Physiological Pharmaceutics

Pulmonary drug delivery 245clearance, particularly in a hypertonic concentration where it facilitates expectoration 41 . Itmay liquefy sputum by enhancing chloride (and water) flux across the bronchial mucosa 45 .Mucolytic aerosols are also widely used; N-acetyl-cysteine (Airbron) being best known inBritain, and 2 mercapto-ethane ethane sulphonate (Mistabron) in Europe. Mistabronappears to enhance mucociliary clearance in patients with chronic bronchitis 46 . Othermolecules such as DL-penicillamine and dithiothreitol act on the sulphhydryl bonds inmucus causing thinning, though nebulization of dithiothreitol causes intense irritation andis therefore unsuitable for clinical exploitation 47 .On rare occasions antihistamines and antibiotics may by given as aerosols. Antibioticsare given because in asthmatics the mucus thickens and “plugs” the bronchiole. This plugmay then become a focus for infection. Some antibiotics, notably the tetracyclines 48 , interactwith mucus glycoprotein causing thickening. The exudates formed during inflammation anddisease probably cause a mucus thickening by physical entrapment of mucus withbiopolymers such as albumin, IgG, or IgA leading to changes in mucus viscoelasticity.Systemically-absorbed drugsAs has been mentioned, the pulmonary route has been used to achieve systemic delivery. Aproduct containing ergotamine tartrate is available as an aerosolized dosage inhaler (360 µgper dose) and has the advantage of avoiding the delay in drug absorption due to gastric stasisassociated with migraine. In vaccine delivery, aerosol administration of para-influenza Type2 vaccine has been found to be more effective than subcutaneous injection 49 ). Penicillinreaches the bloodstream in therapeutic quantities after pulmonary delivery, but kanamycinis poorly absorbed from the lung so can only be used for local drug delivery.The deep lung has been investigated as a site for delivering large molecule proteins andpeptides as it is believed that the morphology of the alveolar epithelium predisposes it toabsorb large molecule compounds. The pulmonary route has been explored for the deliveryof insulin and human growth hormone, and absorption was found to be greatest in thosesubjects with the highest penetration index, implying that deep central deposition is aprerequisite for absorption 50 51 . The pharmacokinetics of these materials, which haveextremely short intravenous half-lives of 3 and 40 minutes respectively, were dominated bythe slower limiting pulmonary absorption rate.REFERENCES1. Straub NC. Pulmonary edema due to increased microvascular permeability to fluid andprotein. Circ. Res. 1978; 43:143–151.2. Newman SP. Scintigraphic assessment of therapeutic aerosols. Crit. Rev. Therapeut. DrugCarrier Syst. 1993; 10:65–109.3. DiSousa S. The Montreal protocol and essential use exemptions. J. Aerosol Med. 1995;8:S13–17.4. Bisgaard H. Delivery of inhaled medication to children. J. Asthma 1997; 34:443–467.5. Ashworth HL, Wilson CG, Sims EE, Wooton PK, Hardy JG. Delivery of propellantsoluble drug from a metered dose inhaler. Thorax 1991; 46:245–247.6. Harnor KJ, Perkins AC, Wastie ML, Wilson CG, Sims EE, Feely LC, Fair SJ.. Effect ofvapour pressure on the deposition pattern from solution phase metered dose inhalers. Int.J. Pharmaceut. 1993; 95:111–116.7. Leach C. Enhanced drug delivery through reformulating MDIs with HFA propellants—drug deposition and its effect on preclinical and clinical programs. In Respiratory drugdelivery V Dalby, R.N., Byron, PR. Fair, S.J (eds). Buffalo Grove, Interpharm Press1996:133–144.8. Newman SP, Weisz AWB, Talaee N, Clarke SW. Improvement of drug delivery with abreath actuated pressurised aerosol for patients with poor inhaler technique. Thorax1991; 46:712–716.