Aerosol formulations asthma

Betamethasone valerate and beclometasone dipropionate both mask the polar hydroxyl groups to increase lipophilicity. This increases the topical penetration for topical formulations used in eczema and psoriasis and aerosol formulations used in asthma. The log P0ctanoi/PH7 value of betamethasone is 2.01, whereas the log P0ctanoi/PH7 value f°r betamethasone (as valerate) is 3.60. 

P2"Agonists are widely used in the symptomatic treatment of asthma. Although both oral and aerosol formulations of these bronchodilators have been available for many years, advances have occurred in deUvery technology with the development of dry powder aerosols (qv) (see Drug delivery systems) (28). The ease of usage of these breath-activated systems has improved patient compliance and therapeutic response. There are several detailed reviews on p2-agonist therapy of bronchial asthma (29—31), and on the stmcture-activity relationships of this class of drugs (32). 

Improvements in asthma treatment include the development of more effective, safer formulations of known dmgs. The aerosol adrninistration of P2-agonists or corticosteroids results in a decrease in side effects. Also, the use of reUable sustained release formulations has revolutionized the use of oral xanthines which have a very narrow therapeutic index (see Controlled release technology). For many individuals, asthma symptoms tend to worsen at night and the inhaled bronchodilatots do not usually last through an entire night s sleep (26,27). 

For many years oral xanthines, shown in Table 2, were the preferred first-line treatment for asthma in the United States, and if the aerosol and oral formulations of P2" go sts are considered separately, as they are in Table 1, this was still the case in 1989. Within this class of compounds theophylline (8), or one of its various salt forms, such as aminophylline [317-34-0] (theophylline ethylenediamine 2 l), have been the predominant agents. Theophylline, 1,3-dimethylxanthine [58-55-9], is but one member of a class of naturally occurring alkaloids. Two more common alkaloids are theobromine (9), isomeric with theophylline and the principal alkaloid in cacao beans, and caffeine, (10), 1,3,7-Trimethylxanthine [58-08-2], found in coffee and tea. 

This chapter is not concerned with specific formulation issues however, referring to the prospect of controlled release of drugs from aerosols in the lung is worthwhile. The immediate benefit of this approach stems from the occurrence of nocturnal asthma and the need to treat this condition [56]. Several approaches have been taken to achieve this aim, ranging from reformulation [57] to the use of drug-carrier systems [58-64], Although oral controlled-release theophylline... 

Patel and coworkers (53) used a spinning-top generator to manufacture monodisperse isoproterenol aerosol composed of 2.5- and 5-pm particles. In patients with mild asthma, dose-response curves for all lung function parameters were shifted to the left for the aerosol with the 2.5-pm particles compared to that with the 5-pm particles, indicating a higher potency for the former aerosol. The authors concluded that this increase in potency could be due to an increase in the dose of drug delivered. These results were similar to those of Ruffin et al. (52) and Johnson et al. (50), because they also indicated that bronchodilator particles appear to be most effective when formulated in the 2.5- to 3.5-pm range. 

A change in particle size and aerosol velocity as a result of the HFA reformulation could also lead to an alteration in the site of deposition of beclometha-sone (BDP) within the lung compartment, perhaps favoring the lung periphery to a greater extent than the CFC formulation. Such a change in the site of deposition is suggested from data by Seale et al., who showed that the area under the cnrve (AUC) of 200 pg of the HFA formulation of BDP was similar to that of 400 pg of the CFC formulation in patients with mild to moderate asthma (61). 

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