Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations

The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler^® inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated.     

Drug-lactose binding aspects in adhesive mixtures: controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces

For dry powder inhaler formulations, micronized drug powders are commonly mixed with coarse lactose carriers to facilitate powder handling during the manufacturing and powder aerosol delivery during patient use. The performance of such dry powder inhaler formulations strongly depends on the balance of cohesive and adhesive forces experienced by the drug particles under stresses induced in the flow environment during aerosolization. Surface modification with appropriate additives has been proposed as a practical and efficient way to alter the inter-particulate forces, thus potentially controlling the formulation performance, and this strategy has been employed in a number of different ways with varying degrees of success. This paper reviews the main strategies and methodologies published on surface coating of lactose carriers, and considers their effectiveness and impact on the performance of dry powder inhaler formulations.     

Lactose modifications enhance its drug performance in the novel multiple dose Taifun DPI

Drug–carrier particle interactions greatly affect the detachment of drug from the carrier in inhalation powders. In this study, a novel multiple dose, reservoir-based Taifun^® was used as a dry powder inhaler, and the effects of carrier physical properties were evaluated on the pulmonary deposition of budesonide, along with physical stability of the inhalation powder. In this study, untreated commercial preparation of -lactose monohydrate, highly amorphous spray dried lactose, crystallized spray dried lactose, Flowlac-100^® and Flowlac-100^® mixed with crystalline micronized lactose were used as carriers. Dry powder formulations were prepared by the suspension method, where the budesonide–carrier ratio was 1:15.1 (w/w). Carriers and formulations were initially characterized, and again after 1 month’s storage at 40 °C/75% RH. The physical properties of the carriers strongly affected the pulmonary deposition of budesonide and the physical stability of the inhalation powder. Initially, amorphous contents of the carriers were 0–64%, but spontaneous crystallisation of the amorphous lactose occurred during storage and, thus all carriers were 100% crystalline after storage. When compared to an untreated -lactose monohydrate, the highly amorphous spray dried lactose and Flowlac-100^® did not improve aerosol performance of the inhalation powder. When crystalline spray dried lactose was used as a carrier, the highest RF% values were achieved, and RF % values did not alter during storage but the emitted budesonide dose was lower than the theoretical dose. When Flowlac-100^® mixed with crystalline micronized lactose was used as a carrier, the emitted budesonide dose was close to the theoretical dose, and high RF % values were achieved but these changed during storage.     

Lactose Composite Carriers for Respiratory Delivery

Purpose  Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug–carrier adhesion, variability in drug–carrier forces and influence on drug aerosol performance from carrier–drug blends. Methods  Lactose carrier particles were prepared by fusing sub units of lactose (either 2, 6 or 10 μm) in saturated lactose slurry. The resultant composite particles, as well as supplied lactose, were sieve fractioned to obtain a 63–90 μm carriers. The carriers were evaluated in terms of size (laser diffraction) morphology (electron microscopy and atomic force microscopy), crystallinity and drug adhesion (colloid probe microscopy). In addition, blends containing drug and carrier were prepared and evaluated in terms of drug aerosol performance. Results  The surface morphology and physico-chemical properties of the composite carriers were significantly different. Depending on the initial primary lactose size, the composite particles could be prepared with different surface roughness. Variation in composite roughness could be related to the change in drug adhesion (via modification in contact geometry) and thus drug aerosol performance from drug–lactose blends. Conclusion  Composite based carriers are a potential route to control drug–carrier adhesion forces and variability thus allowing more precise control of formulation performance.     

Adhesion forces in interactive mixtures for dry powder inhalers--evaluation of a new measuring method.

Dry powder inhalers mostly contain carrier based formulations where micronized drug particles are adhered to coarse carrier particles. The performance of the dry powder inhaler depends on the inhaler device, the inhalation manoeuvre and the formulation. The most important factor influencing the behaviour of the formulation is the adhesion force acting between the active ingredient and the carrier particles, which can be measured using different methods, for example the centrifuge technique or atomic force microscopy. In this study the tensile strength method, usually applied to determine cohesion forces between powder particles of one material, is optimized for adhesion force measurements between powder particles of unlike materials. Adhesion force measurements between the carrier materials lactose or mannitol and the drug substance salbutamol sulphate using the tensile strength method and the atomic force microscopy show higher values with increasing relative humidity. Consequently, the fine particle fraction determined using the Next Generation Impactor decreases with increasing relative humidity as a result of the enhanced interparticle interactions.     

Effects of mild processing pressures on the performance of dry powder inhaler formulations for inhalation therapy (1): Budesonide and lactose

Batch-to-batch variability, whereby distinct batches of dry powder inhaler formulations, though manufactured with identical components and specifications, may exhibit significant variations in aerosol performance, is a major obstacle to consistent and reproducible drug delivery for inhalation therapy. This variability may arise from processing or manufacturing effects that have yet to be investigated. This study focused on the potential effects of mild compression forces experienced during powder manufacture and transport (such as during the filling of, or storage in, a hopper) on the flowability and aerosol performance of a lactose-based dry powder inhaler formulation. Different grades of inhalation lactose were subjected to typical compression forces by either placing a weight of known mass on the sample or by using a Texture Analyzer to apply a constant force while measuring the distance of compaction. Powder flowability was evaluated with a rotating drum apparatus by imaging the avalanching of the powder over time. The average avalanche angle and avalanche time were used to determine the flowability of each sample, both before and after compression treatment. Aerosol performance of treated and untreated lactose/budesonide blends (2% (w/w)) was assessed in dispersion studies using a next generation impactor. At compression forces in excess of 5 kPa, the flowability of milled lactose was decreased relative to the untreated sample. Compression of lactose prior to blending caused a decrease in in vitro aerosol dispersion performance. However, dispersion performance was unchanged when compression occurred subsequent to drug blending. In contrast, inhalation grade sieved lactose, differing from the milled grade with a lower concentration of lactose fines (<10 μm) and larger overall particle sizes, exhibited no statistical differences in either flowability or dispersion performance across all experimental treatments. Thus, the compression of the lactose fines onto the surfaces of the larger lactose particles due to mild processing pressures is hypothesized to be the cause of these observed performance variations. It was shown that simulations of storage and transport in an industrial scale hopper can induce significant variations in formulation performance, and it is speculated that this could be a source of batch-to-batch variations.     

What is the role of particle morphology in pharmaceutical powder aerosols?

Background: The aerosol performance of a powder for inhalation drug delivery is controlled by a number of physicochemical properties of the formulation, including particle size, density and morphology. Objective: The role of particle morphology in powder inhalers will be reviewed. Methods: Original research publications in the literature about the contribution of particle morphology to the aerosol performance of pharmaceutical powders have been selected, including both the lactose carriers and the drugs. Results/conclusion: Existing data showed that morphology of both the lactose carrier and drug particle can affect the aerosol performance of powders significantly, a factor which should be taken into consideration during the development of dry powder inhalation products.     

A critical evaluation of the relevant parameters for drug redispersion from adhesive mixtures during inhalation

In this paper, the parameters that are relevant to the drug redispersion from adhesive mixtures during inhalation are discussed and evaluated. The results obtained with air classifier technology give strong evidence for a dominating influence of carrier surface properties on the fraction of drug detached during inhalation at a low carrier payload (< or =1%, w/w), versus a dominating effect of carrier bulk properties at higher payloads. Furthermore, the results indicate that there is a fundamental difference between so-called active carrier sites and large surface discontinuities. The difference refers to the saturation concentrations, the rates of saturation and their effects on drug detachment during inhalation. The degree of saturation of the active sites appears to be proportional with the square root of the carrier surface payload (after 10 min mixing time in a Turbula mixer at 90 rpm). The storage volume of the discontinuities seems largely independent of the carrier diameter for particles derived from the same batch of crystalline lactose. Saturation of these discontinuities is completed at a much lower carrier surface payload than saturation of the active sites. Relatively large discontinuities are beneficial to de-agglomeration principles that make use of inertial separation forces during inhalation, as they provide shelter from inertial and frictional press-on forces during mixing which increase the strength of the interparticulate bonds in the powder mixture. For de-agglomeration principles generating frictional, drag or lift forces, carrier surface depressions and projections are disadvantageous however, as they also provide shelter from these removal forces.     

Dry powder inhaler device influence on carrier particle performance

Dry powder inhalers (DPIs) are distinguished from one another by their unique device geometries, reflecting their distinct drug detachment mechanisms, which can be broadly classified into either aerodynamic or mechanical-based detachment forces. Accordingly, powder particles experience different aerodynamic and mechanical forces depending on the inhaler. However, the influence of carrier particle physical properties on the performance of DPIs with different dispersion mechanisms remains largely unexplored. Carrier particle trajectories through two commercial DPIs were modeled with computational fluid dynamics (CFD) and the results were compared with in vitro aerosol studies to assess the role of carrier particle size and shape on inhaler performance. Two percent (w/w) binary blends of budesonide with anhydrous and granulated lactose carriers ranging up to 300 μm were dispersed from both an Aerolizer? and Handihaler? through a cascade impactor at 60 L min(-1). For the simulations, carrier particles were modeled as spherical monodisperse populations with small (32 μm), medium (108 μm), and large (275 μm) particle diameters. CFD simulations revealed the average number of carrier particle-inhaler collisions increased with carrier particle size (2.3-4.0) in the Aerolizer?, reflecting the improved performance observed in vitro. Collisions within the Handihaler?, in contrast, were less frequent and generally independent of carrier particle size. The results demonstrate that the aerodynamic behavior of carrier particles varies markedly with both their physical properties and the inhalation device, significantly influencing the performance of a dry powder inhaler formulation.     

Influence of the lactose grade within dry powder formulations of fluticasone propionate and terbutaline sulphate

Dry powder formulations are often composed of fine drug particles and coarser carrier particles, typically alpha-lactose monohydrate. However, the performance of a powder formulation may be highly dependent on the lactose quality and source. This study investigated the characteristics of lactose that influence the drug-to-carrier interaction and the performance of lactose-based dry powder inhaler formulations. The selected lactoses differed in the preparation processes and the content of fine lactose particles. Efficiency testing was done using fluticasone propionate and terbutaline sulphate as model drugs. Inverse gas chromatography was used to determine the surface heterogeneity distribution of different energy sites of the lactose and to understand the mechanism by which the fine carrier particles can improve the performance of dry powder inhalers. To assess the adhesion of respirable-sized drug to carrier particles, a simple method was developed based on aspiration and considering the whole blend as it is used in dry powder inhalers. When the percentage of fine lactose is high, a lower quantity of drug adheres to the lactose and/or the adhesion force is also lower. This was confirmed by the aerosolization assays done in the TSI (twin stage impinger). A correlation was observed between adhesion characteristics and inertial impaction. For both drugs, the fine particle fractions were highest in blends that present a greater proportion of lactose fine particles. A fairly good correlation between the fine particle fractions of both drugs and the peak max value and the AUC (area under curve) were found by inverse gas chromatography. With higher fine particle fraction values, which correspond to higher content of fines, the peak maxima determined by inverse gas chromatography were shifted to higher adsorption potentials, which supports the agglomeration hypothesis.     

Engineered Mannitol Ternary Additives Improve Dispersion of Lactose–Salbutamol Sulphate Dry Powder Inhalations

The aim of this study was to evaluate the influence of novel engineered fine mannitol particles (4.7%, w/w) on the performance of lactose–salbutamol sulphate dry powder inhaler (DPI) formulations to obtain promising aerosolisation properties. The results showed that the more elongated the fine mannitol particles, the weaker the drug–carrier adhesion, the better the drug content homogeneity, the higher the amount of drug expected to be delivered to the lower airways and the higher the total DPI formulation desirability. Linear relationships were established showing that mannitol particles with a more elongated shape generated powders with broader size distributions and that were less uniform in shape. The weaker the drug–carrier adhesion, the higher the fine particle fraction of the drug is upon aerosolisation. It is believed that more elongated fine mannitol particles reduce the number of drug–carrier and drug–drug physical contact points and increase the ability of the drug particles to travel into the lower airways. Additionally, a lower drug–carrier contact area, lower drug–carrier press-on forces and easier drug–carrier detachment are suggested in the case of formulations containing more elongated fine mannitol particles. Ternary ‘drug-coarse carrier-elongated fine ternary component’ DPI formulations were more favourable than both ‘drug-coarse carrier’ and ‘drug-elongated coarse carrier’ binary formulations. This study provides a comprehensive approach for formulators to overcome the undesirable properties of dry powder inhalers, as both improved aerosolisation performance and reasonable flow characteristics were obtained using only a small amount of elongated engineered fine mannitol particles.     

The Rate of Drug Particle Detachment from Carrier Crystals in an Air Classifier-Based Inhaler

No HeadingPurpose. To investigate the rate with which drug particles are detached from carrier particles in adhesive mixtures when the action of the separation forces during inhalation is sustained by circulation of the powder dose in an air classifier.Methods. Residual drug on retained carrier particles from different adhesive mixture compositions has been analyzed after different circulation times in the classifier (0.5 to 6 s). For calculation of the detachment rate within the first 0.5 s of inhalation, the optical concentration of the aerosol from the classifier has been measured with laser diffraction technique.Results. Drug detachment from carrier crystals during inhalation increases not only with the flow rate but also with the time during which the action of the separation forces (at a constant flow rate) is sustained. The detachment rate at the same flow rate varies with the carrier size fraction and carrier payload and is clearly highest within the first 0.5 s of inhalation.Conclusions. Drug detachment from carrier approaches first-order reaction within the first half-second of inhalation. But at longer circulation times in the classifier, the ratio of removal to adhesive forces decreases dramatically. To increase the detached fraction of drug during inhalation at a constant flow rate, a short residence time for the powder in the de-agglomerator between 0.5 and 2 s is desired.     

Effect of separation characteristics between salbutamol sulfate (SS) particles and model carrier excipients on dry powder for inhalation]

Most often dry powder for inhalation are formulated as ordered mixtures of a carrier excipient and a micronized drug substance. In the present study, model powder blends were prepared from a mixture of lactose alpha-monohydrate, micro-crystalline cellulose pellets or synthesized sugar as carrier particles, and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO dry powder inhaler (DPI) and their in vitro deposition properties were evaluated by a twin impinger (TI). The separation force between SS particles and carrier particles was investigated by the centrifuge method. In addition, the use of the air jet sieve (AJS) method was investigated to assess the separation behavior of drug particles from carrier excipient. Powder blends were sieved through a 325 mesh wire screen of an air jet sieve at an air pressure of 1500 Pa. The amount of drug deposited at the carrier surface was analysed before and after the sieving to calculate the percentage of the drug retained. A relationship was found between in vitro deposition properties (fine particle fraction, FPF) and the separation characteristics obtained by the centrifuge method and by the AJS method. The AJS method might be a suitable alternative for evaluating separation of a drug particle from carrier particles and hence can be used for the formulation screening of the dry powder inhalation.     

Air classifier technology (ACT) in dry powder inhalation Part 4. Performance of air classifier technology in the Novolizer multi-dose dry powder inhaler

In this study, the in vitro fine particle deposition from a multi dose dry powder inhaler (Novolizer) with air classifier technology has been investigated. It is shown that different target values for the fine particle fraction (fpf<5 microm) of the same drug can be achieved in a well-controlled way. This is particularly relevant to the application of generic formulations in the inhaler. The well-controlled and predictable fpf is achieved through dispersion of different types of formulations in exactly the same classifier concept. On the other hand, it is shown that air classifier-based inhalers are less sensitive to the carrier surface and bulk properties than competitive inhalers like the Diskus. For 10 randomly selected lactose carriers for inhalation from four different suppliers, the budesonide fpf (at 4 kPa) from the Novolizer varied between 30 and 46% (of the measured dose; R.S.D.=14.2%), whereas the extremes in fpf from the Diskus dpi were 7 and 44% (R.S.D.=56.2%) for the same formulations. The fpf from a classifier-based inhaler appears to be less dependent of the amount of lactose (carrier) fines (<15 microm) in the mixture too. Classifier-based inhalers perform best with coarse carriers that have relatively wide size distributions (e.g. 50-350 microm) and surface discontinuities inside which drug particles can find shelter from press-on forces during mixing. Coarse carrier fractions have good flow properties, which increases the dose measuring accuracy and reproducibility. The fpf from the Novolizer increases with increasing pressure drop across the device. On theoretical grounds, it can be argued that this yields a more reproducible therapy, because it compensates for a shift in deposition to larger airways when the flow rate is increased. Support for this reasoning based on lung deposition modelling studies has been found in a scintigraphic study with the Novolizer. Finally, it is shown that this inhaler produces a finer aerosol than competitor devices, within the fpf<5 microm, subfractions of particles (e.g. <1, 1-2, 2-3, 3-4 and 4-5 microm) are higher.     

A New Powder Design Method to Improve Inhalation Efficiency of Pranlukast Hydrate Dry Powder Aerosols by Surface Modification with Hydroxypropylmethylcellulose Phthalate Nanospheres

Purpose. A new particle design method to improve the aerosolization properties of a dry powder inhalation system was developed using surface modification of hydrophobic drug powders (pranlukast hydrate) with ultrafine hydrophilic particles, hydroxypropylmethylcellulose phthalate (HPMCP) nanospheres. The mechanism of the improved inhalation properties of the surface-modified particles and their deposits on carrier particles (lactose) was clarified in vitro. Methods. Drug particles were introduced to aqueous colloidal HPMCP dispersions prepared by emulsion-solvent diffusion techniques followed by freeze- or spray-drying of the resultant aqueous dispersions. The surface-modified powders obtained with HPMCP nanospheres and their mixture with lactose powders were aerosolized by Spinhaler and their mode of deposition in lung was evaluated in vitro using a twin impinger. To elucidate the inhalation mechanism of these surface modified particles, we measured their modified micromeritic properties, such as surface topography, specific surface area, dissolution rate, and dispersibility in air. Results. Dramatically improved inhalation properties of the surface modified powder, i.e. a two-fold increase in emission and a three-fold increase in delivery to deep lung, were found in vitro compared with the original unmodified powder. Improved inhalation was also found with the surf ace-modified drug deposited on lactose particles. Those improvements were attributed to the increased surface roughness and hydrophilicity of the surface-modified particles, and the resultant increased dispersibility in air. Conclusions. Surface modification of hydrophobic drug particles with HPMCP nanospheres to improve hydrophilicity was extremely useful in increasing the inhalation efficiency of the drug itself and the drug deposited on carrier; this was attributed to increased dispersibility in air and emission from the device, for spray- and freeze-dried particles, respectively.     

Predicting the behavior of novel sugar carriers for dry powder inhaler formulations via the use of a cohesive-adhesive force balance approach

The aim of this work was to utilize the recently developed cohesive-adhesive balance (CAB) technique for analyzing quantitative AFM measurements to compare the relative forces of interaction of micronized salbutamol sulfate particles and a selection of specifically grown sugar substrates (beta cyclodextrin, lactose, raffinose, trehalose and xylitol). The interfacial behavior was subsequently related to the in-vitro delivery performance of these sugars as carrier particles in dry powder inhalation (DPI) formulations. The CAB analysis indicated that the rank order of adhesion between salbutamol sulfate and the sugars was beta cyclodextrin < lactose < trehalose < raffinose < xylitol. The beta cyclodextrin was the only substrate with which salbutamol sulfate demonstrated a greater cohesive behavior. All other sugars exhibited an adhesive dominance. In-vitro deposition performance of the salbutamol sulfate based carrier DPI formulations showed that the rank order of the fine particle fraction (FPF) was beta cyclodextrin > lactose > raffinose > trehalose > xylitol. A linear correlation (R(2) = 0.9572) was observed between the FPF and cohesive-adhesive ratios of the AFM force measurements. The observed link between CAB analysis of the interactive forces and in-vitro performance of carrier based formulations suggested a fundamental understanding of the relative balance of the various forces of interaction within a dry powder formulation may provide a critical insight into the behavior of these formulations.     

Carriers in drug powder delivery

The performance of dry powder inhaler (DPI) systems depends on the design of the powder formulation, the dose-metering system, and the device used to disperse the powder as an aerosol. Multiple factors associated with drug and carrier particles are known to influence dry powder performance. Elucidation of a mechanistic understanding of particulate system properties and how these relate to powder performance and the disruption of inter-particulate forces that cause aggregation has not yet been achieved. However, the complexity of interactions within dry powder formulations has not restricted research in this area. Various strategies of overcoming inter-particulate forces have been devised, ranging from active inhaler designs to powder engineering approaches. The influence of the interactive carrier system’s physicochemical properties (i.e. size, shape, chemical properties, surface roughness, electrostatics, humidity, and ternary excipients) on the performance of carrier-based systems has been examined extensively in the literature. In addition, matrix carriers, which contain drug and functional excipients for promotion of powder performance, control of pharmacokinetics, stability, controlled release of active drug and enhanced control of drug targeting, have also been investigated. Both the interactive carrier and matrix carrier approaches are attempts to develop DPI systems that perform as device-independent formulations and/or provide patient-independent delivery (controlled carrier systems). It seems likely that the future of DPI systems will combine both of these strategies with future developments in device design (formulation independency).     

Functionality testing of inhalation grade lactose.

Lactose monohydrate for inhalation is commonly produced by sieving out customer-specific size fractions of a crystallized bulk material of lactose. It was the aim of this study to investigate the influence of the raw material on the physico-chemical properties of the inhalation grade lactose and on the efficacy of powders for inhalation produced from these batches. The selected raw material lactose batches differed in the size distribution characteristics, the fines and the agglomerate content. These differences in the raw material could also be found to a smaller extent in the intermediate products and could not be completely levelled out in the final inhalation grade lactose. Efficiency testing was done using salbutamol sulphate in two different concentrations (drug-to-carrier ratio of 1:36 and 1:400) as a model drug; the powder blends were delivered using the Aerolizer and the Easyhaler device. With the high drug load, nearly no differences could be observed between both the delivery systems and the different produced lactose batches. The fine particle fraction (FPF) (%<5 microm) was on a high level of >39% in all cases. With the low drug load significant differences between the devices and the lactose batches were found. The FPF was distinctly reduced to 15-30%, with the Easyhaler generating a higher fraction of fine particles than the Aerolizer device. Although the observed differences between the lactose batches could not be linked to one specific physico-chemical parameter determined for the carrier, they led to the conclusion that the differences between the test batches of inhalation grade lactose especially manufactured for this study can affect the functionality of an inhalation powder. The effects are significantly smaller with high drug load formulations than using a low drug concentration.     

Effect of mixing of fine carrier particles on dry powder inhalation property of salbutamol sulfate (SS)

The most commonly used formulations for dry powder inhalations are binary ordered mixes composed of micronized drugs and coarse carriers. An optimal dry powder aerosol formulation should possess an optimal inhalation property and a good flow property. These characteristics are especially important for a multidose dry powder inheler (DPI). In the present study, model powder blend were prepared consisting of synthesized sugar (different particle sized isomalt; IM-PF, IM-FS, IM-F) as a carrier and micronized salbutamol sulfate (SS). These ordered mixtures were aerosolized by the multidose JAGO DPI (SkyePharma AG) and in vitro deposition properties (fine particle fraction, FPF) were evaluated by a twin impinger (TI) at a flow rate of 60 l/min. The separation property between SS and carrier particles was investigated by the centrifuge method and air jet sieve (AJS) method. It was found that FPF decreased with increasing carrier particle size. However, a large carrier particle possesses a good flow property. Therefore, the effect of mixing of fine carrier particles (IM-PF) into the large carrier particles (IM-FS) on dry powder inhalation property was investigated. When the proportion of IM-PF (fine carrier) increase from 0% to 25% of the total carrier powder blend, the FPF also increases from 16.7% to 38.9%. It is concluded that the effect of mixing of fine carrier particles might be a suitable method for improving the dry powder inhalation properties.     

Lactose as a carrier in dry powder formulations: the influence of surface characteristics on drug delivery.

The aim of the study was to investigate the interdependence of carrier particle size, surface treatment of the carrier, and inclusion of fines on the drug delivery from dry power inhaler formulations. Two size fractions (< 63 and 63-90 microm) of alpha-lactose monohydrate were subjected to treatment with 95% (v/v) ethanol to introduce small asperities or cavities onto the otherwise smooth surface without substantially changing the particle shape. After blending with albuterol sulfate [ALB; volume median diameter (VMD), 1.9 microm; geometric standard deviation (GSD), 1.5], the solvent-treated lactose produced a fine particle fraction (FPF; < 6.18 microm) and dispersibility of the drug that was significantly (ANOVA p < 0.01) lower than that which resulted from formulations containing untreated lactose of a similar size fraction, after aerosolization at 60 L min(-1) via a Rotahaler. The two size fractions of the treated lactose resulted in similar deposition profiles of ALB. The effects of such surface asperities or cavities of lactose were offset by introducing a small amount (5% w/w) of smaller-sized lactose (5-10 microm) to the powder formulations. The fine lactose increased the FPF and dispersibility of ALB to such a level that all lactose batches, regardless of particle size or whether solvent treated, produced a similar fraction of aerosolized ALB. The inclusion of recrystallized needle lactose (5-15 microm) was superior to micronized lactose in improving the aerosolization of ALB. The findings of this study indicate that the presence and characteristics of the finer fraction of lactose carrier particles dominate over the particle size and surface smoothness of the carrier particles in determining dispersion and deaggregation of drugs from dry powder formulations for inhalation.