Carrier-based Dry Powder Inhaler Research Articles

Fine excipient materials in carrier-based dry powder inhalation formulations: The interplay of particle size and concentration effects

The contributions of fine excipient materials to drug dispersibility from carrier-based dry powder inhalation (DPI) formulations are well recognized, although they are not completely understood. To improve the understanding of these contributions, we investigated the influences of the particle size of the fine excipient materials on characteristics of carrier-based DPI formulations. We studied two particle size grades of silica microspheres, with volume median diameters of 3.31 μm and 8.14 μm, as fine excipient materials. Inhalation formulations, each composed of a lactose carrier material, one of the fine excipient materials (2.5% or 15.0% w/w), and a drug (fluticasone propionate) material (1.5% w/w) were prepared. The physical microstructure, the rheological properties, the aerosolization pattern, and the aerodynamic performance of the formulations were studied. At low concentration, the large silica microspheres had a more beneficial influence on the drug dispersibility than the small silica microspheres. At high concentration, only the small silica microspheres had a beneficial influence on the drug dispersibility. The results reveal influences of fine excipient materials on mixing mechanics. At low concentration, the fine particles improved deaggregation and distribution of the drug particles over the surfaces of the carrier particles. The large silica microspheres were associated with a greater mixing energy and a greater improvement in the drug dispersibility than the small silica microspheres. At high concentration, the large silica microspheres kneaded the drug particles onto the surfaces of the carrier particles and thus impaired the drug dispersibility. As a critical attribute of fine excipient materials in carrier-based dry powder inhalation formulations, the particle size demands robust specification setting.

Critical attributes of fine excipient materials in carrier-based dry powder inhalation formulations: The particle shape and surface properties

The potential of fine excipient materials to improve the aerodynamic performance of carrier-based dry powder inhalation (DPI) formulations is well acknowledged but not fully elucidated. To improve the understanding of this potential, we studied two fine excipient materials: micronized lactose particles and silica microspheres. Inhalation formulations, each composed of a coarse lactose carrier, one of the two fine excipient materials (0.0–15.0 % w/w), and a spray-dried drug (fluticasone propionate) material (1.5 % w/w) were prepared. The physical structure, the flow behavior, the aerosolization behavior, and the aerodynamic performance of the formulations were studied. The two fine excipient materials similarly occupied carrier surface macropores. However, only the micronized lactose particles formed agglomerates and appeared to increase the tensile strength of the formulations. At 2.5 % w/w, the two fine excipient materials similarly improved drug dispersibility, whereas at higher concentrations, the micronized lactose material was more beneficial than the silica microspheres. The findings suggest that fine excipient materials improve drug dispersibility from carrier-based DPI formulations at low concentrations by filling carrier surface macropores and at high concentrations by forming agglomerates and/or enforcing fluidization. The study emphasizes critical attributes of fine excipient materials in carrier-based DPI formulations.

Exploring the influence of magnesium stearate content and mixing modality on the rheological properties and in vitro aerosolization of dry powder inhaler

Since carrier-based dry powder inhalers (DPIs) suffer from inadequate drug deposition in the lung, an increasing number of marketed products have added magnesium stearate (MgSt) to improve the aerosolization, dispersion, and stability against moisture of DPI. However, for carrier-based DPI, there is a lack of examination of the optimal MgSt content as well as the mixing modality, and there is also a need to verify the applicability of rheological properties to predict the in vitro aerosolization of DPI formulations containing MgSt. Therefore, in this work, DPI formulations were prepared using fluticasone propionate as a model drug and commercial crystalline lactose Respitose® SV003 as a carrier within 1% MgSt content, the effect of MgSt content on the rheological and aerodynamic properties were investigated. After the optimal MgSt content was determined, the effects of mixing modality, mixing order, and carrier size on formulation properties were further investigated. Meanwhile, correlations were established between rheological parameters and in vitro drug deposition parameters, and the contribution of rheological parameters were determined using principal component analysis (PCA). The results showed that the optimal content of MgSt in DPI formulations is 0.25%-0.5% under both high-shear and low-shear, using medium-sized carriers (D50 around 70 μm) and low-shear mixing are beneficial for improving in vitro aerosolization. Good linear relationships between powder rheological parameters such as basic flow energy (BFE), specific energy (SE), Permeability and fine particle fraction (FPF) were established, PCA showed that both flowability and adhesion are key properties affecting FPF. In conclusion, both MgSt content and mixing modality can influence rheological properties of the DPI, which can be used as a screeing tool for DPI formuluation and preparation process optimization.

Discrete Element Method Evaluation of Triboelectric Charging Due to Powder Handling in the Capsule of a DPI.

The generation and accumulation of an electrostatic charge from handling pharmaceutical powders is a well-known phenomenon, given the insulating nature of most APIs (Active Pharmaceutical Ingredients) and excipients. In capsule-based DPIs (Dry Powder Inhalers), the formulation is stored in a gelatine capsule placed in the inhaler just before inhalation. The action of capsule filling, as well as tumbling or vibration effects during the capsule life cycle, implies a consistent amount of particle-particle and particle-wall contacts. A significant contact-induced electrostatic charging can then take place, potentially affecting the inhaler's efficiency. DEM (Discrete Element Method) simulations were performed on a carrier-based DPI formulation (salbutamol-lactose) to evaluate such effects. After performing a comparison with the experimental data on a carrier-only system under similar conditions, a detailed analysis was conducted on two carrier-API configurations with different API loadings per carrier particle. The charge acquired by the two solid phases was tracked in both the initial particle settling and the capsule shaking process. Alternating positive-negative charging was observed. Particle charging was then investigated in relation to the collision statistics, tracking the particle-particle and particle-wall events for the carrier and API. Finally, an analysis of the relative importance of electrostatic, cohesive/adhesive, and inertial forces allowed the importance of each term in determining the trajectory of the powder particles to be estimated.

Elucidation of the using condition and working mechanism of tertiary lactose in dry powder formulations for inhalation

Tertiary lactose has been shown to improve aerosolization performance of carrier-based dry powder inhalation formulations. The working mechanism of the tertiary lactose, however, is still unclear, even the optimal working condition of the lactose fines. Two strategies to incorporate the tertiary lactose were proposed, the “tertiary lactose-carrier-API” and “tertiary lactose-API-carrier”, to decrease the adhesiveness of the drug-carrier by forming different powder aggregates. The effects of the tertiary lactose with different sizes and mass percentages on the aerosolization performance for the two types of formulations were systemically investigated. The results showed that the smaller-sized tertiary lactose is beneficial for powder dispersion and aerosolization, which could be further improved by optimizing its concentration. In terms of the aerosolization performance, the “tertiary lactose-carrier-API” type of ternary formulations obtained highly superior aerosolization performance and significantly enhanced detachment of fine drug particles from large particles in general.

Role of dispersion enhancer selection in the development of novel tratinterol hydrochloride dry powder inhalation formulations

Tratinterol hydrochloride (TH) is a new long-acting bronchodilator with strong β2 adrenoceptor stimulation activity. The aim of this study was to design a new carrier-based dry powder inhalation (DPI) formulation for TH and to investigate the effect of dispersion enhancers on the aerosol performance of TH in vitro. To this end, coarse lactose was used as a carrier. TH was micronized by using a jet mill and blended with the carrier to obtain a reference DPI formulation. Commercial magnesium stearate (MgSt) as received, micronized MgSt (MgSt-M), and fine lactose (FL) were used as the dispersion enhancers and formulated with the micronized TH (TH-M) and the carrier as DPI formulations. The obtained DPI formulations were characterized using dynamic light scattering (DLS), X-ray powder diffraction (XRPD), thermal analysis, powder rheometer, and Raman microscopy. A next generation pharmaceutical impactor (NGI) was used to evaluate the aerodynamic performance of the dry powders. The results showed that TH-M was in an inhalable particle size range, and based on the XRPD and thermal analysis, the solid form of TH-M did not change compared to the starting materials. The NGI results showed that the fine particle fraction (FPF) of TH could be increased with the addition of MgSt and FL as dispersion enhancers in the reference formulation. In addition, the FPF of TH could be increased with a decrease in the particle size of MgSt or an increase in the amount of FL. A combination of MgSt-M and FL could further improve the aerosol performance of TH. Raman spectroscopic imaging confirmed the spatial location of MgSt and TH at the surface of the carrier. This study demonstrates that TH could be formulated into carrier-based dry powder formulation for inhalation using coarse lactose as the carrier. The dual strategy based on using both MgSt and FL as dispersion enhancers improved the aerosol performance of a novel TH dry powder formulation.

DEM analysis of powder deaggregation and discharge from the capsule of a carrier-based Dry Powder Inhaler

In carrier-based Dry Powder Inhalers (DPI), fine API powder covers the surface of bigger carrier particles giving rise to dry coated particles, such that their flow properties are improved. In the hard-shell capsule of Cyclohaler DPI, powder deaggregation and discharge occurs as a result of the centrifugal motion and the subsequent aerodispersion to the mouthpiece induced by the patient’s inhalation. In this work, the crucial initial transient of this dispersion process was analysed through DEM (Discrete Element Method) simulations, by considering the solid phase only. The accelerated rotational motion of the capsule was simulated in the frame of reference of an observer rotating with the capsule, appropriately considering fictitious forces. The effect of the vibrations due to collisions between the capsule and the inhaler on powder discharge was evaluated as well for carrier particle systems. The results provide a punctual mapping of the particle-wall collisions within the capsule, allowing the path of the solids to be tracked until discharge. Simulations were carried out on drug-carrier blends with extreme size difference, considering adhesive interactions, elucidating the early-stage dynamics of the detachment process that occurs inside the capsule due to the interactions between particles and between particles and walls.

Dry Powder Inhalers Based on Chitosan-Mannitol Binary Carriers: Effect of the Powder Properties on the Aerosolization Performance.

Carriers play an important role in improving the aerosolization performance of dry powder inhalers (DPIs). Despite that intensive attention had been paid to the establishment of the advanced carriers with controllable physicochemical properties in recent years, the design and optimization of carrier-based DPIs remain an empiricism-based process. DPIs are a powder system of complex multiphase, and thus their physicochemical properties cannot fully explain the powder behavior. A comprehensive exposition of powder properties is demanded to build a bridge between the physicochemical properties of carriers and the aerosolization performance of DPIs. In this study, an FT-4 powder rheometer was employed to explore the powder properties, including dynamic flow energy, aeration, and permeability of the chitosan-mannitol binary carriers (CMBCs). CMBCs were self-designed as an advanced carrier with controllable surface roughness to obtain enhanced aerosolization performance. The specific mechanism of CMBCs to enhance the aerosolization performance of DPIs was elaborated based on the theory of pulmonary delivery processes by introducing powder properties. The results exhibited that CMBCs with appropriate surface roughness had lower special energy, lower aeration energy, and higher permeability. It could be predicted that CMBC-based DPIs had greater tendency to fluidize and disperse in airflow, and the lower adhesion force between particles enabled drugs to be detached from the carrier to achieve higher fine particle fractions. The specific mechanism on how physicochemical properties influenced the aerosolization performance during the pulmonary delivery processes could be figured out with the introduction of powder properties.

Development of drug alone and carrier-based GLP-1 dry powder inhaler formulations

The study aimed to develop two types of dry powder inhaler (DPI) formulations containing glucagon-like peptide-1(7–36) amide (GLP-1): carrier-free (drug alone, no excipients) and carrier-based DPI formulations for pulmonary delivery of GLP-1. This is the first study focusing on the development of excipient free GLP-1 DPI formulations for inhaled therapy in Type 2 diabetes. The aerosolisation performance of both DPI formulations was studied using a next generation impactor and a DPI device (Handihaler®) at flow rate of 30 L min−1. Carriers employed were either a 10% w/w glycine-mannitol prepared by spray freeze drying or commercial mannitol. Spray freeze dried (SFD) carrier was spherical and porous whereas commercial mannitol carrier exhibited elongated particles (non-porous). GLP-1 powder without excipients for inhalation was prepared using spray drying and characterised for morphology including size, thermal behaviour, and moisture content. Spray dried (SD) GLP-1 powders showed indented/dimpled particles in the particle size range of 1–5 µm (also mass median aerodynamic diameter, MMAD: <5 µm) suitable for pulmonary delivery. Across formulations investigated, carrier-free DPI formulation showed the highest fine particle fraction (FPF: 90.73% ± 1.76%, mean ± standard deviation) and the smallest MMAD (1.96 µm ± 0.07 µm), however, low GLP-1 delivered dose (32.88% ± 7.00%, total GLP-1 deposition on throat and all impactor stages). GLP-1 delivered dose was improved by the addition of SFD 10% glycine-mannitol carrier to the DPI formulation (32.88% ± 7.00%–45.92% ± 5.84%). The results suggest that engineered carrier-based DPI formulations could be a feasible approach to enhance the delivery efficiency of GLP-1. The feasibility of systemic pulmonary delivery of SD GLP-1 for Type 2 diabetes therapy can be further investigated in animal models.

Insights into the potential of rheological measurements in development of dry powder inhalation formulations

Study of flow is a key to development of dry powder inhalation formulations. Various static (bulk) and dynamic rheological measurements are used to study different aspects of powder flow and packing. Among rheological measurements, the permeability and the fluidization energy are, conceptually, most relevant to dispersion of dry powder inhalation formulations. The aim of the current study was to test the robustness and the range of applications of the two measurements, among other rheological measurements. To this end, we prepared and studied a series of ternary, carrier-based dry powder inhalation formulations. The formulations were mixtures of coarse-fine excipient (α-lactose monohydrate) blends, with different fine excipient concentrations (0.0–15.0 % w/w), and a spray-dried drug (fluticasone propionate) material. The excipient blends were characterized in terms of morphology, size, crystallinity, and rheological properties. The formulations were evaluated in vitro using a low resistance inhalation device, the Cyclohaler®, and a high resistance inhalation device, the Handihaler®. The study design aimed to complement literature data. Bulk rheological measurements, specifically the bulk density, the compressibility, and the permeability, exhibited satisfactory precision and could demonstrate changes in powder composition and structure. They hold a potential for use as critical material attributes to aid monitoring and optimization of carrier-based dry powder inhalation formulations in quality-by-design systems. On the other hand, dynamic rheological measurements, specifically the basic flowability energy, the specific energy, and the fluidization energy, generally exhibited high variability, which obscured interpretation of the measurements and implied heterogeneous powder structures. The fluidization energy could, nevertheless, convey structural changes taking place during powder fluidization.

Newly designed mouthpiece to improve spray characteristics of pharmaceutical particles in dry powder inhaler

This study presents the effects of mouthpiece designs in carrier-based dry powder inhalation on aerosol particle characteristics. Simulation models are developed to investigate drug powder spray characteristics from mouthpieces of four different-shaped flow channels. The simulation results agree well with the results of two experiments, one involving particle image velocimetry and the other the Anderson cascade impactor. A mouthpiece with a spiral channel and mixing chamber is discovered to be effective for low axial-flow velocities in the forward direction and yielded a more uniform dispersion of particles in the radial direction as the drug particles are ejected through the mouthpiece. This results in more effective delivery of the drug particles to the peripheral target regions of the respiratory system.

The Influence of Relative Humidity and Storage Conditions on the Physico-chemical Properties of Inhalation Grade Fine Lactose.

Dry powder inhalers (DPIs) are favorable devices for the delivery of dry formulations to the lungs; still, they largely fail to deliver higher doses of active pharmaceutical ingredient (API) to the lower airways. Addition of fine particles of excipient (fines) to the blend of API and carrier was shown to improve aerosolization performance. Lactose monohydrate is ubiquitous excipient used for this purpose. Lactose exists in a thermodynamically stable crystalline form; however, processes like milling, sieving, or even mixing may induce alteration of crystalline structure and introduce amorphous domains, which could further affect the physico-chemical properties of the material. Therefore, the aim of this work is a detailed characterization of two commercially available types of inhalation grade fine lactose powders (Inhalac 400 and Inhalac 500) prepared using different air-jet milling parameters, with a focus on impact of storage conditions on material properties. We found that the different milling parameters resulted in variable particle size distribution (PSD), and thus surface areas, variable initial amorphous content, cohesivity, flowability, and moisture sorption of materials. In addition, exposure of fine powders to higher humidity reduced the amorphous content present in the materials, but also affected agglomeration tendency and dispersion behavior of both powders. We believe the obtained findings to be important for the aerosolization performance of carrier-based DPIs containing fines and thus need to be duly considered during formulation development.

Machine learning approach for carrier surface design in carrier-based dry powder inhalation

In this study, a machine learning approach was applied to evaluate the impact of operating and design variables on dry powder inhalation efficiency. Emitted dose and fine particle fraction data were extracted from the literature for a variety of drug and carrier combinations. Carrier surface properties are obtained by image analysis of SEM images reported. Models combining artificial neural network and genetic algorithm were developed to determine the emitted dose and fine particle fraction. Design strategies for the carrier surface were also proposed to enhance the fine particle fractions.

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.

Effect of USP induction ports and modified glass sampling apparatus on aerosolization performance of lactose carrier-based fluticasone propionate dry powder inhaler

In the present study, a lactose based dry powder inhaler (DPI) was formulated to probe the effect of three different US Pharmacopeia (USP) induction port (IP) on aerosolization performance DPIs. Additionally, the delivered dose uniformity (DDU) and drug-carrier detachment were studied using the USP modified glass sampling apparatus and force-displacement concept, respectively. Initially, median sized lactose carrier (InhaLac® 160) and a model drug fluticasone propionate (FP) were studied for numerous physicochemical properties. The homogenous drug-carrier blend was prepared using a low shear 3D shaker mixer. The InhaLac® 160 showed typical tomahawk-shaped particles with mean particle size (d50) and average surface roughness of 109.46 μm and 2.70 μm, respectively. Additionally, the laser Raman spectrometry demonstrated the uniform surface distribution of FP across the carrier surface. In the drug-carrier detachment study, FP DPI required >600 g-force to detach the 50% of the FP particles from lactose surface. During cascade analysis, all three USP IPs showed a remarkable variation in drug retention within the IP and pre-separator. The USP modified IP showed superior % fine particle fraction as compared to the USP IP. The difference in aerodynamic dispersion can be attributed to the variation in the design of the USP IPs. Moreover, developed FP DPI showed satisfactory DDU (>88%) when studied using the modified glass sampling apparatus. Briefly, the present study offers a detailed report on aerosolization performance of median sized lactose carrier-based DPIs using different USP IPs.

3D characterisation of dry powder inhaler formulations: Developing X-ray micro computed tomography approaches

Carrier-based dry powder inhaler (DPI) formulations need to be accurately characterised for their particle size distributions, surface roughnesses, fines contents and flow properties. Understanding the micro-structure of the powder formulation is crucial, yet current characterisation methods give incomplete information. Commonly used techniques like laser diffraction (LD) and optical microscopy (OM) are limited due to the assumption of sphericity and can give variable results depending on particle orientation and dispersion. The aim of this work was to develop new three dimensional (3D) powder analytical techniques using X-ray computed tomography (XCT) that could be employed for non-destructive metrology of inhaled formulations. α-lactose monohydrate powders with different characteristics have been analysed, and their size and shape (sphericity/aspect ratio) distributions compared with results from LD and OM. The three techniques were shown to produce comparable size distributions, while the different shape distributions from XCT and OM highlight the difference between 2D and 3D imaging. The effect of micro-structure on flowability was also analysed through 3D measurements of void volume and tap density. This study has demonstrated for the first time that XCT provides an invaluable, non-destructive and analytical approach to obtain number- and volume-based particle size distributions of DPI formulations in 3D space, and for unique 3D characterisation of powder micro-structure.

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.

Tribo-Charging Behaviour of Inhalable Mannitol Blends with Salbutamol Sulphate

PurposeThe performance of carrier-based dry powder inhaler (DPI) formulations can be critically impacted by interfacial interactions driven by tribo-electrification. Therefore, the aim of the present work was to understand how distinct API particle characteristics affect the charging behaviour of blends intended for DPI delivery.MethodsSalbutamol sulphate (SBS) particles engineered via spray-drying and jet milling were used as model APIs. D-mannitol was selected as a model carrier. The materials were characterized concerning their different particle properties and their charge was analysed alone and in blends before and after flow over a stainless-steel pipe.ResultsThe spray-dried SBS (amorphous and spherical) charged positively and to a higher extent than jet milled SBS (crystalline and acicular) that charged negatively and to a lower extent. D-mannitol charged positively and to a higher extent than the APIs. All drug-excipient blends charged negatively and differences were found between the spray-dried and jet milled SBS blends at 2% and 5% drug loads.ConclusionsIt was demonstrated how distinct solid-states, particle shape, size and morphology as well as different water contents of the different materials can affect tribo-charging. For their binary blends, the amount and nature of fines seem to govern inter-particle contacts critically impacting charge evolution.

Spiral mouthpiece design in a dry powder inhaler to improve aerosolization

This study presents the effect of a spiral mouthpiece design in a carrier-based dry powder inhalation on particle aerosol characteristics. Two kinds of mouthpieces, with spiral and non-spiral shaped flow channels, were fabricated by 3D-printing; particle image velocimetry and Anderson cascade impactor were performed to evaluate the drug aerosol characteristics. The obtained experimental results were in agreement with the simulation results of the computational fluid dynamics analysis. The spiral channel created a strong swirl motion of the air flow emitted from the mouthpiece exit, which produced angular momentum rather than the axial flow velocity in the forward direction. This is beneficial in terms of liberating the micronized drug particles from the carrier surface, and leads to more effective delivery of these drug particles to the peripheral target regions of the respiratory system. The spiral device could produce drug particles with significantly smaller mass median aerodynamic diameters and higher fine particle fraction than the non-spiral device.

Evaluation of carrier size and surface morphology in carrier-based dry powder inhalation by surrogate modeling

In this work, design parameters of carrier-based dry powder inhalation were studied using surrogate modeling technique. The surrogate models constructed were then used to evaluate the key design parameters independently, which were otherwise difficult to determine based on experimental studies alone. Artificial neural network (ANN) was chosen as the surrogate modeling technique and models were constructed based on experimental data obtained from the literature. Twenty-eight variables describing the carrier size distribution, density, surface characteristics and operating conditions of dry powder inhaler were used as the input variables and emitted dose (ED) and fine particle fraction (FPF) were used as the output variables. Carrier surface characteristics were evaluated by applying image analysis on carrier SEM images. Genetic algorithm (GA) was used for the selection of important variables to be included in the surrogate models. Sensitivity analysis was also performed to determine the key variables affecting ED and FPF. Key design criteria for carrier-based dry powder inhalation were proposed based on the surrogate models constructed.