Development of High Dose Oseltamivir Phosphate Dry Powder for Inhalation Therapy in Viral Pneumonia.

Oseltamivir phosphate (OP) is an antiviral drug available only as oral therapy for the treatment of influenza and as a potential treatment option when in combination with other medication in the fight against the corona virus disease (COVID-19) pneumonia. In this study, OP was formulated as a dry powder for inhalation, which allows drug targeting to the site of action and potentially reduces the dose, aiming a more efficient therapy. Binary formulations were based on micronized excipient particles acting like diluents, which were blended with the drug OP. Different excipient types, excipient ratios, and excipient size distributions were prepared and examined. To investigate the feasibility of delivering high doses of OP in a single dose, 1:1, 1:3, and 3:1 drug/diluent blending ratios have been prepared. Subsequently, the aerosolization performance was evaluated for all prepared formulations by cascade impaction using a novel medium-resistance capsule-based inhaler (UNI-Haler). Formulations with micronized trehalose showed relatively excellent aerosolization performance with highest fine-particle doses in comparison to examined lactose, mannitol, and glucose under similar conditions. Focusing on the trehalose-based dry-powder inhalers' (DPIs) formulations, a physicochemical characterization of extra micronized grade trehalose in relation to the achieved performance in dispersing OP was performed. Additionally, an early indication of inhaled OP safety on lung cells was noted by the viability MTT assay utilizing Calu-3 cells.

Powder flow analysis: A simple method to indicate the ideal amount of lactose fines in dry powder inhaler formulations.

Many efforts have been made in the past to understand the function of lactose fines which are given as a ternary component to carrier-based dry powder inhaler formulations. It is undisputed that fines can significantly improve the performance of such formulations, but choosing the right amount of fines is a crucial point, because too high concentrations can have negative effects on the dispersion performance. The aim of this study was to indicate the optimal concentration of fines with a simple test method. For this purpose, mixtures with salbutamol sulfate and two different lactose carriers were prepared with a high shear mixer, measured with a FT4 powder rheometer and tested for fine particle delivery with two different inhaler devices. A correlation between the fluidization energy, measured with the aeration test set up, and the fine particle fractions (FPF) could be proven. This also applied for the aeration ratio, as well as the permeability of the powder samples. In addition, drug-free mixtures hardly differed in their rheological properties from mixtures containing the active pharmaceutical ingredient (API), which indicates that the method could be suitable for cost-saving screening trials. Furthermore, important aspects that explain the function of fines, such as the saturation of active sites, the formation of agglomerates and an increase in fluidization energy, could be shown in this study.

The influence of high shear mixing on ternary dry powder inhaler formulations.

The blending process is a key step in the production of dry powder inhaler formulations, but only little is known about the influence of process parameters. This is especially true for high shear blending of ternary formulations. For this reason, this study aims to investigate the influence of high shear mixing process parameters (mixing time and rotation speed) on the fine particle fraction (FPF) of ternary mixtures when using budesonide as model drug, two different carrier materials and two different mixing orders. Prolonged mixing time and higher rotation speeds led to lower FPFs, possibly due to higher press-on forces acting on the active pharmaceutical ingredients (API). In addition, a clear correlation between the energy consumption of the blender (the energy input into the blend) and the reduction of the FPF could be shown. Furthermore blending the carrier and the fines before adding the API was also found to be favorable.

Nano- and Microstructured model carrier surfaces to alter dry powder inhaler performance.

The present study investigates the effect of different carrier surface modifications on the aerosolisation performance and on the effective carrier payload of interactive blends for inhalation. Two different active pharmaceutical ingredients (APIs) were used: Formoterol fumarate dihydrate (FF) and budesonide (BUD). Blends were prepared with glass beads as model carriers which have been subjected to mechanical surface modifications in order to introduce surface roughness via treatment with hydrofluoric acid (HF) and/or milling with tungsten carbide (TC). As far as effective carrier payload, in this study expressed as true surface coverage (TSC), is concerned, surface modification had varying effects on blends containing BUD or FF. Aerodynamic characterisation in vitro showed a significant decrease in respirable fraction for glass beads treated with HF (40.2-50.1%), due to the presence of clefts and cavities, where drug particles were sheltered during inhalation. In contrast, grinding with TC leads to surface roughness on a nano scale, ultimately increasing aerodynamic performance up to 20.0-38.1%. These findings are true for both APIs, regardless of their chemical properties.

Applicability of the one-step DVS method for the determination of amorphous amounts for further different hydrophilic and hydrophobic drugs.

In a former publication the authors showed that low amounts of amorphous content (LOQ of 0.5%) in a hydrophobic model API (Ciclesonide) can be measured with an individually adjusted one-step dynamic organic vapor sorption (DVS). In this investigation the applicability is tested on various APIs which differ in lipophilicity (poor water solubility) and hygroscopicity (absorption of water). The vapor sorption method proved to be applicable in almost all cases. Moisture sorption isotherms were determined for all five investigated crystalline and amorphous APIs. However, it was necessary to select the parameters individually for each API. The used solvents (water, methanol, isopropanol and methylene chloride) and the humidity-levels (0.05 p/p0 until 0.5 p/p0) were chosen carefully because otherwise the amorphous amounts switch to their crystalline counterparts and are not detectable. The production of fully amorphous samples (absence of crystalline material measured by DSC, mDSC and XRPD) was optimized over several trials. As successfully methods proved ball-milling, freeze-drying, spray-drying and/or quench cooling. In the next step these fully amorphous amounts were blended with crystalline starting material to calibration curves (Turbula blender, influence of electrostatic charge to homogeneity) for the calculation of amorphous content. In summary, the following presented methods were used to determine and quantify low amorphous amounts (between 1.5% and 17.0%) in jet-milled powders (grinding pressure of 8bar, 1-3 grinding cycles), respectively.

Influence of small amorphous amounts in hydrophilic and hydrophobic APIs on storage stability of dry powder inhalation products.

The effects of different manufacturing methods to induce formation of amorphous content, changes of physico-chemical characteristics of powder blends and changes of aerodynamic properties over storage time (6months) analyzed with the Next Generation Impactor (NGI) are investigated. Earlier studies have shown that standard pharmaceutical operations lead to structural disorders which may influence drug delivery and product stability. In this investigation, fully amorphous drug samples produced by spray-drying (SD) and ball-milling (BM) as well as semi-crystalline samples (produced by blending and micronization) are studied and compared to fully crystalline starting material. The amorphous content of these hydrophilic and hydrophobic active pharmaceutical ingredients (APIs) was determined using a validated one-step DVS-method. For the conducted blending and micronization tests, amorphous amounts up to a maximum of 5.1% for salbutamol sulfate (SBS) and 17.0% for ciclesonide (CS) were measured. In order to investigate the impact of small amorphous amounts, inhalable homogenous powder mixtures with very high and low amorphous content and a defined particle size were prepared with a Turbula blender for each API. These blends were stored (6months, 45% RH, room temperature) to evaluate the influence of amorphous amounts on storage stability. The fine particle fraction (FPF: % of emitted dose<5µm) was determined with the NGI at defined time points. The amorphous amounts showed a major effect on dispersion behavior, the mixtures of the two APIs showed differences at the beginning of the study and significant differences in storage stability. The FPF values for SBS decreased during storage (FPF: from 35% to <27%) for the blend with high amorphous amounts, in contrast the initially re-crystallized sample achieved a comparable constant level of about 25%. For the hydrophobic CS a constantly increasing FPF (from 6% to >15%) over storage time for both types of blends was determined. Therefore, prolonged stability of amorphous parts and an incalculable behavior for CS blends are supposed, in contrast, SBS showed a controllable FPF after conditioning.

Measurement of low amounts of amorphous content in hydrophobic active pharmaceutical ingredients with dynamic organic vapor sorption.

Today, a variety of devices for dry powder inhalers (DPIs) is available and many different formulations for optimized deposition in the lung are developed. However, during the production of powder inhalers, processing steps may induce changes to both, the carrier and active pharmaceutical ingredients (APIs). It is well known that standard pharmaceutical operations may lead to structural changes, crystal defects and amorphous regions. Especially operations such as milling, blending and even sieving generate these effects. These disorders may induce re-crystallization and particle size changes post-production which have a huge influence on drug delivery and product stability. In this study, pilot tests with a polar solvent (water) and hydrophilic drug (Salbutamol sulfate) were performed to receive a first impression on further possible implementation of hydrophobic samples with organic solvents. Thereafter, a reliable method for the accurate detection of low amounts of amorphous content is described up to a limit of quantification (LOQ) of 0.5% for a hydrophobic model API (Ciclesonide). The organic vapor sorption method which is a gravimetric method quantifies exactly these low amounts of amorphous content in the hydrophobic powder once the suitable solvent (isopropanol), the correct p/p0 value (0.1) and the exact temperature (25°C) have been found. Afterward it was possible to quantitate low amorphous amounts in jet-milled powders (0.5-17.0%). In summary, the data of the study led to a clearer understanding in what quantity amorphous parts were generated in single production steps and how variable these parts behave to fully crystalline material. Nevertheless it showed how difficult it was to re-crystallize hydrophobic material with water vapor over a short period. For the individual samples it was possible to determine the single humidity at which the material starts to re-crystallize, the behavior against different nonpolar solvents and the calculation of the reduction of the glass transition temperature (Tg) according to the Gordon-Taylor equation.

Formulation considerations for dry powder inhalers.

The market for inhalable dry powder medication has consistently grown over past years. Targeting the lungs has been recognized to offer several advantages compared with oral application of drugs. The successive development of inhalation products has led to advances in local treatment of different respiratory diseases, but has also demonstrated the possibility to utilize the lungs for systemic drug delivery. Since a dry powder inhalation product is always a combination of drug formulation and inhalation device, the requirements for the development of such a system may be particularly complex. Therefore, this review aims to give an overview of the necessary considerations for a successful dry powder inhaler development.

Stability of urea in solution and pharmaceutical preparations.

The stability of urea in solution and pharmaceutical preparations was analyzed as a function of temperature (25°-60°C), pH (3.11-9.67), and initial urea concentration (2.5%-20%). This study was undertaken to (i) obtain more extensive, quantitative information relative to the degradation of urea in both aqueous and non-aqueous solutions and in pharmaceutical preparations, and (ii) test the effects of initial urea concentration, pH, buffer, and temperature values on urea degradation. The stability analysis shows that urea is more stable at the pH range of 4-8 and the stability of urea decreases by increase in temperature for all pH values. Within the experimental range of temperature and initial urea concentration values, the lowest urea degradation was found with lactate buffer pH 6.0. The urea decomposition rate in solution and pharmaceutical preparations shows the dependence of the initial urea concentrations. At higher initial urea concentrations, the rate of degradation is a decreasing function with time. This suggests that the reverse reaction is a factor in the degradation of concentrated urea solution. For non-aqueous solvents, isopropanol showed the best effort in retarding the decomposition of urea. Since the losses in urea is directly influenced by its stability at a given temperature and pH, the stability analysis of urea by the proposed model can be used to prevent the loss and optimize the operating condition for urea-containing pharmaceutical preparations.

Analytical challenges and regulatory requirements for nasal drug products in europe and the u.s.

Nasal drug delivery can be assessed by a variety of means and regulatory agencies, e.g., the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have published a set of guidelines and regulations proposing in vitro test methods for the characterization of nasal drug products. This article gives a summary of the FDA and EMA requirements regarding the determination of droplet size distribution (DSD), plume geometry, spray pattern and shot weights of solution nasal sprays and discusses the analytical challenges that can occur when performing these measurements. In order to support findings from the literature, studies were performed using a standard nasal spray pump and aqueous model formulations. The aim was to identify possible method-, device- and formulation-dependent influencing factors. The literature review, as well as the results from the studies show that DSD, plume geometry and spray pattern are influenced by, e.g., the viscosity of the solution, the design of the device and the actuation parameters, particularly the stroke length, actuation velocity and actuation force. The dominant factor influencing shot weights, however, is the adjustment of the actuation parameters, especially stroke length and actuation velocity. Consequently, for routine measurements assuring, e.g., the quality of a solution nasal spray or, for in vitro bioequivalence studies, the critical parameters, have to be identified and considered in method development in order to obtain reproducible and reliable results.

Co-precipitation of tobramycin into biomimetically coated orthopedic fixation pins employing submicron-thin seed layers of hydroxyapatite.

The migration, loosening and cut-out of implants and nosocomial infections are current problems associated with implant surgery. New innovative strategies to overcome these issues are emphasized in today's research. The current work presents a novel strategy involving co-precipitation of tobramycin with biomimetic hydroxyapatite (HA) formation to produce implant coatings that control local drug delivery to prevent early bacterial colonization of the implant. A submicron- thin HA layer served as seed layer for the co-precipitation process and allowed for incorporation of tobramycin in the coating from a stock solution of antibiotic concentrations as high as 20 mg/ml. Concentrations from 0.5 to 20 mg/ml tobramycin and process temperatures of 37 °C and 60 °C were tested to assess the optimal parameters for a thin tobramycin- delivering HA coating on discs and orthopedic fixation pins. The morphology and thickness of the coating and the drug-release profile were evaluated via scanning electron microscopy and high performance liquid chromatography. The coatings delivered pharmaceutically relevant amounts of tobramycin over a period of 12 days. To the best of our knowledge, this is the longest release period ever observed for a fast-loaded biomimetic implant coating. The presented approach could form the foundation for development of combination device/antibiotic delivery vehicles tailored to meet well-defined clinical needs while combating infections and ensuring fast implant in-growth.

Biomechanical and antibacterial properties of Tobramycin loaded hydroxyapatite coated fixation pins.

The present study investigates the use of nanoporous, biomimetic hydroxyapatite (HA) coatings deposited on TiO2 coated fixation pins as functional implant surfaces for the local release of Tobramycin in order to prevent bacterial colonization. The impact of HA-coating thickness, coating morphology and biomechanical forces during insertion into synthetic bone on the drug loading and release properties are analyzed. The coatings are shown to exhibit bactericidal effects against Staphylococcus aureus in agar medium for a duration of 6 days after loading by adsorption with Tobramycin for only 5 min at elevated temperature and pressure. Furthermore, high performance liquid chromatography analysis shows a drug release in phosphate buffered saline for 8 days with antibiotic concentration remaining above the minimal inhibitory concentration for S. aureus during the entire release period. Biomechanical insertion tests into synthetic bone and conventional scratch testing demonstrate adhesive strength at the HA/TiO2 interface. Biocompatibility is verified by cell viability tests. Outgrowth endothelial cells, as well as primary osteoblasts, are viable and firmly attached to both HA and TiO2 surfaces. The results presented are encouraging and support the concept of functional HA coatings as local drug delivery vehicles for biomedical applications to treat as well as to prevent post-surgical infections.

A model for treating avian aspergillosis: serum and lung tissue kinetics for Japanese quail (Coturnix japonica) following single and multiple aerosol exposures of a nanoparticulate itraconazole suspension.

Aspergillosis is frequently reported in parrots, falcons and other birds held in captivity. Inhalation is the main route of infection for Aspergillus fumigatus, resulting in both acute and chronic disease conditions. Itraconazole (ITRA) is an antifungal commonly used in birds, but administration requires repeated oral dosing and the safety margin is narrow. We describe lung tissue and serum pharmacokinetics of a nanoparticulate ITRA suspension administered to Japanese quail by aerosol exposure. Aerosolized ITRA (1 and 10% suspension) administered over 30 min did not induce adverse clinical reactions in quail upon single or 5-day repeated doses. High lung concentrations, well above the inhibitory levels for A. fumigatus, of 4.14 ± 0.19 µg/g and 27.5 ± 4.58 µg/g (mean ± SEM, n = 3), were achieved following single-dose inhalation of 1% and 10% suspension, respectively. Upon multiple dose administration of 10% suspension, mean lung concentrations reached 104.9 ± 10.1 µg/g. Drug clearance from the lungs was slow with terminal half-lives of 19.7 h and 35.8 h following inhalation of 1% and 10% suspension, respectively. Data suggest that lung clearance is solubility driven. Lung concentrations of hydroxy-itraconazole reached 1-2% of the ITRA lung tissue concentration indicating metabolism in lung tissue. Steady, but low, serum concentrations of ITRA could be measured after multiple dose administration, reaching less than 0.1% of the lung tissue concentration. This formulation may represent a novel, easy to administer treatment modality for fungal lung infection, preventing high systemic exposure. It may also be useful as metaphylaxis to prevent the outbreak of aspergillosis in colonized animals.

Drug loading and release of Tobramycin from hydroxyapatite coated fixation pins.

This paper evaluates the loading and release properties of Tobramycin incorporated by adsorptive loading from a solution into plasma sprayed and biomimetically coated Hydroxyapatite (HA) fixation pins. The aim of this study is to contribute towards designing a functional implant surface offering local release of the antibiotic agent to prevent post-surgical infections. Cathodic arc deposition is used to coat stainless steel fixation pins with a bioactive, anatase phase dominated, TiO2 coating onto which a HA layer is grown biomimetically. The loading and release properties are evaluated by studying the subsequent release of Tobramycin using high performance liquid chromatography and correlated to the differences in HA coating microstructure and the physical conditions under loading. The results from these studies show that a dual loading strategy consisting of a solution temperature of 90 °C and a pressure of 6 bar during a loading time of 5 min release a sufficient amount of Tobramycin to guarantee the inhibition of Staphylococcus aureus up to 2 days for plasma sprayed HA coatings and for 8 days for biomimetic coatings. The present study emphasizes the advantages of the nanoporous structure of biomimetically deposited HA over the more dense structure of plasma sprayed HA coatings in terms of antibiotic incorporation and subsequent sustained release and provides a valuable outline for the design of implant surfaces aiming for a fast-loading and controlled, local drug administration.

Physico-chemical characterisation of surface modified particles for inhalation.

Surface modification of drugs for inhalation is a possibility to influence interparticulate forces. This can be necessary to achieve a sufficient aerosolisation during powder inhalation as the cohesiveness of the micronised drug can be reduced. In addition, the interaction with propellants in pressurised metered dose inhaler can be changed. This can be used to improve the physical stability of the suspension based formulations. A dry particle coating process was used for the alteration of particle surfaces. The blending of micronised salbutamol sulphate (SBS) with different concentrations of magnesium stearate (Mgst) or glycerol monostearate (GMS) was followed by co-milling with an air jet mill. The powder properties were characterised by SEM, EDX, laser diffraction, BET and inverse gas chromatography. Physical mixtures generated by Turbula blending were compared to co-milled samples. A slight particle size reduction was determined. The Mgst deposition on SBS particles was detected by EDX measurements. The dispersive surface energy of SBS is lowered and the energy distribution is more homogenous for the co-milled samples. This study proves the application of co-milling for surface modification in the inhalation area.

Locally enhanced early bone formation of zoledronic acid incorporated into a bone cement plug in vivo.

OBJECTIVES: The aim of the study was to gain experience about the short-term effects of zoledronic acid (ZOL) on bone-implant contact (BIC), bone regeneration and bone area (BA). METHODS: In this in-vivo study, ZOL was released locally from a drug-loaded pre-shaped calcium phosphate bone cement plug which was implanted into a bone defect in the proximal tibia of rats. At 1 and 3 weeks post implantation, tissue reactions as well as bone regeneration capabilities at the implant site were investigated. Furthermore, tissue samples, harvested at placebo and verum plug sites were used to analyse the gene expression of selected bone-specific markers by using quantitative polymerase chain reaction. Data were normalized against ribosomal RNA (Rn18s) subunits. KEY FINDINGS: In the placebo interface a higher amount of cells could be detected as indicated by higher expression of small subunit Rn18s. Nevertheless, comparing the normalized data of the selected gene expression levels, no significant differences were detected. The histomorphometric results showed a significant higher BIC and BA for ZOL-loaded plugs at 3 weeks after implantation. CONCLUSIONS: In this model, ZOL was demonstrated to be effective in impacting the bone regeneration process towards reduction of early bone resorption and enhanced bone formation.

Bone substitute materials delivering zoledronic acid: physicochemical characterization, drug load, and release properties.

Calcium phosphate-like bone substitute materials have a long history of successful orthopedic applications such as bone void filling and augmentation. Based on the clinical indications, these materials may be loaded with active agents by adsorption offering a perspective for providing innovative drug-delivery systems. The highly effective bisphosphonate zoledronic acid (ZOL) demonstrated a strong affinity to biominerals and is known to significantly reduce osteoclastic activity. Support of early bone formation and reduction of bone resorption can be promoted after implantation of bioceramics releasing ZOL. The aim of this study was to develop an easy to handle approach to combine ZOL with bone substitutes by use of a dipping technique. The properties of three different materials were investigated by using a number of physicochemical methods such as light microscopy, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), true density, and surface area measurement to evaluate the feasibility of being potential drug carriers. Besides physicochemical characterization, the bone substitutes were evaluated by their ZOL-loading capacity in a time- and concentration-dependent manner. Additionally, the materials were assessed as release systems in an in vitro study. A controlled ZOL load in a range of 0.04-1.86 µg/mg material and a release of 0.02-0.18 µg/mg within 30 min is demonstrated. The findings support using the investigated bioceramics as carrier systems to release ZOL. Overall, the results create the base for further development of drug-delivery systems with controlled drug loading and prolonged release and need to be further analyzed in an in vivo study.

Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis.

Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection. The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment. While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species. About 10-20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA). While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA. However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis. The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8°C for 3 months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7 days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4µg/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h. The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure.

Solvent free fabrication of micro and nanostructured drug coatings by thermal evaporation for controlled release and increased effects.

Nanostructuring of drug delivery systems offers many promising applications like precise control of dissolution and release kinetics, enhanced activities, flexibility in terms of surface coatings, integration into implants, designing the appropriate scaffolds or even integrating into microelectronic chips etc. for different desired applications. In general such kind of structuring is difficult due to unintentional mixing of chemical solvents used during drug formulations. We demonstrate here the successful solvent-free fabrication of micro-nanostructured pharmaceutical molecules by simple thermal evaporation (TE). The evaporation of drug molecules and their emission to a specific surface under vacuum led to controlled assembling of the molecules from vapour phase to solid phase. The most important aspects of thermal evaporation technique are: solvent-free, precise control of size, possibility of fabricating multilayer/hybrid, and free choice of substrates. This could be shown for twenty eight pharmaceutical substances of different chemical structures which were evaporated on surfaces of titanium and glass discs. Structural investigations of different TE fabricated drugs were performed by atomic force microscopy, scanning electron microscopy and Raman spectroscopy which revealed that these drug substances preserve their structurality after evaporation. Titanium discs coated with antimicrobial substances by thermal evaporation were subjected to tests for antibacterial or antifungal activities, respectively. A significant increase in their antimicrobial activity was observed in zones of inhibition tests compared to controls of the diluted substances on the discs made of paper for filtration. With thermal evaporation, we have successfully synthesized solvent-free nanostructured drug delivery systems in form of multilayer structures and in hybrid drug complexes respectively. Analyses of these substances consolidated that thermal evaporation opens up the possibility to convert dissoluble drug substances into the active forms by their transfer onto a specific surface without the need of their prior dissolution.

Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance.

Dry powder inhalers play a major role in today's treatment of various respiratory diseases. A lot of effort has been put into the optimization of a device and the appropriate formulation regarding its local lung deposition. However, the complexity and interactions of different factors governing powder dispersion and, therefore, its inhalable fraction challenge research groups around the world. In the current work, binary lactose blends and adhesive ternary powder mixtures containing additional budesonide fines were produced and analyzed with dispersion measurements on the one hand and permeability and aeration measurements conducted with a powder rheometer on the other hand. By comparing the results of the bulk property and dispersion tests, it was expected to gain a better understanding about the effect of excipient fines addition to an adhesive powder mixture. It could be observed that with permeability testing it was possible to clearly differentiate between different amounts of fines within mixtures. However, no correlation between permeability or aeration test values and drug fine particle fraction could be determined for the observed range. Nevertheless, the use of different characterization techniques led to a clearer understanding about the influence of fines addition to an adhesive mixture. It could be demonstrated that after the surface of carrier crystals had been fully saturated, drug particles got incorporated in more stable fines' agglomerates, which resulted in a decrease in fine particle fraction upon dispersion.