Powder nebulizers

Administration via metered-dose inhaler (MDI) or dry-powder inhaler is at least as effective as nebulization therapy and is usually favored for reasons of cost and convenience. Refer to Table 80-1 in Chap. 80 for a comparison of the available agents. 

The preparation of aqueous solutions from solids is usually performed after the sample has been ground to a powder of uniform size. Sometimes, samples can be only sparingly soluble in water and therefore organic solvents may be used to dissolve the sample. Organic solvents can increase the sensitivities of atomic spectrometric analyses as a result of increases in the efficiencies of the nebulization of the analyte solutions. When organic solvents are used to dissolve samples non-selective ligands should be added to complex ionic species that would otherwise be insoluble in the organic solvent. 

The first aerosol experiments in this series utilizing quantitative techniques were performed by the writer in 1954. Two types of delivery were employed (a) powdered LSD diluted with talc, administered by means of a simple inertia device (Fig. la) (b) aqueous solutions of LSD administered intranasally by means of the nebulizer illustrated in Fig. lb. When a talc-LSD powder was administered intranasally, very severe reactions occurred rapidly. With a maximum dose of 256 meg delivered intranasally in the form of LSD-talc powder, subject J.M. had a most severe reaction, withdrawing to one part of my home in which the experiment took place and refusing to cooperate in his usual fashion. The data on Subject J.M. in this experiment are available. In order to study liquid aerosols, aqueous solutions of LSD-25 were administered intranasally to Subject J.M. The questionnaire was again used to estimate the severity of the reaction. The following technique of comparison was employed. 

To measure lung deposition by imaging, the aerosol must be first labelled or tagged with a suitable radionuclide. Radiolabelling techniques have been developed for current inhalation products including nebulizers, propellant-driven metered dose inhalers, and dry powder inhalers. 

Zainudin, B.M.Z., Biddiscombe. M., Tolfree, S.E.J., Short, M., and Spiro, S.G., Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurized metered dose inhaler, as a dry powder, and as a nebulized solution, Thorax, 45 469-473 (1990). 

As described in Section 3.3 in more detah, particles in the aerosol cloud should preferably have an aerodynamic diameter between 0.5 and 7.5 pm. Currently three different types of devices are used to generate aerosol clouds for inhalation nebulizers (jet or ultrasonic), (pressurized) metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). The basic function of these three completely different devices is to generate a drug-containing aerosol cloud that contains the highest possible fraction of particles in the desired size range. 

Nebulizers and dry powder inhalers seem more appropriate systems to be used in the early stages of development of drug products for pulmonary drug delivery. However, it should not be concluded from this that the development of formulations for nebulizers or DPIs is easier and exhibits fewer theoretical and practical problems. 

Zanamivir (2) is a potent competitive inhibitor of viral neuraminidase glycoprotein, which is essential in the infective cycle of both influenza A and B viruses. It inhibits a wide range of influenza A and B types in vitro as well as in vivo. The concentrations of inhibiting in vitro plaque formation of influenza A and B virus by 50% in Madin-Darby canine kidney (MDCK) cells were 0.004-0.014 p.mol/L in laboratory-passaged strains, and 0.002-16 p.mol/L in assays of clinical isolates. Due to its low bioavailability, it is delivered by inhalation via the Diskhaler , 10 mg twice daily, or intranasally 2-4 times daily for 5 days. After an intravenous dose of 1 -16 mg, the median elimination half-life was ti/2 = 7 h, the volume of distribution at steady state was Vdss = 16 L, and 90% of the dose was excreted unchanged in the urine. After intranasal and inhaled (dry powder) administration, maximum serum concentrations occurred within 2h and the terminal phase half-lives were 3.4 and 2.9 h, respectively. The bioavailabilities were 10 and 25%, respectively, and 20% after inhalation of zanamivir (2) by nebulizer. 

Aerosolized medications are available as pressurized or breath-actuated metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulized or wet aerosols. Most inhaled medications currently used are available as metered-dose inhalers (Table 3). For the patient who has difficulty to coordinate activation of a MDI, a spacer improves delivery. Spacers reduce deposition of the drug in the... 

There are a number of techniques for generating aerosols, and these are discussed in detail in the LBL report (1979) and in volumes edited by Willeke (1980) and Liu et al. (1984). We briefly review here the major methods currently in use these include atomizers and nebulizers, vibrating orifices, spinning disks, the electrical mobility analyzer discussed earlier, dry powder dispersion, tube furnaces, and condensation of vapors from the gas phase. 

The bronchial mucosa and lungs are treated with inhalations, aerosols (in the form of fine powder with the help of nebulizer) e.g. salbutamol (ASTHALIN) inhaler. 

There are other aerosol methods which can yield uniform powders, such as by dispersing aqueous dispersions of particles (e.g. of latex) and evaporating the water (12). In this case each droplet should contain only one particle, a task not easily accomplished. Alternatively, it is possible to nebulize solutions of electrolytes or other substances, which on removal of the liquid result in solid particles, dispersed in the carrier gas (13,14). This process has been expanded to include sintering of resulting solid aerosols in a continuous process to produce powders for various applications (15-18). 

Both evaporation/condensation and nebulization equipments have been employed to generate droplets of reactive organic monomers, which could undergo the polymerization to powders when exposed to an initiator vapor. 

The reaction of aerosol droplets with gases can also be used to prepare particles of internally mixed composition, such as consisting of different metal oxides. In principle, these powders can be obtained by first cocondensing vapor of the two or more volatile metal compounds (preferably alkoxides), or by nebulizing liquids of mixed composition. In both cases the droplets are then reacted with vapors. 

The nebulization was also employed to generate composite powders for specific applications, such as in ceramics, by hydrolyzing with water vapor droplets containing Al(5ec-OBu) and silicon methoxide in the atomic ratio Al/Si = 3. This ratio of alkoxides was chosen in order to produce mullite, which was achieved by calcination of the resulting amorphous particles at rather high temperatures (up to I400 C) (52). In another approach a mixed Al-Mg-Si ethoxide was first synthesized, and then nebulized and hydrolyzed as usual (77). Depending on the experimental conditions, the powders calcined at 500 C exhibited structures of pure cordierite, or mixed with forsterite. In all of these described cases the nebulization yielded spherical but polydisperse particles. 

Inhalant 12 mcg/unit inhalant powder 1% solution for nebulization Isoetharine (generic)... 

Pentamidine is an aromatic diamidine (Figure 52-3) formulated as an isethionate salt. Pentamidine is only administered parenterally. The drug leaves the circulation rapidly, with an initial half-life of about 6 hours, but it is bound avidly by tissues. Pentamidine thus accumulates and is eliminated very slowly, with a terminal elimination half-life of about 12 days. The drug can be detected in urine 6 or more weeks after treatment. Only trace amounts of pentamidine appear in the central nervous system, so it is not effective against central nervous system African trypanosomiasis. Pentamidine can also be inhaled as a nebulized powder for the prevention of pneumocystosis. Absorption into the systemic circulation after inhalation appears to be minimal. The mechanism of action of pentamidine is unknown. 

Aerosols can be generated by three main drug delivery systems nebulizers, pressurized metered dose inhaler (pMDI), and dry powder inhaler (DPI). 

Inhalation drug products include inhalation aerosols (metered dose inhalers) inhalation solutions, suspensions, and sprays (administered via nebulizers) inhalation powders (dry powder inhalers) and nasal sprays. The CMC and preclinical considerations for inhalation drug products are unique in that these drug products are intended for respiratory tract-compromised patients. This is reflected in the level of concern given to the nature of the packaging components that may come in contact with the dosage form or the patient. 

Finally, beta-2 drugs can be delivered via a dry powder inhaler (DPI).33,81 This method offers the portability and convenience similar to an MDI. Again, the therapeutic effects of delivering a beta-2 drug via a DPI are not superior to other methods of inhalation (MDI, nebulizer), but DPIs may be easier for certain patients who lack the coordination and timing needed to use an MDI.33,78... 

Delivery devices play a major role in the efficiency of pulmonary delivery, and major advances have been made in the development of new devices in recent years. The most commonly used devices for pulmonary drug delivery include nebulizers, metered-dose inhalers (MDIs) and dry-powder inhalers (DPIs). These de-... 

In order to overcome the inherent problem associated with pulmonary aqueous solution and dry powder aerosols, Choi et al. [2] developed an ethanol suspension of insulin for inhalation, in which the solid insulin is suspended in ethanol and aerosolized with a commercial compressor nebulizer. The aerosol insulin particles were found to be 1.5 pm, with a geometric standard deviation of 1.3 pm. Exposure of rats to 10 mg/mL insulin aerosol resulted in a drastic fall in blood glucose and a marked rise in serum insulin level. The bioavailability of insulin/ethanol aerosol was 33% relative to SC injection, and comparable to that of insulin aerosols in aqueous solution and dry powder form. No acute toxic effects were detected in the rat lungs or airways [2]. 

---