Intratracheal delivery

Figure 10.2 Apparent permeability coefficients (Papp) observed in vitro across Calu-3 ( ) [62] and 16HBE14o- (o) [72] cell layers vs. in vivo rate constants (Ka) determined for absorption from the rat lung after intratracheal delivery of various molecules.

Techniques used to administer G-CSF have an important impact on its absorption profile. The plasma G-CSF concentration-time profiles were strikingly different for aerosol and intratracheal deliveries. The peak plasma level was much higher and achieved earlier, and the estimated bioavailability was also significantly greater, after aerosol than after intratracheal administration [21]. It is believed that permeation and enzymatic degradation are rate-limiting steps in the absorption of G-CSF after intratracheal administration. The co-administration of surfactants or protease inhibitors may increase the absorption of G-CSF [86]. 

Komada, F., S. Iwakawa, N. Yamamoto, H. Sakakibara, and K. Okumura. 1994. Intratracheal delivery of peptide and protein agents absorption from solution and dry powder by rat lung. J. Pharm. 

Okumura, K. Iwakawa, S. Yoshida, T. Seki, T. Komada, F. Intratracheal delivery of insulin absorption from solution and aerosol by rat lung. Int. J. Pharm. 1992, 88, 63-73. 

Kharasch VS, Sweeny TD, Fredberg J, Lehr J, Damokosh Al, Avery ME, et al. Pulmonary surfactant as a vehicle for intratracheal delivery of technetium sulfur colloid and pentamidine in hamster lungs. Am Rev Respir Dis 1991 144 909-913. 

For the treatment of lung surfactant deficiency in premature human infants suffering from respiratory distress syndrome, limited clinical trials were performed showing that liposomes in the lung-instilled intratracheally either as an aerosolized mist (Ivey et al., 1977) or as a suspension via an endotracheal tube (Fujiwara et al., 1980)—rapidly improved lung function. No adverse effects were observed as a result of the supplementation with surfactant-like material. It appears, therefore, that liposomes are a suitable system for the delivery of major phospholipid components of endogenous lung surfactant. 

MacIntyre NR (2001) Intratracheal catheters as drug delivery systems. Respir Care 46 193-197. 

Taljanski W, Pierzynowski SG, Lundin PD, Westrom BR, Eirefelt S, Podlesny J, Dahlback M, Siwinska Golebiowska H, Karlsson BW (1997) Pulmonary delivery of intratracheally instilled and aerosolized cyclosporine A to young and adult rats. Drug Metab Dispos 25 917-920. 

Sporadic clinical reports, without the support of data from controlled studies, repeatedly indicate the effectiveness of intratracheal administration of parenteral antimicrobial preparations in the treatment of tracheobronchitis and pneumonia in cattle. The expectation when using this route of administration is that a greater therapeutic effect will be achieved when the drug is placed as close to the infection site as possible, rather than relying on the systemic circulation for drug delivery. 

The therapeutic efficacy of either systemic or local pulmonary delivery of the IFN-y gene was evaluated in a murine allergen-induced airway hyperresponsiveness (AHR) model (Dow et al. 1999) and it was found that a high efficiency of gene transfer could be achieved. Intratracheal administered cationic liposomes were prepared from a mixture of l,2-diacylglycero-3-ethylphosphocholine (EDMPC) and cholesterol. Intravenous injections were prepared from l,2-dioleyl-3-trimethylammo-ninm propane (DOTAP) and cholesterol and compared with pulmonary administered... 

Das A, Niven R (2001) Use of perfluorocarbon (Fluorinert) to enhance reporter gene expression following intratracheal instillation into the lungs of Balb/c mice implications for nebulized delivery of plasmids. J Pharm Sci 90 1336-1344... 

Schreier et al. [85] examined the effects of liposome encapsulation on the pharmacokinetics in sheep of amikacin, a water-soluble aminoglycoside. The dmg was formulated in 200 nm liposomes and administered by means of intratracheal instillation. The liposome formulations were soy PC/phosphatidyl glycerol (PG) (7 3 molar ratio) and soy PC/PG/CH (4 3 3). They found that both liposome formulations reduced plasma Cmax and prolonged the plasma half-life of the amikacin compared with the dmg administered as a solution, once again indicating that liposomes were controlling dmg delivery in the lungs. The inclusion of cholesterol in liposomes more than tripled the plasma half-life for the dmg compared with the liposomes without cholesterol. Cholesterol reduces the fluidity and permeability of liposomes in their liquid crystalline phase. 

Compared with insulin aqueous solution, low-viscosity insulin containing hyalur-onate (0.1-0.2%) greatly enhanced the pharmacological availability of insulin via pulmonary delivery routes to rats [57]. Morimoto et al. [57] subsequently examined the effects of intratracheal administration of different concentrations and pH va-... 

Later, Lizio et al. [78] used a new aerosol delivery system (ASTA-ADS) to investigate the pulmonary absorption and tolerability of four different cetrorelix formulations delivered as nebulized aerosols to orotracheally cannulated rats. After only 5 min exposure to the cetrorelix aerosol, serum testosterone concentrations were reduced to subnormal levels over a 24-h period. After dose adjustment (dose delivered minus exhaled amount), the bioavailabilities for pulmonary delivery ranged from 48.4 27.0% to 77.4 44.0% compared to IV administration. In addition, the lung function parameters did not reveal any formulation-related changes. Overall, the results of cetrorelix aerosol administration compared well with those obtained with intratracheal instillation of cetrorelix solution [77]. 

C.M. Lehr. 2000. Systemic delivery of the GnRH antagonist cetrorelixby intratracheal instillation in anesthetized rats. 

Since the human respiratory tract is anatomically and physiologically a very heterogeneous system, the rate and extent of absorption of macromolecules as well as their potential adverse reactions depend on the regional doses. The most convenient method to deliver drugs to the respiratory tract is by inhalation. Other methods of delivery such as intratracheal instillation are used in experimental settings but are generally unsuitable for real-life therapeutic products. This section... 

Meyer KB, Thompson MM, Levy MY, Barron LG, Szoka FC. Intratracheal gene delivery to the mouse airway characterization of plasmid DNA expression and pharmacokinetics. Gene Ther 1995, 2, 450-460. 

Lizio, R., Klenner, T., Borchard, G., Romeis, P., Sarlikiotis, A.W., Reissmann, T. and Lehr, C.-M. (2000) Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation in anaesthetized rats. European Journal of Pharmaceutical Sciences, 9, 253-258. 

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