Pulmonary administration

Liquid instillation and nebulised aerosols are the most common methods for pulmonary administration to experimental animals [22, 54, 109, 134], The use of pressurised metered dose inhaler (pMDIs) and dry powder inhaler (DPIs) in preclinical studies is limited by the need for formulation development, which often cannot be performed in early drug discovery due to short supply of test materials. A number of alternative techniques for intra-tracheal administration of coarse sprays and powder formulations have been described [9, 15, 21, 36, 71, 80, 99, 138],... 

Okamoto H, Aoki M, Danjo K (2000) A novel apparatus for rat in vivo evaluation of dry powder formulations for pulmonary administration. J Pharm Sci 89 1028-1035. 

It should be noted that the permeability per surface unit of alveolar epithelium per se is not particularly high. The significant absorption found for various substances after pulmonary administration is rather explained by a number of beneficial factors such as the large surface area of the alveoli, the low volume of the epithelial lining fluid, the relatively thin diffusion layer, the absence of mucociliary clearance from the alveoli as well as the limited enzymatic activity in the lining fluids. 

Table 3.2. Absorption data after pulmonary administration of peptides and proteins. Data from reference [32].

In conclusion, it can be stated that the pulmonary administration of drugs is likely to expand rapidly in the coming years. Yet many questions still exist and extensive basic research is required before its therapeutic potential can be fully exploited in daily therapeutic practice. 

Insulin is the protein that has been most investigated for pulmonary administration. Insulin levels are not maintained in diabetic patients, and precise control over blood glucose levels is needed. Insulin is a small protein, 5.8 kDa, which is composed of two chains that are covalently linked by an interchain disulfide bond. Currently, insulin is administered by injection, several times a day for many diabetics. The ability to deliver insulin via a noninvasive route would free diabetics from inconvenient, invasive insulin delivery methods and possibly eliminate secondary problems associated with diabetes, such as diabetic retinopathy. 

FIGURE 10.4 Reduction in blood glucose following pulmonary administration of 1 U/kg insulin (a), insulin encapsulated in positively charged liposomes ( ), insulin encapsulated in negatively charged liposomes ( ), insulin encapsulated in neutral liposomes ( ). (Adapted from Li and Mitra 1996). 

Pulmonary administration of PNAs has great potential for the same reasons that pulmonary protein and peptide delivery have been successful. Predominantly, the distance for transport and ease of administration of agents are the advantages of pulmonary delivery, but the formulation of labile molecules for eventual pulmonary administration as lipid-based aerosols may be problematic. 

By the use of a breath-powered unit dose dry powder inhaler, which was adapted to the physical properties of TI, relative bioavailability was 50% for the first 3 hours and 30% over the entire 6-hour period in 12 healthy volunteers (Pfutzner et al. 2002). However, although the studies demonstrated pulmonary administration of TI has the advantages of fast onset of action, short duration of action, and lower variability over the SC injections of insulin no attempt has been made to compare pulmonary administration of insulin alone with the same inhaler device. This method of encapsulating biomacromolecules has some advantages and must be considered when electing to deliver a molecule. 

Even when the appropriate inhaler is chosen, the influence of the disease state cannot be ignored. Disease states can influence the dimension and properties of the airways and hence the disposition of any inhaled drug. Thus, great care must be taken when extrapolating the findings based on intratracheal administration to different animal species in order to predict deposition profiles after inhalation of aerosol formulations by patients suffering from airway disease. DPIs are not appropriate in many diseases when the ability to have sufficient airflow is hindered. Since many diseases that we would like to treat via pulmonary administration of biomolecules cause a decrease in airflow, we must be careful in the decision of which type of inhalation mechanism to choose. 

The field of pulmonary administration of biomacromolecules is just now in its infancy, and much promise is held in this field. By carefully examining the methods and types of delivery that are possible we may be able to better design easy to use and inexpensive methods for delivering biotechnology-derived products. This chapter was neither all-inclusive nor comprehensive, but was intended to be a starting point for the examination of pulmonary administration of biotechnology derived drugs. 

Zhang, Q., Shen, Z.C., and Nagai, T. (2001). Prolonged hypoglycemic effect of insulin-loaded polybutylcyanoacrylate nanoparticles after pulmonary administration to normal rats. Int. J. Pharmaceutics, 218, 75-80. 

The major expansion in this present volume concerns the subjects of proteomics and gene therapy, both of which offer so much promise for the future. Pulmonary administration is another likely route of delivery for the future and this is reviewed separately. Conventional wisdom suggests that proteins cannot be delivered orally but there is strong evidence suggesting that this is not always true and this is another exciting area that is reviewed here. The earlier review of vaccines has been expanded considerably since this is another area of current interest with potential for wider future application. 

In addition to injections, pulmonary administration also allows rapid absorption of analgesics into the blood stream. The AerX pain management system, which is currently being developed jointly by Aradigm and Glaxo Smith Kline for morphine and fentanyl, produces an aerosol from an active substance solution (Fig. 17). 

Plasma levels on pulmonary administration corresponded to those resulting from i.v. administration, Tmax being reached in 2 min (Fig. 18). The electronic control of the AerX system offers interesting opportunities, for example with regard to narcotic safety, such as user identification or lock-out times after a certain number of applications within a certain period to prevent overdosing. 

M. E. Ward, A. Woodhouse, L. E. Mather, S. J. Farr, J. K. Okikawa, P. Lloyd, J. A. Schuster, and R. M. Rubsamen, Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system, Clin. Pharmacol Ther 62 596 (1997). 

Fig. 2.2 Plasma bioavailability of therapeutic peptides versus molecular weight (MW) after pulmonary administration. Bioavailability is expressed as percentage of the dose deposited in the lungs relative to subcutaneous administration in humans (open symbols) and various animal species (solid symbols square and circle rodents triangle monkey).

In the A region the tight junction gap between type-I alveolar cells is reported as 1 nm. Other pores with equivalent radii of about 10 nm have also been identified. Consequently the permeability of the paracellular route is much greater than seen with other membranes. Large molecules up to 150 kDa are reported to be absorbed to a small extent into the bloodstream after pulmonary administration. 

Ohmori, Y., Onoue, S., Endo, K., Matsumoto, A., Uchida, S., and Yamada, S. (2006), Development of dry powder inhalation system of novel vasoactive intestinal peptide (VIP) analogue for pulmonary administration, Life Sci.,19,138-143. 

Pulmonary administration of pharmaceutioal oompounds using aerosols is a oommon olinioal practice due to its relatively easy use. It is generally accepted that aerosol particles of 1-5 pm in size are required for deposition in the alveolar region of the lung, which exhibits the highest systemic absorption however, particles less than 1 pm in diameter are more easily incorporated into the "respirable percentage" of aerosolized droplets. 

Drugs for pulmonary administration can be administered via dry powder inhaler or by inhalation of an aerosolized or vaporized formulation. In order to deliver a drug to the deep lung, particles must not be large or heavy enough to remain in the back of the throat or in the upper part of the lung, where... 

The feasibility of pulmonary administration for a wide variety of proteins and peptides has been evaluated in animal models and some human proof-of-concept studies, and the results of this work have been reviewed. A wide range of bioavailabilities (commercial development is progressing in earnest for most of the molecules examined due to a lack of published information appearing in the peer-reviewed scientific... 

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