Metered-dose inhaler deposition

Pharmaceutical powder aerosols have more stringent requirements placed upon the formulation regarding moisture, particle size, and the valve. For metered-dose inhalers, the dispensed product must be deflvered as a spray having a relatively small (3—6 -lm) particle size so that the particles can be deposited at the proper site in the respiratory system. On the other hand, topical powders must be formulated to minimize the number of particles in the 3—6-p.m range because of the adverse effects on the body if these materials are accidently inhaled. 

A number of other peptide molecules are currently being explored for delivery via inhalation (6). Very recently, a much smaller peptide (leuprolide, about 9 amino acid residues) has been delivered by metered dose inhaler (MDI) in a characterized fashion to humans (7). This work revealed that about 50% of a dose deposited in the lung could be bioavailable. This value is much greater than those reported for nasal bioavailabilities of this and similar molecules (8). These results, and ours in the rat lung (9), imply that inhalation administration of some peptide and polypeptide molecules is perfectly feasible. 

M Vidgren, J Arppe, P Vidgren, P Vainio, M Silvasti, H Tukiainen. Pulmonary deposition of 99mTc-labelled salbutamol particles in healthy volunteers after inhalation from a metered-dose inhaler and from a novel multiple-dose powder inhaler. S.T.P. Pharm Sci 4 29-32, 1994. 

The development pharmaceutics section should also include consideration of possible overdosing of the active ingredient that might arise from normal use of the dosage form—e.g., deposition of drug substance from a metered dose inhalation product in the mouth. 

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. 

Newman, S.P., Clark, A.R., Talaee, N., and Clarke, S.W., Pressurized aerosol deposition in the human lung with and without an open spacer device. Thorax, 44 706-710 (1989). Newman, S.P., Clark, A.R., Talaee, N., and Clarke, S.W., Lung deposition of 5 mg Intal from a pressurized metered dose inhaler assessed by radiotracer technique, Int. J. Pharm., 74 203-208 (1991). 

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). 

Hardy, J.G., Everard, M L., Coffiner, M., and Fossion, J., Lung deposition of a Nacystelyn metered dose inhaler formulation, J. Aerosol Med., 6 37-44 (1993). 

Hammermaier, A., Bidlingmaier, A., Waitzinger, J., Stechert, R., Wenske, H., and Jaeger, H., Radiolabelling of drugs in a metered dose inhaler (MDI) and lung deposition in human subjects, J. Aerosol Med., 7 173-176 (1994). 

Farr, S.J., Rowe, A.M., Rubsamen, R., and Taylor, G., Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler. Thorax, 50 639-644 (1995). 

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... 

Wilkes W, Fink J, Dhand R. 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. J Aerosol Med 2001 14(3)251-360. 

The systemic availability of inhaled budesonide has been measured in 15 healthy volunteers, using an open crossover design. Each subject was given three treatments, intravenous budesonide 0.5 mg, inhaled budesonide (from a metered-dose inhaler with a Nebuhaler) 1 mg (200 micrograms x 5) plus oral charcoal, and inhaled budesonide 1 mg without oral charcoal. The treatment order was randomized. The mean systemic availability of inhaled budesonide compared with intravenous budesonide was 36% with charcoal and 35% without charcoal, indicating that the absorption of budesonide from the gastrointestinal tract did not contribute to its systemic availability. Pulmonary deposition was 36% with charcoal and 34% without. When the inhaler was used incorrectly, that is, the canister was shaken only before the first of the five inhalations, systemic availability fell by 50%. This shows that the performance of each inhaler is very dependent on proper use (16). 

Thorsson L, Edsbacker S. Lung deposition of budesonide from a pressurized metered-dose inhaler attached to a spacer. Eur Respir J 1998 12(6) 1340-5. 

Pulmonary deposition efficiency depends on physicochemical characteristics, such as density of the aerosol or dry powder particles [33-35], Generally, particle diameters less than than 5 pm are required for efficient pulmonary delivery [36, 37], Pulmonary deposition also depends on the nature of the delivery device and differs between metered dose inhalers (MDIs). For example, pulmonary deposition expressed as the ratio of pulmonary versus total (pulmonary + oral) absorbed drug, ranged from 15-55% for a number of salbutamol devices and from 66-85% for drugs with lower oral bioavailabilities such as budesonide. 

S. P. Newman, Aerosol physiology, deposition, and metered dose inhalers, Allergy Proc. 72 41 (1991). 

S. P. Newman, J. Brown, K. P. Steed, S. J. Reader, and H. Kladders, Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines Comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices, Chest 113 951 (1998). 

R. Pauwels, S. Newman, and L. Borgstrom, Airway deposition and airway effects of antiasthma drugs dehvered from metered-dose inhalers, Eur. Respir. J. 70 2127 (1997). 

S. Newman, K. Steed, G. Hooper, A. Kallen, and L. Borgstrom, Comparison of gamma scintigraphy and a pharmacokinetic technique for assessing pulmonary deposition of terbutaline sulphate delivered by pressurized metered dose inhaler, Pharm. Res. 72 231 (1995). 

Patients who have difficulty in coordination with inhalers can use a spacer device. These remove the need for coordination between actuation of a pressurised metered dose inhaler and inhalation. The spacer device reduces the velocity of the aerosol and subsequent impaction on the oropharynx. In addition, the device allows more time for evaporation of the propellant so that a larger proportion of the particles can be inhaled and deposited in the lungs. The size of the spacer is important, the larger spacers with a one-way valve (Nebuhaler, Volumatic) being most effective. Spacer devices are particularly useful for patients with poor inhalation technique, for children, for patients requiring higher doses, for nocturnal asthma, and for patients who have poor coordination. 

Harnor, K. J., Perkins, A. C., Wastie, M., et al. (1993), Effect of vapor pressure on the deposition pattern from solution phase metered dose inhalers, Int. J. Pharm., 95, 111-116. 

Leach, C. L., Davidson, P. J., Hasselquist, B. E., and Boudreau, R. J. (2005), Influence of particle size and patient dosing technique on lung deposition of HFA-beclomethasone from a metered dose inhaler,./. Aerosol Med., 18, 379-385. 

Pitcairn, G, Reader, S., Pavia, D., and Newman, S. (2005), Deposition of corticosteroid aerosol in the human lung by respimat soft mist inhaler compared to deposition by metered dose inhaler or by turbuhaler dry powder inhaler, J. Aerosol Med., 18, 264-272. 

Adams, W.P. Poochikian, G. Taylor, A.S. Patel, R.M. Burke, G.P. Williams, R.L. Regulatory aspects of modifications to innovator bronchodilator metered dose inhalers and development of generic substitutes. J. Aerosol Med. Deposition, Clearance, and Effects in the Lung 1994, 7 (2), 119-134. 

Constantinou, M. Waters, S. Steel, C. Poole, K. Marino, P.P.I. Phodes, C. A birhio, F. Moore, A. Pike, V. Luthra, S. Flixotide -pressurized metered dose inhalers loaded with [ F] fluticasone propionate particles for drug deposition studies in humans with PET-formulation and analysis. J. Label. Comp. Radiopharm 2004, 47, 55-70. 

Newman, S.P. Clark, A.R. Talaee, N. Clarke, S.W. Lung deposition of 5 mg Intal from a pressurized metered dose inhaler assessed by radiotracer technique. Int. J. Pharm. 1991, 74, 203-208. 

Newman, S. Picairn, G.R. Steed, K. Harrison, A. Nagel, J. Deposition of fenoterol from pressurized metered dose inhalers containing hydrofluoroalkanes. J. Allergy Clin. Immunol. 1999, 104 (6), S253-S257. 

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