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.

Spray-Congealing and Wet-Sieving as Alternative Processes for Engineering of Inhalation Carrier Particles: Comparison of Surface Properties, Blending and In Vitro Performance.

PURPOSE: Traditionally, α-lactose monohydrate is the carrier of choice in dry powder inhaler (DPI) formulations. Nonetheless, other sugars, such as D-mannitol, have emerged as potential alternatives. Herein, we explored different particle engineering processes to produce D-mannitol carriers for inhaled delivery. METHODS: Wet-sieving and spray-congealing were employed as innovative techniques to evaluate the impact of engineering on the particle properties of D-mannitol. To that end, the resulting powders were characterized concerning their solid-state, micromeritics and flowability. Afterwards, the engineered carrier particles were blended with inhalable size beclomethasone dipropionate to form low dose (1 wt%) DPI formulations. The in vitro aerosolization performance was evaluated using the NEXThaler®, a reservoir multi-dose device. RESULTS: Wet-sieving generated D-mannitol particles with a narrow particle size distribution and spray-congealing free-flowing spherical particles. The more uniform pumice particles with deep voids and clefts of wet-sieved D-mannitol (Pearl300_WS) were beneficial to drug aerosolization, only when used in combination with a ternary agent (10 wt% of 'Preblend'). When compared to the starting material, the spray-congealed D-mannitol has shown to be promising in terms of the relative increase of the fine particle fraction of the drug (around 100%), when used without the addition of ternary agents. CONCLUSIONS: The wet-sieving process and the related aerosolization performance are strongly dependent on the topography and structure of the starting material. Spray-congealing, has shown to be a potential process for generating smooth spherical particles of D-mannitol that enhance the in vitro aerosolization performance in binary blends of the carrier with a low drug dose.

Spherical agglomerates of lactose as potential carriers for inhalation.

We report here on spherical lactose agglomerates as potential carriers for inhalation applications. Micromeritic properties of three spherical lactose agglomerates (SA-A, SA-B, SA-C) and a standard lactose inhalation grade carrier (Lactohale 100; LH100) were evaluated and compared. Ordered mixtures with micronized salbutamol sulfate as the model active pharmaceutical ingredient (API) and lactose carriers at two drug loadings (2 wt%, 5 wt%) were prepared, and in-vitro aerosolization performance was assessed. The spherical crystallization process led to particles with tailored micromeritic properties. These had larger specific surface area and greater fine fraction < 10 µm, compared to LH100, due to their coarse morphology. Their properties were reflected in the flowability parameters, where two types of spherical agglomerates of lactose showed more cohesive behavior compared to the other lactose grades. Blend uniformity showed improved homogeneous distribution of the API at higher drug load. In-vitro aerosolization tests showed that the spherical agglomerates of lactose enhanced the dose of API, compared to LH100. SA-B and SA-C showed significantly higher fine particle fractions at low drug load compared to the others, whereas overall, the largest fine particle fraction was for SA-B at high drug load. The carrier material attributes related to particle size, specific surface area, compressibility, flowability (cohesion, flow function), and air permeability were critical for aerosolization performance.

Evaluation of the Physico-mechanical Properties and Electrostatic Charging Behavior of Different Capsule Types for Inhalation Under Distinct Environmental Conditions.

Capsule-based dry powder inhaler (DPI) products can be influenced by a multitude of interacting factors, including electrostatic charging. Tribo-charging is a process of charge transfer impacted by various factors, i.e., material surface characteristics, mechanical properties, processing parameters and environmental conditions. Consequently, this work aimed to assess how the charging behavior of capsules intended for inhalation might be influenced by environmental conditions. Capsules having different chemical compositions (gelatin and hydroxypropyl methylcellulose (HPMC)) and distinct inherent characteristics from manufacturing (thermally and cold-gelled) were exposed to various environmental conditions (11%, 22% and 51% RH). Their resulting properties were characterized and tribo-charging behavior was measured against stainless steel and PVC. It was observed that all capsule materials tended to charge to a higher extent when in contact with PVC. The tribo-charging of the thermally gelled HPMC capsules (Vcaps® Plus) was more similar to the gelatin capsules (Quali-G™-I) than to their HPMC cold-gelled counterparts (Quali-V®-I). The sorption of water by the capsules at different relative humidities notably impacted their properties and tribo-charging behavior. Different interactions between the tested materials and water molecules were identified and are proposed to be the driver of distinct charging behaviors. Finally, we showed that depending on the capsule types, distinct environmental conditions are necessary to mitigate charging and assure optimal behavior of the capsules.

Searching for physiologically relevant in vitro dissolution techniques for orally inhaled drugs.

Inhalation is the preferred route for the treatment of lung diseases. More recently, also formulations for systemic treatment have been developed. For efficient development of inhalation products it is necessary to identify a link between particle parameters and in vivo performance. Such a relation exists for oral drugs where dissolution and permeation across Caco-2 monolayers are correlated to in vivo absorption. By contrast, the only in vitro parameter with established link to absorption for inhalation is particle size. In vitro dissolution could be another important parameter because low solubility determines bioavailability of inhaled drugs. The review highlights the importance of dissolution for drug availability in general and lists important differences in dissolution testing of oral and inhaled formulations. Dissolution testing protocols are summarized with focus on the composition of the various fluids, which are used to mimic particle dissolution in the deep lung. Finally, a role of in silico modelling in identification of physiologically relevant dissolution fluids and in in vitro in vivo correlation is suggested.

Delivery of Dry Powders to the Lungs: Influence of Particle Attributes from a Biological and Technological Point of View.

Dry powder inhalers are medical devices used to deliver powder formulations of active pharmaceutical ingredients via oral inhalation to the lungs. Drug particles, from a biological perspective, should reach the targeted site, dissolve and permeate through the epithelial cell layer in order to deliver a therapeutic effect. However, drug particle attributes that lead to a biological activity are not always consistent with the technical requirements necessary for formulation design. For example, small cohesive drug particles may interact with neighbouring particles, resulting in large aggregates or even agglomerates that show poor flowability, solubility and permeability. To circumvent these hurdles, most dry powder inhalers currently on the market are carrier-based formulations. These formulations comprise drug particles, which are blended with larger carrier particles that need to detach again from the carrier during inhalation. Apart from blending process parameters, inhaler type used and patient's inspiratory force, drug detachment strongly depends on the drug and carrier particle characteristics such as size, shape, solid-state and morphology as well as their interdependency. This review discusses critical particle characteristics. We consider size of the drug (1-5 µm in order to reach the lung), solid-state (crystalline to guarantee stability versus amorphous to improve dissolution), shape (spherical drug particles to avoid macrophage clearance) and surface morphology of the carrier (regular shaped smooth or nano-rough carrier surfaces for improved drug detachment.) that need to be considered in dry powder inhaler development taking into account the lung as biological barrier.

Assessment of Dry Powder Inhaler Carrier Targeted Design: A Comparative Case Study of Diverse Anomeric Compositions and Physical Properties of Lactose.

The pulmonary administration landscape has rapidly advanced in recent years. Targeted design of particles by spray-drying for dry powder inhaler development offers an invaluable tool for engineering of new carriers. In this work, different formulation and process aspects of spray-drying were exploited to produce new lactose carriers. Using an integrated approach, lactose was spray-dried in the presence of polyethylene glycol 200 (PEG 200), and the in vitro performance of the resulting particles was compared with other grades of lactose with varying anomeric compositions and/or physical properties. The anomeric composition of lactose in lactose-PEG 200 feed solutions of variable compositions was analyzed via polarimetry at different temperatures. These results were correlated with the solid-state and anomeric composition of the resulting spray-dried particles using modulated differential scanning calorimetry and wide-angle X-ray scattering. The distinct selected grades of lactose were characterized in terms of their micromeritic properties using laser diffraction, helium pycnometry, and gas adsorption, and their particle surface morphologies were evaluated via scanning electron microscopy. Adhesive mixtures of the different lactose carriers with inhalable-sized salbutamol sulfate, as a model drug, were prepared in low doses and evaluated for their blend homogeneity and aerodynamic performance using a Next Generation Impactor. Characterization of the spray-dried particles revealed that predominantly crystalline (in an anomeric ratio 0.8:1 of α to ß) spherical particles with a mean size of 50.9 ± 0.4 µm could be produced. Finally, it was apparent that micromeritic, in particular, the shape, and surface properties (inherent to solid-state and anomeric composition) of carrier particles dominantly control DPI delivery. This provided an insight into the relatively inferior performance of the adhesive blends containing the spherical spray-dried lactose-PEG 200 composites.

Nebulized coenzyme Q10 nanosuspensions: A versatile approach for pulmonary antioxidant therapy.

Coenzyme Q10 (CoQ10) is an antioxidant substance indicated as a dietary supplement which has been proposed as adjuvant in the treatment of cardiovascular disorders and cancer for its protective and immunostimulating activities. The aim of this work was the production by high-pressure homogenization, characterization and stability investigation of three different CoQ10 nanosuspensions designed to be administered to the lungs by nebulization. Three surfactants, i.e. lecithin, PEG32 stearate and vitamin-E TPGS, were selected to stabilize CoQ10 formulations. Preparations were identified as nanosuspensions (particle size in the range 35-60nm): the smallest particles were obtained with vitamin-E TPGS and denoted a core-shell structure. The CoQ10 delivered from a commercial air-jet nebulizer was in all the cases around 30% of the loaded dose. The nanosuspension containing PEG32 stearate presented the highest respirable fraction (70.6%) and smallest MMAD (3.02µm). Stability tests showed that the most stable formulation, after 90days, was the one containing vitamin-E TPGS, followed by the CoQ10-lecithin formulation. Interestingly, those formulations were demonstrated to be suitable also for nebulizers using other mechanisms of aerosol production such as ultrasound and vibrating mesh nebulizers. Studies focused on in vitro cellular toxicity of the formulations and their single components using A549 human lung cells showed no obvious cytotoxicity for the formulations containing lecithin and PEG 32 stearate. Vitamin-E TPGS alone was shown to be able to damage the plasma membrane, nevertheless, cell damage was decreased when vitamin-E TPGS was present in the formulation with CoQ10.

How does secondary processing affect the physicochemical properties of inhalable salbutamol sulphate particles? A temporal investigation.

As pulmonary drug delivery is extended from low doses to high doses, physicochemical characteristics of the active pharmaceutical ingredient gain importance in the development of dry powder inhalers. Therefore, the present work aims to understand the impact of distinct engineering techniques on the process induced physicochemical characteristics of salbutamol sulphate particles over time. The particle engineering techniques chosen were jet-milling and spray-drying, two well used processes in the production of predominately crystalline and amorphous inhalable particles, respectively. Fourier transform infrared spectroscopy, modulated differential scanning calorimetry, particle size distribution and tensiometry experiments were used to characterise the engineered powders immediately, 7, 14 and 21 days after production. The rugged spherical amorphous particles (3.75±0.08µm) obtained via spray-drying showed that they were capable of forming strong agglomerates (5.01±0.22µm) through "amorphous bridging". On the other hand, jet-milling produced smaller (2.06±0.08µm), crystalline, irregular shaped particles with a very large surface area (11.04±0.10m2/g) that, over time, formed looser particle aggregates of decreasing size (3.76±0.10µm). Temporal evolution of the properties of spray-dried and jet milled particles showed a notable influence on the efficiency of blending with a model carrier at 0, 7 and 21 days (e.g. relative standard deviation of drug content of 11.3, 7.0 and 21.6%, respectively).

An in vitro and in silico study of the impact of engineered surface modifications on drug detachment from model carriers.

In silico modeling was used to predict the impact of carrier surface modifications on the in vivo plasma concentration of an active pharmaceutical ingredient (API) and as a tool to support formulation development. In vitro fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of salbutamol sulphate delivered from Cyclocaps®, detached from unmodified and surface engineered glass beads were measured using a Next Generation Impactor (NGI). Surface roughness was chosen to classify surface modification/engineering and it was evaluated via scanning electron microscopy (SEM) and image analysis. An in silico pharmacokinetic (PK) model was built and the quality confirmed with available literature data. Plasma profiles were generated combining the PK model with in silico deposition models for salbutamol sulphate released from Cyclocaps®, unmodified and surface engineered glass beads. The increased roughness of the surface of engineered beads resulted in a FPF 1.36 times higher than that of untreated beads. Cmax from the in silico plasma profile of salbutamol released from the surface engineered beads was 1.20 fold higher than that from untreated beads. Increasing the surface roughness was found to augment the amount of drug loading and detaching from the carrier both in vitro and in silico.

Carrier-based dry powder inhalation: Impact of carrier modification on capsule filling processability and in vitro aerodynamic performance.

This study aims to investigate the effect of carrier characteristics and dosator capsule filling operation on the in vitro deposition of mixtures containing salbutamol sulphate (SS) and lactose and mannitol as model carrier materials. The carrier surfaces of lactose and mannitol were modified via wet decantation. The impact of the decantation process on the properties of carriers was investigated by laser diffraction, density and powder flow measurements, N2 physisorption, small and wide angle X-ray scattering (SWAXS) and scanning electron microscopy (SEM). Differences in carrier type and untreated and decanted materials were identified and the SAXS measurements proved to be a promising technology confirming the successful removal of fines. Adhesive carrier API mixtures with carrier-to-API ratio of 99:1 wt% were prepared, mixture homogeneity was tested and subsequently the mixtures were filled into capsules at different process settings. Finally, the influence of the decantation process on the in vitro performance of the adhesive mixtures was tested with a next generation impactor. For lactose, the decantation decreased the fine particle fraction (FPF) of SS, whereas the FPF of mannitol as a carrier was only affected by the capsule filling process. In summary, the DPI formulation based on untreated lactose, especially by capsule filling using a dosing chamber to powder layer (compression) ratio of 1:2, proved to be superior in terms of the dosing accuracy (RSD<0.8%) and the in vitro aerodynamic performance (FPF of 12%).

Crystallization speed of salbutamol as a function of relative humidity and temperature.

Spray dried salbutamol sulphate and salbutamol base particles are amorphous as a result of spray drying. As there is always the risk of recrystallization of amorphous material, the aim of this work is the evaluation of the temperature and humidity dependent recrystallization of spray dried salbutamol sulphate and base. Therefore in-situ Powder X-ray Diffraction (PXRD) studies of the crystallization process at various temperature (25 and 35 °C) and humidity (60%, 70%, 80%, 90% relative humidity) conditions were performed. It was shown that the crystallization speed of salbutamol sulphate and base is a non-linear function of both temperature and relative humidity. The higher the relative humidity the higher is the crystallization speed. At 60% relative humidity salbutamol base as well as salbutamol sulphate were found to be amorphous even after 12 h, however samples changed optically. At 70% and 90% RH recrystallization of salbutamol base is completed after 3 h and 30 min and recrystallization of salbutamol sulphate after 4h and 1h, respectively. Higher temperature (35 °C) also leads to increased crystallization speeds at all tested values of relative humidity.

Influence of surface characteristics of modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization performance.

The aim of this work is to investigate the effect of surface characteristics (surface roughness and specific surface area) of surface-modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization, and thus, the in vitro respirable fraction often referred to as fine particle fraction (FPF). By processing glass beads in a ball mill with different grinding materials (quartz and tungsten carbide) and varying grinding time (4 h and 8 h), and by plasma etching for 1 min, glass beads with different shades of surface roughness and increased surface area were prepared. Compared with untreated glass beads, the surface-modified rough glass beads show increased FPFs. The drug detachment from the modified glass beads is also more reproducible than from untreated glass beads indicated by lower standard deviations for the FPFs of the modified glass beads. Moreover, the FPF of the modified glass beads correlates with their surface characteristics. The higher the surface roughness and the higher the specific surface area of the glass beads the higher is the FPF. Thus, surface-modified glass beads make an ideal carrier for tailoring the performance of DPIs in the therapy of asthma and chronically obstructive pulmonary diseases.

Preparation and characterization of physically modified glass beads used as model carriers in dry powder inhalers.

The aim of this work is the physical modification and characterization of the surface topography of glass beads used as model carriers in dry powder inhalers (DPIs). By surface modification the contact area between drug and carrier and thereby interparticle forces may be modified. Thus the performance of DPIs that relies on interparticle interactions may be improved. Glass beads were chosen as model carriers because various prospects of physical surface modification may be applied without affecting other factors also impacting interparticle interactions like particle size and shape. To generate rough surfaces glass beads were processed mechanically by friction and impaction in a ball mill with different grinding materials that were smaller and harder with respect to the glass beads. By varying the grinding time (4 h, 8 h) and by using different grinding media (tungsten carbide, quartz) surfaces with different shades of roughness were generated. Depending on the hardness of the grinding material and the grinding time the surface roughness was more or less pronounced. Surface roughness parameters and specific surface area were determined via several complementary techniques in order to get an enhanced understanding of the impact of the modifying procedure on the surface properties of the glass beads.