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.

Air classifier technology (ACT) in dry powder inhalation Part 3. Design and development of an air classifier family for the Novolizer multi-dose dry powder inhaler.

In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023-0.041 kPa(0.5) min l(-1)). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.

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.

Comparative in vitro performance evaluation of the Novopulmon 200 Novolizer and Budesonid-ratiopharm Jethaler: two novel budesonide dry powder inhalers.

A special single dose collector and a multi stage liquid impinger were used to assess the consistency of delivered dose and fine particle fraction respectively, of the Novopulmon 200 Novolizer (Viatris, Frankfurt, Germany) and Budesonid-ratiopharm Jethaler (Ratiopharm, Ulm, Germany). The obtained average delivered dose from the Jethaler at 4 kPa is 199 microg (99.5% of the label claim) versus 219 microg (109.6%) for the Novolizer (mean of 90 doses from the same device). The corresponding relative standard deviation (RSD) for the Jethaler is on average 14.05% (maximal and minimal dose are 289 and 148 microg respectively), versus an RSD of 5.56% for the Novolizer (max. is 240; min. is 187 microg). It can be shown that the rather extreme spread in the delivered dose from the Jethaler is caused by a variation in metered mass, and to less extent by a poor content uniformity of the drug-lactose compact. The fine particle fractions (FPFs, as percent of label claim, for particles <5.1 microm) of both devices show an increase with increasing pressure drop across the inhalers, although at 4 kPa already 62% (Jethaler), respectively 72% (Novolizer) of the 'maximal' value (at 8 kPa) is achieved. FPF from the Novolizer is highest at all pressure drops and varies between 23.2% (at 2 kPa) and 54.3% (at 8 kPa). The difference in FPF between both devices increases with decreasing upper class for the FPF: the ratio of FPF from Novolizer to that from Jethaler (at 4 kPa) is 1.42 for particles < 5.1 microm versus 2.14 for particles < 1.8 microm, suggesting that the aerosol produced by the Novolizer has much greater potential for deep lung deposition.

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 microm 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 6s and classifier payloads between 0 and 30mg. 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 3s circulation time, whereas at 60 l/min only 0.5s is necessary to release more than 70%. More detailed information of the change of detachment rate within the first 0.5s 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.

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 200M) 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.

Characterization of inhalation aerosols: a critical evaluation of cascade impactor analysis and laser diffraction technique.

Cascade impactor analysis is the standard technique for in vitro characterization of aerosol clouds generated by medical aerosol generators. One important reason for using this inertial separation principle is that drug fractions are classified into aerodynamic size ranges that are relevant to the deposition in the respiratory tract. Measurement of these fractions with chemical detection methods enables establishment of the particle size distribution of the drug in the presence of excipients. However, the technique is laborious and time consuming and most of the devices used for inhaler evaluation lack sufficient possibilities for automation. In addition to that, impactors often have to be operated under conditions for which they were not designed and calibrated. Particularly, flow rates through impactors are increased to values at which the flow through the nozzles is highly turbulent. This has an uncontrolled influence on the collection efficiencies and cut-off curves of these nozzles. Moreover, the cut-off value varies with the flow rate through an impactor nozzle. On the other hand, the high air flow resistances of most impactors are rather restricting to the attainable (fixed) inspiratory flow curves through these devices. Especially for breath actuated dry powder inhalers, higher flow rates and flow increase rates may be desirable than can be achieved in combination with a particular type of impactor. In this paper, the applicability of laser diffraction technology is evaluated as a very fast and highly reliable alternative for cascade impactor analysis. With this technique, aerodynamic diameters cannot be measured, but for comparative evaluation and development, comprising most in vitro applications, this is not necessary. Laser diffraction has excellent possibilities for automated recording of data and testing conditions, and the size classes are independent of the flow rate. Practical limitations can be overcome by using a special inhaler adapter which enables control of the inspiratory flow curve through the inhaler, analysis of the emitted fine particle mass fraction and pre-separation of large particles during testing of dry powder inhalers containing adhesive mixtures.

Design and application of a new modular adapter for laser diffraction characterization of inhalation aerosols.

An inhaler adapter has been designed for the characterization of the aerosol clouds from medical aerosol generators such as nebulizers, dry powder inhalers (dpis) and metered dose inhalers (mdis) with laser diffraction technology. The adapter has a pre-separator, for separation of large particles (i.e. carrier crystals) from the aerosol cloud before it is exposed to the laser beam. It also has a fine particle collector for measuring the emitted mass fraction of fines by chemical detection methods after laser diffraction sizing. The closed system enables flow control through the aerosol generators and all test conditions, including ambient temperature and relative humidity, are automatically recorded. Counter flows minimize particle deposition onto the two windows for the laser beam, which make successive measurements without cleaning of these windows possible. The adapter has successfully been tested for nebulizers, mdis and dpis. In a comparative study with ten nebulizers it was found that these devices differ considerably in droplet size (distribution) of the aerosol cloud for the same 10% aqueous tobramycin solution (volume median diameters ranging from 1.25 to 3.25 microm) when they are used under the conditions recommended by the manufacturers. The droplet size distribution generated by the Sidestream (with PortaNeb compressor) is very constant during nebulization until dry running of the device. Comparative testing of dpis containing spherical pellet type of formulations for the drug (e.g. the AstraZeneca Turbuhaler) with the adapter is fast and simple. But also formulations containing larger carrier material could successfully be measured. Disintegration efficiency of a test inhaler with carrier retainment (acting as a pre-separator) could be measured quite accurately both for a colistin sulfate formulation with 16.7% of a lactose fraction 106-150 microm and for a budesonide formulation with a carrier mixture of Pharmatose 325 and 150 M. Therefore, it is concluded that, with this special adapter, laser diffraction may be a valuable tool for comparative inhaler evaluation, device development, powder formulation and quality control. Compared to cascade impactor analysis, laser diffraction is much faster. In addition to that, more detailed and also different information about the aerosol cloud is obtained.

Equivalence testing of salbutamol dry powder inhalers: in vitro impaction results versus in vivo efficacy.

The aim of the study was to evaluate several impactors for in vitro equivalence testing of salbutamol with respect to efficacy and to define in vitro equivalence limits validated with in vivo efficacy data. The four impactors described in Supplement 2000 of the European Pharmacopoeia were used: Glass Impinger (GI), Metal Impinger (MI), Multistage Liquid Impinger (MSLI) and Andersen Cascade Impactor (ACI). Three salbutamol dry powder formulations with different fine particle doses (FPDs) were prepared and the aerodynamic particle size distribution was measured. For each impactor also the recovery was determined. The same three preparations were administered to 12 asthmatic patients in a randomized, placebo-controlled, four-way crossover study. Cumulative doses from 50 microg up to 400 microg were given. The FEV(1) was measured at baseline and 15 min after each dose. The in vitro results showed large differences between the FPDs of the three preparations with all impactors, whereas only small differences were observed between the four impactors. Since the recoveries of the MI and GI were low, in vitro equivalence testing should only be performed with the MSLI or ACI. The in vivo measurements did not show significant differences in efficacy between the three active preparations, even at the most discriminatory dose of 50 microg. It is concluded that in case there are no relevant differences between delivered dose, inhalation device and excipients, for salbutamol dry powder inhalers equivalence can be assumed when the 90% confidence interval for the FPD ratio of the test product and reference product is within 0.50-1.20 and each of the two products has a FPD (particles <6 microm) of at least 10 microg.

Inhalation of tobramycin in cystic fibrosis. Part 1: the choice of a nebulizer.

Forteen commercially available jet and ultrasonic nebulizers were investigated with the aim to select the most suitable type of apparatus for the inhalation of a 10% tobramycin solution. Two different techniques for measurement of particle size distribution were evaluated: laser diffraction and cascade impactor analysis. The final selection of the nebulizers is based on particle size distribution, output and stable performance during nebulization. All 14 nebulizers (eight jet and six ultrasonic) were filled with a solution of 10% m/v tobramycin (as sulphate) in water. The volume in the tested devices ranged from 4.5 to 10 ml (=450-1000 mg tobramycin) in accordance with the prescribed usage by the suppliers. The nebulizers were connected with a special designed adapter to a laser diffraction analyser in order to measure particle size distribution of the aerosol. Inhalation was simulated with a static flow of 40 l/min. The particle size distribution (expressed as X(10), X(50), and X(90)) was determined after 10 s, 1.5, 3, 4.5, 6, 9 and 12 min of nebulization. Furthermore, the tobramycin solutions were assayed for tobramycin content before and after nebulization. For all nebulizers, the mean particle size distribution, depicted as X(50), was within the range of 1-5 mm. There were no relevant differences between the nebulizers in concentration or particle size distribution during nebulization. The output of the nebulizers is a result of both nebulization and evaporation. The output, expressed as volume of tobramycin solution, ranged from 0.06 to 0.50 ml/min. The output of tobramycin ranged from 1.2 to 39.5 mg/min. For clinical practice 300-600 mg have to be nebulized within 20-30 min. It was concluded that only three jet nebulizers [Porta-Neb Sidestream (PNS), Porta-Neb Ventstream (PNV) and Pariboy Pari LC+ (PLC)] have a reasonable output and an acceptable particle size distribution for the administration of a 10% tobramycin solution in the therapeutic dosage range.

Inhalation of tobramycin in cystic fibrosis. Part 2: optimization of the tobramycin solution for a jet and an ultrasonic nebulizer.

The inhalation of tobramycin is part of current cystic fibrosis (CF) therapy. Local therapy with inhaled antibiotics has demonstrated improvements in pulmonary function. Current inhalation therapy is limited by the available drug formulations in combination with the nebulization time. The aim of this study is to develop a highly concentrated tobramycin solution for inhalation. Several tobramycin solutions, ranging from 5 to 30% (m/v), were compared after aerosolation with a jet and with an ultrasonic nebulizer. Laser diffraction and cascade impactor analysis were used for characterization of the aerosolized solutions. The output rate was determined in volume and mass output per minute. From the output rate measurements, it was concluded that a 20% tobramycin solution is the optimal and maximal concentration to be aerosolized. The jet nebulizer was most suitable. Using the jet nebulizer and the 20% solution, it is possible to administer a dosage of 1000 mg tobramycin by inhalation within 30 min.