Paul Hagedoorn

Technological and practical challenges of dry powder inhalers and formulations

In the 50 years following the introduction of the first dry powder inhaler to the market, several developments have occurred. Multiple-unit dose and multi-dose devices have been introduced, but first generation capsule inhalers are still widely used for new formulations. Many new particle engineering techniques have been developed and considerable effort has been put in understanding the mechanisms that control particle interaction and powder dispersion during inhalation. Yet, several misconceptions about optimal inhaler performance manage to survive in modern literature. It is, for example still widely believed that a flow rate independent fine particle fraction contributes to an inhalation performance independent therapy, that dry powder inhalers perform best at 4 kPa (or 60 L/min) and that a high resistance device cannot be operated correctly by patients with reduced lung function. Nevertheless, there seems to be a great future for dry powder inhalation. Many new areas of interest for dry powder inhalation are explored and with the assistance of new techniques like computational fluid dynamics and emerging particle engineering technologies, this is likely to result in a new generation of inhaler devices and formulations, that will enable the introduction of new therapies based on inhaled medicines.

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.

Inhalation characteristics and their effects on in vitro drug delivery from dry powder inhalers Part 2: Effect of peak flow rate (PIFR) and inspiration time on the in vitro drug release from three different types of commercial dry powder inhalers

Abstract Three commercial dry powder inhalers with completely different dosing and powder disintegration principles were evaluated in an in vitro deposition study. A four-stage cascade impactor was used for the range of flow rates between 20 and 60 1/min. Turbuhaler, Diskhaler and Spinhaler showed increasing amounts of drug discharged from the dose system with increasing peak inspiratory flow rate (PIFR). Only for the Spinhaler, was discharge influenced by total inspiration time as well. All three inhalers also showed improved powder disintegration with increasing PIFR. Highest fine particle yield was obtained from the Turbuhaler, reaching a maximum of 35–40% of the nominal dose at flow rates of 50–60 l/min. In comparison, less than 10% of the nominal dose from the Spinhaler and on average 23% from the Diskhaler were released as fine drug particles at 60 l/min. From the work of inspiration involved, it has been concluded that a short and fast inspiration through the Turbuhaler gives an optimal result from fine particle output and from efficiency point of view.

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.

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.

Dry powder inhalation of antibiotics in cystic fibrosis therapy, part 1: development of a powder formulation with colistin sulfate for a special test inhaler with an air classifier as de-agglomeration principle.

The aim of this study was to investigate the pulmonary administration of antibiotics as dry powder to patients with cystic fibrosis (CF), as an alternative for nebulization. This part of the study describes the development of a powder formulation with colistin sulfate as model substance. The aim of the new dosage form was to increase pulmonary deposition, therapeutic efficiency and, by that, compliance by the CF patients. A physical powder mixture of colistin and a size fraction of lactose (106-150 microm) was prepared and the mixture was optimized with respect to colistin content (83.3%) for use in a special test inhaler. A laser diffraction apparatus with special inhaler adapter was applied for analysis of the size distribution of the aerosol cloud from the inhaler. The size distributions of the aerosol clouds from the test inhaler at flow rates between 30 and 60 l/min for the optimized formulation showed nearly the same median diameter as that for the primary drug particles. But the X(100)-value was much lower, because of an effective large particle separation from the inspiratory air by an air classifier in the test inhaler. The results suggest that dry powder inhalation might be a suitable and highly efficient alternative for nebulization of antibiotic drugs in CF therapy.

The clinical relevance of dry powder inhaler performance for drug delivery

BACKGROUND Although understanding of the scientific basis of aerosol therapy with dry powder inhalers (DPIs) has increased, some misconceptions still persist. These include the beliefs that high resistance inhalers are unsuitable for some patients, that extra fine (<1.0 μm) particles improve peripheral lung deposition and that inhalers with flow rate-independent fine particle fractions (FPFs) produce a more consistent delivered dose to the lungs. OBJECTIVES This article aims to clarify the complex inter-relationships between inhaler design and resistance, inspiratory flow rate (IFR), FPF, lung deposition and clinical outcomes, as a better understanding may result in a better choice of DPI for individual patients. METHODS The various factors that determine the delivery of drug particles into the lungs are reviewed. These include aerodynamic particle size distribution, the inspiratory manoeuvre, airway geometry and the three basic principles that determine the site and extent of deposition: inertial impaction, sedimentation and diffusion. DPIs are classed as either dependent or independent of inspiratory flow rate and vary in their internal resistance to inspiration. The effects of these characteristics on drug deposition in the airways are described using data from studies directly comparing currently available inhaler devices. RESULTS Clinical experience shows that most patients can use a high resistance DPI effectively, even during exacerbations. Particles in the aerodynamic size range from 1.5-5 μm are shown to be optimal, as particles <1.0 μm are very likely to be exhaled again while those >5 μm may impact on the oropharynx. For DPIs with a constant FPF at all flow rates, less of the delivered dose reaches the central and peripheral lung when the flow rate increases, risking under-dosing of the required medication. In contrast, flow rate-dependent inhalers increase their FPF output at higher flow rates, which compensates for the greater impaction on the upper airways as flow rate increases. CONCLUSIONS The technical characteristics of different inhalers and the delivery and deposition of the fine particle dose to the lungs may be important additional considerations to help the physician to select the most appropriate device for the individual patient to optimise their treatment.

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.