> RECIRCULATED LIQUID
Figure 7 Schematic diagram of the Babington nebulizer.
flowing over the spherical surface. Excess liquid is collected and recirculated. Smaller quantities of liquid are required for use in the Babington than ultrasonic devices due to the need for more material to saturate the atmosphere at the elevated ambient temperatures in the latter nebulizer. Jet nebulizers, in general, require a higher operating pressure than the Babington system to produce therapeutic aerosols. Of note, however, is that in recent years, improvements in jet and ultrasonic nebulizer design have rendered these advantages of less significance than originally.
Different auxiliary methods of administration can be used in conjunction with nebulizers to deliver aerosol to the patient . A mouthpiece may be inserted in the mouth or a face mask may be attached tightly to the face. A large-bore inlet adapter attaches tubing from the nebulizer outlet to the mouthpiece or mask. It is possible to compensate for exhaled aerosol without increasing resistance to prevent condensation. A face tent fits more loosely around the patient's mouth, allowing speech. The latter arrangement is frequently used with ultrasonic nebulizers. A tracheostomy mask may be fitted to the patient's tracheostomy tube directly and requires a T-shaped adapter. Environmental chambers are used to enhance therapy and include incubators, pediatric croup tents, and hoods.
There appear to be many contradictions in the literature concerning the efficacy of nebulizer therapy. It has been suggested that although an MDI delivers a much smaller dose than a nebulizer, the same effect is observed clinically. This may be explained in terms of the time taken to administer a dose using a nebulizer. The generally smaller-particle-size output from nebulizers in comparison with that of MDIs and the delivery as solution rather than as suspension explains the time required to deliver the dose by this method. The particle size advantage of nebulizers leads to their use when patients are admitted to hospitals with severe airways obstructions. Once their condition has stabilized, the patients are placed on MDI aerosol therapy, which is more convenient.
Clinical complications related to the use of nebulizers have been observed. Facial dermatitis with superimposed bacterial infections have been described and are caused by the prolonged use of a face mask . Contamination of the small-volume nebulizers has been linked with oropharyngeal colonization [146,147]. In one report, infections were seen four times more frequently in patients receiving inhalation therapy for respiratory diseases than in those who are not. At least one example of death resulting from contamination has been reported.
It has been suggested that the increased popularity of nebulizer treatment for asthma has been the cause of an elevation of the number of deaths due to asthma. An effect that has been observed is the paradoxical bronchoconstriction, in which compounds that are administered to the airways to cause bronchodilatation cause constriction [148-150]. It has been proposed that this effect is caused by a component of the nebulizer formulation. More specifically, the presence of preservatives, the possibility of contamination, and the effects of ionic strength have all been implicated. It seems appropriate, therefore, to suggest the development of a unit-dose form with increased likelihood of sterility, without preservatives and formulated as isotonic solutions.
Hypoxia resulting from the home use of nebulizers has been reported. This would appear to result from misuse of the devices. Indeed, patient misuse may not be the only problem. A poll of 67 physicians with a stated interest in chest disease showed that there was a significant difference in their prescribing of b-adrenergic receptor agonists for delivery by nebulizer . There was a fivefold difference in the dose of albuterol, a 20-fold difference in the volume of the diluent solution, and a 10-fold variation in the flow of gas driving the nebulizer that the physicians used. Undoubtedly, some of this variation may be attributed to the use of different devices. However, implicit in these observations is a significant potential dose-delivery problem.
A completely new nebulizer principle was introduced in the late 1990s . A vibrating multicrifice plate system was employed. This electronic system does not require the cumbersome air pump of the jet nebulizers and employs a principle that can be scaled up to handheld systems .
Despite some drawbacks, the successful use of these nebulizers in the treatment of serious incidents of asthma, which do not respond to MDI or dry powder treatment, renders them a useful method in respiratory therapy.
Figure 8 shows a schematic diagram of an MDI. These devices are most frequently used to deliver suspension aerosols, consisting of solid particles of drug suspended in a liquid propellant. The original particle size of the suspended powder is very important because this dictates the smallest particle size generated from the device. The powder is prepared by milling to the appropriate size. Micronized powders prepared in this fashion are approximately 3-5 mm in size. The powder is suspended in the propellant by means of a surfactant, for example, oleic acid. Because of the size of the particles, the suspension is not colloidal and, therefore, is stable for only minutes. This means that it is important to shake the suspension to redisperse the particles before use. The propellant, in which the particles are suspended, in either a CFC blend or HFA/ethanol mixture. These have high vapor pressure and must be packed under pressure, at room temperature, or cold-filled as a liquid at a temperature well below their boiling point . The most common propellants used are propellants 11, 12, and 114 . The containers that are available for packaging are numerous, but aluminum cans or plastic-coated glass bottles are most common for pharmaceutical products. The cans are crimp-sealed with a valve through
Figure 8 Schematic of diagram of a metered-dose inhaler. (With permission of Drug Topics.)
Figure 8 Schematic of diagram of a metered-dose inhaler. (With permission of Drug Topics.)
which the contents can be dispensed. The principle of operation of these devices is that (1) a metering chamber fills with suspension as the can is inverted; (2) by depressing the valve stem, the metering chamber is simultaneously closed to the reservoir within the container and opened to the atmosphere by the actuator jet; and (3) because atmospheric pressure is much lower than the equilibrium vapor pressure in the can, the propellent vaporizes rapidly, which propels the suspended particles, surfactant, and some unevaporated propellant through the jet into the atmosphere and eventually to the patient. A variety of physical and analytical tests have been described for characterizing these systems [155-158]. Metered-dose valves have been shown to deliver 10-15% of the mean valve delivery for each actuation . Increasing the metering volume of an MDI has been shown to have no effect on the total lung deposition . The same study showed that increasing the vapor pressure of the propellant mixture resulted in both increased total lung deposition and lower airways deposition. Doses administered in each bolus vary according to the active ingredient. Albuterol sulfate, for example, has a single dose of 200 mg (Ventolin), whereas beclomethasone dipropionate is 42 mg (Beclovent). Despite dose variation, most MDIs call for administration of one or two puffs three or four times daily for adults. Figure 9 shows a number of common MDIs. These deliver albuterol, beclomethasone, and sodium cromoglycate. The inverted canisters are seen protruding above the actuator
sheath. Although components may vary, the overall design is very similar from one product to another.
A number of studies comparing metered-dose pressure-packed inhalers with other methods of inhalation have been described [161-168]. In general, MDIs are considered appropriate for patients who are ambulatory and subject to mild or moderate bronchoconstriction. The rationale for this treatment is the ability of the aerosol produced by the MDI to penetrate the lungs of the patient. The dose delivered may result in immediate relief or serve as a prophylactic, depending on the drug used. In more severe cases, particularly those requiring hospitalization of the patients, the smaller droplets produced by the nebulizer systems may be required to deliver the drug to the lung. The dose will require some time to deliver; thus, relief may be delayed, but, notably, MDI treatment is unlikely to succeed under these circumstances.
MDIs, as with other devices, are subject to misuse by patients. The administration problems associated with the delivery of aerosols from MDIs generally appear to be related to inappropriate technique, particularly coordination of breathing and actuation [169-171]. There are particular problems in the use of this technique by children, who may not respond as readily to instruction . Also of note, there is still some debate on the most appropriate methods of administration, particularly with respect to the use of different drugs.
To avoid the need for coordination in breathing and actuation of the inhaler, a breath-actuated system has been devised. Patients who inhaled at 50 L/min did not experience significantly greater bronchodilation using a breath-actuated device than those using a conventional MDI . The Autohaler, shown in
Fig. 10, is a more recent version of the breath-actuated device. For those patients who find coordination of breathing and actuation difficult, this device is convenient, providing there is no therapeutic disadvantage.
The most significant developments in metered-dose inhaler technology to occur since the early 1990s have been the introduction of hydrofluoroalkane (HFA) systems as alternatives to chlorofluorocarbon (CFC) systems . This has largely been caused by the link between the use of CFC systems and ozone depletion in the upper atmosphere [152,175]. Albuterol and beclomethasone have been reformulated in HFA products, but as yet the CFC products are still subject to an annually renewable medical exemption. The Food and Drug Administration has recently published its position on alternative propellant formulations, which should initiate the phase-out of CFCs . In the meantime, a number of generic CFC products of albuterol have been manufactured. The opportunity for reformulation of products as they come of patent is likely to increase research and development in this area in the near future. New formulation opportunities will also arise from these developments, including solutions , micellar [178,179], and microemulsion .
Dry Powder Generators
The delivery of aerosol powders by generation with minimal formulation has been an attractive prospect to many researchers. The early use of a dry powder artificial phospholipid in the treatment of neonatal respiratory distress syndrome proved very successful . Because no delivery system was available to facilitate this treatment, a simple system was devised. A Laerdal neonatal resuscitation bag was modified to hold a capsule containing the artificial surfactant, as shown schematically in Fig. 11. However, where MDIs of the prescribed medication are available, both physicians and patients prefer their use. The powders themselves have to be prepared in the same way as those used in MDIs, by milling. Often, excipients are added to carry the fine powder. Lactose has been used in both cromolyn sodium and albuterol formulations. As a consequence of the interest in dry powders, a number of products have been
Figure 11 Modified Laerdal neonatal resuscitation bag. (With permission of Lancet.)
developed for this purpose. The principle of operation of this type of generator is to use the patient's breathing to govern the airflow in which the aerosol powder is dispersed. The Spinhaler (Fisons Pharmaceuticals)  for the delivery of cromolyn sodium, shown in Fig. 12, delivers the active ingredient from a capsule that is pierced before operation. The mechanism for piercing the capsule is incorporated in the device. The Spinhaler rotates the capsule under the influence of the patient's breath, ejecting aerosol particles into the airstream. These particles pass though rotor blades, driving the capsule rotation, and are collected or deaggregated to ensure that smaller particles are administered to the patient. The Turbuhaler (AB Draco) , for delivery of terbutaline sulfate and budesonide, uses a reservoir of drug that fills a series of conical-shaped holes with the powder. By twisting a grip at the base of the Turbuhaler, the holes are filled and scraped at the surface to eliminate excess material. Thus, the dose is governed by the volume of the holes. The preparation of drug in this device is important. Micronized powder is spheronized into soft aggregates that are easily handled, for loading, but readily deaggregate for inhalation. This drug is deaggregated and delivered to the patient in the turbulent flow of air passing the conical holes as inhalation occurs. Cromolyn sodium (Intal) is supplied in 20-mg capsules, which must be administered in one inhalation four times daily, for adults. The Turbuhaler delivers less than 1 mg per actuation. The Rotahaler (Glaxo) , for delivery of albuterol, and the Berotec (Boehringer Ingelheim) , for the delivery of fenoterol, operate on a similar principle. A twisting motion of the device cracks a gelatin capsule containing the drug, which is then available for inhalation. The Inhalator (Boehringer Ingelheim), of the Berotec system, involves blister piercing and inhalation. It has been shown that the pressure drop across these devices, the Rotahaler and Inhalator, represent the extremes of low and high values, respectively . This observation is consistent with a shift in the focus of in vitro characterization based on pressure drop  as a relevant measure of performance. The importance of this feature can be considered in the following terms. A low-pressure-drop device offers little resistance to patient inspiratory flow; however, it does not induce significant shear in the powder bed. Consequently, inhalation is easy but the powder is not dispersed well. In contrast, a high-resistance device offers significant resistance to patient inspiratory flow; however, considerable shear is applied to the powder. Consequently, inhalation is more difficult but powder is dispersed well. Therefore, comparison of devices at the same pressure drop is a relevant measure of their performance, if not a truly controlled study. It is possible to go one step further to account for both pressure drop and airflow rate using a power performance criterion that then allows direct comparison of device performance, since all data are normalized for these variables .
Figure 13 shows the Spinhaler (Fisons), Rotahaler (GSK), and Diskhaler (GSK), and Fig. 14 shows a Turbuhaler (Astra-Zeneca) and Discus (GSK). While
Figure 14 Photograph of the (A) Turbuhaler and (B) Diskus.
Figure 14 Photograph of the (A) Turbuhaler and (B) Diskus.
the original DPIs appear to be similar to the pressurized-pack inhalers, the newer products can now be distinguished as operating by different principles. Since this publication of the first edition of this volume, the Rotahaler product has been discontinued and the Diskhaler and Discus products have been more prominently employed to deliver different drugs. Figure 15 shows the original Inhalator Ingelheim, used in the Berotec system described in the previous paragraph, and the Handihaler (Boehringer Ingelheim), which operates on a similar principle but has a different configuration. In addition, the Foradil Aerolizer (Novartis), which is intended to deliver formoterol fumarate (12.5 mg) from a capsule, is shown, since its principle of operation is similar to that of the other two products, that is, piercing a gelatin blister containing the drug, which is then drawn, under the patient's effort, with high resistance from the device.
As with the metered-dose inhalers, some old drugs have been repackaged in new devices. For dry powder inhalers these are not true generics but have a similar impact on the marketplace. Most notable of these in the Clickhaler (Innovata Biomed), which is marketed in Europe, for the delivery of albuterol (salbutamol) and beclomethasone.
Dry powder generation is hindered by aggregation of the particles . This property may be attributed to surface charge characteristics of the powder and van der Waals forces. A factor that exacerbates this problem is the hygroscopic nature of many pharmaceutical powders [43,45,47]. Hygroscopicity is known to change the powder flow properties . Attempts have been made to modify the surface characteristics of dry powders to reduce both aggregation
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