**1. Introduction**

298 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

Tasbakan, M. S., et al. (2007). "[Role of atypical pathogens in infectious exacerbations of

This chapter deals with recent advances in the nanovector approach to the pulmonary delivery of therapeutic substances; it also describes briefly the physiology of the lungs and the main factors affecting pulmonary delivery (Figure 1).

The development of an innovative nanocarrier, able to deliver the drug to the desired site of action, is highly dependent on the nature of the active substance and on its desired mode of action.

A delivery technology can thus be used to:


Numerous approaches involving non - parenteral routes, such as intestinal, nasal, buccal, transdermal and rectal, have been examined, but most of them are inadequate for a satisfactory therapeutic response. On the other hand, the pulmonary route represents a great promise for the systemic delivery and bioavailability of peptides and proteins, since lungs are highly permeable and accessible by normal inhalation methods. Actually, the pulmonary

diseases. Inhalation of drugs is convenient and extremely efficient to treat diseased airways. It allows a targeted therapy with high drug concentrations in the tissue of interest and low systemic drug exposure (and thereby reduced side effects). Inhalation aerosols have also been developed for systemic drug administration. The large absorptive surface area, the very thin diffusion path to the bloodstream and the elevated blood flow make the lung a port of entry to the systemic circulation and proteins are absorbed more efficiently from the

Only one inhaled therapeutic protein is currently available on the market. It is recombinant human deoxyribonuclease I (Dornase alfa) indicated for the treatment of cystic fibrosis (CF)

Recombinant human deoxyribonuclease I is a glycoprotein of 37 kDa, which selectively cleaves DNA. In CF patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbation of infection. Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes. Dornase alfa is delivered to CF patients by inhalation of an aerosol mist produced by a pneumatic nebulizer. It hydrolyses the DNA in airway secretions and

Inhalation can represent the most favourable non-invasive route of administration for insulin (5.8 kDa) because insulin bioavailability can reach 37% following inhalation while it reaches at most 1% following oral, sublingual, nasal or transdermal administration without chemical enhancers (Cefalu, 2004; Illum, 2002). The first inhaled insulin product, Exubera®, was approved in January 2006 but withdrawn from the market already in October 2007 due

Another inhaled insulin product, AFREZZA™, is currently under review by the FDA for the treatment of type 1 and type 2 diabetes (Neumiller & Campbell 2010; Rossiter et al., 2010). AFREZZA™ is an ultra rapid acting insulin comprising Technosphere® insulin powder in unit dose cartridges for administration with the inhaler. The Technosphere® powder formulation is prepared by precipitating insulin from solution onto preformed diketopiperazine particles, which readily dissolve once in the lung environment. AFREZZA™ appears to overcome several limitations of Exubera®. Technosphere® insulin is both rapidly absorbed and eliminated and its pharmacokinetic profile mimics more closely normal physiologic insulin release than injection of regular human insulin as well as

A few small-scale clinical trials have been conducted on inhalation of other systemicallyacting therapeutic proteins, including interferon alpha-2b (19.3 kDa), human growth hormone (22 kDa) (Walvoord et al., 2009), an erythropoietin-Fc fusion protein (112 kDa) (Dumont et al., 2005). Inhalation of growth hormone is a potential alternative to growth hormone injection, which could offer improved patient adherence especially in pediatric patients. The bioavailability of inhaled growth hormone was 3.5% relative to subcutaneous injection in children, while it reached 7.6% in adults (Walvoord et al., 2009). The hypothesis behind this difference is that children have smaller oropharynx and larynx, which results in different deposition patterns as compared to adults. Although children preferred the inhalation route of therapy, ongoing development of growth hormone inhalation has been delayed due to its low bioavailability. An erythropoietin-Fc fusion protein was absorbed in

lungs than from any other non-invasive route of drug administration.

and marketed since 1994.

reduces their viscoelasticity.

to disappointing sales.

of rapid-acting analogues.

Fig. 1. Factors affecting pulmonary delivery

route typically shows from 10 to 200 times greater bioavailability with respect to other non invasive routes (Patton & Byron, 2007 ). Thus, various pharmaceutical techniques have been introduced to take advantage of this route. These include formulations using specific and innovative excipients, chemical modifications of drugs, polymeric and/or amphiphilic Drug Delivery Systems (DDSs), particle engineering, inhalation devices.

In particular, over the past decade, the use of DDSs involving micro or nanocarriers and particle engineering techniques were remarkably developed and the resulting pharmaceutical techniques have been eagerly applied to the pulmonary delivery of drugs.

Inhalation is also a proven means of systemic delivery for drugs that have limited bioavailability by other routes or would benefit from rapid onset of action and a variety of products are being developed for this purpose (Gonda, 2006; Patton & Byron, 2007 ).

At the same time, in recent decades, advances in device design and formulation science have addressed the need for more efficient inhalers that are capable of delivering larger doses to the lung with low extrathoracic deposition. Once deposited in the lungs, drug disposition (dissolution, absorption, distribution, metabolism and elimination) and the influence of pulmonary pharmacokinetics (PK) are the critical determinants of clinical outcomes in terms of drug efficacy and safety. Pulmonary disposition remains poorly understood despite modern capabilities in imaging, analytical and biological science which make measurement of drug disposition and mode of action more accessible. For these reasons the development of new inhaled medicines capable to allow improvements in current therapy is a promising challenge in the development new DDSs.

A number of benefits result from inhalation of drugs and a continuously increasing number of inhaled drugs and nanomedicines are becoming available for the treatment various

route typically shows from 10 to 200 times greater bioavailability with respect to other non invasive routes (Patton & Byron, 2007 ). Thus, various pharmaceutical techniques have been introduced to take advantage of this route. These include formulations using specific and innovative excipients, chemical modifications of drugs, polymeric and/or amphiphilic Drug

In particular, over the past decade, the use of DDSs involving micro or nanocarriers and particle engineering techniques were remarkably developed and the resulting pharmaceutical techniques have been eagerly applied to the pulmonary delivery of drugs. Inhalation is also a proven means of systemic delivery for drugs that have limited bioavailability by other routes or would benefit from rapid onset of action and a variety of

At the same time, in recent decades, advances in device design and formulation science have addressed the need for more efficient inhalers that are capable of delivering larger doses to the lung with low extrathoracic deposition. Once deposited in the lungs, drug disposition (dissolution, absorption, distribution, metabolism and elimination) and the influence of pulmonary pharmacokinetics (PK) are the critical determinants of clinical outcomes in terms of drug efficacy and safety. Pulmonary disposition remains poorly understood despite modern capabilities in imaging, analytical and biological science which make measurement of drug disposition and mode of action more accessible. For these reasons the development of new inhaled medicines capable to allow improvements in current therapy is a promising

A number of benefits result from inhalation of drugs and a continuously increasing number of inhaled drugs and nanomedicines are becoming available for the treatment various

products are being developed for this purpose (Gonda, 2006; Patton & Byron, 2007 ).

Fig. 1. Factors affecting pulmonary delivery

challenge in the development new DDSs.

Delivery Systems (DDSs), particle engineering, inhalation devices.

diseases. Inhalation of drugs is convenient and extremely efficient to treat diseased airways. It allows a targeted therapy with high drug concentrations in the tissue of interest and low systemic drug exposure (and thereby reduced side effects). Inhalation aerosols have also been developed for systemic drug administration. The large absorptive surface area, the very thin diffusion path to the bloodstream and the elevated blood flow make the lung a port of entry to the systemic circulation and proteins are absorbed more efficiently from the lungs than from any other non-invasive route of drug administration.

Only one inhaled therapeutic protein is currently available on the market. It is recombinant human deoxyribonuclease I (Dornase alfa) indicated for the treatment of cystic fibrosis (CF) and marketed since 1994.

Recombinant human deoxyribonuclease I is a glycoprotein of 37 kDa, which selectively cleaves DNA. In CF patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbation of infection. Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes. Dornase alfa is delivered to CF patients by inhalation of an aerosol mist produced by a pneumatic nebulizer. It hydrolyses the DNA in airway secretions and reduces their viscoelasticity.

Inhalation can represent the most favourable non-invasive route of administration for insulin (5.8 kDa) because insulin bioavailability can reach 37% following inhalation while it reaches at most 1% following oral, sublingual, nasal or transdermal administration without chemical enhancers (Cefalu, 2004; Illum, 2002). The first inhaled insulin product, Exubera®, was approved in January 2006 but withdrawn from the market already in October 2007 due to disappointing sales.

Another inhaled insulin product, AFREZZA™, is currently under review by the FDA for the treatment of type 1 and type 2 diabetes (Neumiller & Campbell 2010; Rossiter et al., 2010).

AFREZZA™ is an ultra rapid acting insulin comprising Technosphere® insulin powder in unit dose cartridges for administration with the inhaler. The Technosphere® powder formulation is prepared by precipitating insulin from solution onto preformed diketopiperazine particles, which readily dissolve once in the lung environment. AFREZZA™ appears to overcome several limitations of Exubera®. Technosphere® insulin is both rapidly absorbed and eliminated and its pharmacokinetic profile mimics more closely normal physiologic insulin release than injection of regular human insulin as well as of rapid-acting analogues.

A few small-scale clinical trials have been conducted on inhalation of other systemicallyacting therapeutic proteins, including interferon alpha-2b (19.3 kDa), human growth hormone (22 kDa) (Walvoord et al., 2009), an erythropoietin-Fc fusion protein (112 kDa) (Dumont et al., 2005). Inhalation of growth hormone is a potential alternative to growth hormone injection, which could offer improved patient adherence especially in pediatric patients. The bioavailability of inhaled growth hormone was 3.5% relative to subcutaneous injection in children, while it reached 7.6% in adults (Walvoord et al., 2009). The hypothesis behind this difference is that children have smaller oropharynx and larynx, which results in different deposition patterns as compared to adults. Although children preferred the inhalation route of therapy, ongoing development of growth hormone inhalation has been delayed due to its low bioavailability. An erythropoietin-Fc fusion protein was absorbed in

Bilayers are also the structural form in which surfactant is assembled and stored by pneumocytes in lamellar bodies. At the air–liquid interface, phospholipids form oriented monolayers, with the hydrophilic headgroups oriented towards the aqueous phase and the hydrophobic acyl chains pointing towards the air. The higher the concentration of phopholipid molecules at the interface, the lower the surface tension, the lower the energy

Specific surfactant proteins include SP-A, SP-B, SP-C and SP-D. SP-A and SP-D are hydrophilic while SP-B and SP-C are hydrophobic. SP-A is able to bind multiple ligands, including sugars, Ca2+ and phospholipids. This property allows SP-A to bind to the surface of pathogens, contributing to their elimination from the airways. Recognition of SP-A by specific receptors on alveolar macrophages stimulates phagocytosis of the pathogens. SP-B is strictly required for the biogenesis of pulmonary surfactant and its packing into lamellar bodies. Both, SP-B and SP-C promote rapid transfer of phospholipids from bilayers stores

Luminal airway and alveolar macrophages are at the forefront of lung defence and their primary role is to participate in innate immune responses, that is, chemotaxis, phagocytosis, and microbial killing (Geiser, 2010). They also downregulate adaptive immune responses and protect the lung from T-cell-mediated inflammation (Holt et al., 2008). Macrophages are tightly applied on the surface of respiratory epithelia. They are immersed in the lung

Although they occupy only 1% of the alveolar surface, they are capable to clean particles from the entire alveolar surface due to amoeboid movements (Geiser, 2010). In contrast to surface macrophages, interstitial macrophages are primarily involved in adaptive immunity by interfacing with lymphocytes via antigen presentation and production of cytokines

The lung presents a lower level of metabolism than the gastrointestinal tract and liver. Yet, various peptidases are distributed on the surface of different cell types in the lung, including bronchial and alveolar epithelial cells, submucosal glands, smooth muscles, endothelial cells, connective tissue. Proteases are largely present in lysosomes (Buhling et al., 2004). Proteases that degrade the extracellular matrix are secreted by different structural cells or

Proteases play an essential role in cell and tissue growth, differentiation, repair, remodelling, cell migration and peptide-mediated inflammation (van der Velden & Hulsmann, 1999). Proteases can also be released in the airspaces by activated macrophages and neutrophils in case of inflammatory reactions in the respiratory tract (Buhling et al., 2006; Tetley, 2002). Blood supply to the lungs is divided among the pulmonary and systemic circulations (Altiere & Thompson, 1996). The pulmonary circulation consists of the pulmonary artery that leaves the right heart, branches into a dense pulmonary capillary bed that surrounds the alveoli and finally coalesces into the pulmonary vein that drains into the left heart. One hundred percent of the cardiac output flows through the pulmonary circulation. Its principal functions are gas exchange with air in the alveoli and nutrients supply to terminal respiratory units. The lungs receive a second blood supply via the systemic circulation, commonly referred to as the bronchial circulation. The bronchial circulation originates from the aorta and provides oxygenated blood and nutrients to all

required to enlarge the alveolar surface during inspiration.

into air– liquid interfaces.

(Geiser, 2010).

lining fluid beneath the surfactant film.

are membrane bound (Stamenkovic, 2003).

the bloodstream following delivery to the central lung regions in humans, with a dosedependent concentrations in the serum, suggesting that large therapeutic molecules can be delivered to humans via the lungs using the FcRn-mediated transport pathway (Dumont et al., 2005).
