key: cord-0006995-mal0112q authors: Köhler, Dieter title: Aerosols for systemic treatment date: 1990 journal: Lung DOI: 10.1007/bf02718194 sha: 6911cffd682a3f0e72f3dc1f2c7ec978650186d3 doc_id: 6995 cord_uid: mal0112q The development of a new group of drugs (polypeptides) have recently increased the interest of alternative administration to the enteral route because of its proteolytic activity and the catabolism of the “first-pass effect.” Aside from the “needle,” the administration in the respiratory tract via aerosol is the method with the best efficiency. But several problems prohibited its spreading: (1) the accuracy and the reproducibility of the inhaled dose (range ca. 1:4); (2) the small amount of inhaled drug in relation to the dose in the aerosol delivery system (range ca. 1%–10%); (3) the fear of allergic reactions of the respiratory system; (4) the variability of the drug transport into the systemic circulation. New approaches and data raise hopes in reducing the problems: (1) aerosol delivery systems with defined particle spectrum and storage systems; slow vital capacity inhaling maneuver; (2) delivery systems that nebulizes nearly the total amount of drug; (3) all studies with the inhalation application of insulin, heparin, ergotamin, ribavirin, aminoglycosides, and “cigarette smoke” do not reveal any relevant allergic reaction; (4) many studies were performed in the last 10 years on the influence of substances and especially of diseases on the transport of molecules through the respiratory tract. Only a few of them are relevant (exogen allergic alveolitis, active sarcoidosis, active smoking). Aerosols for systemic drug treatment seems to be a gained alternative to the “syringe.” . With the exception of the administration of antibiotics, antiviral agents, and vaccines, the other indications have not been widely used and are therefore uncertain. Some of them are only anecdotal. A similar situation exists with respect to the administration of aerosols for systemic purposes is shown in Table 2 . Only the treatment of headache with ergotamine [14] as a metered-dose inhaler is established (Table 3) . Some work has been done on the aerosol administration of insulin [28, 42, 50] . All these studies have shown rapid transport of insulin into the blood with a half-life of approximately 15-25 min. However, the total amount of insulin deposited in the respiratory tract was unknown in all these studies. The poor reproducibility of the inhaled dose was always the reason for terminating these experiments. We performed a study with inhalation of human insulin in 12 volunteers (five smokers and seven nonsmokers) using a special aerosol administration device (AMMD < 2/xm), which allows the estimation of the intrabronchially deposited dose [28, 42] . The inhalation device was calibrated with 99mTc-DTPAaerosol in each volunteer. The time course of the serum insulin (the endogenous insulin is subtracted) and the plasma glucose is given in Figs. 1 and 2 . The dose of insulin transported into the blood was approximately 30% in the nonsmoking group and approximately 65% in the smoking group. It can be assumed that the missing proportion is either stored in the bronchial cells or disturbed by the proteolytic enzymes in the bronchial tree. Interestingly the serum insulin peaks occurred at a similar time in both groups ( Fig. 1) . This leads to the assumption that the transport across the bronchial mucosa is an active mechanism, not simply diffusion. Bhalla and Crocker have shown this mechanism for albumin and peroxidase [2] . Completely different are the problems encountered with the inhalation of heparin. The inhaled heparin seems to be stored and slowly released from the [3, 31] , because the antithrombotic effect of heparin was seen over more than 24 h. No data are available about the characteristics of low-molecular-weight heparin. Heparin generally seems to be a promising substance, because it has an antithrombotic and preventive effect not only on the postmyocardial survival rate [35] , but also on atherosclerosis [9, 23] . As yet, heparin is the only drug known to be able to reverse sclerosis [43] . Less information exists about the intrabronchial administration of polypeptides and prostaglandins by aerosol. Nasal administration is most common. But in future polypeptide drugs will be of greater interest owing to their short haftlife and primary influence on the biologic cybernetic system. To ameliorate the side effects associated with cessation of smoking, a nicotine aerosol is sometimes used [5, 39] . The aerosol administration of nicotine is superior to oral or transcutaneous administration, because it imitates administration via cigarette smoke. The pulsatile pharmacokinetics of nicotine are primarily responsible for abuse [40] . The two main factors preventing the spread of this route of administration are the unsteadiness in dosimetry and the interdisciplinarity of this problem. The influences on the action of the drug from its generation to transport into the blood are very complex and can be divided into six steps (Fig. 3) : The drug itself must be acceptable for inhalation (pK, solubility, taste [26, 40] . In addition, hygroscopy influences its growth in the water-saturated part of the bronchial tree [10, 29, 30] . For the development of a convenient administration system it would be better if the drug could be micronized [7] . The aerosol generator (or delivery system if the drug is micronized) must produce particles that are small enough to achieve an adequate intrabronchial deposition [4, 8, 18, 27, 32, 44, 46] . On the other hand, the aerosols must be big enough to transport a sufficient amount of substance into the lung (volume diameter3). Furthermore, the particle spectrum from the nebulizer should not be influenced by the inspiratory flow (closed system) [13, 26] . -Breathing pattern (4,6,13,18,26,32.38.44) DEPOSITION -Anatomy of the respiratory tract -Site -Homogeneity (4,8,11,18,26,32,38.44 ) TRANSPORT into BLOOD -Size of the molecules -Solubility -Diseases (2, 7, 19, 21, 28, 31, 33, 36, 37, 40, 42) BIOLOGICAL RESPONSE Fig. 3 . Flow chart representing the influences on the action of the drug from its generation to transport into the blood and final biological response. alteration of the particles constant, the time between generation and inhalation should not differ remarkably. The humidity of the ambient air is rarely noticed to determine the additional weight loss of the nebulizer solution by evaporation [13, 32] . This itself influences the concentration of the drug in the aerosol generator during nebulization [13, 26, 5 I] . Ultrasonic nebulizers should be used with caution because they can alter complex organic molecules [50, 51] . The inhalation maneuver has a noticeable influence on the amount of aerosol deposited in the bronchial tree [4, 8, 13, 18, 26, 32, 38, 44] . The most reliable maneuver is the slow deep breath (similar to a slow vital capacity maneuver) with a breath-holding time of >5 s. The above-mentioned influences on the aerosol deposition in the respiratory tract are modified by anatomy, especially from the area glottica [4, 8, 11, 18, 26, 38, 41] . The site of deposition varies with the anatomy and the degree of bronchial obstruction. This also influences the exhaled dose and the inhomogeneity of the deposition [8, 26, 41] . The transport of the drug into the blood must be measured separately for each chosen drug. It depends on the size of the molecules [2, 19, 28, 36, 37, 40, 42] , the water/lipid solubility and pK [7, 19, 31, 36, 40] and is increased by cigarette smoking as well as some other diseases (e.g. active sarcoidosis, exogenic allergic alveolitis, ARDS, pneumocystis carinii infection [19, 21, 28, 33, 36, 41] . In summary, the administration of drugs for systemic purposes via aerosol inhalation should be more appreciated. Improved aerosol administration devices now available that allow a more precise aerosol deposition in the bronchial tree raise hope for advances in this form of drug administration. Prophylaxis of viral respiratory infection with aerosolized vaccine Tracheal permeability in rats exposed to ozone Clinical use of intrapulmonary heparin Deposition of aerosol in the respiratory tract Hiller FC Plasmia nicotine levels after inhalation of aerosolized nicotine Outpatient inhaled antibiotic therapy in CF: a therapeutic success Pharmacokinetics of inhaled substances Physical principles underlying aerosol therapy Heparin and the atherosclerosis process The size of soluble aerosol particles as a function of the humidity of the air. Application to the human respiratory tract der Lunge suspendierter Teilchen in der menschlichen Lunge bei der Atmung Biochemistry and clinical applications of ribavirin Grunds~itzliche Untersuchungen zur Deponierung yon Aerosolen aus radioaktiven L6sungen in den Atemwegen Aerosol ergotamine tartrate for migraine and Horton's Syndrome Aerosolized treatment of acute pulmonary infections Aerosolized ribavirin treatment of infants with respiratory syncytial viral infection. A randomized double-blind study Pulmonary strategies of antioxidant defense Inhalation of aerosols: particle deposition and retention. In: Willeke K (ed) Generation of aerosols and facilities for exposure experiments Respiratory clearance of solutes Quantitative deposition of aerosolized Gentamicin in cystic fibrosis Radioaerosol lung clearance in patients with active pulmonary sarcoidosis Drug prophylaxis in atherosclerosis Pulmonary alveolar Proteinosis. Successful treatment with aerosolized trypsin Surfactant for the treatment of respiratory distress syndrom Prevention of nosocomial pneumonia using topical and parenteral antimicrobial agents Aerosolverteilungsmuster von 16 handesliJblichen Aerosolger/iten Nicht radioaktives Verfahren zur Messung der Lungenpermeabifit~it: Inhalation von Insulin Room temperature influences output from the Wright jet nebulizer Evaporative mass loss from particle samples Vascular distribution of intratracheally administered heparin I98t) Production of therapeutic aerosols. Principles and techniques I981) Rapid improvement in abnormal pulmonary epithel permeability after stopping cigarettes Status of aerosolized pentamidine for treatment and prophylaxis of Pneumocystis carinii pneumonia Effectiveness of low-dose heparin in prevention of myocardial reinfarction Oberdrrster G (t988) Lung clearance of inhaled insoluble and soluble particles Bronchial and alveolar absorption of inhaled 99mTc-DTPA Deposition and clearance of inhaled particles Pharmacological approach to smoking cessation Cigarette smoking: A dependence on high-nicotine boli Bronchoskopische Beobachtungen nach Inhalation yon Farbstoffen bei normalen und krankhaften Verh/iltnissen im Atemtrakt Pulmonary administration of human insulin in volunteers and type I-diabetes Heparin for prevention of atherosclerosis Generation and administration of aerosols for medical and physiological research studies Regional deposition of an anti-elastase drug delivered to arised dog lungs with a metered-dose inhaler Generation and respiratory deposition of therapeutic aerosols Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants Local hyperthermia benefits natural and experimental common colds Clinical indications for and effect of bland mucolytic and antimicrobial aerosols Insulin across respiratory mucosa by aerosol delivery Untersuchungen fiber die Ultraschallvernebelung von oberfl~ichenaktiven Stoffen aus Lungengewebe und Lecithin-Dispersionen im Hinblick auf die ktinstliche Befilmung von Lungen