Early inhalation systems

The first commercially available DPI system appeared on the market in 1949, developed and marketed by Abbott under the name Aerohaler. Like all early pulmonary drug-delivery devices, it delivered small-molecule compoimds (bronchodilators or inhaled corticosteroids) to the airways (not necessarily the deep limg) for the treatment of asthma or chronic obstructive pulmonary disease. Table 6 lists some of the early DPI systems used for asthma and COPD the energy somces in these devices were mechanical and patient inspiration. 

Pressurized metered dose inhalers are still the most frequently used systems and they have proven their value in therapy. However, their application in early phases of biopharmaceuti-cal research and further development of dosage forms seems less convenient, since they require special components including propellants, special containers, metering valves, and controlled filling conditions (pressure-filling or cold-filling). 

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. 

Mechanism of Action A mast cell stabilizer that prevents the activation and release of inflammatory mediators, such as histamine, leukotrienes, mast cells, eosinophils, andmonocytes.T herapeuticEffect Prevents both early and late asthmatic responses. Pharmacokinetics The extent of absorption is 7% to 9% of a single inhaled dose of 3.5 to 4 mg and 17% of multiple inhaled doses, with absorption largely from the respiratory tract. Although most of the inhaled dose is subsequently swallowed, only 2% to 3% is absorbed from the G1 tract. Less than 4% of the total dose is systemically absorbed following multiple doses of ophthalmic solution. Protein binding 89%. Not metabolized. Excreted in urine. Half-life 1.5-3.3 hr. 

Urgent treatment is often begun with an oral dose of 30-60 mg prednisone per day or an intravenous dose of 1 mg/kg methylprednisolone every 6 hours the daily dose is decreased after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in a week or 10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels. Because adrenal suppression by corticosteroids is related to dose and because secretion of endogenous corticosteroids has a diurnal variation, it is customary to administer corticosteroids early in the morning after endogenous ACTH secretion has peaked. For prevention of nocturnal asthma, however, oral or inhaled corticosteroids are most effective when given in the late afternoon. 

It is likely that the effect of white phosphorus in the oral cavity is local, resulting from contact of "inhaled" white phosphorus particles with tissue in the mouth. White phosphorus may affect the oral mucosa. Dull, red spots in the oral mucosa, an early sign of phossy jaw, have been reported to precede its development in occupationally exposed workers (Kennon and Hallam 1944). The oral mucosa of workers exposed to white phosphorus has been described as having a dull, red, unhealthy appearance (Hughes et al. 1962). Exposed bones may be especially susceptible to the irritating affects of white phosphorus. It is not known whether white phosphorus ingested and absorbed into the systemic circulation contributed to the development of phossy jaw. 

Some of the early entrants into this field have expanded their activities into delivery routes other than their original core technology, so that they can offer solutions in the transdermal, inhalation and other fields as well as oral formulations. This is hue of Alza, Elan and 3M, the latter being something of a hybrid since it is also a pharmaceutical company in the conventional sense. By contrast, some companies in this field are linked to specific routes of administration Inhale Therapeutic systems, as its name implies, focuses on inhalation technology, while Pharmatec International, one of the oldest-established advanced drag delivery concerns, remains committed to the oral route. 

Early dry powder inhaler devices were all unit-dose systems and depended on loading and triggering procedures. The Spinhaler and Rotahaler are two early examples of DPI technology. Both utilize premetered doses packed into hard gelatin capsules although different mechanisms of powder delivery are employed ... 

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