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History and Evolution of Aerosolized Therapeutics^*

Overview and Introduction

^* From the Division of Pulmonary and Critical Care Medicine, MCP Hahnemann School of Medicine, Philadelphia, PA.

Correspondence to: Stanley B. Fiel, MD, FCCP, Medical College of Pennsylvania Hospital, Division of Pulmonary and Critical Care Medicine, 4th Floor, 3300 Henry Ave, Philadelphia, PA 19129; e-mail: stanley.fiel{at}drexel.edu

	Introduction

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Aerosolized therapeutic agents have been used to relieve diseases of the airways since early in medical history. The earliest versions were medicines that were added to boiling water and inhaled. Today’s more sophisticated aerosolized therapeutic agents are delivered via ultrasonic compressors, jet nebulizers, dry powder inhalers, and metered-dose inhalers. The delivery of aerosolized therapeutic agents for systemic activity or locally to the airways via inhalation confers numerous advantages. Advances in the formulation of pharmacologic agents, coupled with newly designed aerosol devices, have expanded treatment options to accommodate various and specific patient factors (ie, incoordination, breathing, breath holding, and flow rate). Investigators are working in a variety of clinical areas, including systemic disorders such as diabetes, Paget’s disease, and pain management, and in diseases localized to the airways, such as cystic fibrosis, asthma, and bronchiectasis.

	Challenges in Administration of Aerosolized Therapeutics

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The most efficient delivery of systemic therapeutic agents historically has been via the parenteral route. However, there are several disadvantages associated with parenteral administration. Among these, systemic toxicity, injection site reactions, in-hospital administration to provide accurate dosing by a medically competent individual, patient adherence to therapy, and cost represent a few of the major concerns. When it is available, aerosolized therapeutic delivery provides solutions to some of the shortcomings inherent in parenteral drug therapy. In this issue, Dr. Paula Anderson discusses the evolution of aerosol device technology in a comprehensive review of current and future products, describing the features, benefits, and limitations of various device models and configurations.

	Applications for Aerosolized Therapeutics

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Diseases of the airways are logical candidates for treatment with aerosolized therapeutics, and aerosolized formulations of corticosteroids have been used in the treatment of asthma, cystic fibrosis, and obstructive lung disorders for several years. Other airway diseases in which aerosolized drug delivery may be effective include bronchiectasis, pulmonary and bronchial infections, ventilator-associated infections such as pneumonia, and sinusitis.

Among those on a lengthy list, some of the more promising agents include the following: leuprolide acetate for the treatment of infertility, postmenopausal breast cancer, and prostate cancer; morphine and fentanyl for analgesia; cyclosporine for the prevention of allograft rejection; ₁-antitrypsin proteinase inhibitor for the treatment of congenital emphysema; and growth hormone-releasing factor for the treatment of pituitary short stature.

In his article, Dr. Robert Kuhn discusses recent experiences that have enhanced our understanding of the conditions and requirements for successful aerosolization of therapeutics. He reviews issues of dosing and drug deposition in relation to particle size, delivery device, and delivery target as he describes some of the challenges encountered in creating new formulations that are both safe and effective for inhalation. Such research has resulted in the refinement of some existing aerosol devices. In addition, the development of new technologies has stimulated further clinical investigation with aerosolized agents in a number of therapeutic areas.

Diabetes and Aerosolized Insulin Therapy
Early scientific pursuits to develop an alternative insulin delivery system were aimed at enhancing therapeutic compliance and optimizing disease management. These researchers encountered many obstacles throughout their efforts to formulate an inhaled insulin product that would allow patients to avoid injections and provide efficacious treatment results. In the mid-1980s, two studies^{1 2} demonstrated that intranasal insulin therapy was effective in lowering plasma glucose levels in diabetics. However, these initial formulations required the addition of surface-active agents, which improved intranasal absorption but also were irritating to the nasal mucosa. Other early studies in humans³ with intranasal insulin therapy failed to achieve the delivery of sufficient therapeutic concentrations for adequate diabetes management. Thus, the aerosolization of insulin was largely abandoned.

Advances throughout the last decade have expanded our knowledge of the pharmacokinetics and pharmacodynamics of aerosolized therapeutics, and our understanding of the diabetic disease process has improved stimulating research activity with aerosol devices for insulin delivery. In her review of the aerosolization of insulin to treat diabetes, Dr. Beth Laube provides an update on recent technologic and clinical achievements in the management of this disease.

Cystic Fibrosis and Aerosolized Antibiotic Therapy
Establishing and maintaining effective antibiotic concentrations is of particular concern in treating cystic fibrosis patients, coupled with physical and chemical conditions that increase the complexity and difficulty of treatment. The viscosity of mucus in cystic fibrosis patients may impede drug distribution throughout the lung. Moreover, the sputum of cystic fibrosis patients is chemically antagonistic to the bioactivity of aminoglycoside antibiotics.^{4 5} In addition, studies with ß-lactam antibiotics have shown that only 10 to 20% of the maximum serum concentration can be detected in sputum following IV administration.⁶ This helps to explain why, despite adequate parenteral antibiotic therapy, patients with cystic fibrosis continue to experience an annual 2% decline in lung function.⁷ In his article, Dr. Richard Moss reviews findings of long-term treatment with aerosolized tobramycin solution for inhalation and assesses the prospective benefits of this therapy for cystic fibrosis.

Looking forward, scientists have recently observed changes in certain infectious airways diseases. Of particular interest, the reemergence of bronchiectasis, observed with tuberculosis, AIDS, and other immune-deficient conditions, has stimulated new studies with inhaled antibiotics. Dr. Leslie Couch presents early data from an aerosolized tobramycin study in bronchiectasis patients and prospectively discusses long-term administration in patients with other infectious respiratory conditions.

Cystic Fibrosis Sputum and Aminoglycoside Penetration
To elucidate some of the dosing issues and microbiological implications of long-term antibiotic administration, Dr. John LiPuma provides an overview of our current experience with an inhaled tobramycin solution to combat Pseudomonas aeruginosa in cystic fibrosis patients. He contrasts parenteral therapy, which has been shown to reach serum aminoglycoside levels below the minimal inhibitory concentration in vitro,⁴ with aerosol therapy. A pharmacokinetic evaluation of aerosolized tobramycin solution for inhalation⁶ showed that the mean peak concentrations of the drug in sputum were > 15-fold higher following aerosol administration compared with parenteral administration. This suggests that aerosol administration of this antibacterial agent was capable of maintaining a high concentration in the sputum without elevating serum levels to toxic levels. Additionally, targeted drug delivery direct to the site of infection also may allow the use of a lower total dose to achieve effective treatment.

	On the Therapeutic Horizon...

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Beyond inhaled protein and antibiotic therapies, great strides have been made in the research and development of aerosolized gene therapy. In an article coauthored by Drs. Terence Flotte and Beth Laube, some recent investigational techniques and advances in aerosolized gene delivery using retroviral vectors and liposomes are presented.

Technologic and scientific progress in aerosolized therapeutics to manage chronic disease conditions, such as diabetes, and acute exacerbations and infections, such as those occurring in cystic fibrosis and bronchiectasis, offer hope and new-found freedom to these patients. In addition, quality-of-life benefits and the conservation of health-care dollars make continued research and clinical trials of aerosolized therapeutics essential. A number of new therapeutic agents are being explored for aerosol delivery that may have important implications for disease management in the future.

	Footnotes

 
Dr. Fiel serves on the speakers’ bureau for GlaxoWellcome and Boehringer Ingelheim and has active research grants from Genentech and Chiron.

	References

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1. Moses, AC, Gordon, GS, Carey, MC, et al (1983) Insulin administered intranasally as an insulin-bile salt aerosol: effectiveness and reproducibility in normal and diabetic subjects. Diabetes 32,1040-1047[Abstract]
2. Salzman, R, Manson, JE, Griffing, GT, et al (1985) Intranasal aerosolized insulin: mixed-meal studies and long-term use in type I diabetes. N Engl J Med 312,1078-1084[Abstract]
3. Wigley, FM, Londono, JH, Wood, SH, et al (1971) Insulin across respiratory mucosae by aerosol delivery. Diabetes 20,552-556[ISI][Medline]
4. Mendelman, PM, Smith, AL, Levy, J, et al (1985) Aminoglycoside penetration, inactivation and efficacy in cystic fibrosis sputum. Am Rev Respir Dis 132,761-765[ISI][Medline]
5. Potter, JL, Matthews, LW, Specor, S, et al (1965) Complex formation between basic antibiotics and deoxyribonucleic acid in human pulmonary secretions. Pediatrics 36,714-720[Abstract/Free Full Text]
6. Valcke, Y, Pauwels, R, Van Der Straeten, M (1990) Pharmacokinetics of antibiotics in the lung. Eur Respir J 3,715-722[Abstract]
7. Levy, J, Smith, AL, Kenny, MA, et al (1983) Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum. J Infect Dis 148,1069-1076[ISI][Medline]

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