2. The research progress of PDDS

#### 2.1 The physiological basis of pulmonary administration

Lung is the respiratory organ of the human body. It cooperates with the trachea to constitute the main place for gas exchange. The bronchi and lung can provide a large absorption area for drugs, and the total number of human alveoli is as high as 5.6 108 , and the total surface absorption area can reach up to 140 m<sup>2</sup> [15]. Moreover, the distance from the alveoli surface to the capillaries is only about 1 μm. By contrast, the distance is about 40 μm from the microvilli of the small intestine mucosa to the capillaries. Therefore, the transport distance required for the pulmonary absorption process is much shorter than that of intestinal absorption, and the drugs can be rapidly absorbed through pulmonary administration. At the same time, the lung contains the most abundant capillaries compared with other organs in human, and about 90% of the alveolar area is covered with capillaries. The area of pulmonary capillaries in adults can be as wide as 80 m2 . Moreover, the volume of blood flowing through the lung is very high, as almost all of the blood discharged

## Applications of Chitosan in Pulmonary Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.87932

through the trachea for the local treatment of lung diseases. Compared with systemic administration, pulmonary administration is an ideal way for treating lung disease. It can significantly reduce the dosage, and decrease the drug distribution in nontarget tissues, thereby reducing the toxicity and side effects [5]. After administration through the lung, the drugs can be transported into the systemic circulation through the thin alveolar epithelial cell layer. Thus, PDDS can also be used for systemic drug delivery. Due to the large absorption area of the lung and the lack of degrading enzymes, pulmonary administration can be used as a convenient and effective noninjection administration method for biomacromolecular drugs, such as proteins and nucleic acids [6–8]. The PDDS can maintain local drug concentration, reduce systemic side effects, control drug release, promote drug absorption, prolong the drug action time, and improve patient compliance. Therefore, PDDS has become a hotspot to prevent and treat diseases in current research [9, 10].

Role of Novel Drug Delivery Vehicles in Nanobiomedicine

Chitosan (CS) is a natural and widely available polycationic polysaccharide, and it has many unique physicochemical properties, good biocompatibility, and satisfactory biodegradability [11]. CS has been a popular biomaterial in pharmaceutical research for decades and is widely used in drug delivery [12]. As a drug carrier, CS can control drug release and improve the dissolution of poorly soluble drugs. A large number of studies have reported the developments and applications of CS-based materials as drug delivery carriers with versatile functions, such as CS-based beads, films, sponges, hydrogels, microspheres, and nanoparticles (NPs) [13]. Moreover, CS contains a large number of positively charged amino groups. These positive charges can interact strongly with the negatively charged mucosa membranes and adsorb on the mucosal surface, thereby avoiding the drugs being removed by the cilia, improving the adhesion rate, reducing drug clearance, and providing conditions for the drugs to penetrate through the cell membrane. At the same time, studies have shown that CS can open the tight junctions between the cells, which will promote drug transportation through the epithelial tissues, and increase the drug absorption rate and bioavailability [14]. Thus, CS is a suitable material espe-

In this chapter, we focus on the applications of CS in pulmonary drug delivery. The research progress of PDDS and the applications of CS in PDDS are reviewed, and many representative and advanced studies on CS-based PDDS are enumerated

Lung is the respiratory organ of the human body. It cooperates with the trachea to constitute the main place for gas exchange. The bronchi and lung can provide a large absorption area for drugs, and the total number of human alveoli is as high as

, and the total surface absorption area can reach up to 140 m<sup>2</sup> [15]. Moreover, the distance from the alveoli surface to the capillaries is only about 1 μm. By contrast, the distance is about 40 μm from the microvilli of the small intestine mucosa to the capillaries. Therefore, the transport distance required for the pulmonary absorption process is much shorter than that of intestinal absorption, and the drugs can be rapidly absorbed through pulmonary administration. At the same time, the lung contains the most abundant capillaries compared with other organs in human, and about 90% of the alveolar area is covered with capillaries. The area of

blood flowing through the lung is very high, as almost all of the blood discharged

. Moreover, the volume of

cially for PDDS.

2. The research progress of PDDS

2.1 The physiological basis of pulmonary administration

pulmonary capillaries in adults can be as wide as 80 m2

in detail.

5.6 108

164

from the right ventricle will pass through the lung, which is up to 5 L per minute. This blood flow volume is the equivalent of the total blood flow in all other organs and tissues of the body [16]. Besides, the chemical and enzymatic degradation activity in the lung is relatively low, which can reduce the hydrolysis of the bioactive macromolecules, such as proteins, peptides, and nucleic acids. Thus, these drugs can maintain a good biological activity after pulmonary administration, which will be beneficial to improve the drug bioavailability.

In summary, the huge absorption area, abundant capillaries, and minimal transport distance together contribute to the rapid absorption of pulmonary administration. After being quickly absorbed in the lung, the drugs will directly enter the systemic blood circulation, avoiding the first-pass effect of the liver, which is beneficial to improve the bioavailability of the drugs. And due to the low enzyme activity in the lung, the drug's adverse reactions during local administration can be reduced, which is especially suitable for the patients who need long-term administration of the medicine [17–19].

## 2.2 The characteristic and development of pulmonary administration

Pulmonary administration has been initially used to relax the tracheal smooth muscles to treat the acute exacerbation of asthma, and the disease is treated by inhaling the drugs through the trachea and the lung in the forms of drug aerosol particles or dry powder particles [20]. In general, there are two therapeutic purposes for pulmonary administration. One is the treatment of diseases in the lung, such as bronchial asthma and chronic obstructive pulmonary disease. The other purpose is to achieve systemic treatment through the pulmonary absorption of the drugs. Pulmonary inhalation administration can deliver the therapeutic agents directly to the lesion site, which can reduce the drug distribution in nontarget tissues. Therefore, for the treatment of pulmonary diseases, inhalation administration has a higher therapeutic index and fewer side effects than oral administration. And pulmonary inhalation is the preferred administration method for bronchodilators, β2-receptor agonists and corticosteroids [21].

With the deep understanding of lung functions and lung diseases in medicine field, pulmonary inhalation is recognized as a simple and effective administration route for the respiratory tract and other disease treatments. The types of the pulmonary inhalation-treated diseases have been gradually increasing, such as the insulin aerosol for treating diabetes, and the salmon calcitonin powder for the treatment of osteoporosis and osteoarthritis [22]. In recent years, the number of studies on pulmonary inhalation of macromolecular drugs, such as proteins and peptides, has been increasing. These macromolecular drugs (such as insulin, growth hormone, vaccines, and cytokines) can be formulated into pulmonary administration preparations for local or systemic treatment. However, most of the pulmonary inhalation drugs currently used in clinical treatment is short-acting preparations, which require frequent administrations (about 3–4 times a day). Therefore, the long-acting preparations should be developed, because they can maintain stable blood concentrations and also increase the compliance of the patients [23]. At the same time, the sustained or controlled drug release preparations for pulmonary administration can effectively regulate drug release behavior and promote drug absorption rate, thereby contributing to the achievement of ideal therapeutic effects [10].

The particle size of the pulmonary inhalation preparations directly affects the deposition form and deposition site in the lung [24–26]. The particles of sizes >5.0 μm produce inertial impact and are deposited in the pharynx, larynx, and upper respiratory tract. Particles of sizes 1.0–5.0 μm mainly reach the deep part of the respiratory tract, trachea, bronchi, and alveolar surface by gravity deposition.

The particles of sizes 0.5–1.0 μm are deposited on the respiratory bronchioles and alveolar walls. The particles of sizes <0.5 μm will be discharged out with airflow due to the Brownian motion, and typically 80% of them will be expelled out of the respiratory tract. Therefore, the particles with a size range of 1.0–5.0 μm have the highest deposition rate in the bronchioles and alveoli, and they are generally selected as the main components of the pulmonary inhalation preparations. Studies have shown that the pulmonary absorption of the drugs is a passive process, a small molecular weight contributes to fast drug absorption, and the absorption of the macromolecular drug is relatively slow [16]. The drugs with molecular weight below 1000 Da present short absorption half-life and good bioavailability. As the alveolar wall is very thin, macromolecular drugs can also be absorbed through the large gap between the cells or be swallowed into the lymphatic system by the macrophages in alveoli, before finally entering the blood circulation [27].

retention after mucosal administration [38]. Therefore, CS has a wide range of applications in drug delivery. It can increase the stability of the drug, prolong the drug action time, change the administration route, increase the targeting ability of the drug, control the drug release, improve the dissolution of drugs with poor solubility, and adjust the cell membrane permeability of the hydrophobic drugs. At the same time, the positively charged CS can be easily adsorbed on the mucosal surface and also hard to be removed by the cilium, thereby providing conditions for the drug to penetrate the cell membrane. Moreover, CS can open the tight junctions between the cells, which will promote drug transportation in the epithelial tissues and increase the drug absorption rate and bioavailability. Thus, CS is especially applicable for PDDS [39, 40]. CS also has inherent immunogenicity, which is absent in other polymers, and this enables its use as an adjuvant for vaccine delivery into the lung [5]. Therefore, research on the applications of the CS-based PDDS has

Traditional pulmonary administration preparations have drawbacks such as relatively short drug onset time, high frequency of administration, and poor patient compliance. In order to overcome these problems, research has been focused on the development of new PDDS with sustained or controlled drug release properties, also with active targeting abilities, for increasing the drug retention time in the lung, improving the drug concentration in treated areas, reducing the damage to normal tissues or cells, and enhancing the bioavailability of the drugs. The new formulations for PDDS in recent studies mainly include microspheres, polymeric NPs, liposomes, and active targeted systems [41]. In the following content, we will

Microspheres are microparticulate disperse systems formed by drugs dispersed or adsorbed in the polymer matrix. Microspheres have some unique advantages as a DDS for pulmonary administration [42]. They can be deposited in the lung, delay the drug release, and protect biomacromolecules, such as proteins and peptides from hydrolysis by enzymes. By optimization of the preparation process, a microsphere with an aerodynamic diameter of 1–5 μm and with suitable shape and porosity can be obtained, for meeting the requirements of pulmonary administration. In addition, microspheres usually have good stability with high moisture resistance ability. These characteristics have determined the wide applications of

There are many kinds of carrier materials for preparing microspheres. At present, the use of biodegradable microsphere as controlled release carrier is popular in DDS research [44]. Poly(lactic-co-glycolic acid) copolymer (PLGA) and CS are the commonly used biodegradable materials for microsphere preparation [45]. The

crosslinking, solvent evaporation, ion induction, and spray drying [46–49]. Among these, crosslinking is the most commonly used method in the preparation of drugloaded CS microspheres with controlled-release property. The reaction can be carried out under mild conditions, and it also can be industrially prepared easily [50]. Moreover, as CS is positively charged, it can combine with the negatively charged drugs by electrostatic binding interaction to form a complex, which can help to

attracted great attention all over the world.

Applications of Chitosan in Pulmonary Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.87932

3.2 Novel PDDS based on CS and its derivatives

introduce the above-mentioned formulations one by one.

microspheres in pulmonary administration formulations [43].

improve the drug loading capacity of the microspheres.

conventional methods for preparing CS microspheres include emulsion

3.2.1 CS-based microspheres

167

In recent years, with the development of biomaterial science, biotechnology, and medical technology, the research of new PDDS for drug-loading has focused on polymer-based microspheres, liposomes, and NPs, which can be inhaled into the lung and deposited in the lung mucosa through atomization and in the form of dry powder or other forms [28]. Compared with the atomized injections currently used in clinic, the pulmonary administration preparations based on new PDDS have the advantages of convenience, sustained or controlled drug release, prolonged drug action time, enhanced bioavailability, and improved therapeutic efficiency. PDDS with better efficacy will be designed with the development of new materials and the advancement of pharmaceutical preparation technologies. Pulmonary administration will have broad prospects for disease treatment in the medical field.
