Latest advances in the development of dry powder inhalers

The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least another 30 under development. Clinicians recognize that DPIs are a suitable alternative to pressurized metered dose inhalers (pMDIs) for some patients but the relative performance of devices is often unclear. The problem is compounded by the need to reformulate pMDIs with new propellants, introducing further products to the market with associated variations in performance. This article reviews the DPIs currently available, the driving forces governing new designs, and the claimed advantages of DPIs in the development pipeline.     

Inhaled corticosteroid delivery systems: clinical role of a breath-actuated device

Several devices have been developed to overcome the need to co-ordinate actuation with inhalation required during use of a pressurised metered dose inhaler (MDI) and to improve drug delivery to the lung. These include spacer attachments for MDIs, dry powder inhalers and breath-actuated MDIs. The breath-actuated Autohaler (3M Pharmaceuticals) is a compact, multidose inhaler device that, unlike dry powder inhalers, does not rely on the patient's inspiratory effort to aerosolise the dose of medication. Due to its simple operation, the Autohaler is suitable for patients unable to operate a conventional MDI efficiently, including the elderly, children, patients with arthritis and patients with low inspiratory flow rates. The mandatory replacement of chlorofluorocarbon propellants with non-ozone-depleting propellants has given the opportunity to improve drug delivery characteristics of MDIs. Recently, a formulation of beclomethasone dipropionate in hydrofluoroalkane-134a (HFA-BDP), has been developed in a conventional MDI that delivers most of the emitted dose to the lung. Drug deposition studies show that the HFA-BDP formulation in the Autohaler device has a similar lung deposition pattern to drug delivered from the MDI, when used correctly, and dose delivery is consistent across a wide range of inspiratory flow rates. Furthermore, HFA-BDP Autohaler has similar clinical benefits to CFC-BDP Autohaler but at less than half the dose. HFA-BDP Autohaler offers a useful CFC-free delivery option for patients challenged by the conventional MDI device.     

Switching to CFC-free beclometasone for asthma

Chlorofluorocarbon (CFC) compounds, the traditional propellants in aerosol metered-dose inhalers (MDIs), damage the ozone layer in the atmosphere. Following adoption of the Montreal Protocol on Substances that Deplete the Ozone Layer almost 20 years ago, the UK Government produced a transition strategy to enable CFC-containing MDIs to be phased out as quickly as possible.(1, 2) Hydrofluoroalkanes (HFAs) are now being used as propellants in most MDIs (i.e. CFC-free inhalers). However, there have been particular difficulties in developing CFC-free beclometasone inhalers, as this drug dissolves in the new propellant. There are now two CFC-free beclometasone inhalers available in the UK - Qvar (Teva) and black triangle [see text for formula]Clenil Modulite (Trinity-Chiesi), both licensed for asthma. CFC-containing beclometasone MDIs will become unavailable as stocks run out (within the next year). Here we discuss the issues around switching to the CFC-free beclometasone inhalers.     

Nebulizer possibilities and limitations.

The ban of chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDIs) gives rise to many alternatives and innovations: 1. CFC substitution by non-CFC propellants in MDIs. 2. battery driven miniaturized mechanical and piezoelectric nebulizers 3. revitalization of hand driven pocket nebulizers 4. self actuated dry powder inhalers (DPI's). All devices can be used with or without spacers. The choice for solid or liquid particles, e.g. powder or droplet aerosols, will also depend on the drug properties and the availability on the market for aerosol use. The nebulizer device will be chosen according to the medical need (emergency or long term treatment), the technical alternatives available in different countries, the possibility of patient cooperation (children, severely ill patients), and last not least marketing strategies and costs. The bronchial circulation is an important distribution system for medicine deposited by aerosol routes in the lung.     

Review of dry powder inhalers

The search for alternatives to metered-dose inhalers has accelerated recently in a bid to find effective products that do not use chlorofluorocarbon (CFC) propellants. This paper reviews the factors to be considered in developing dry powder inhalers (DPIs), particularly the formulation, metering design and flow path in the device. The advantages and disadvantages of current DPIs are discussed and possible future approaches outlined.     

In vitro evaluation of dry powder inhalers I: drug deposition of commonly used devices

Inhalation of aerosolized drugs has become the therapy of choice for the treatment of lung diseases. The most commonly used device, the pressurized metered-dose inhaler (pMDI), however, relied on propellants that were found to deplete the ozone layer. To overcome this drawback dry powder inhalers (DPI) have been developed and MDIs with alternative propellants have been introduced recently. Several products are available by now. This study was carried out to evaluate the accuracy of the dose and the theoretically respirable fraction emitted from commonly used DPIs. In vitro measurements were performed using the Twin Impinger (Appendix A, British Pharmacopoiea, 1993) and a self constructed Four Stage Impinger at the standard flow rate of 60 l min⁻¹. Eleven dry powder formulations that are commercially available on the german market were tested with eight dry powder devices: Pulmicort™ and Aerodur™ Turbuhaler™, Intal™ Spinhaler™, Flui™ SCG and Cromolyn™ Orion Inhaler, Sultanol™ Diskhaler™, Flutide™ Diskus™, Atrovent™ with Inhalator M™, Ventilat™ with Inhalator Ingelheim and Buventol™ and Beclomet™ Easyhaler™. As every dry powder inhaler has a specific air flow resistance that limits flow under in vivo conditions, inhaler devices should be tested at corresponding flow conditions in vitro. Though this is not yet reflected in the pharmacopeias, a general consensus can be seen in the scientific literature. Therefore DPIs having a high resistance were tested at 30 l min⁻¹ and those showing a low resistance at 90 l min⁻¹ with the Twin Impinger additionally. Most products were found to emit a fine particle dose of 20–30% of total emitted dose at 60 l min⁻¹. The results of the Twin Impinger and the Four Stage Impinger were in good agreement. Measurements at increasing flow rates generally resulted in increasing fine particle fractions.     

Transition to CFC-free metered dose inhalers--into the new millennium

Metered dose inhalers (MDIs) are the most popular vehicle for drug delivery into the lungs and some 500 million are manufactured each year. All MDIs marketed prior to 1995 contained chlorofluorocarbons (CFC) as a propellant. These are implicated in the depletion of stratospheric ozone and, except for specific exemptions, their production has been banned since 1996 under the terms of the Montreal Protocol. Hydrofluoroalkanes have been identified as suitable alternatives for MDI propellants but their physico-chemical properties differ significantly from CFCs and an extensive redevelopment and testing programme has been required to demonstrate the safety, quality and efficacy of HFA containing MDIs. Hydrofluoroalkanes contribute to global warming but the benefit to human health through continued MDI availability currently outweighs the environmental concern. Several HFA-MDIs have reached the market and the transition to replace existing CFC-MDIs is now underway.     

Advances in Inhalation Therapy: IBC Conference

A 2-day conference on Advances in Inhalation Therapy drew together 16 speakers, experts in their respective fields, to summarize recent developments in delivery device design, drug formulation, in vitro and in vivo assessment, and to provide a clinical overview of the future of drug aerosol therapy. Concurrent advances are being made in the design of aerosol delivery devices in all areas. Reformulation of non-CFC pressurized metered dose inhalers (pMDIs) is overcoming technical, legal and engineering obstacles, although whether the new hydrofluorocarbon (HFA) products will already be limited and dated is a distinct possibility. New 'soft mist inhalers' offer a viable alternative for drug aerosol delivery that has potential advantages in efficiency in design and aerosol delivery compared to conventional pMDIs and DPIs. The reproducible generation and delivery of micronized macromolecules to the peripheral lung offers an efficient and novel means for the effective and safe delivery of peptides and proteins, with notable successes in delivery of analgesics and insulin. Novel means of designing 'smart drugs' through supercritical fluid engineering promises to further enhance the advantages of inhalation for routine drug administration.     

Comparison of beclomethasone dipropionate delivery by easyhaler dry powder inhaler and pMDI plus large volume spacer.

Dry powder inhalers (DPIs) provide a means of delivering inhaled asthma drugs without the use of propellants. Easyhaler is a multidose DPI, delivering 200 doses of beclomethasone dipropionate (BDP), 200 microg/dose. A gamma scintigraphic study has been carried out in 10 healthy volunteers to compare the deposition of BDP from Easyhaler with that from a pressurized metered dose inhaler (pMDI) coupled to a Volumatic spacer device delivering 250 microg BDP per dose. The spacer was used without any pretreatment to reduce static charge on the spacer walls. The study was conducted according to an open, randomized, crossover design. The volunteers inhaled the study drug using optimal inhalation technique for both devices. Lung deposition of 99mTc-labeled BDP averaged 18.9% (SD 9.5%) of the metered dose for Easyhaler, and 11.2% (SD 5.3%) for pMDI plus spacer (p < 0.05); when the data were expressed as mass of BDP deposited in the lungs, the difference in lung deposition just failed to reach statistical significance (Easyhaler 37.8 microg; pMDI plus spacer 28.0 microg). Oropharyngeal deposition was significantly reduced by use of the spacer. The results of this study show that Easyhaler delivers drug more efficiently to the lungs than pMDI plus Volumatic spacer when no measures are taken to eliminate static charge on the spacer walls.     

Pulmonary drug delivery systems: recent developments and prospects

Targeting drug delivery into the lungs has become one of the most important aspects of systemic or local drug delivery systems. Consequently, in the last few years, techniques and new drug delivery devices intended to deliver drugs into the lungs have been widely developed. Currently, the main drug targeting regimens include direct application of a drug into the lungs, mostly by inhalation therapy using either pressurized metered dose inhalers (pMDI) or dry powder inhalers (DPI). Intratracheal administration is commonly used as a first approach in lung drug delivery in vivo. To convey a sufficient dose of drug to the lungs, suitable drug carriers are required. These can be either solid, liquid, or gaseous excipients. Liposomes, nano- and microparticles, cyclodextrins, microemulsions, micelles, suspensions, or solutions are all examples of this type of pharmaceutical carrier that have been successfully used to target drugs into the lungs. The use of microreservoir-type systems offers clear advantages, such as high loading capacity and the possibility of controlling size and permeability, and thus of controlling the release kinetics of the drugs from the carrier systems. These systems make it possible to use relatively small numbers of vector molecules to deliver substantial amounts of a drug to the target. This review discusses the drug carriers administered or intended to be administered into the lungs. The transition to CFC-free inhalers and drug delivery systems formulated with new propellants are also discussed. Finally, in addition to the various advances made in the field of pulmonary-route administration, we describe new systems based on perfluorooctyl bromide, which guarantee oxygen delivery in the event of respiratory distress and drug delivery into the lungs.     

Novolizer: how does it fit into inhalation therapy?

Inhalation therapy is the preferred route of administration of anti-asthmatic drugs to the lungs. However, the vast majority of patients cannot use their inhalers correctly, particularly pressurised metered dose inhalers (pMDIs). The actual proportion of patients who do not use their inhalers correctly may even be under-estimated as GPs tend to over-estimate correct inhalation technique. Dry powder inhalers (DPIs) have many advantages over pMDIs. Unlike pMDIs, they are environmentally-friendly, contain no propellant gases and, more importantly, they are breath-activated, so that the patient does not need to coordinate actuation of the inhaler with inspiration. Three key parameters for correct inhaler use should be considered when evaluating existing or future DPI devices and especially when choosing the appropriate device for the patient: (1) usability, (2) particle size distribution of the emitted drug and (3) intrinsic airflow resistance of the device. The Novolizer is a breath-activated, multidose, refillable DPI. It is easy to use correctly, has multiple feedback and control mechanisms which guide the patient through the correct inhalation manoeuvre. In addition, the Novolizer has an intelligent dose counter, which resets only after a correct inhalation and may help to monitor patient compliance. The Novolizer has a comparable or better lung deposition than the Turbuhaler at similar or higher peak inspiratory flow (PIF) rates. A flow trigger valve system ensures a clinically effective fine particle fraction (FPF) and sufficient drug delivery, which is important for a good lung deposition. The FPF produced through the Novolizer is also relatively independent of flow rate and the device shows better reproducibility of metering and delivery performance compared to the Turbuhaler. The low-to-medium airflow resistance means that the Novolizer is easy for patients to use correctly. Even children, patients with severe asthma and patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) have no problems to generate the trigger inspiratory flow rate required to activate the Novolizer. The Novolizer uses an advanced DPI technology and may improve patient compliance.     

Computer-aided design of dry powder inhalers using computational fluid dynamics to assess performance

Dry powder inhalers (DPIs) are gaining popularity for the delivery of drugs. A cost effective and efficient delivery device is necessary. Developing new DPIs by modifying an existing device may be the simplest way to improve the performance of the devices. The aim of this research was to produce a new DPIs using computational fluid dynamics (CFD). The new DPIs took advantages of the Cyclohaler® and the Rotahaler®. We chose a combination of the capsule chamber of the Cyclohaler® and the mouthpiece and grid of the Rotahaler®. Computer-aided design models of the devices were created and evaluated using CFD. Prototype models were created and tested with the DPI dispersion experiments. The proposed model 3 device had a high turbulence with a good degree of deagglomeration in the CFD and the experiment data. The %fine particle fraction (FPF) was around 50% at 60?L/min. The mass median aerodynamic diameter was around 2.8–4?μm. The FPF were strongly correlated to the CFD-predicted turbulence and the mechanical impaction parameters. The drug retention in the capsule was only 5–7%. In summary, a simple modification of the Cyclohaler® and Rotahaler® could produce a better performing inhaler using the CFD-assisted design.     

Drug-surfactant-propellant interactions in HFA-formulations.

The required replacement of chlorofluorocarbon (CFC) with hydrofluoroalkane (HFA) propellants has challenged formulators of pressurized metered dose inhalers in several major respects. Conventional (CFC soluble) surfactants are effectively insoluble in the major CFC replacement candidates, HFA 134 and HFA 227ea, in the absence of co-solvents. While these ethane and propane derivatives have comparable boiling points and vapor pressures to dichlorodifluoromethane (CFC 12), their increased polarity demands that formulators use either alternative (soluble) surfactants, or co-solvents along with traditional surfactants, in order to stabilize pressurized suspension products. The use of either approach is complicated by the existence of many competing patents and the fact that the science in the area is empirical; predictive theoretical approaches are frustrated by the lack of an adequate database. Technical developments in this area must also take into account the need to avoid crystal growth and/or adhesion of micronized, suspended drugs to internal container surfaces, problems which may be catalyzed by some combinations of surfactant type/concentration, vehicle(s) and physical form/type(s) of drug substance. For some drugs, it appears simpler to use co-solvents with HFA propellants to dissolve the drug, avoiding the need for suspension stabilization. This article presents an overview of the present state of the art with respect to the formulation of MDIs.     

Inhalation therapy: alternative systems--an overview.

Three possibilities exist, in principle, to apply medication by inhalation: (1) Inhalation from Pressurized Metered Dose Inhalers (2) Direct Inhalation of Dry Powder (3) Inhalation of Nebulized Aqueous Solutions. Chlorofluorocarbons that are necessary for pressurized metered dose inhalers have unwanted environmental properties. Therefore, alternative gases are being developed (HFA-134a and HFA 227) on the premise that pressurized metered dose aerosols in airways therapy have distinct advantages which are reflected in the high acceptance and application of these MDIs worldwide. Dry powder inhalation requires sophisticated devices to provide for exact dosing. For nebulizers the major problem was their size and consequently their restricted use. Multi-dose pocket-size systems are on the market for (1) and (2). For nebulization such a system is currently being introduced. A critical comparison of benefits and disadvantages of the existing drug delivery systems to the airways leads to the conclusion that all three modes will remain essential to cover the therapeutic needs for a wide variety of drugs and patient populations.     

Innovations and perspectives of metered dose inhalers in pulmonary drug delivery.

The phase-out of chlorofluorocarbons (CFCs) has spurred the development of alternative pulmonary drug delivery systems to pressurized metered dose inhalers (MDIs), such as dry powder inhalers and pocket size nebulizers. Reformulation of CFC-MDIs with hydrofluoroalkanes (HFAs) 134a and 227 is also an opportunity to improve these widely accepted systems with respect to ease of handling, compliance, dosing, and more reliable and efficient lung deposition. MDIs have the advantage to protect the drug substance from external parameters such as temperature and humidity and to meter and de-agglomerate the drug independent from patients inspiratory flow rates. Novel formulation technologies combined with improved valves and actuators should help to overcome dose uniformity and priming problems and will increase the percentage of fine particles capable of reaching the deeper regions of the lungs. Spacer mouthpieces can reduce the cold freon effect and undesired oropharyngeal deposition caused by the rapid evaporation of the propellant and plume velocity of the aerosol cloud. More advanced delivery devices may allow the patient to inhale at predetermined flow rates (fast/slow) to target the deposition of fine drug particles (1-6 microm) to specific sites into the lungs. Breath-actuated devices make these systems more effective and patient friendly. The above features in combination with numerical counters showing the remaining number of shots, and built-in blocking mechanisms to avoid tail-off dependent dose uniformity problems of the last labeled shots, should help to improve both acceptance and compliance of pMDIs compared to other inhalation devices. However, only those inhalation systems, which are accepted and appreciated by patients and offering an ambulatory treatment at reasonable cost, will be successful in a more and more competitive market. These issues must be considered in the development of future devices and formulations.     

Metering performance of several metered-dose inhalers with different spacers/holding chambers.

Metered-dose inhalers (MDI) are routinely used to administer inhaled antiasthma drugs. Actuation-inhalation coordination problems are overcome and systemic side effects are reduced by using spacers/holding chambers (SP/HCHs). Many of these devices do not allow the use of the manufacturer's actuator. The objectives of this study were (a) to investigate the effect of the interaction of eight MDI products with four different SP/HCHs on their metering performance (MP); and (b) to test the hypothesis whether the MP obtained with a SP/HCH and a given drug (MDI) can be extrapolated to other MDIs, even for members of its particular drug class. The procedure outlined in The United States Pharmacopeia-The National Formulary was used (determination of canister weight changes after actuation). The SP/HCH tested were Aerochamber, Inspirease, and ACE. The MDIs tested were salmeterol xinafoate; albuterol with chlorofluorocarbons and 1,1,1,2-tetrafluoroethane as propellants; cromolyn sodium; nedocromil sodium; flunisolide; beclomethasone dipropionate; and fluticasone propionate. Only flunisolide-Inspirease presented an unacceptable MP. Although within the acceptable limits, the MP varied significantly between the following MDI-SP/HCH combinations: Optihaler-fluticasone propionate and Optihaler-cromolyn sodium < to Aerochamber-fluticasone propionate and Aerochamber-cromolyn sodium (p = 0.0015 and p = 0.0007, respectively); and Inspirease-flunisolide and Optihaler-flunisolide < Aerochamber flunisolide (p = 0.003 and p = 0.005, respectively). MP did not significantly vary when albuterol with chlorofluorocarbons or 1,1,1,2-tetrafluoroethane as propellants, salmeterol xinafoate, beclomethasone dipropionate, and nedocromil sodium were attached to any of the SP/HCHs studied. Our results emphasize the capital importance of choosing the right combination of MDI and SP/HCH for aerosol delivery. The MP obtained with a drug and a SP/HCH cannot be expected to be similar for other MDIs, even for members of its drug class. These data also suggest the need for regulatory agencies to approve an MDI to be used only with the SP/HCHs tested.     

Issues surrounding MDI formulation development with non-CFC propellants.

Reformulation of metered-dose inhalers (MDIs) without the use of chlorofluorocarbon (CFC) propellants presents numerous obstacles because there are no alternative propellants that can serve as immediate replacements for pharmaceutical use. Hydrofluorocarbons (HFCs), hydrochlorofluorocarbons (HCFCs) and hydrocarbons (HCs) are all under consideration as possible alternatives for CFC propellants. However, no single propellant or combination of propellants has been identified with all of the physical-chemical properties of CFCs. Based on their zero ozone depletion potentials, relatively low global warming potentials, non-flammabilities, densities, and vapor pressures, HFA-134a and HFA-227 are the most attractive replacement propellants identified to date. Yet, their use in MDIs will still require: (1) identification of a metering valve with propellant and formulation-compatible gaskets, (2) use of current suspending agents at levels much lower than in present MDIs or identification (and characterization) of new suspending agents, and (3) modification of existing manufacturing technologies. Demonstration of acceptable final product stability, safety and efficacy will be necessary prior to submission to worldwide registration authorities.     

Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler.

Accessory devices reduce common problems with metered-dose inhalers (MDIs), namely high oropharyngeal deposition of aerosol and incoordination between actuation and inhalation by the patient. The objective of this study was to systematically compare the performance of various accessory devices in vitro. MDIs were tested alone or in combination with four spacers (Toilet paper roll, Ellipse, Optihaler, Myst Assist) and five holding chambers (Aerochamber, Optichamber, Aerosol Cloud Enhancer, Medispacer, and Inspirease). An Anderson cascade impactor was used to measure aerosol mass median aerodynamic diameter (MMAD) and fine particle dose (MMAD < 4.7 microm). In separate experiments, the influence of asynchronous MDI actuation on drug delivery was determined with a simulated spontaneous breathing model. Compared with the MDI alone, all of the accessory devices reduced aerosol MMAD and increased lung-throat ratio (fine particle dose/throat impaction; p < 0.05 for both parameters). The fine particle dose of albuterol was 40% higher with the Ellipse (p < 0.01), was equivalent with the Toilet Paper Roll, Aerochamber, Optichamber, and Medispacer, and was 33-56% lower with the Optihaler, Myst Assist, Aerosol Cloud Enhancer, and Inspirease (p < 0.03). MDI actuation in synchrony with inspiration produced highest drug delivery; when MDI actuation occurred 1-sec before inspiration or during exhalation, decrease in drug delivery with holding chambers (10-40% reduction) was less than that with spacers (40-90% reduction). Accessory device selection is complicated by variability in performance between devices, and in the performance of each device in different clinical settings. In vitro characterization of a MDI and accessory device could guide appropriate device selection in various clinical settings.