aerosol performance variability, pierced-flap detachment, as well as capsule hardness and stiffness, may all influence capsule type selection in a carrier-based formulation. The capsule type influenced EF, RF, FPF, and MMAD in the carrier-free formulation.

Development of meloxicam potassium-containing co-spray-dried inhalation powder with sodium stearate

Pulmonary drug delivery (PDD) has potential for both local and systemic therapy. Our research group is focus- ing on the development of dry powder inhalation (DPI) systems for PDD due to their beneficial properties. Although there is not yet a marketed inhalation product for non-steroidal anti-inflammatory drugs (NSAIDs), their therapeutic use in sev- eral lung diseases is well established and successful DPI developments have been performed with them. Sodium stearate (NaSt) is a promising excipient for DPI development, but its role in NSAIDs has not yet been investigated. Thus, the aim was to study DPI samples produced by co-spray-drying, applying meloxicam potassium (MXP) as an NSAID drug, and different concentrations (0-2 w/w%) of NaSt. Physicochemical investigations, in vitro lung deposition, and in vitro drug release measurements were performed. It can be stated that co-spray-drying of MXP with NaSt resulted in remarkable morphological differences by increasing the concentration of NaSt, which had a positive effect on cohesive work. Further- more, applying of NaSt accelerates the dissolution in simulated lung fluid (SLF). NaSt as excipient has a future for the formulation of the DPI systems because there are in the development focus the attaintment of the higher FPF values and improvement of dissolution in SLF.

Spray-Dried Inhalable Powder Formulations of Therapeutic Proteins and Peptides.

Respiratory diseases are among the leading causes of morbidity and mortality worldwide. Innovations in biochemical engineering and understanding of the pathophysiology of respiratory diseases resulted in the development of many therapeutic proteins and peptide drugs with high specificity and potency. Currently, protein and peptide drugs are mostly administered by injections due to their large molecular size, poor oral absorption, and labile physicochemical properties. However, parenteral administration has several limitations such as frequent dosing due to the short half-life of protein and peptide in blood, pain on administration, sterility requirement, and poor patient compliance. Among various noninvasive routes of administrations, the pulmonary route has received a great deal of attention and is a better alternative to deliver protein and peptide drugs for treating respiratory diseases and systemic diseases. Among the various aerosol dosage forms, dry powder inhaler (DPI) systems appear to be promising for inhalation delivery of proteins and peptides due to their improved stability in solid state. This review focuses on the development of DPI formulations of protein and peptide drugs using advanced spray drying. An overview of the challenges in maintaining protein stability during the drying process and stabilizing excipients used in spray drying of proteins and peptide drugs is discussed. Finally, a summary of spray-dried DPI formulations of protein and peptide drugs, their characterization, various DPI devices used to deliver protein and peptide drugs, and current clinical status are discussed.

The effect of ethanol on the habit and in vitro aerodynamic results of dry powder inhalation formulations containing ciprofloxacin hydrochloride

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.

Stability and In Vitro Aerodynamic Studies of Inhalation Powders Containing Ciprofloxacin Hydrochloride Applying Different DPI Capsule Types.

In the case of capsule-based dry powder inhalation systems (DPIs), the selection of the appropriate capsule is important. The use of gelatin, gelatin-PEG, and HPMC capsules has become widespread in marketed capsule-based DPIs. We aimed to perform a stability test according to the ICH guideline in the above-mentioned three capsule types. The results of the novel combined formulated microcomposite were more favorable than those of the carrier-free formulation for all capsule types. The use of HPMC capsules results in the greatest stability and thus the best in vitro aerodynamic results for both DPI powders after six months. This can be explained by the fact that the residual solvent content (RSC) of the capsules differs. Under the applied conditions the RSC of the HPMC capsule decreased the least and remained within the optimal range, thus becoming less fragmented, which was reflected in the RSC, structure and morphology of the particles, as well as in the in vitro aerodynamic results (there was a difference of approximately 10% in the lung deposition results). During pharmaceutical dosage form developments, emphasis should be placed in the case of DPIs on determining which capsule type will be used for specific formulations.

Optimization of Very Low-Dose Formulation of Vitamin D3 with Lyophilizate for Dry Powder Inhalation System by Simple Method Based on Time-of-Flight Theory.

It has been previously reported that active vitamin D3 (VD3) is a candidate drug that can repair alveolar damage in chronic obstructive pulmonary disease at a very low dose. We herein report the optimization of a very low-dose formulation of VD3 for dry powder inhalation by a simple method based on time-of-flight (TOF) theory. As the preparation content of VD3 is very low, aerodynamic particle size distribution cannot be measured by pharmacopeial methods that require quantification of the main drug. Thus, a simple method based on TOF theory, which can measure aerodynamic particle size distribution without quantification, was used. The optimized formulation for an inhalation system using a lyophilized cake contained phenylalanine as the excipient (VD3 1 μg/vial + phenylalanine 0.3 mg/vial) and showed high performance with fine particle fraction ≤ 3 μm = 47.2 ± 4.4%. The difference between the results of pharmacopeial methods and simple method was examined using the formulation containing 10 µg/vial of VD3 and was within 5.0%. The preparation is expected to efficiently deliver VD3 to the lungs. Our simple method can optimize dry powder inhalation formulations more easily and rapidly even when the content of the main drug in a preparation is very low.

Extending the range of back-lit imaging in two-phase flows using an interrogation-window based method

This paper introduces a novel image processing methodology to enable an extension of the range of applicability of the back-lit imaging method to provide the simultaneous measurement of size and velocity in turbulent flows with a high concentration of objects having various shapes and sizes. The new image processing methodology applies an interrogation-window method similar to that used in particle image velocimetry, alongside interface identification as used in backlight imaging. The matching of droplets or particles of arbitrary shape is achieved by dividing the image into several small windows and cross-correlating objects in each window to obtain a coefficient of dissimilarity, extracted using a variety of metrics of droplet or particle morphology. To demonstrate its utility this technique is applied to measurement of velocities from (i) a highly turbulent spray flow and (ii) a swirling particle-laden flow as applicable to dry powder inhalation systems. Results are validated against phase Doppler anemometry data and a sensitivity analysis of the controlling parameters of the image processing methodology demonstrate that the technique is robust for a variety of input conditions. A key advantage of this approach lies in complementing the diagnostics capability of PDA methods to span a broader range of particle sizes irrelevant of shape and particle concentration.

Systemic Delivery of hGhrelin Derivative by Lyophilizate for Dry Powder Inhalation System in Monkeys.

Ghrelin is the peptide that increases the hunger sensation and food intake and is expected to be clinically applied for treatment of diseases such as cachexia and anorexia nervosa. In the clinical application of ghrelin, injections are problematic in that they are invasive and inconvenient. Thus, we aimed to develop a formulation that can eliminate the need for injections and can be applied clinically. We prepared formulations of an hGhrelin derivative, in which the octanoyl group essential for expression of activity is modified to avoid rapid des-acylation, using lyophilizate for a dry powder inhalation (LDPI) system. The formulation of hGhrelin derivative was optimized by the addition of phenylalanine, of which the fine particle fraction of 5 µm or less was 41.7 ± 3.8%. We also performed pharmacokinetic/pharmacodynamic tests in monkeys using the optimum formulation that can be applied clinically. The absolute bioavailability of inhaled hGhrelin derivative with respect to that intravenously injected was 16.9 ± 2.6%. An increase in growth hormone was shown as an effect of the inhaled hGhrelin derivative similar to intravenous injection. The LDPI formulation can deliver the hGhrelin derivative systemically, and it is expected to be applied clinically as a substitute for injections.

Comparison of l-Carnitine and l-Carnitine HCL salt for targeted lung treatment of pulmonary hypertension (PH) as inhalation aerosols: Design, comprehensive characterization, in vitro 2D/3D cell cultures, and in vivo MCT-Rat model of PH

Disrupted l-Carnitine (L-Car) homeostasis has been implicated in the development of pulmonary hypertension (PH). L-Car has been administered orally and intravenously causing systemic side effects. To the authors’ knowledge, there are no reports using L-Car or L-Car HCl as an inhaled aerosol through the respiratory route in a targeted manner either from dry powder inhaler (DPI) or liquid delivery system. The purpose of the comprehensive and systematic comparative study between L-Car and L-Car HCl salt was to design and develop dry powder inhalers (DPIs) of each. This was followed by comprehensive physicochemical characterization, in vitro cell viability as a function of dose on 2D human pulmonary cell lines from different lung regions and in vitro cell viability on 3D small airway epithelia human primary cells at the air-liquid interface (ALI). In addition in vitro transepithelial electrical resistance (TEER) in air-interface culture (AIC) conditions on 2D human pulmonary cell line and 3D small airway epithelia human primary cells was carried out. In vitro aerosol dispersion performance using three FDA-approved human DPI devices with different device properties was also examined. Following advanced spray drying under various conditions, two spray drying pump rates (low and medium) were found to successfully produce spray-dried L-Car powders while four spray drying pump rates (low, medium, medium-high, and high) all resulted in the production of spray-dried L-Car HCl powders. Raw L-Car and L-Car HCl were found to be crystalline. All SD powders retained crystallinity following spray drying and polymorphic interconversion in the solid-state was identified as the mechanism for retaining crystallinity after the advanced spray drying process. All SD powders aerosolized readily with all three human DPI devices. However, the in vitro dispersion parameters for the SD powders was not conducive for in vivo administration to rats in DPIs due to hygroscopicity and nanoaggreation. In vivo rat studies were successfully accomplished using inhaled liquid aerosols. Safety was successfully demonstrated in vivo in healthy Sprague Dawley rats. Furthermore, therapeutic efficacy was successfully demonstrated in vivo in the monocrotaline (MCT)-rat model of PH after two weeks of daily L-Car inhalation aerosol treatment.

Fragmentation dynamics of single agglomerate-to-wall impaction

The de-agglomeration characteristics of single agglomerate-wall impaction are examined using high-resolution shadowgraph imaging. Experiments are performed to investigate the effects of constituent particle size (D50 from 3 to 7 μm) and air velocity on the individual size and velocity of de-agglomerated fragments at conditions relevant to dry powder inhalation systems. De-agglomerated fragment area and trajectories were used to differentiate between pseudo-elastic and inelastic collisions during de-agglomeration. Advanced image processing techniques have enabled provision of joint population distributions of fragment area and aspect ratio, which identify a bimodal dispersion of fragments during de-agglomeration. The bimodality is destroyed with increasing air velocity and also generally diminishes with time after impact. The experiment presented forms a platform for the detailed quantitative characterisation of de-agglomeration behaviour and can be useful towards the development and validation of related computational models for pharmaceutical dry powder inhalers.

Development of an Innovative, Carrier-Based Dry Powder Inhalation Formulation Containing Spray-Dried Meloxicam Potassium to Improve the In Vitro and In Silico Aerodynamic Properties.

Most of the marketed dry powder inhalation (DPI) products are traditional, carrier-based formulations with low drug concentrations deposited in the lung. However, due to their advantageous properties, their development has become justified. In our present work, we developed an innovative, carrier-based DPI system, which is an interactive physical blend of a surface-modified carrier and a spray-dried drug with suitable shape and size for pulmonary application. Meloxicam potassium, a nonsteroidal anti-inflammatory drug (NSAID), was used as an active ingredient due to its local anti-inflammatory effect and ability to decrease the progression of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The results of the in vitro and in silico investigations showed high lung deposition in the case of this new formulation, confirming that the interparticle interactions were changed favorably.

Influence of Composition and Spray-Drying Process Parameters on Carrier-Free DPI Properties and Behaviors in the Lung: A review.

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.

Lung–Restricted Inhibition of Janus Kinase 1 Is Effective in Rodent Models of Asthma

Multiple type 2 cytokines, including interleukin-4, interleukin-5, interleukin-9, interleukin-13, and thymic stromal lymphopoietin, drive the pathophysiology of an important subset of asthma. These and other cytokines, such as interleukin-6 and type I and type II interferons, depend on Janus kinase 1 (JAK1) for signal transduction. iJak-381 is a synthesized, small, and inhalable molecule that was specifically designed for lung-restricted JAK1 inhibition. The purpose of this study was to conduct preclinical studies to test whether local inhibition of JAK1 can inhibit allergic inflammation in the lungs.The study tested iJak-381 in mice and guinea pigs. Guinea pigs are an ideal species to study lung inflammation because their lung anatomy is similar to humans, and they mount a robust response to inhaled challenges.The authors developed a dry powder inhalation system for iJak-381 and tested its ability to suppress inhaled ovalbumin-induced pulmonary inflammation and airway hyperresponsiveness in murine and guinea pig models.iJak-381 suppressed signal transducer and activator of transcription 6 activation by interleukin-13. iJak381 also suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models. Using human allergens (Aspergillus, Alternaria, and house dust mite Dermatophagoides farinae), iJak-381 had a strong suppressive effect on neutrophilic inflammation compared with systemic corticosteroids. Lastly, iJak-381 reduced lung pathology without inhibiting systemic JAK1 activity.The authors concluded that lung-restricted inhibition of JAK1 suppressed asthma-related lung inflammation in 2 rodent models without systemic JAK inhibition. Because iJak-381 also suppressed neutrophilic inflammation in the lungs, the authors suggest that a combination of inhaled JAK1 inhibition with corticosteroid administration may be an efficacious approach to asthma treatment.This study highlights the importance of JAK1 signaling in asthma pathogenesis and suggests a therapeutic benefit to lung-restricted JAK1 inhibition. JAK1 inhibition may improve lung function by inhibiting both type 2 cytokine signaling and antigen-driven eosinophilic and neutrophilic inflammation in the lungs. More importantly, the inhaled route may provide clinical relief without systemic side effects. These promising preclinical findings suggest that clinical studies should be pursued to test iJak-381 efficacy and safety in asthma.

MULTI-DOSE DRY POWDER INHALER: ADVANCE TECHNOLOGY FOR DRUG DELIVERY TO AIRWAYS

Multi-dose dry powder inhaler (M-DPI) is a unique inhaler device from Teva Pharmaceutical developed for treatment of chronic respiratory diseases. It is a metered-dose dry powder inhaler system designed to appear as a typical pressurized metered-dose inhaler, but its internal geometry is very unique. The formulation of the inhaled corticosteroid and long-acting β2 agonist in M-DPI has been approved for use in the United States (US) [RespiClick®] and European Union (EU) [Spiromax®] as a treatment for asthma and chronic obstructive pulmonary disease (COPD). This M-DPI is easy to handle and does not need coordination between dose actuation and inhalation. The unique design of M-DPI ensures patients receive consistent doses of the drug with each actuation. The present article is a comprehensive account of the M-DPI with special emphasis on its dose metering system, deagglomeration mechanism and clinical outcomes.

Development of a Carrier Free Dry Powder Inhalation Formulation of Ketotifen for Pulmonary Drug Delivery.

Pulmonary drug delivery route is gaining much attention because it enables to target the active ingredients directly to lung both for local and systemic treatments, which maximize the therapeutic effect and minimize unwanted systemic toxicity. Dry powder inhaler (DPI) systems for asthma therapy have shown several merits to the other pulmonary delivery systems such as nebulizers and metered dose inhalers. The present study aims to develop and optimize a DPI formulation for Ketotifen fumarate through spray drying technique. Particles size and morphology, crystallinity, and drug-excipient interaction of fabricated DPI formulations were evaluated by scanning electron microscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier Transform Infrared Spectroscopy methods, respectively. The aerosolization indexes and aerodynamic properties of dry powders were determined by next generation impactor. The powder flowability was assessed by measuring the Hausner ratio and compressibility index. Among solvent systems, ethanol-water mixture produced the most desirable powder property for inhalation after spray drying. Although co-spray dried formulations with ammonium bicarbonate resulted in the porous structure, it was not beneficial for DPI formulations due to the interaction with Ketotifen. DSC and XRD experiments proved the amorphous structure of prepared powders, which were stable for 12 months. The results of this study demonstrate the potential of Ketotifen DPI formulation and pave a way to use it easily in an industrial scale.

Microstructural characterization of carrier-based dry powder inhalation excipients: Insights and guidance.

The growing interest in development of dry powder inhalation (DPI) products raises a need for development of standard testing methods and specifications for DPI excipients. The pharmaceutical industry, meanwhile, yet lacks compendial guidance on this topic. Despite of the complexity of interactions taking place in DPI systems and the large number and variety of interplaying factors, understanding of key determinants of performance (critical quality attributes) of DPI excipients have considerably developed over the past years. In light of the current knowledge in this area, this article provides technical guidance and insights on testing and quality control of carrier-based-DPI excipients. These excipients are, typically, blends of coarse, carrier particles and fine, performance-modulating particles. The article explores techniques used for measurement of key microstructural attributes, namely the particle size distribution, the porosity and the particle surface roughness, the particle shape, rheological properties, and the permeability, of these excipients. The technical relevance of each measurement to the functionality of the excipients is critically discussed. In this regard, caveats concerning use of some measurements and data analysis procedures are raised. The guidance lends itself for compendial adoption.