Air classifier technology (ACT) in dry powder inhalation. Part 2. The effect of lactose carrier surface properties on the drug-to-carrier interaction in adhesive mixtures for inhalation

The effect of carrier surface properties on drug particle detachment from carrier crystals during inhalation with a special test inhaler with basic air classifier has been studied for mixtures containing 0.4% budesonide. Carrier crystals were retained in the classifier during inhalation and subsequently examined for the amount of residual drug (carrier residue: CR). Carrier surface roughness and impurity were varied within the range of their appearance in standard grades of lactose (Pharmatose 80, 100, 110, 150 and 200 M) by making special sieve fractions. It was found that roughness and impurity, both per unit calculated surface area (CSA), tend to increase with increasing mean fraction diameter for the carrier. Drug re-distribution experiments with two different carrier sieve fractions with distinct mean diameters showed that the amount of drug per CSA (drug load) in the state of equilibrium is highest for the coarsest fraction. This seems to confirm that surface carrier irregularities are places where drug particles preferentially accumulate. However, a substantial increase in surface roughness and impurity appears to be necessary to cause only a minor increase in CR at an inspiratory flow rate of 30 l/min through a classifier. At 60 l/min, CR is practically independent of the carrier surface properties. From the difference in CR between 30 and 60 l/min, it has been concluded that particularly the highest adhesive forces (for the largest drug particles) in the mixture are increased when coarser carrier fractions (with higher rugosity) are used. Not only increased surface roughness and impurities may be responsible for an increase in the adhesive forces between drug and carrier particles when coarser carrier fractions are used, but also bulk properties may play a role. With increasing mean carrier diameter, inertial and frictional forces during mixing are increased too, resulting in higher press-on forces with which the drug particles are attached to carrier crystals and to each other.     

The interaction between carrier rugosity and carrier payload, and its effect on drug particle redispersion from adhesive mixtures during inhalation.

The effectiveness of press-on forces (defined as the adhesive forces between drug and carrier particles) in relation to carrier payload as the result of collisions between carrier particles during the mixing process of an adhesive mixture, has been investigated. Three different carriers of the same size fraction (250-355 microm), but with completely different surface rugosity were studied. It could be shown that this effectiveness depends on the carrier rugosity. The fraction of drug detached from the carrier particles during inhalation appeared to decrease faster with increasing carrier payload for crystalline carriers than for granular carriers. Apparently, increasing the volume of the carrier surface cavities increases the drug mass that can find shelter from the press-on forces during mixing. By measuring the size distribution in the aerosol, it could also be shown that the press-on forces may increase the size of the particles that are detached. This seems to be the result of drug particle re-agglomeration on the carrier surface during mixing. On the other hand, when press-on forces are highly ineffective, an increase in the size of detached particles may also be the result of incomplete break-up of natural drug agglomerates. Finally, it could be shown that when the press-on forces are highly effective, the effect of mixing time is small.     

The effect of budesonide particle mass on drug particle detachment from carrier crystals in adhesive mixtures during inhalation.

The different fine particle fractions (FPFs) that are obtained, when different dry powder inhalers (DPIs) are used for the same powder formulation at the same flow rate, is the result of different powder de-agglomeration efficiencies for these DPIs. For adhesive mixtures, this is the efficiency with which the kinetic energy of the air flow through the DPI is converted into separation forces that detach drug particles from carrier crystals. We investigated the effect of drug particle diameter (mass) on drug-carrier separation during inhalation with three different inhalers (Sofotec Novolizer, Inhalator Ingelheim and a special test inhaler), at two different flow rates (30 and 60l/min). Two different size fractions were used as carrier material (45-63 and 100-150 microm). We measured decreasing amounts of residual drug on the carrier crystals after inhalation with increasing drug particle mass for all inhalers at both flow rates. The observed trends were the same for both carrier fractions. The decrease in residual drug on carrier is in agreement with increasing FPFs in an Erweka impactor. However, it has been calculated that the magnitude of the effect decreases with increasing de-agglomeration efficiency.     

The effect of carrier surface treatment on drug particle detachment from crystalline carriers in adhesive mixtures for inhalation

In this study, the effect of lactose carrier surface treatment on drug particle detachment during inhalation has been investigated. Crystals of marketed brands of alpha lactose monohydrate brands normally exhibit a certain surface rugosity and contain natural fines and impurities on their surface, which influence the drug-to-carrier interaction in adhesive mixtures for inhalation. Submersion treatment may change these surface characteristics. Two different sieve fractions (63-90 and 250-355microm) were submerged in mixtures of ethanol and water (96 and 80% v/v, respectively). Microscopic observation and laser diffraction analysis revealed that neither the shape nor the size of the carrier particles was changed by the submersion treatment. However, the specific surface area and the amount of impurities appeared to decrease substantially after submersion, and the magnitude of the decrease was different for the different ethanol-water mixtures. The reduction in specific surface area was attributed particularly to the removal of the adhering lactose fines from the carrier surface. Mixtures with budesonide (in a wide range of carrier payloads) were prepared before and after treatment. Drug particle detachment from the various mixtures was studied with a sieve test and with a cascade impactor analysis at 30 and 60l/min. Two different types of inhalers were used, one generating lift- and drag-forces (ISF inhaler) and one generating inertial forces (test inhaler), respectively. The cascade impactor and sieve test experiments showed that an increase in carrier surface smoothness results in a reduced drug particle detachment during inhalation, which was independent of the type of inhaler used. This reduction could be attributed to the removal of the adhering lactose fines which may provide shelter for the drug particles from press-on forces during mixing.     

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

No HeadingPurpose. To investigate the mode of drug particle detachment from carrier crystals in an air classifier as a function of the carrier size fraction, payload, and the circulation time in the classifier.Methods. Laser diffraction analysis of the aerosol cloud from the classifier has been performed at 10, 20, 30, and 60 l/min, using a special adapter, for different adhesive mixture compositions.Results. A significant part of the drug particles is detached from carrier crystals during inhalation as small agglomerates. Such agglomerates originate from the starting material or are newly formed on the carrier surface during mixing. The degree of agglomeration during mixing depends on the carrier size, payload, and surface rugosity. The size of the agglomerates that are formed during mixing, increases with the size of the carrier particles. Predominantly the largest drug particles and agglomerates are detached within the first 0.5 s of inhalation. After 0.5 s, smaller primary particles are dislodged.Conclusions. A high ratio of removal forces to adhesive forces causes a high drug detachment rate from carrier crystals in a classifier within the first 0.5 s of inhalation. The high ratio can be explained by dislodgment of agglomerates and the largest primary particles in the early phases of inhalation. At higher flow rates, detached agglomerates may be further disintegrated into primary particles before they are discharged from the classifier. Agglomeration of drug particles on the carrier surface is the result of the same forces that are responsible for pressing these particles firmly to the carrier crystals during mixing.     

Air classifier technology (ACT) in dry powder inhalation. Part 1. Introduction of a novel force distribution concept (FDC) explaining the performance of a basic air classifier on adhesive mixtures

Air classifier technology (ACT) is introduced as part of formulation integrated dry powder inhaler development (FIDPI) to optimise the de-agglomeration of inhalation powders. Carrier retention and de-agglomeration results obtained with a basic classifier concept are discussed. The theoretical cut-off diameter for lactose of the classifier used, is between 35 and 15 μm for flow rates ranging from 20 to 70 l/min. Carrier retention of narrow size fractions is higher than 80% for flow rates between 30 and 60 l/min, inhalation times up to 6 s and classifier payloads between 0 and 30 mg. The de-agglomeration efficiency for adhesive mixtures, derived from carrier residue (CR) measurement, increases both with increasing flow rate and inhalation time. At 30 l/min, 60% fine particle detachment can be obtained within 3 s circulation time, whereas at 60 l/min only 0.5 s is necessary to release more than 70%. More detailed information of the change of detachment rate within the first 0.5 s of inhalation is obtained from laser diffraction analysis (LDA) of the aerosol cloud. The experimental results can be explained with a novel force distribution concept (FDC) which is introduced to better understand the complex effects of mixing and inhalation parameters on the size distributions of adhesion and removal forces and their relevance to the de-agglomeration in the classifier.     

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.     

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.     

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.     

The effects of carrier size and morphology on the dispersion of salbutamol sulphate after aerosolization at different flow rates

We have investigated the interdependence of various factors (particle size, surface smoothness, carrier particle shape, inhalation flow rate) on the deposition of a model drug (salbutamol sulphate) after aerosolization from a model inhaler device (Rotahaler). Different batches of alpha-lactose monohydrate were prepared to have different particle size, particle shape and surface smoothness. Each batch of lactose was then mixed separately with salbutamol sulphate in a ratio of 67.5 : 1 (w/w), under similar conditions. Drug deposition from each formulation was investigated using a 4-stage liquid impinger after aerosolization at 28.3, 60.0 and 96.0 L min(-1) via a Rotahaler. At a flow rate of 28.3 L min(-1), a large portion of drug particles was not emitted from the inhaler, the % emission varying from 29.6% to 66.6% for all formulations investigated. Drug emission tended to increase with particle size of the carrier whilst fine particle fraction, fine particle dose and dispersibility appeared to increase with decreasing particle size but increasing elongation ratio of the carrier particles. Increasing the flow rate to 60.0 L min(-1) was shown to increase drug emission since > 75% total dose was found to be emitted from the inhaler. Again, smaller or more elongated lactose particles resulted in a higher fine particle dose or fine particle fraction of salbutamol sulphate than the coarser carrier, although they produced a similar (analysis of variance P > 0.05) drug emission. Increasing the flow rate to 96.0 L min(-1) did not increase drug emission. Increasing the flow rate resulted in an increase in the fine particle fraction and fine particle dose of salbutamol sulphate from all formulations. The flow rate of the airstream appeared to play the most important role, followed by particle size and elongation ratio of the carrier particles, with the surface smoothness relatively less significant in determining the deposition of salbutamol sulphate from the Rotahaler.     

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.     

A critical view on lactose-based drug formulation and device studies for dry powder inhalation: which are relevant and what interactions to expect?

Many years of research have not led to a profound knowledge of the mechanisms involved in the formulation and dispersion of carrier based mixtures for inhalation. Although it is well understood that the mixing is a key process in DPI carrier based formulation, there remains a limited understanding of how blending processes affect in-process material properties and the resulting distribution of the drug in the final dosage form. A great number of variables are considered relevant to the interfacial forces in adhesive mixtures, but their effects have mostly been investigated individually, without taking account of the influence they may have on each other. Interactions may be expected and without proper choices made and definitions given for all the variables involved, conclusions from studies on adhesive mixtures are of less relevance. By varying any of the variables that are not subject of the study, an opposite effect may be obtained. Currently, there is a strong focus on exploring techniques for the characterisation of drug and carrier surface properties that are believed to have an influence on the interparticulate forces in adhesive mixtures. For a number of surface properties it may be questioned whether they are really the key parameters to investigate however. Their orders of magnitude are subordinate to the effects they are supposed to have on the drug-to-carrier forces. Therefore, they seem rather indicators of other variability and their influence may be dominated by other effects. Finally, the relevance of inhaler design is often ignored. By using powerful inhalers, the effect of many variables of current concern may become less relevant. Carrier properties that are considered disadvantageous at present may even become desirable when a more appropriate type of dispersion force is applied. This can be shown for the effect of carrier surface rugosity when inertial separation forces are applied instead of the more widely applied lift and drag forces. Therefore, inhaler design should be taken into consideration when evaluating studies on adhesive mixtures. It should also become an integral part of powder formulation for inhalation.     

Lactose characteristics and the generation of the aerosol

The delivery efficiency of dry-powder products for inhalation is dependent upon the drug formulation, the inhaler device, and the inhalation technique. Dry powder formulations are generally produced by mixing the micronised drug particles with larger carrier particles. These carrier particles are commonly lactose. The aerosol performance of a powder is highly dependent on the lactose characteristics, such as particle size distribution and shape and surface properties. Because lactose is the main component in these formulations, its selection is a crucial determinant of drug deposition into the lung, as interparticle forces may be affected by the carrier-particle properties. Therefore, the purpose of this article is to review the various grades of lactose, their production, and the methods of their characterisation. The origin of their adhesive and cohesive forces and their influence on aerosol generation are described, and the impact of the physicochemical properties of lactose on carrier-drug dispersion is discussed in detail.     

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.     

Back to basics: the development of a simple, homogenous, two-component dry-powder inhaler formulation for the delivery of budesonide using miscible vinyl polymers

It was hypothesised that formulating a dry-powder inhaler (DPI) using a refined, smooth grade of lactose, without fines and a polymer coated drug microparticle should produce an homogeneous formulation in which aerosolization behaviour could be modified. Hence, the aim of this study was to develop a simple two component polymer coated-budesonide/lactose blend in which the drug microparticle adhesive forces could be optimised by modifying the drug coating in order to improve aerosolization from a DPI. Budesonide microparticles (1.83 +/- 0.03 microm) were coated with the vinyl polymers by adsorption and then spray-dried. The drug was blended with three different types of lactose, checked for uniformity of mixing and loaded into Pulvinal devices. The median volume particle size of all but one of the polymer coated microparticles remained below 4 microm after spray-drying and the content uniformity for all the blends >96%. Coating the budesonide with 0.01% poly(vinyl alcohol) increased the fine particle fraction (FPF) in the next generation impactor (NGI) from 29.1 +/- 0.7% to 52.8 +/- 1.0% and reduced the force of adhesion from 410 +/- 182 to 241 +/- 82 nN with smooth lactose. This illustrates that vinyl polymers could effectively modify adhesive interactions without the need for ternary components such as fines.     

载体对微粉型粉雾剂呼吸道沉降的影响

目的：研究载体对微粉型粉雾剂呼吸道沉降的影响，筛选适合的载体组成和制备工艺。方法：以硫酸沙丁胺醇为模型药物，选用双冲程碰撞试验仪，评价以乳糖、甘露醇为载体的微粉型粉雾剂对药物在呼吸道沉降的影响。结果：含药甘露醇溶液喷雾干燥微粉，在模拟肺部药和沉降量最大（30．2％），明显高于两者分别喷雾干燥微粉的物理混合物（4．9％），处方中加入2％泊洛沙姆，并不显著增加药物沉降量；而以乳糖为载体时，呼吸道沉降量并不受乳糖介入方式的影响，但处方加入2％洛沙姆有助于提高药物在模拟肺部沉降。结论：选用甘露醇为载体以喷雾干燥法可制得较理想的微粉型粉雾剂。     

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.     

Characterisation of adhesional properties of lactose carriers using atomic force microscopy

The atomic force microscopy (AFM) colloid probe technique was investigated as a method for the characterisation of adhesional properties of pharmaceutical powder surfaces. Lactose carriers used in dry powder inhaler (DPI) formulations were chosen for investigation since adhesion between the carrier surface and drug particles has been proposed to affect the dispersion of drug particles. Individual adhesion forces were determined by measuring the detachment forces in air between the colloid probe and the lactose particle surface. The colloid probe consisted of a silica sphere (10 microm diameter) attached to a V-shaped silicon nitride cantilever (spring constant, k=0.42 N/m). Adhesion forces were calculated from individual force-distance curves using Hooke's Law. Individual forces measured at various adhesion sites were observed to be reproducible and stable over 10 min (coefficient of variation, CV below 5%). The adhesion force distribution determined from measurements at multiple sites (n>50) on each sample followed a log-normal relationship (regression coefficient, r(2) ranged between 0.95 and 0.99). This enabled characterisation in terms of the geometric mean adhesion force and a geometric standard deviation (GSD). Significant differences (P<0.001) in adhesion force were observed between samples, ranging from 37.47+/-1.95 to 117.48+/-2.20 nN. This study demonstrates the suitability of AFM as sensitive technique for the characterisation of adhesional properties of pharmaceutical particles.     

The influence of lactose carrier on the content homogeneity and dispersibility of beclomethasone dipropionate from dry powder aerosols

Dry powder formulations for inhalation usually comprise a mixture of coarse lactose (CL), employed as a carrier, and micronized drug. It was the aim of this study to determine the effects of fine lactose (FL), blended as a tertiary component on the mixing homogeneity and dispersibility of a model hydrophobic drug, beclomethasone dipropionate (BDP). BDP particles (volume median diameter (VMD) 4.6 microm) existed mainly as agglomerates, the majority of which were not dispersed into primary particles after aerosolization at a high shear force (4.7 psi). The resultant particle size distribution of BDP was multi-modal with VMD varying between 4.7 and 30.2 microm. Ternary interactive mixtures were prepared to consist of CL, FL and BDP with a fixed ratio of lactose to BDP of 67.5:1 w/w, but two concentrations of FL, i.e. 2.5 and 5%, w/w. The mixing was carried out using different sequences of adding the three components for two mixing times (15 and 60 min). Binary mixtures composed of CL and BDP were prepared for both mixing times as the controls, and these exhibited a coefficient of variation (COV) in BDP content <= 5%. Addition of FL to the binary formulations greatly reduced the content uniformity of BDP if the final powder were prepared by first mixing CL with FL before mixing with the drug (COV>20%, after mixing for 15 min). However, the mixtures, prepared using other mixing sequences, had a similar uniformity of BDP content to the binary mixtures. All ternary mixtures containing 2.5% FL consistently produced a significantly higher (ANOVA P<0.01) fine particle fraction (FPF, 3.1--6.1%) and fine particle dose (FPD, 13.6--30.1 microg) of BDP than the binary mixtures (FPF, 0.3-0.4%; FPD, 1.6-2.1 microg) after aerosolization at 60 l min(-1) via a Rotahaler into a twin stage liquid impinger. The mixing sequences exerted a significant (P<0.05) effect on the dispersion and deaggregation of BDP from the formulations prepared using a mixing time of 15 min but such an effect disappeared when the mixing time was lengthened to 60 min. The dispersibility of BDP was always higher from the ternary mixtures than from the binary mixtures. BDP delivery from dry powder inhalers was improved markedly by adding FL to the formulation, without substantial reduction in the content uniformity of the drug.     

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.