Strategies for pulmonary delivery of drugs

C H A P T E R

3 Strategies for pulmonary delivery of drugs Rohitas Deshmukh1, Nabamita Bandyopadhyay2, Sara Nidal Abed3, Shantanu Bandopadhyay4, Yogendra Pal5 and Pran Kishore Deb3 1

Institute of Pharmaceutical Research, GLA University, Mathura, India 2Institute of Business Excellence and Clinical Research, Kanpur, India 3Faculty of Pharmacy, Philadelphia University, Amman, Jordan 4Faculty of Pharmacy, Naraina Vidya Peeth Group of Institutions, Kanpur, India 5Department of Pharmacy, Pranveer Singh Institute of Technology, Kanpur, India O U T L I N E 3.1 Pulmonary tract: an overview 3.1.1 Physiological aspects 3.1.2 Disorders of pulmonary tract

3.5 Aerosol-generation deposition mechanisms 3.5.1 Inertial impaction 3.5.2 Sedimentation 3.5.3 Diffusion

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3.2 Pulmonary drug delivery: cutting edge of modern drug delivery research 95 3.2.1 Transepithelial transport of drug 95 3.2.2 Mechanisms and ways of pulmonary drug administration 97 3.3 Modes of pulmonary drug delivery

3.6 Drug 3.6.1 3.6.2 3.6.3

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3.4 Pulmonary delivery of drug molecules: formulation aspect 100 3.4.1 Lung compatibility of formulation excipients/polymers 100 3.4.2 Mechanisms of drug absorption from the lung 101 3.4.3 Preparation of particulate matter 104

Drug Delivery Systems DOI: https://doi.org/10.1016/B978-0-12-814487-9.00003-X

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delivery devices 109 Nebulizers 109 Pressurized metered-dose inhalers 112 Dry powder inhalers 114

3.7 Pulmonary products in market

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3.8 Regulatory considerations

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3.9 Conclusion

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Abbreviations

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References

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Copyright © 2020 Elsevier Inc. All rights reserved.

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3.1 Pulmonary tract: an overview 3.1.1 Physiological aspects 3.1.1.1 Organs and structures of the respiratory system The synchronous functions of different organs of the respiratory system (or pulmonary tract) are to supply oxygen to various tissues in the body for cellular respiration, exhale the waste product (i.e., carbon dioxide), and sustain the acid base balance. Different parts of the respiratory system are also utilized for nonvital functions, such as speech, sensing odors, and under tense conditions such as during coughing or childbirth (Adamson, 1991; Huh et al., 2010; Canning et al., 2014; Hamm et al., 2015). The upper compartment of pulmonary tract consists of the organs that are present outside thorax, that is, nose, pharynx, and larynx, while the lower compartment includes the organs within thorax, that is, trachea, bronchi, bronchioles, alveolar duct, and alveoli. The upper part reaches out from the sino-nasal region to the larynx. The upper part’s cells are sometimes found in the lower respiratory tract specimens, which are the significant focal point of diagnostic respiratory cytopathology, reaching out from the trachea to the lungs. The tracheobronchial tree divides into dynamically smaller units, that is, bronchi, bronchioles, and respiratory acini (Ortiz Berrocal, 1967; Patwa and Shah, 2015). Fig. 3.1 illustrates the various parts of the upper and lower respiratory tract. 3.1.1.2 Structure of the nose The nose is a vital part of the respiratory system for proper passage and exit. It is divided into two major segments, namely, the external nose and internal nose (i.e., nasal cavity). Fig. 3.2 depicts the structure of the nose with various segments. External nose forms a pyramidal projection in the middle of the face (Elad et al., 2008). It presents with the following features: • Tip (or apex): It is the lower free end of the nose. • Root: The upper narrow part attached to the forehead is the root of the nose. • Dorsum of the nose: It is formed by a rounded border between the tip and root of the nose along with the adjoining area. FIGURE 3.1 Parts of the upper and lower respiUpper respiratory track

ratory tract.

Nasal cavity Pharynx Larynx Lower respiratory track Trachea Primary bronchi Lungs

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FIGURE 3.2 Illustration of the nose shows features of the external nose (top) and skeletal features of the nose (bottom).

• Nostrils or anterior nares: These are two piriform-shaped apertures present at the broad lower part of the nose The external nose is made up of the cartilaginous framework supported by bones and is covered with skin. The bony framework comprises • two nasal bones, forming the bridge of the nose, and • frontal processes of maxillae. The cartilaginous framework comprises five main cartilages and several additional tiny ones. The five main cartilages are as follows: • Two lateral alar cartilages, one upper and one lower. • Two major alar cartilages: Each major alar cartilage comprises a medial and a lateral cru. • A single median septal cartilage. Fig. 3.2 depicts the skeletal structures lying beneath the thin skin of the nose. The lower parts, that is, root and bridge portion of the nose consists of bone while the distending portion is made of cartilage. Therefore the nose is absent in the images of a skull. The nasal bone comprises a couple of bones that lie under the root and extension of the nose. The nasal bone is fenestrated with the frontal bone on the upper side and maxillary bones on the sides. The dorsum nasi comprises septal cartilage that is a stretchable hyaline cartilage connected to the nasal bone. Surrounding this naris is the alar cartilage present in the top of the nose (Morris, 1988). The nares open into the nasal hole, wherein the nasal septum divides it into left and right areas. In the front the nasal septum is formed of the septal ligament (the flexible part

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which can be touched by fingers) as well as by the ethmoid bone’s the perpendicular plate, which is a cranial bone found only posterior to the nasal bones, along with thin vomer bones in the back. Each nasal cavity’s lateral wall is shown to have three hard bony projections, known as the superior, middle, and inferior nasal conchae. The inferior conchae consist of independent bones, whereas the middle and superior conchae are considered as parts of the ethmoid bone (Carstens, 2000). Functionally, conchae provide an enhanced surface area in the nasal cavity. It serves as an interruption to the stream of air entering the nasal cavity, which when touches the epithelium of the lining to generate a clean and warm air. Besides, conchae and meatuses prevent dehydration by trapping water in the nasal epithelium, which aids in water conservation during exhalation (Cappello and Dublin, 2018). The bottom of the nasal cavity is termed as the palate and consists of two parts, that is, hard palate and soft palate. The frontal area is the hard palate, which is made of bone, whereas the back area is termed as soft palate composed of muscle tissue. The surrounding air enters into the nasal cavity through the internal nares and finally into the pharynx (Cappello and Dublin, 2018). On the basis of the functions of the respiratory system, it can be classified into two regions: • conducting zone: extending from nose to bronchioles and forming a way for the flow of inhaled gases, and • respiratory zone: extending from the alveolar duct to alveoli where the gaseous exchange occurs. 3.1.1.3 Exchange of gases The gas exchange occurs when the blood diffuses in the capillaries as well as the body cells. This exchange of gases at the cellular level in lungs and tissues is described as internal respiration. Two gases, namely, oxygen (O2) and carbon dioxide (CO2), are transported between the lungs and tissues through the blood. The blood vessels supplying blood from the heart to the tissues do not support the exchange of gases owing to thick arterial walls. These exchange mechanisms work on the principle of biophysics that gases try to equalize the pressure on either side by the process of diffusion if there is a pressure gradient (Hughes, 1974). In the pulmonary capillaries the exchange of CO2 and O2 occurs with the aid of alveoli model. The blood with increased O2 level and decreased CO2 level is carried by the lungs and pumped by the left side of the heart to the various tissues. In the expiration process an elevated level of CO2 is exhaled from the body. Relaxation and contraction of the lungs occur with each breath, which ensures normal gaseous exchange between alveoli and the surrounding air. A schematic diagram for the exchange of gases within the respiratory system is shown in Fig. 3.3.

3.1.2 Disorders of pulmonary tract Based on the anatomy of the lungs, the pulmonary system is separated into the upper and lower respiratory tract. The upper tract consists of nose airway, larynx, and pharynx, while the lower tract consists of the trachea, the primary bronchi, and lungs.

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89 FIGURE 3.3 A schematic diagram of the gas exchange function of the respiratory system.

The inflamed upper respiratory tract can result from inhaling irritants but generally due to diseases. These diseases and/or disorders are initiated by viruses and thus lowering the resistance to additional infections. This allows dormant bacteria lying in the tract to attack the healthy tissues (Budden et al., 2019). These infections are life-threatening only if: • they extend to the lungs and onto new organs, and • the airway was blocked by exudate and inflammatory swelling. Microbe spreading usually occurs by droplet infection, in dust, or by contaminated dressings and equipment. If it was not resolved completely, this might result in an acute infection which can become chronic. Owing to the large surface area, the pulmonary tract is consistently exposed to bacteria. This enables the pulmonary system to protect itself via various mechanisms and obstructs the inflow of pathogens into the body. The viral infection causes acute inflammation of the mucosa layer, leading to tissue clogging and abundant exudates of watery fluid. Purulent discharge usually results from bacterial secondary infection (Budden et al., 2019). The disorders of the pulmonary system can be categorized into four common areas: • Obstructive conditions (e.g., emphysema, asthma attacks, bronchitis). • Restrictive conditions (e.g., alveolar damage, pleural effusion sarcoidosis, fibrosis). • Vascular diseases (e.g., pulmonary hypertension, pulmonary edema, pulmonary embolism). • Infectious, environmental, and other “diseases” (e.g., tuberculosis, pneumonia, asbestosis, particulate pollutants): Coughing has considerable significance as it is a principal mechanism to expel dust, saliva, mucus, and other waste from the lungs. Failure of coughing mechanism leads to infection. Exercises involving deep breathing help in maintaining the feathery parts of the lungs clear from any particulate matter, etc.

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3.1.2.1 Asthma Repetitive occurrences of coughing, wheezing, chest tightness, and breathlessness mainly at night or early morning are major symptoms of asthma. It is a chronic inflammatory disorder of respiratory airways, which can be divided as either atopic or nonatopic. Atopic asthma is most common and categorized as extrinsic, which means it is triggered with the environment. Atopic asthma involves inflammation mediated by systemic IgE production. On the other hand, nonatopic asthma is an intrinsic type and far less common. Nonatopic asthma, therefore, refers to the airway’s constriction and inflammation that does not result from the exposure to the allergen, and the inflammation is mediated by the local IgE production (Davies et al., 1976). Many cells and cellular elements, such as mast cells, T cells, eosinophils, neutrophils, macrophages, and epithelial cells, play a vital role in the development of this disease. Asthma symptoms are often linked with erratic airway obstruction that is frequently reversible, either suddenly or with treatment. Existing bronchial hyperresponsiveness to various stimuli also increases due to inflammation in the pulmonary airway (Bernstein, 2008). In clinical practice a broad clinical range is commonly observed, and also numerous comorbidities, perplexing and/or precipitating conditions that include atopy, gastroesophageal reflux, rhinosinusitis, aspirin intolerance, the impact of cigarette smoking as well as occupation-related contacts. Controlling asthma alludes to brief asthma side effects and the nonattendance of intensifications. Nonexplicit bronchial hyperresponsiveness is a typical result in patients having rhinitis, despite the fact that asthma symptoms may initially be lacking. Exacerbations of asthma require immediate visits to medicinal providers and a vital modification on the pharmacological management—more often than not a short course of oral corticosteroids (Chechani, 1991; Bush, 2019). The everlasting lack of control, repetitive exacerbations, and high prescription prerequisites regardless of ideal administration characterize “troublesome asthma.” This ought to be examined by step-by-step examinations to ensure the security of the analysis of asthma, evaluate consistency issues and comorbidities and, sometimes, will prompt to the severe asthma diagnosis (Chanez et al., 2007). In these circumstances the role of rhinosinusitis is ought to be cautiously reassessed utilizing clinical and imaging examinations. Rhinosinusitis is shown to be frequent as well as extensive in serious asthma (Bresciani et al., 2001). It has been demonstrated that ethmoidal association is considered to serve as a specific feature in severe asthma; in addition, it has been found that there is a relationship between extensive sinusitis and aviation route inflammation and indirect indices of distal aviation route changes (Ten Brinke et al., 2002). 3.1.2.2 Bronchitis Bronchitis is defined as an acute inflammation of the tracheobronchial tree, for the most part self-limiting, and with eventual complete recuperating and return of function. Bronchitis is typically a result of a weakened immune system that is overwhelmed by exposure to an external factor, such as bacteria or viruses, or air pollution. Bronchitis is a segment of almost all (if not all) airway diseases. In the exacting interpretation of the word, bronchitis alludes to the inflammation of either the bronchus or bronchi. Nonetheless, bronchitis is observed to show characteristic major overlapping constructs according to the span

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(e.g., acute, subacute, chronic), type of inflammation (e.g., neutrophilic, eosinophilic, neurogenic, lymphocytic), clinical syndromes, and phenotype (e.g., protracted bacterial bronchitis, acute bronchitis, larygno-tracheobronchitis, aspiration bronchitis). Bronchitis is classified into the following: 1. Acute bronchitis Acute bronchitis is a common respiratory disease, which in the typical case, an inflammation of the tracheobronchial tree occurs as a result of an infection in the lower respiratory tract; however, it is less severe than pneumonia. Moreover, the infectious agent in acute bronchitis is usually viral. Symptoms of acute bronchitis include cough with or without associated sputum formation which does not settle within 5 days and thus distinguishing it from the common cold. Symptoms of acute bronchitis usually do not last for more than 3 weeks; however, if persist, other diagnoses must be considered (Albert, 2010). Very young as well as the elderly, smokers, immunocompromised people, people with comorbid conditions, such as CVD, diabetes, pulmonary disease, and alcoholics are shown to have a higher risk to develop acute bronchitis. Moreover, these individuals show increased risk to develop problems of acute bronchitis, for example, pneumonia. 2. Chronic bronchitis Chronic bronchitis is a widespread form of perpetual chronic obstructive lung disease (COPD), with emphysema (alveolar pulverization), and is considered to be the second-most frequently detected manifestation. COPD is usually characterized by the excessive sputum formation over 3 months or more and for a minimum of 2 sequential years. Opposed to acute bronchitis, the key causative affront is a distorted reaction to noxious stimuli, mainly tobacco smoke, and to a lesser extent, other air pollutants as well as occupational exposures. Different viral, as well as bacterial, pathogens are found to cause acute exacerbations of chronic bronchitis/COPD. However, noninfective actions were also shown to increase exacerbations of COPD that include pulmonary thromboembolism (de Palo, 2004; Poole et al., 2019). Nonremittent asthma can also be classified as COPD. It is common for patients having COPD to show characteristics of emphysema, chronic bronchitis, and/or bronchospastic disease (Drain, 1996). Individuals with COPD are more likely to develop lower respiratory infections including pneumonia and acute bronchitis (Yatera et al., 2018). Moreover, in advanced conditions, these patients may have aspiratory hypertension that results in right ventricular enlargement and further results in rightsided heart failure (corpulmonale) (Zangiabadi et al., 2014). 3.1.2.3 Emphysema Emphysema is described as a condition wherein there is an irregular and permanent swelling of the alveoli that are distal to the terminal bronchioles along with damage in their walls without obvious fibrosis (Takahashi et al., 2008). It can be of following mentioned types: 1. Pulmonary emphysema It is a pathologic lesion differentiated as atypical and stable enlargement of the airspaces and accompanied by pulverization of bronchiole walls without obvious

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fibrosis. Alongside chronic bronchitis, emphysema has been perceived as one of the two principal types of COPD. All the more frequently, emphysema has been lumped into the COPD class, and the remarkable impact of parenchymal destruction caused by emphysema was not adequately emphasized. There are two main types and both are usually present (Busarova and Vorob’ev, 1991). 2. Panacinar emphysema The dividers between nearby alveoli separate, the alveolar pipes widen, and there is lost interstitial flexible tissue. The lung progresses toward becoming extended and their ability is expanded. Since the volume of air in each breath stays unaltered, it establishes a little extent of the all-out volume of air in the expanded alveoli, diminishing the incomplete weight of oxygen. The result of this is to lessen the fixation slope of O2 over the alveolar film, subsequently diminishing the dispersion of O2 into the blood (Seadler and Sharma, 2019). A breakdown of the walls between nearby alveoli occurs, the alveolar ducts dilate, and there is a loss of interstitial flexible tissue. The lung progresses toward becoming extended, and their capacity is expanded. Since the air volume in each breath stays unaltered, it accounts for a small proportion of the total air volume in the expanded alveoli, causing a reduction in the partial pressure of oxygen. Consequently, the concentration gradient of O2 decreases across the alveolar membrane causing a decrease in the O2 diffusion into the blood. The converging of alveoli diminishes the surface area for diffusion of gases. Homeostasis of arterial blood O2 and CO2 levels is kept up very still by hyperventilation. As the disease advances the consolidated impact of these progressions may incite hypoxia, pulmonary hypertension, and inevitably right-sided heart failure (Seadler and Sharma, 2019). 3. Centrilobular emphysema Centrilobular emphysema is the commonest type of pulmonary emphysema. The respiratory bronchioles in this form expand irreversibly in the center of the lobule. When the air breathed reaches the dilated area, this will cause a drop in the pressure, which leads to a further decrease in the alveolar pneumatic stress, and hence reduce the efficiency of ventilation and a reduction in the oxygen partial pressure. Inclining conditions, exacerbated by persistent severe coughing, include recurrent bronchiolitis, chronic bronchitis, and cigarette smoking (Takahashi et al., 2013). 4. Interstitial emphysema Interstitial emphysema occurs when there is air in the thoracic interstitial tissues, which may happen by either of two ways (Barcia et al., 2014): a. by injury from the outside, for example, cracked rib, stab wound and b. by alveolus ruptures from the inside through the pleura, for example, asthma, bronchiolitis, coughing (whooping cough). 3.1.2.4 Pneumonia Pneumonia is a condition that refers to an acute respiratory infection by which the lungs are influenced. The lungs comprise small sacs referred to as alveoli, which are filled with air upon breathing in healthy individuals. In pneumatic patient, alveoli are known to be filled with pus and fluid instead of air; hence, painful breathing as well as limitation in the oxygen intake result. There are different symptoms of pneumonia including coughing

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which may be accompanied by phlegm (mucus) production, breath shortening, pain in the chest, fever, sweating, and chills (Marrie, 1992). Pneumonia infection results from a complex process in which the lower respiratory tract undergoes an infective microorganism invasion. Pneumonia can either be acquired from the community or the hospital. Pneumonia can be transmitted via either the aspiration of these pathogens or by the inward breath of a pathogenic microorganism. It is of great importance to identify the exact role of the pathogens in the etiology of pneumonia so that proper clinical management is taken. Globally, Streptococcus pneumoniae (pneumococcus) is considered to be the commonest pathogen that causes community-acquired pneumonia (Grousd et al., 2019). Pneumococcus was recently reported as one of nine bacterial species having an international concern according to a recent report regarding global antibiotic resistance published by the World Health Organization (WHO) in 2014 and 2016. Nevertheless, nosocomial pneumonia was found to result from a wide range of pathogens that might be acquired community or hospital environment. However, in such cases, it was found that Gramnegative bacteria are more likely to be involved than Gram-positive bacteria. Pneumonia can also be spread in different ways. Viruses, as well as bacteria, which are usually found in a youngster’s nose or throat, may taint the lungs when inhaled. In addition, such pathogens are also spread via airborne droplets that result from a cough or a sneeze of other patients. Moreover, pneumonia can also spread via blood, particularly during and shortly after birth (Roquilly et al., 2019; Savvateeva et al., 2019). Pneumonia is classified based on the infectious agent to the following: • Bacterial pneumonia: This class is considered to be the most widely recognized, and examples of bacteria are S. pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila (Marchello et al., 2016). • Viral pneumonia: Viruses are frequently causing pneumonia, especially in young individuals and the elderly. Viral pneumonia is usually considered to be not serious and lasts for a quite shorter time as compared to bacterial pneumonia (Greenberg, 1991). • Mycoplasma pneumonia: Mycoplasma organisms can neither be classified as viruses nor bacteria; however, they share common traits to both of them. Mycoplasma, generally, results in mild pneumonia and is frequent in older children as well as young adults (Mansel et al., 1989). • Fungal pneumonia: Fungi from soil or bird droppings are considered to be the possible causes of this type of pneumonia and especially when inhaled in large amounts. People having chronic diseases or compromised immune system are more susceptible to develop this type of pneumonia. Pneumocystis jirovecii pneumonia (PCP) is a type of fungal pneumonia, which is usually affecting people with compromised immune systems, such as patients having AIDS. In fact, PCP is considered as one of the primary signs of AIDS (Cereser et al., 2019). 3.1.2.5 Bronchiectasis Bronchiectasis is referred to as a chronic necrotizing infection that affects both of the bronchi and bronchioles in which these airways are usually dilated. The clinical

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manifestation of this condition includes fever, cough, and expectoration of considerably large amounts of purulent, noxious sputum. Several factors were shown to be responsible for bronchiectasis including severe respiratory infections that previously occurred (e.g., tuberculosis or bacterial pneumonia), allergic bronchopulmonary aspergillosis, ciliary clearance impedance (e.g., primary ciliary dyskinesia), as well as primary or secondary immunodeficiency, in addition to other diseases that might be associated with this condition such as COPD and severe asthma (Westcott, 1991). On the pathological basis, bronchiectasis is classified into four varieties: • Cylindrical bronchiectasis: It is manifested by a consistent dilatation of the bronchi extending into lung periphery, devoid of tapering (Kim et al., 1997). • Varicose bronchiectasis: It is typified by the beaded and sporadic outline of bronchi, along with alternating zone of dilatation and constriction (Strange, 2013). • Cystic or saccular bronchiectasis: It is considered to be the most serious. As the dilation of the bronchi occurs, large cysts will be formed, which is typically filled with both air as well as fluid (Strange, 2013). • Follicular bronchiectasis: It is known by the extensive lymphoid nodules that are observed within the walls of the bronchi (Reittner et al., 1997). Anyhow, the clinical usefulness of designating bronchiectasis to one of these patterns is still unclear, and to date, there is no investigation showing a clinical, pathophysiologic, or epidemiologic difference between the abovementioned patterns. Bronchiectasis can either be a local disease or might diffuse to involve the two lungs. Focal bronchiectasis might result from the bronchial lumen blockage by foreign bodies, tumor, or from an extrinsic compression that directly affects the bronchi. An example of focal bronchiectasis resulting from outside compression of the bronchi is the middle lobe syndrome, which is caused by distended lymph node secondary to fungal or mycobacterial infection. Diffuse bronchiectasis results from either a congenital disease or might be an association with a systematic disease (Chandrasekaran et al., 2018). 3.1.2.6 Tuberculosis This disease results from either of two types of mycobacteria namely Mycobacterium tuberculosis and Mycobacterium bovis (Andersen and Scriba, 2019). 3.1.2.6.1 Mycobacterium tuberculosis

Human beings are mainly the primary host. The microbes lead to pulmonary tuberculosis and can be spread by either droplet infection from a patient with active tuberculosis or in dust that is contaminated by infected sputum (Youmans, 1963). 3.1.2.6.2 Mycobacterium bovis

Animals are usually the main host. The microorganisms are can spread to humans by from infected cows by untreated milk, leading to infection in the alimentary tract (Vayr et al., 2018). Pulmonary tuberculosis goes through various phases including the following:

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3.1.2.6.2.1 Primary tuberculosis After inhalation of microbes, colonization of these microbes occurs in the bronchiole, typically near the apex of the lung. No evidence may show any clinical ailments during this underlying phase of nonexplicit inflammation. Subsequently, a response from cell-mediated T-lymphocytes is sent to the microbes, leading to sensitization of the individual. Corruption (caseation) may cause a reduction in the center of foci cheddar like substance that comprises dead macrophages, dead tissues of the lung, as well as living and dead organisms. Macrophages engulf the microorganisms at the infection site, resulting in Ghon foci (tubercles). Some macrophages that contain living microorganisms can spread in lymph and cause contamination of the hilar lymph nodes. Primary complexes result, comprising Ghon foci as well as infected hilar lymph nodes. In general, primary tuberculosis is found to be asymptomatic. It may spread within the lung, resulting in multiple small foci, which will cause bronchopneumonia or bronchiectasis, to the pleura leading to pleurisy, with or without emanation to various parts of the body by lymphatic system and blood circulation stimulating the infection to further spread, forming various small foci all over the body (military tuberculosis) (Milburn, 2001). 3.1.2.6.2.2 Secondary tuberculosis This phase happens only when the patient is previously sensitized by a primary lesion, generally observed in the apex of either one or both lungs. It might occur by another infection or an infection that results when a microorganism surviving in Ghon foci is reactivated. The microorganism causing the infection may spread via blood circulation or lymphatic system, stimulating the infection to spread forming numerous small foci all over the body (Hunter, 2011).

3.1.2.7 Pleural effusion It is a condition of too much liquid retention in the pleural cavity and showing unevenness between pleural fluid production and removal. Excessive fluid in the pleural cavity is not due to a particular infection, but instead an outcome of a basic pathology. Pleural effusions include a broad range of disorders pertaining to lungs, pleura, and systemic disorders. A history of pneumonia proposes parapneumonic effusion, either complicated (empyema or empyema-like) or uncomplicated (Karkhanis and Joshi, 2012).

3.2 Pulmonary drug delivery: cutting edge of modern drug delivery research 3.2.1 Transepithelial transport of drug Among modern drug delivery systems (DDSs), pulmonary delivery shows its importance not only due to fast action and high bioavailability of drug but also due to its capability of the engrossing drug for local deposition as well as systemic delivery. Thorough knowledge of healthy as well as the diseased, lung is obligatory to develop pulmonary delivery of a drug (Forbes and Ehrhardt, 2005). The human respiratory system is a perplexing organ system having an in-depth structure work relationship. The conducting airway, first elementary part of the respiratory system, is composed of the nasal cavity, related sinuses, nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. The second elementary part is known as

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respiratory region which comprises the lungs consisting of five lobules of which three lobules are the part of right lung known as the superior, middle, and inferior lobes while two lobules are the part of left lung known as the superior and inferior lobes (Patwa and Shah, 2015). Right lung comprises 10 bronchopulmonary segments, while the left lung comprises eight bronchopulmonary segments. Each bronchopulmonary segment of lung is supplied by definite tertiary bronchus or segmental bronchus arteries, which means each segment obtains air from the tertiary bronchus of its own and receives blood supply from its artery. The tertiary bronchus is further divided into lobular bronchioles that further divided into terminal bronchioles, and the terminal bronchioles further divided into respiratory bronchioles. Each respiratory bronchiole is responsible to supply the very little structural units of the lung, that is, the acinus comprising alveolar ducts, alveolar sacs, as well as alveoli (Patwa and Shah, 2015). Alveolar epithelial type I cells characterize the principal cell type, lining the surface of the alveoli. The noteworthy utilities of these cells, which constitute the 93% of the alveolar space, are for providing a surface for gases to exchange and for serving as a permeability hindrance. On the other hand, alveolar epithelial type II cells are having a smaller surface area per cell and account for 16% of the entire cells in the lung. Synthesis, secretion as well as recycling of surface-active material (i.e., lung surfactant) are a basic function of alveolar epithelial type II cells. The morphologic course of a single epithelial cell, a basement membrane, and a single endothelial cell constitute a chief obstruction to bulky molecules while quickly promote the exchange (Castranova et al., 1988; Johnson et al., 2002). In the alveolar province to reach systemic circulation, solutes must pass through a skinny layer of fluid known as epithelial lining fluid, which is enclosed with a conical layer of surfactant. This surface-active layer is composed of phospholipids (for the most part, phosphatidylcholine and phosphatidylglycerol) and a few kinds of apoproteins. The functions of this surfactant lining fluid are supposed to sustain alveolar fluid homeostasis and permeability as well as participating in various defense mechanisms (Guillot et al., 2013). Less significant surface area and small regional blood flow are the two major factors that restrict the transportation of drug in upper airways region of the respiratory system. A major role in regulating the airway tone and producing airway lining fluid render the respiratory epithelial cells accountable for the transepithelial transport of medication (Patil and Sarasija, 2012). The nasal respiratory region, which extends in reverse by roughly 6 8 cm to the nasopharynx, is the essential site for drug absorption. The mucosa in this region comprises an epithelium laying on a basement membrane connected with two to four layers of the submucosa. In the anterior one-third of the region the surface cells are covered with varying types of epithelial tissue: squamous epithelium, transitional epithelium, and pseudostratified columnar epithelium. The entry of nostril is covered with skin. The squamous epithelium is essential without microvilli, whereas the transitional epithelium is lined with scattered microvilli, and the pseudostratified columnar epithelium has only a few ciliated cells (Fig. 3.4). However, in the posterior two-thirds of the respiratory region, the mucosa is secured by pseudostratified columnar epithelium in which most of the cells are ciliated (Gizurarson, 2012).

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FIGURE 3.4 Types of the cell of the nasal epithelium with covering mucous layer.

Depending on the area of initial drug deposition, cilia clearance can affect the resident time of drug on the surface of the epithelium. The nasal epithelium is covered by a double fluid layer: a less viscous periciliary fluid (Sol layer) surrounding the cilia and microvilli and more viscous mucus (gel layer) resting on the surface membrane. The mucus is a protecting film that comprises a complex combination of glycoprotein’s released essentially by the goblet cells and local glands. This mucus or gel-like film contains mucin as a significant component (Gizurarson, 2012). The mucus layer eliminates inhaled elements from the airways by entrapment and mucociliary transport at a rate relying upon viscosity and elasticity. The lung tissue is extremely vascularized, which creates pulmonary targeting complicated due to quick absorption of nearly every drug (particularly lipophilic and low molecular weight drugs). Besides, the mucus layer area holds an elevated filtering capability and expels up to 90% of transported tranquilize particles. Similarly, ciliated cells existing in this area cause forward motion of mucus in the upward direction and away from the lung. As a result, unfamiliar particles get cleared from the lungs (Gizurarson, 2012). Conversely, the smaller airway and alveolar space represents over 95% of the surface area of the lungs and is specifically associated with the systemic circulation via the pulmonary circulation. Nevertheless, the major alveolar epithelial cells’ morphology, the pulmonary blood gas barrier system, pores size, and tight intersection profundity of both the alveolar and endothelial cells are the main factors controlling the transepithelial tranquilize transport (West, 2009).

3.2.2 Mechanisms and ways of pulmonary drug administration In recent years the systemic absorption of therapeutic agents through the pulmonary application has been shown a wide scope in animals as well as humans. In the course of the pulmonary route the medicament can be delivered by two essential approaches: intranasal and oral inhalation administration. As the nasal inhalation is constrained by anatomical highlights, for example, narrower airway lumen, oral inhalation of compounds is commonly favored. Intranasal administration offers an assortment of appealing choices for both local and systemic delivery of therapeutic agents. The idea of the nasal mucosa gives a progression of unique attributes, all of which may boost the patient’s safety, convenience as well as consistency (Newman, 2017). The nasal mucosa is fenestrated with different mucous membranes effectively available and offers realistic access for substantial molecules. Intranasal administration accounts for

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the benefits of rapid onset of action, no first-pass metabolism, no gastrointestinal degradation or lung toxicity, noninvasive, generally painless, simple, and prepared to be used by patients, especially kids, or by doctors in urgent situations (Patil and Sarasija, 2012). By applying the inhalation technique, we could accomplish increasingly homogeneous distribution with more prominent degree of diffusion into the peripheral or the alveolar area of the lung. By oral inhalation administration, far better outcomes can be anticipated as it allows administering tiny elements with a concentration loss of merely 20% in contrast with 85% by nasal route (Patil and Sarasija, 2012; Nelson, 2016). Intratracheal instillation and intratracheal inhalation are the two forms of oral inhalation administration. The most well-known form used in the research vicinity is the intratracheal instillation, in which a minute quantity of drug solution or dispersion is transported into the lungs by a particular syringe. This method provides quick delivery of the quantified drug to the lungs. The localized drug deposition is accomplished with a relatively small absorptive region. Along these lines the instillation procedure is much straightforward, inexpensive, and has uneven drug distribution (Goel et al., 2013). In preclinical animal studies, intratracheal instillation has every now and again been utilized to evaluate the pulmonary absorption and fundamental bioavailability, particularly concerning with respect to the precise dosing and efficiency related to this method. However, consequences acquired from these preclinical studies may not be transferable to aerosol applications in humans, because this instillation method is certainly not a physiological route for administration (Kunda et al., 2018). On the contrary the inhalation technique utilizes the aerosol systems in order to achieve higher and consistent distribution with immense diffusion. Be that as it may, this technique is costlier and more complicated to quantify the exact dose in the lungs (Smola et al., 2008). A drug deposits in the pulmonary airway after aerosol administration by the means of mainly four mechanisms: impaction (inertial deposition), sedimentation (gravitational deposition), Brownian diffusion, interception, as well as electrostatic precipitation. The occurrence of each of these four mechanisms depends on the inhaled particles’ characteristics, in addition to the breathing patterns as well as the anatomy of the respiratory tract. All of the four mechanisms occur simultaneously; however, the initial two of them are considered to be the most essential for the deposition of large particles within the airways (1 mm, AD, 10 mm) (Deb et al., 2019). Diffusion, however, is considered as the ultimate determinant for depositing smaller particles in the lung’s peripheral regions. Impaction occurs when a particle’s momentum is preventing it from changing course in an area where the direction of the bulk airflow is adjusted. It is the main mechanism of deposition in the region of the upper airway, as well as at or near bronchial branching points. An increase in the impaction was observed as the air velocity, breathing recurrence, as well as particle size increase. Sedimentation occurs when the gravitational force affecting the particles is larger than the absolute force of the air obstruction. Consequently, inhaled particles sediment from the airstream at a constant rate. This deposition mechanism is vital in small airways that have low air velocity. There is a relationship between the likelihood of sedimentation and the residence time in the airway as well as to the particle size and decreases as the breathing rate expands (Deb et al., 2019).

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Diffusion occurs when the collision of gas molecules with small aerosol particles applies discrete nonuniform pressures at the particles’ surfaces, resulting in an irregular Brownian motion. There is an inverse relationship between the effectiveness of Brownian movement in particles deposition and the diameter of particles. The diameter of these particles is 0.5 μm and is vital in bronchioles, alveoli, as well as at bronchial airway bifurcations. Moleculesized particles can deposit by the mechanism of diffusion in the upper respiratory tract, trachea, as well as larger bronchi (Deb et al., 2019). Aside from the morphology of lungs and ventilation factors, the particles/droplets size is considered to be a very essential factor. The size (i.e., diameter) of particle or droplet, zeta potential on its surface, the fibrous nature of the particles, and hygroscopy also have a significant impact on the deposition of the drug administered via the pulmonary route (Deb et al., 2018). The term mass median aerodynamic diameter across is utilized, and it relies upon the size, shape, as well as density of the particulate system.

3.3 Modes of pulmonary drug delivery For systemic medication, drugs are administered customarily by oral and parenteral routes. Be that as it may, in numerous examples, oral administration is inadmissible if a drug is fundamentally degraded in the gastrointestinal tract or is significantly metabolized by the liver. Also, the parenteral route can be undesirable or unfeasible if a drug is planned for treating perpetual diseases. An optional route of delivery would be certainly preferable. In recent years the intranasal route of administration for nonorally absorbed compounds has been broadly assessed (Turker et al., 2004; Gavhane and Yadav, 2012; Tiwari et al., 2012). Targeted drug delivery to the lungs has evolved to be a standout among the most broadly investigated systemic or local drug delivery approaches. The utilization of DDS for treating aspiratory diseases is shown to expand due to their potential to be applied as localized topical therapies in the lungs. This route likewise makes it conceivable to deposit drugs more site-explicit at high concentrations within the diseased lung, thereby reducing the overall amount of medicament given to patients (10% 20% of the peroral amount), just as expanding local drug activity while reducing systemic side effects and first-pass metabolism (Patil and Sarasija, 2012). Pulmonary DDS has been broadly utilized for the treatment of lung diseases and is acclaimed for the asthma treatment and chronic obstructive pulmonary diseases. The basic framework is based on a needle-free technique. The starting point of inhaled therapy seen in 4000 years back in India, where patient smoked the Atropa belladonna leaves to suppress cough. In the early 20th century, asthmatics smoked asthma cigarettes that contain stramonium powder mixed with tobacco to treat the indications of their disease (Labiris and Dolovich, 2003; Pepper et al., 2016). In any case the administration of the drug by this route is technically challenging because oral deposition can be high, and variety inhalation techniques may influence the quantity of the drug delivered to the lungs (Patil and Sarasija, 2012). Delivery of locally acting drugs to the site of activity decreases the measure of dose needed to produce the pharmacological action, but now the lungs have been contemplated as a

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conceivable route to administer the treatment of systemic disease such as diabetes mellitus, cancer, bone disorders, angina pectoris, migraine, tuberculosis, acute lung injury, and others. Pulmonary delivery is secured by different ways such as aerosols, metered-dose inhaler (MDI) systems, dry powder inhalers (DPIs), and nebulizers. These kinds of the framework may contain nanoformulations, such as microemulsions, biodegradable nanoparticles, micelles, biodegradable nanoparticles, and liposomes (Lexmond and Forbes, 2017). To deliver a drug into the airways, it must be introduced as an aerosol. An aerosol is characterized as a two-phase system of solid particles or liquid droplets dispersed in the air or another gaseous phase, having an adequately small size to show considerable stability as a suspension. Pulmonary aerosol administration is done by either of two methods; the first is the nasal inhalation and the second is the oral inhalation. Since there are anatomical features such as the narrower airway lumen constraining the nasal inhalation, oral inhalation is commonly considered to be more preferable. Moreover, the three main mechanisms of deposition followed in these methods of drug administration are the inertial impaction, sedimentation as well as diffusion. There are distinct parameters with a significant impact on the site, efficacy as well as the extent of explicit deposition of aerosol drugs. The deposition of a drug/aerosol in the airways is reliant on four factors: the physicochemical properties of the drug, the formulation, the delivery/liberating device, and the patient (Patil and Sarasija, 2012). Nonetheless, the particle/droplet size, as well as the geometry, is generally considered as essential factors. Within this area, there are various variables with an effect on the deposition, including particle size (diameter), density, electrical charge, hygroscopy, or shape. In addition, deposition is affected by the particle source, which can be a solution, powder, or suspension. The presently accessible standard inhalation devices generally produce aerosols that are heterodisperse in size. Although monodisperse particle-sized aerosols are better explicitly targeted to the lower airways, the production of these is to a great extent restricted by intricate and expensive generation processes such as a vibrating orifice, spinning disk method, or electrostatic precipitation (Lin et al., 2015; Deb et al., 2019).

3.4 Pulmonary delivery of drug molecules: formulation aspect 3.4.1 Lung compatibility of formulation excipients/polymers The excipients of the pulmonary DDS play an important role in the absorption of drug molecules. It is important to establish the compatibility of the excipients and polymers used with the drug molecules. In addition, compatibility of the excipients and polymer used in the formulation with the lungs should be assured. The polymer employed for the sustained release for a longer period of time may get deposited in the lung periphery and escape by mucociliary clearance. During the prolonged inhalation of the drug carriers, there is a reduction of surfactant with subsequent recruitment of phagocytic cells (Perez-Gil, 2008). The solvent remaining in the finished product can also lead to toxicity in the lungs. Therefore it is important to validate the processing techniques and check the compatibility of excipients/polymers with drug and lungs in order to prevent toxicity. It has been

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reported that sugars and cyclodextrin, which are used as a carrier for DPIs formulation, can cause bronchoconstriction in hypersensitivity peoples (Hickey and Garcia-Contreras, 2001). Moreover, prolonged use of enzyme inhibitors and proteins can produce irritation, immunogenicity, and toxicity. The chronic use of absorption enhancers increases the permeability of epithelium barriers results in infiltration of various toxins and antigens. Therefore these important issues should be rectified through the use of proper models (Patil and Sarasija, 2012).

3.4.2 Mechanisms of drug absorption from the lung There are various mechanisms by which an inhaled drug can be absorbed from the lungs, all of which may be quite similar to those occurring following oral administration. The inhaled drugs are absorbed from the lungs by a mechanism similar to those occurring after the oral route of drug administration. However, the rate and extent of drug absorption may vary in the lungs as compared to those taking place through oral administration. The epithelium of lung tissue is the primary barrier to inhaled drugs and shows a huge variation in the thickness. The thickness of trachea is 50 60 μm, and it goes on decreasing to 0.2 μm in alveoli. The change in thickness is due to the variation in the cell type and morphology of constituting cells present in the pulmonary system (Ibrahim and Garcia-Contreras, 2013). The pulmonary membrane of the lung is permeable to small molecules and many proteins and peptides. Cationic small molecule shows a prolonged permeability. Many chemically altered peptidase inhibitor enzymes are also known to have very high permeability through the pulmonary route. Although higher permeability and absorption rates of drug molecules are beneficial for medical use, there are circumstances where one has to slow down the absorption rate either for acting locally into the lungs or to control the absorption rates in the body (Smola et al., 2008; El-Sherbiny et al., 2015). The schematic diagram of drug absorption mechanism through the lung epithelium is given in Fig. 3.5. The mechanisms involved in the absorption of the drug through pulmonary route are: • transcellular/intracellular transport, • paracellular/intercellular transport, and • transcytosis/vesicular transport. FIGURE 3.5 Various mechanism for the transport of drug molecules in the lungs.

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3.4.2.1 Transcellular/intracellular transport It is defined as the passage of drugs across the lung epithelium. It is the most common pathway for drug transport. This transport mechanism is responsible for the absorption of most of the through the lungs. It is the major process of absorption of more than 90% of the drugs that usually occur with no need for mediators (passive diffusion). However, it also includes transport mechanisms mediated by a transport molecule (receptor-mediated) (Ibrahim and Garcia-Contreras, 2013). Passive diffusion also called nonionic diffusion is a process that does not require an energy source, and the concentration/electrochemical gradient is considered to be the driving force for this process. Drug movement is a result of the kinetic energy of molecules. In the process of passive diffusion the drug in the aqueous solution will partition and dissolve at the site of absorption in the membrane’s lipid layer, then the drug will leave it by getting dissolved again in an aqueous medium inside of the membrane (Sporty et al., 2008). Apart from passive diffusion drug molecules can also be absorbed by carrier-mediated transport. It occurs via the action of transporter molecules situated on the cellular membranes’ surface. But as compare to transporters of other organs, a little information is known for the lungs. There are two major families of transporters that are expressed in lung cells: the solute carrier transporters (SLC) superfamily and ATP-binding cassette (ABC) transporters (Bosquillon, 2010). Table 3.1 provides a list of major drug transporter molecules expressed in the intact human lungs with their location. Transporters in the SLC family facilitate the uptake of the drug into the cells and also across the cells. The subtype of these transporters includes organic cation transporters (OCT) and organic anion transports (OAT), which have the capability to transport organic cationic and anionic molecules, respectively. The most studied isoforms of OCTs are OCT1, OCT2, and OCT3 (Roth et al., 2012). Through OCTs, Salbutamol (albuterol), a positively charged bronchodilator, was found to be absorbed into the lung. But till date, OAT expression has not yet been verified in the lungs. It is also reported that the two carnitine/cation transporters OCTN1/2 are able of transporting the zwitterionic L-carnitine and the organic cations. PEPT2, an SLC transporter, has been found expressed in alveolar type II pneumocytes and within bronchi epithelial cells. It is capable of transporting peptides, as well as some peptidomimetic drugs. Antibiotics such as β-lactams and cefadroxil were found to be PEPT2 substrates, and therefore the efficacy of treatment with these drugs can be increased by targeting delivery of these drugs to areas where PEPT2 is expressed (Ingoglia et al., 2016). The drug transporter of the ABC transporters family includes some very important efflux transporters acting through an ATP-dependent mechanism. Examples of ABC transporters expressed in the lung are multidrug-resistant proteins, breast cancer resistance protein, and P-glycoprotein. Depending on the location of expression, they can either augment or reduce the drug absorption. These receptors have a wide range of substrate; therefore it is important to consider these receptors during dose calculations (Choi, 2005). 3.4.2.2 Paracellular/intercellular transport It is a passive transport process where the drug molecules across the epithelium through the intercellular space in between epithelial cells. The tight junction present in

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TABLE 3.1 List of major drug transporter molecules expressed in the intact human lungs with their location. Family Transporter Localization with remarks

References

SLC

OCT1

Apical on bronchial ciliated epithelial cells and airway smooth muscle cells

Lombry et al. (2004)

SLC

OCT2

Apical on bronchial ciliated cells and entire membrane of basal cells

SLC

OCT3

Smooth muscle cells

SLC

OCTN1, N2 Apical on airway epithelial cells and OCTN2 also expressed in alveolar epithelia. High expression

Huh et al. (2010)

SLC

PEPT2

Apical on trachea, bronchial epithelium, and alveolar type II pneumocytes

Groneberg et al. (2004)

ABC

P-gp

Apical, bronchial epithelium (including ciliated cells), alveolar type I, endothelium

Liao and Wiedmann (2003) and van der Deen et al. (2006)

ABC

MRP1

Basolateral/Lateral, bronchial epithelium, goblet cells, alveolar macrophages, mucus-secreting cells of the bronchial mucosa

Brechot et al. (1998)

Horvath et al. (2007)

Basal cells of the bronchial mucosa. High expression ABC

MRP2,3,4,5

Primary bronchial and epithelial cells

van der Deen et al. (2006)

ABC

BCRP

Bronchial epithelial cells and seromucinous glands

Schmekel et al. (1991)

Small endothelial capillaries of the lung Alveolar pneumocytes Basolateral, bronchial epithelium, endothelium ABC, ATP-binding cassette; BCRP, breast cancer resistance protein; MRP, multidrug-resistant proteins; OCT, organic cation transporters; P-gp, P-glycoprotein; PEPT2, peptide transporter 2; SLC, solute carrier transporters.

between the cells plays a pivotal role in the transport of drug molecules. The tight junction is considered as a primary rate-limiting pathway for the entry of the biomolecules through the epithelium in paracellular transport. The tight junction is complex in nature. The compositional element of tight junction is transmembrane integral proteins, occludin, claudins, and junctional adhesion molecules, several intracellular plaque proteins, and regulatory proteins that hold the transmembrane proteins to the actin cytoskeleton (Tsukita et al., 2001; Markov and Amasheh, 2014). 3.4.2.3 Transcytosis/vesicular transport This is a transport mechanism that involves the formation of vesicles by the invaginations in the cellular plasma membrane that finally separates out as vesicles surrounding the particles inside (Parkar et al., 2009). Depending on the particle size, transcytosis can be either caveolae or clathrin-mediated. Transport of particle size less than 120 nm usually involves caveolin-mediated, while the clathrins transport larger drug particles of size in the range 150 200 nm (Herd et al., 2013).

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In 1953 caveolae were first noticed as a small invagination in the plasma membranes of endothelial cells. Caveolae-1 is the major structural protein of the caveolae, which is highly expressed in lung type I epithelial cells. Vesicular transport through caveolae is either constitutive (e.g., fluid phase transport) or controlled by binding the drug to its related receptor in caveolae. Vesicular transport through caveolae is responsible for the transport of many macromolecules such as albumin, insulin, IgG, transferring, and low density lipids (LDLs) through endothelial cells (Mondavio and Ghiazza, 1989; Gumbleton, 2001; Forbes and Ehrhardt, 2005). Clathrin is also small invaginations that separate out either from the plasma membrane of the cell or from some organelles and transport their fillings by combining with the target membrane. Clathrin-mediated drug transport carries the particles of the size range of 150 200 nm (Parkar et al., 2009).

3.4.3 Preparation of particulate matter 3.4.3.1 Spray drying technique It is one of the important techniques used for the production of the pulmonary colloidal particles in the solid state. In 1980 this method was investigated for the preparation of fine drug particles for pulmonary delivery. This technique is mostly utilized for the preparation of DPIs. In this process the fluid materials such as solutions, slurries, and thin paste are atomized into fine droplets, which are radially thrown into a moving stream of hot gas. The hot gas tends to increase the temperature of the droplets and evaporates the moisture present in them. As a result, instant drying of the droplet takes place and fine spherical-shaped particles are formed. This process completes in a few seconds before the droplets reach the wall of the dryer. The temperature of hot gas is maintained in such a way that the liquid droplets get dried completely before arriving the walls of the drying chambers. This process is carefully monitored to prevent the overheating of the final product. Depends on the type of atomizer, the size of the final product can vary (Seville et al., 2007). Spray drying technique can produce drug particle of more than 2 μm size. This is a rapid process where a product can be obtained in 3 30 seconds. This technique is a continuous process that produces a free-flowing, uniform, and controllable size particle, and therefore it can be easily transformed into large-scale production. Spray drying finds great utility in the manufacturing of DPIs because of the rapidity of drying and unique form of the final product. As the contact time between droplets and hot gas is very less, thermolabile materials, such as proteins and peptides, can also be processed by this technique (Dellamary et al., 2000; Chow et al., 2007; Lin et al., 2015). 3.4.3.2 Supercritical fluid technology This is a technique in which there is a controlled crystallization of drugs from dispersion in supercritical fluids (SCF). The SCF is normally gassed but behaves as liquids above their critical temperature and critical pressure. Under these circumstances the molecules show the properties of liquids and gases. The liquid-like properties are solvency, flow, and polarity, and gases-like properties are diffusion and reactivity. SCF technique can be

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achieved using trifluoromethane, chlorodifluoromethane, diethyl ether, water, acetone, CO2, propane, nitrous oxide (N2O), or CO2 with ethanol. Among all, CO2 is the most commonly employed SCF for this technology. CO2 is nontoxic, nonflammable, and inexpensive. Moreover, under suitable low critical conditions, it is a good solvent for water-insoluble as well as water-soluble compounds (Deshpande et al., 2011). There are two different methods for the formation of powders. In the first method the SCF is used as a solvent and the method employed is rapid expansion of a supercritical solution. In this technique the solvent dissolves in SCF and then subjected to sudden decompression. Again, the solution is quickly expanded at low pressure, subjecting it through an orifice. In the second method the SCF is used as an antisolvent. Here the drug molecule dissolves in organic solvents and then get precipitated by addition of SCF (Rehman et al., 2004; Shoyele and Cawthorne, 2006). This technology has been used for controlled production of pulmonary delivery systems such as nanoparticles, microparticles, liposomes, proteins, and peptides of the intended size. This method also improves the formulation characteristics of many drug candidates for pulmonary DDS (Phillips et al., 1990). 3.4.3.3 Crystallization Crystallization is a process where there is the formation of supersaturation solution, followed by nucleation and crystal growth. The basic driving force behind the crystallization is the difference in the chemical potential between the solid crystal face and supersaturated solution. In the crystallization process, supersaturation can be achieved in media by cooling, evaporation of the solvent, and/or the addition of an antisolvent (Verma et al., 2015). The cooling crystallization method is a technique mainly employed for the manufacture of high-value chemicals. The advantages associated with this technique are minimum agglomeration, fewer faults in the crystal lattice, high product purity, and maximum yield. But the main disadvantage of the cooling crystallization is the slow crystallization rate (Kaialy and Nokhodchi, 2015). Antisolvent crystallization is a process in which the drug product can be obtained from aqueous solutions by the addition of nonsolvent compounds (antisolvent), which results in a reduction of solute solubility. An ideal antisolvent should be completely miscible in the mother liquid but is insoluble for the solute drug material. An antisolvent precipitation technique is employed using hydroxypropyl methylcellulose (growth-retarding stabilizing additive) for controlled crystallization for the hydrophobic drugs of in the respirable size range (Raj and Kurup, 2016). Moreover, the smaller particle size can be attained by using higher concentrations of additives. The various drug crystals use in respiratory disease obtained by employing this process are prednisolone, budesonide, fluticasone, and disodium cromoglycate. These drugs exhibit a higher fine particle fraction and are more stable as compared to drug obtained by jet-mill or mechanically micronized processed (Rasenack et al., 2003; Steckel et al., 2003). Antisolvent precipitation techniques are also employed in the preparation of more stable zinc-free insulin crystals in the inhalation size range of 0.2 5 μm (Kwon et al., 2004).

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3.4.3.4 Double emulsion/solvent evaporation technique This method involves the formulation of double oil/water or triple water/oil/water emulsion followed by the exclusion of the oil phase through evaporation, nonsolvent (antisolvent, solvent exchange) extraction, or solvent dilution (Chattopadhyay et al., 2007). The diffusion and evaporation of organic solvent from the polymer phase and into the aqueous phase result in drug-loaded polymeric particles. Traditionally, these techniques have been utilized to prepare sustained and controlled release injectable. However, in the recent past a substantial amount of study had been done in respiratory formulations. Among a wide variety of biodegradable polymers, poly (lactide-co-glycolide) acid, poly(glycolic) acid, and poly(L-lactic acid) have received special attention for the purpose of drug carrier or encapsulation materials. The manufacturing complexity is the main drawbacks of emulsion-based precipitation techniques. In addition the process of emulsion evaporation usually takes place at a very slow rate in a batch process; however, possible adverse effects might occur regarding the uniformity and stability of the emulsion; therefore it has to be well monitored and controlled. Moreover, it is quite challenging to completely remove residues of organic solvents from the polymer matrix is another major problem (Chow et al., 2007). 3.4.3.5 Particle replication in nonwetting templates Particle replication in nonwetting templates (PRINT) technology is developed in Dr. Joseph De Simone lab in 2004. It is a nanomolding technique that enables the fabrication of uniform-sized organic micro- and nanoparticles with complete control over the size, shape, composition, and surface functionality. This technique aids the loading of peptides, proteins, oligonucleotides, siRNA, small organic therapeutics, and fluorophores. In the PRINT procedure, using a lithographic technique, a master template of silicon is fabricated. To this template surface a liquid PEFE fluoro-polymer is added. This helps in wetting of the master template with a high degree of fidelity. Thereafter it is cross-linked photochemically and stripped away to produce an exact shape, the mold having nanoscale pits or cavities (Xu et al., 2013). The PRINT molds possess low surface energy and high gas permeability, which enable the organic liquid precursor to the drug carrier particles to pack the pits or cavities through the capillary mechanism. When the fluid in the form cavities gets solidified, it is removed from the cavity either by physical methods or with the help of adhesives. The nanosized particles are then purified, characterized, and used for further study purpose (Gratton et al., 2007, 2008).

3.5 Aerosol-generation deposition mechanisms The respiratory tract of humans is a complex system. The respiratory pathway is divided into three major regions: (1) extrathoracic, (2) thoracic, and (3) pulmonary regions. The deposition of aerosol in the lungs has been studied exhaustively using in vivo, in vitro, and through mathematical models. The studies show that the amount of drug reaching the respiratory tract is proportional to the clinical efficacy of the inhaled drug (Pauwels et al., 1997;

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FIGURE 3.6 Schematic representation of mechanisms of drug particle deposition in the human respiratory tract.

Chrystyn, 2001). The size of the aerosolized particle and its flow rate are responsible for the deposition of it in the various part of the respiratory tract (Labiris and Dolovich, 2003; Carvalho et al., 2011). The deposition of the aerosols (Fig. 3.6) is the interplay of five basic physical mechanisms: inertial impaction, sedimentation, diffusion, interception, and electrostatic precipitation (Pilcer and Amighi, 2010). However, for nasal drug delivery, the first three mechanisms play important roles. These mechanisms are discussed below:

3.5.1 Inertial impaction The drug particles and droplets may have a tendency to travel in a straight direction. This possibility makes the particle to impact (colloid) and deposit in the upper respiratory tract. By this mechanism the drug particle having a large size and high mass (density) gets deposited in areas where the air pipe of the upper respiratory tract bifurcates. Particles having a size larger than 5 μm show impaction in the upper respiratory tract (Pilcer and Amighi, 2010). Consider a particle with mass, m, with mechanical mobility (the velocity/unit force), B, traveling by an initial velocity, vo, through the still air. The frictional force will stop the particle after traveling the stopping distance, S: S 5 B 3 m 3 vo Therefore the greater the particle mobility, mass, and initial velocity of the drug particle, the longer it will travel in the original direction with more probable chances of striking the obstacle in front of it (Gonda, 2004).

3.5.2 Sedimentation It is the time-dependent sedimentation or deposition of the dispersed phase under the force of gravity or by an imposed centrifugal force in the lung regions. Sedimentation

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usually occurs where particles are in the size range of 0.5 5 μm (Darquenne and Prisk, 2004; Carvalho et al., 2011). The terminal settling velocity, Vts, of a spherical particle is given by Vts 5

d 3 D2 3 g 5 B 3 Fg 18η

where d is the density of the particle, D is the diameter of the sphere, Fg is the gravitational force, g is the gravitational acceleration, and η is the viscosity of air. The preceding equation shows that as there is an increase in particle mobility and the probability of deposition of drug particle by sedimentation increases (Gonda, 2004).

3.5.3 Diffusion The drug particle having size smaller than 2 μm gets deposited into the alveoli of the lungs by the Brownian motion. The random motion of the particles results in a rapid collision of the drug particles that result in drug deposition and diffusion from the alveoli. With the decreased particle size and flow rate, deposition by diffusion increases. The shorter airways and increased residence time also result in increased diffusion deposition in the alveoli region (O’Riordan and Smaldone, 2016). According to the Stokes Einstein equation, the diffusion coefficient, Dif, can be calculated as: Dif 5

k T Cc 3πηD

where k is the Boltzmann constant, T is the absolute temperature, η is the gas viscosity, D is the particle diameter, Cc is the correction factor for slip flow conditions. From the preceding equation with the decrease in the particle size, there is an increase in diffusional deposition, and it is independent of the particle density. Thus for the deposition of the ultrafine particles diffusion coefficient is the more suitable independent variable in comparison to the aerodynamic diameters (Gonda, 2004). Table 3.2 shows the interlink between aerosol particle size and deposition percentage of the various deposition sites of the respiratory tract. TABLE 3.2 Relationship between aerosol particle size and deposition percentage of the various deposition sites of the respiratory tract (Vyas and Khar, 2002). Particle diameter (µm)

Deposition site

Deposition percent

$ 10

Oropharynx

100

.5

Central airways (tracheobronchial)

20

,3

Peripheral airways (alveoli)

60

Tracheobronchial

10

Extrathoracic

10

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3.6 Drug delivery devices The pulmonary route is the most preferable choice for DDS for the management of pulmonary disease namely, COPD and asthma. This system is an easy, painless, and needle-free technique. In India around 4000 years ago, smoke of A. belladonna leaves was used to cure cough (Grossman, 1994; Bhavna et al., 2018). Today new modern devices are employed for the targeting of drugs in the lungs for the treatment and prevention of various lung diseases. It has been reported that for the asthma treatment, only pulmonary drug delivery industry has a business of approximately half a billion inhalers globally. This clearly indicates the scope and importance of the pulmonary DDS (Dalby and Suman, 2003). Usually, the choice and design of pulmonary delivery systems are predisposed by the following factors: • • • •

physicochemical properties of the drug; target patient population (e.g., infants, aged, and ambulatory); the clinical objective to be met (i.e., for chronic or acute treatment); and political and regulatory developments [e.g., chlorofluorocarbon (CFC) legislation]. The pulmonary delivery system can be classified into the following main categories:

• nebulizers, • MDIs, and • DPIs.

3.6.1 Nebulizers A nebulizer is a device employed to deliver drug solutions or suspensions in the form of aerosol into the respiratory tract. In the 1860s Siegle developed the first nebulizer, using a pressurized steam spray. These are one of the earliest clinically used aerosol-generation DDS (Sanders, 2007). Nebulizers have been successfully employed for drug delivery to the lungs. It offers ideal features for the precise care of nonambulatory and hospitalized patients having dexterity or coordination problems. Nebulizers are the choice of treatment for the infants and children suffering from a cough, other acute respiratory problems, and conditions where inhalation is compromised. It has also been examined for local drug delivery to the trachea as for local anesthesia for a bronchoscopy. The drug, to be delivered by the nebulizer, is dispersed into a sterile liquid (usually aqueous) medium and a dispersing force is applied (either a jet of compressed air or ultrasonic vibrations). The dispersion force results in the formation of aerosol droplets of drug solutions or suspensions. The cloud of aerosol form was then inhaled by the patient with the help of a mask. Presently, the commercially available nebulizers are classified as (Rau, 2002): • air-jet nebulizers and • ultrasonic nebulizers. 3.6.1.1 Air-jet nebulizers The working of jet nebulizers is based on the Venturi’s rule, according to which there is a decrease in the fluid pressure as it flows through a limited (narrow) sectional region.

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FIGURE 3.7 Schematic diagram of an air-jet nebulizer.

A jet nebulizer unit has a T-shaped mouthpiece and a compressor employed in forcing the gas through a plastic bottle (i.e., nebulizer reservoir). The nebulizer reservoir and compressor are connected with a plastic tube. A jet nebulizer also consists of a venture nozzle and baffles, which play a vital role in aerosol-generation mechanism (O’Callaghan and Barry, 1997; Waldrep and Dhand, 2008). In these nebulizers a jet of high-pressure airstream travels at high velocity through a narrow hole called the venturi nozzle into the drug solution which is placed in the plastic bottle. This results in the development of low pressure on the top of the drug solution. This drives the drug solution to be aerosolized up the narrow capillary tube. The small aerosol particles are inhaled by the patient through the mouthpiece and the larger droplets will hit the baffles located in various numbers and positions as per the design of the nebulizer. These impactions further atomize the bigger droplets into smaller estimated size droplets that will leave the nebulizer (Fig. 3.7). In addition, baffles also regulate and reduce the velocity of aerosol releasing through the nebulizer (Ali, 2010). The lowered impaction protects the oropharyngeal region of the patient during inhalation. The major issues with jet nebulizers are the compulsion for a bulky blower to produce the aerosol and the sound which get produced during the operation of the air compressor. The advantages to jet nebulization are that dose of drug alteration and dose compounding are possible. The nebulization process requires only simple and tidal breathing for drug delivery (Labiris and Dolovich, 2003; Elhissi and Taylor, 2005). 3.6.1.2 Ultrasonic nebulizers Ultrasonic nebulizers are the devices that utilize a ceramic piezoelectric crystal to produce ultrasound waves, which vibrates on electrical excitation. Thus within the device chamber, high-energy waves of a specific frequency are produced in the solution. The surface waves produce small droplets (Faraday crispations) that are carried away by an airstream for inhalations (Fig. 3.8) (Khatri et al., 2001; Rau, 2002; Labiris and Dolovich, 2003).

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3.6 Drug delivery devices

111 FIGURE 3.8 Schematic diagram of simple ultrasonic nebulizer.

In addition to the piezoelectric crystal, the ultrasonic nebulizer consists of a nebulizer chamber, fan, and baffle system. During the operations, piezoelectric crystal owing to electric current produce vibrations of high frequency (1 3 MHz) and thus forming fountainlike structures of the drug solution. The smaller droplets are formed at the bottom of the fountain, whereas large droplets are formed at the peak of the fountain. The larger droplets are deflected by the baffles and then fragmented into smaller droplets that are then nebulized as inhalable aerosols (Elhissi and Taylor, 2005). The major features of ultrasonic nebulizer are as follows: • They generate aerosol with the higher median aerodynamic diameter and thus a coarser aerosol. • They offer greater output (if the parameters are optimized) than air-jet nebulizers. • They maintain a higher dead volume. • They generate a huge amount of heat within a few minutes and can increase the temperature of the drug solution by 20 C. This heat is harmful to thermolabile drugs, but at the same time, it may increase the solubility of poorly soluble drug substances. 3.6.1.3 Formulation of nebulizer solution The nebulizers are mostly formulated with aqueous solutions. Suspensions are also used in nebulizers, but the major concern is the concentration of the suspension, which get increases as the time course of nebulization progress (Cockcroft et al., 1989). Water is normally used to make nebulizer solutions. In addition, glycerin, ethanol, and propylene glycol may also be used as a solvent. While developing the nebulizer solution, physicochemical properties such as solubility (with respect to pH, ionic strength, buffer, and cosolvent level), isoelectric pH (for peptides and proteins), pKa, and log P are important parameters to be considered. Tonicity and pH of the solution are important parameters for the formulation of nebulizers. Sometimes it is required to have osmotic agents for drug delivery to asthmatic patients, as it has been observed that hypoosmotic and hyperosmotic solutions may cause

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bronchoconstriction. Bronchoconstriction depends on the hydrogen ion concentration; therefore the pH of the nebulizer solution should be ideally higher than 5.0 (Beasley et al., 1987). A hydrochloride or sulfate salt of a weakly basic drug which forms a strongly acidic solution may be a challenging proposition since the pH adjustment of the solution with buffers may compromise the optimal tonicity desired.

3.6.2 Pressurized metered-dose inhalers Riker Laboratories in the mid-1950s develop the first pressurized MDIs (pMDIs), which was a major development in pulmonary therapy, especially for the treatment of asthmatics and COPD. For the first pMDIs the device for pulmonary drug delivery is portable, compact, cost-efficient, and easy to use (Brand et al., 2008; Murnane et al., 2014). The pMDIs, also commonly known as an inhaler, made up of a pressurized canister and filled with an aerosol medicine to be inhaled. Around 500 million people globally use pMDIs devices to deliver medicines to their pulmonary airways, who suffer from asthma, bronchitis, emphysema, and chronic lung disease (Murnane et al., 2014). A typical pMDIs includes four essential components: the base formulation (drug, propellants, excipient, etc.), the canister (container), the metering valve, and the actuator (or mouthpiece). The constituents of typical pMDIs are shown in Fig. 3.9. In addition, surfactants are also added to the base formulation. Surfactants help to reduce the frictional force inside the metering valve and aid the dispersion or dissolution of partially soluble drug (Vaswani and Creticos, 1998). 3.6.2.1 Propellants The most commonly used propellant for aerosol preparation is a CFC. The different type of CFC with their properties is given in Table 3.3. At room temperature, propellants FIGURE 3.9 The schematic diagram of a typical metered-dose inhaler.

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3.6 Drug delivery devices

TABLE 3.3 Properties of common chlorofluorocarbons (CFCs). Type

Abbreviation

Boiling point ( F)

Vapor pressure (at 70 F)

Trichlorofluoromethane

CFC-11

75

Dichlorofluoromethane

CFC-12

222

70

Dichlorofluoroethane

CFC-114

39

13

have a high vapor pressure of around 400 kPa. Before the propellant exits from the atomizing nozzle (flashing), it is partially (15% 20%) evaporated. Beyond this point the droplets are broken up by the violent evaporation of the propellant generating droplets with wide distribution (1 5 μm). However, ozone depletion reports of CFC lead to the banned the manufacture of certain CFC propellants by developed countries. However, a temporary relaxation was permitted to propellants that are employed in an inhaler for the treatment and management of asthma and COPD. This leads to the search for environmentally acceptable hydrofluoroalkane (HFA) propellants (El-Sherbiny et al., 2015). But the major limitation associated with these propellants is their poor solubility. The solubility of these surfactants can be improved by the addition of a cosolvent such as ethanol. The remarkable enhancement in drug delivery has been observed with HFAs in contrast to CFCs. For example, delivery of betamethasone dipropionate to the lungs is 51% with HFA (in which it is soluble) and only 4% in CFC (in which it is a suspension) (Dolovich and Dhand, 2011). 3.6.2.2 Container or canisters The canister is a disposable chamber containing the formulation and made of plastic, stainless steel, glass, or aluminum. Canisters are capable to resist pressures of up to 150 psig, which is a prerequisite to have the propellant gas in liquefied form. Ideally, the canister should be light and able to carry 15 30 mL of liquid drug formulation. 3.6.2.3 Metering valve The metering valve is a vital component of pMDIs. It is designed to dispense a precise amount of aerosolized drug formulation through the mouthpiece (20 100 μL) at every time when the device is actuated. Moreover, it also functions as a seal over the canister and forms a barrier to the outer environment. At resting position, an inner valve between the meter chamber and the container is open, which results in the complete filling of liquefied propellant drug mixture into the chamber. At this time, an outer valve, which is present between the meter chamber and the outside air, is closed. During activation, when the canister is being pressed by the patient, the inner valve get closes down and the outer valve opens which release the drug propellant mixture present in the chamber as an aerosol form through the actuating orifice (Khan et al., 2013). An ideal metering valve should have the properties of precision, uniform drug delivery, and reproducibility (Newman, 2005; Hess and Mishoe, 2011).

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3.6.2.4 Actuator or mouthpiece The actuator or mouthpiece is the means by which the valve stem in the metering chamber is depressed, and the patients can inhale the dose by cupping their lips around the squat. The actuator comprises a spray nozzle (actuator orifice) and the expansion chamber where the released propellant expands and moderately volatizes due to the drop in pressure. The pMDIs performance is significantly governed by the design of the actuator. The diameter of the actuator orifice and the expansion chamber determines the spray pattern and the emitted particle size of the formed aerosols. Presently, modification of actuators makes it possible to count the number of remaining doses (Smyth, 2005; ElSherbiny et al., 2015).

3.6.3 Dry powder inhalers These are the devices that deliver aerosolizes micronized dry, powdered formulation of the single drug, or blend of the drug with an inert carrier in a stream of inspired air. The formed aerosolizes drug particle deposit either locally in the upper part of the respiratory tract or into the deep lung. The particle size and velocity are the two important factors responsible for the deposition of aerosolizes drug particle in the respiratory tract. The drug particle size of more than 5 μm is deposited in the upper part of the respiratory tract and the smaller drug particle size of below 4 μm get accumulated in the lower part of the respiratory tract (Atkins, 2005). The advantages of DPI include ease of handling, drug stability, and least coordination of patient is required to deliver medications while breathing and actuation of the device. Moreover, the drug is in powdered form; therefore separation, microbiological contamination, and decomposition are minimal compared to liquid formulations. They are commercially available in two types: single-dose and multidose options (Fig. 3.10). Unit dose devices utilize drug-filled gelatin capsules (e.g., Spinhaler), whereas the multidose units have a reservoir (e.g., Turbuhaler) (El-Sherbiny et al., 2015). FIGURE 3.10 Various types of unit dose and multiple dose DPIs. DPIs, Dry powder inhalers.

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3.8 Regulatory considerations

115

3.6.3.1 Unit dose devices In Spinhaler the drug mixture, including a bulk carrier to facilitate powder flow, is loaded into a hard gelatin capsule and loaded into the device. On device activation, the capsule is pierced and the vibrating capsule dispenses the drug, which is inhaled by the patient with inspired air. Another device with a slight variation is Rotahaler. In this device the drug-filled hard capsule is placed in the device, where it is broken open and the powder is inhaled through a screened tube. These devices are in clinical use for nearly 30 years. In spite of their fine performance, they have some limitations. The loading of the device appears to be cumbersome for a patient under an asthmatic attack. Also, normally to achieve an equivalent clinical effect higher doses are required for DPIs than MDIs (Vyas and Khar, 2002). 3.6.3.2 Multidose devices Turbuhaler is a multidose device and, in fact, is considered as a metered-dose powdered DDS. It comprises a reservoir to store the drug which can be dispensed by a simple back and forth twisting action into the dosing chamber on the base of the unit. The salient feature of this device is that it can deliver carrier-free particles at considerably low flow rates as low as 28.3 L/min. Another device is Diskhaler, which contains a circular disk with eight powder charges in separate aluminum blister reservoirs. Prior to inspiration, the device is primed, when the aluminum blister is pierced and the contents of the pouch released into the dosing chamber (Vyas and Khar, 2002).

3.7 Pulmonary products in market The list of various pulmonary products such as nebulizers, pMDIs, and DPIs available in the market are mentioned in Tables 3.4 3.6.

3.8 Regulatory considerations The patient’s safety and the drug efficacy with its performance are of utmost importance while seeing regulatory aspects for any drug, particularly pulmonary DDS. The regulatory bodies such as European Medicines Agency (EMEA), Food and Drug Administration (FDA), and Health Canada have set various guidelines on the development of pulmonary drug delivery products (nebulizer, pMDIs, and DPI). The patent expiration of many pulmonary drug delivery device especially Advair Diskus gives a way to the pharmaceutical industry to introduce generic products. Therefore the regulatory bodies of various countries issued a set of regulations to maintain the standard of inhalation products. In 2009 the EMEA has framed guidelines for the approval of generic inhalation drug products. This is based on the performance of therapeutic equivalence between two inhaled products. The generic and the reference (standard) product must have the same active substance and should in an identical dosage form. In addition, it also states that the

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3. Strategies for pulmonary delivery of drugs

TABLE 3.4 List of various nebulizers available in the market. Products

Manufacturer

Active pharmaceutical ingredients (APIs)

AccuNeb

Mylan

Salbutamol inhalation

Focus

Formulation

Device

Albuterol sulfate

Drug, sodium chloride, sulfuric acid (solution)

Salbutamol

Drug, sodium chloride, dilute sulfuric acid, sodium hydroxide solution (solution)

Pari LC Plus nebulizer (with a face mask or mouthpiece) and Proneb Ultra compressor

Perforomist Mylan

Formoterol fumarate

Drug, sodium chloride, sodium citrate, citric acid (solution)

Brovana

Sunovion

Arformoteroltartrate

Drug, sodium citrate, citric acid (solution)

Pari LC Plus nebulizer (with mouthpiece) and Pari Dura-Neb 3000 compressor

Striverdi Respimat

Boehringer Ingelheim

Olodaterol

Drug, benzalkonium chloride, edetate disodium, anhydrous citric acid (solution)

Spiriva Respimat inhaler

Spiriva Respimat

Boehringer Ingelheim

Tiotropium

Drug, edetate disodium, benzalkonium chloride, hydrochloric acid (solution)

Spiriva Respimat inhaler

Pulmicort Respules

AstraZeneca

Budesonide

Drug, sodium chloride, sodium citrate, citric acid, disodium edetate, Polysorbate 80 (suspension)

Pari-LC-Jet Plus Nebulizer/ Pari Master compressor system

Stiolto Respimat

Boehringer Ingelheim

Tiotropium 1 Olodaterol Drug, water for injection, benzalkonium chloride, edetate disodium, hydrochloric acid (solution)

Combivent Respimat

Boehringer Ingelheim

Ipratropium bromide 1 albuterol

Drug, benzalkonium chloride, edetate disodium, hydrochloric acid (solution)

Combivent Respimat inhaler

Duoneb

Mylan

Ipratropium bromide 1 albuterol sulfate

Drug, sodium chloride, hydrochloric acid, edetate disodium (solution)

Pari LC Plus nebulizer (with face mask or mouthpiece) and Proneb, compressor

Ventolin Solution

GlaxoSmithKline Albuterol sulfate

Drug, benzalkonium chloride, sulfuric acid (solution) (Continued)

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3.8 Regulatory considerations

TABLE 3.4 (Continued) Products

Manufacturer

Active pharmaceutical ingredients (APIs)

Formulation

Device

Xopenex

Boehringer Ingelheim

Levalbuterol hydrochloride

Drug, sodium chloride, sulfuric acid (solution)

Pari-LC-Jet and Pari LC Plus nebulizers and PARI Master Dura-Neb 2000 and Dura-Neb 3000 compressors

Bethkis

Chiesi

Tobramycin

Drug, sodium chloride, sulfuric acid (solution)

Pari LC Plus Reusable Nebulizer and Pari Vios Air compressor

Tobi

Novartis

Drug, sodium chloride, sulfuric acid, sodium hydroxide (solution)

Pari LC Plus Reusable Nebulizer and DeVilbiss Pulmo-Aide compressor

Kitabis Pak

Pulmoflow

Drug, sodium chloride, sulfuric acid, sodium hydroxide (solution)

Pari LC Plus Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor

Cayston

Gilead

Aztreonam

Drug, sodium chloride, lysine (solution)

Altera Nebulizer System

Pulmozyme Genentech

Dornase alfa

Drug, sodium chloride, dornase alfa, calcium chloride dihydrate (solution)

eRapid Nebulizer System (eRapid)

Ribavirin Iloprost

Virazole Ventavis

Valeant actelion

Drug, ethanol, sodium chloride, tromethamine, hydrochloric acid (solution)

I-neb AAD System

Tyvaso

United therapy

Treprostinil

Drug, sodium chloride, sodium citrate, sodium hydroxide, hydrochloric acid (solution)

Tyvaso inhalation system

Nicotrol

Pfizer

Nicotine

Drug, menthol (solution)

Nicotrol inhaler

I-neb AAD (adaptive aerosol delivery) system

difference in polymorphic form and/or crystalline structure of the active substance and substitutions of excipients must not alter the safety profile and performance of the product. The reference and generic products should have some resistance to airflow. The particle size distribution profile and dose delivery uniformity should be similar (within 15%). The generic product is acceptable for product approval by EMEA if it fulfills all of the above criteria for equivalence. If not, in vivo studies (pharmacodynamics or pharmacokinetics) should be performed for the equivalence. The EMEA usually issue a general guideline for the equivalence study of the pulmonary drug delivery device (Farina, 2010a,b). In contrast the FDA starting from 2013 has issued five individual guidelines for each specific inhalation product: pMDIs of budesonide/formoterol fumarate, levalbuterol tartrate, albuterol sulfate, ipratropium bromide, and DPIs of fluticasone propionate/ salmeterol. The FDA for the approval of the generic pulmonary product requires

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TABLE 3.5 List of various pressurized metered-dose inhalers available in the market. Products

Manufacturer

APIs

Formulation

Proair

Teva

Albuterol sulfate

Drug, HFA-134a, ethanol (suspension)

Proventil

Merck

Drug, HFA-134a, ethanol, oleic acid (suspension)

Ventolin

GlaxoSmithKline

Drug, HFA-134a (suspension)

AirSalb

Sandoz

Salbutamol xinafoate

Drug, HFA-134a, ethanol, oleic acid (suspension)

Xopenex

Sunovion

Levalbuterol tartrate

Drug, HFA-134a, ethanol, oleic acid (suspension)

Atimos Modulite

Chiesi

Formoterol fumarate

Drug, HFA-134a, ethanol, hydrochloric acid (solution)

Atrovent

Boehringer Ingelheim

Ipratropium bromide

Drug, HFA-134a, water, ethanol, citric acid (solution)

Intal

Sanofi Aventis

Sodium cromoglycate

Drug, HFA-227, polyvidone K30, polyethylene glycol 600 (suspension)

Clenil Modulite

Chiesi

Beclomethasone dipropionate

Drug, HFA-134a, ethanol, glycerol (solution)

Qvar

Teva

Qvar 3M Autohaler Alvesco

Drug, HFA-134a, ethanol (solution) Ciclesonide

Drug, HFA-134a, ethanol (solution)

Flunisolide

Drug, HFA-134a, Ethanol (solution)

Aerospan Fluticasone propionate

Drug, HFA-134a, ethanol (solution)

Flovent

Beclomethasone dipropionate 1 Formoterol fumarate

Drug, HFA-134a (suspension)

Fostair

Chiesi

Drug, HFA-134a, ethanol, hydrochloric acid (solution)

Symbicort AstraZeneca

Budesonide 1 Formoterol fumarate

Drug, HFA-227, Povidone K25, polyethylene glycol 1000 (suspension)

Flutiform

Napp

Fluticasone propionate 1 Formoterol fumarate

Drug, HFA-227, sodium cromoglicate, ethanol (suspension)

Advair

GlaxoSmithKline

Fluticasone propionate 1 Salmeterol xinafoate

Drug, HFA-134a (suspension)

Dulera

Merck

Mometasne furoate 1 Formoterl Fumarate

Drug, HFA-227, ethanol, oleic acid (suspension)

HFA, Hydrofluoroalkane.

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3.8 Regulatory considerations

TABLE 3.6 List of various dry powder inhalers devices available in the market. Products

Manufacturer

APIs

Compositions

ProAir Respiclick

Teva

Albuterol sulfate

Drug, lactose monohydrate

Pulvinal Salbutamol

Chiesi

Salbutamol sulfate

Drug, lactose monohydrate

Easyhaler Salbutamol Sulfate

Orion

Salbutamol sulfate

Drug, lactose monohydrate

Terbutaline sulfate

Drug

Bricanyl Turbohaler AstraZeneca Serevent Diskus

GlaxoSmithKline Salmeterol xinafoate

Drug, lactose monohydrate

Foradil Aerolizer

Novartis

Drug, lactose

Foradil Certihaler

Novartis

Drug, lactose monohydrate, magnesium stearate

Oxis Turbohaler

AstraZeneca

Drug, lactose monohydrate

Easyhaler Formoterol

Orion

Drug, lactose monohydrate

Arcapta Neohaler

Novartis

Onbrez Breezhaler

Novartis

Spiriva Handihaler

Boehringer Ingelheim

Tiotropium bromide

Drug, lactose monohydrate

Tudorza Pressair

Forest

Aclidiniumbromide

Drug, lactose monohydrate

Seebri Breezhaler

Novartis

Glycopyrronium bromide

Drug, lactose monohydrate, Magnesium stearate

Incruse Ellipta

GlaxoSmithKline Umeclidinium

Drug, lactose monohydrate, Magnesium stearate

Easyhaler Budesonide

Orion

Drug, lactose monohydrate

Formoterol fumarate

Indacaterol maleate

Drug, lactose monohydrate Drug, lactose monohydrate

Budesonide

Pulmicort Flexhaler AstraZeneca

Drug, lactose monohydrate

Pulmicort Turbuhaler

Drug, lactose monohydrate

AstraZeneca

Asmanex Twisthale Merck

Mometasone furoate

Drug, lactose Anhydrate

Pulvinal Beclometasone Dipropionate

Chiesi

Drug, lactose monohydrate, magnesium stearate

Easyhaler Beclometasone

Orion

Drug, lactose monohydrate

Flovent Diskus

GlaxoSmithKline Fluticasone propionate

Drug, lactose monohydrate

Arnuity Ellipta

GlaxoSmithKline Fluticasone furoate

Drug, lactose monohydrate (Continued)

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3. Strategies for pulmonary delivery of drugs

TABLE 3.6 (Continued) Products

Manufacturer

APIs

Compositions

Fostair Nexthaler

Chiesi

Beclomethasone dipropionate 1 Formoterol fumarate

Drug, lactose monohydrate, magnesium stearate

Symbicort Turbohaler

AstraZeneca

Budesonide 1 Formoterol fumarate

Drug, lactose monohydrate

DuoResp Spiromax

Teva

Drug, lactose monohydrate

Breo Ellipta

GlaxoSmithKline Fluticasone furoate 1 Vilanterol

Drug, lactose monohydrate, Magnesium stearate

Advair Diskus

GlaxoSmithKline Fluticasone propionate 1 Salmeterol

Drug, lactose monohydrate

Anoro Ellipta

GlaxoSmithKline Umeclidinium 1 Vilanterol

Drug, lactose monohydrate, Magnesium stearate

Ultibro Breezhaler

Novartis

Glycopyrronium bromide 1 Indacaterol maleate

Drug, lactose monohydrate, Magnesium stearate

Duaklir Genuair

AstraZeneca

Aclidinium bromide 1 Formoterol fumarate

Drug, lactose monohydrate

TOBI Podhaler

Novartis

Tobramycin

Drug, 1,2-distearoyl-sn- glycero-3phosphocholine, calcium chloride, sulfuric acid

Relenza Diskhaler

GlaxoSmithKline Zanamivir (for influenza)

Drug, lactose

Afrezza

Sanofi Aventis

Drug, fumaryl diketopiperazine, Polysorbate 80

Insulin human

equivalence of all in vitro, pharmacokinetics, and pharmacodynamics tests with the reference product. Therefore it is a quite tedious and difficult process to get approval from the FDA. The in vitro tests for generic pMDIs consist of aerodynamic particle size distribution, priming and repriming studies, spray pattern, plume geometry, and single actuation content. The test for DPI device consists of size, shape, operating procedures, device mechanism, premetered multidose format, device resistance doses, and a dose counter. The generic should have the same inactive ingredient(s) as the reference product. A maximum limit of 5% in the concentration of the inactive ingredient(s) used in the generic product should is allowed as compared to the reference product (Hou et al., 2015; Lee et al., 2015). Table 3.7 provides a glimpse of the requirements for both the regulatory bodies.

3.9 Conclusion In the current global scenario the lower respiratory tract infection(s) is the third primary reason for death, as reported by WHO. In such scenarios, pulmonary formulations provide

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3.9 Conclusion

TABLE 3.7 Details of the various tests for pulmonary drug delivery device given by FDA and European Medical Agency (EMA) (Farina, 2010a,b). Test class

Test or specification name

Oral pMDIs

DPIs

Inhalers spray

Labeling

Appearance and color/description

F

F

F

E

E

E

F

F

F

E

E

E

F

F

F

E

E

E

F

F

F

E

E

Net content (fill) weight/number of actuations per container

F

F

F

E

E

E

Priming/repriming

F

F

F

Cleaning instructions

Drug content (assay)

Identification

E Profiling of actuation near exhaustion (tail off)

E

F

F

F

E

E

E

Pump/valve delivery (shot weight)

F

F

Shaking (suspensions)

F

F

Stability of primary (unprotected) package

F

F

F

Determination of appropriate storage conditions

F

F

F

Device robustness/ruggedness

F

F

F

E

E

E

E

Patient use/ misuse

Dose buildup and flow resistance Drug deposition on mouthpiece and/or accessories

E

F F E

Effect of moisture

F E

E

F E

E

E

F

F

F

E

E

E

Effect of patient use

F

F

F

Effect of resting time

F

Effect of orientation/weight loss (stability)

F (Continued)

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3. Strategies for pulmonary delivery of drugs

TABLE 3.7 (Continued) Test class

Test or specification name

Oral pMDIs

DPIs

Inhalers spray

Effect of storage on the particle size distribution

F

F

F

Effect of varying flow rates

F

F

F

E

General properties

Low-temperature performance

E

E

Temperature cycling

F

F

E

E

Chemical compatibility

F

F

Dehydrated alcohol content

F

F

Delivery device development

F

F

F

E

E

E

F

F

F

E

E

E

F

F

F

E

E

E

F

F

F

E

E

E

Fine particle mass through container life

E

E

Fine particle mass with spacer use

E

Impurities and degradation products

F

F

F

In vitro dose proportionality

F

F

F

Leachables and extractables

F

F

F

Dose content uniformity

Dose content uniformity through container life

Drug particle size distribution/fine particle mass

Leak rate

Microbial challenge

Microbial limits

Microscopic evaluation/foreign particulate matter Photostability

F

E

E

F

F

E

E

F

F

E

E

F

F

F

E

E

E

F

F F

F (Continued)

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Abbreviations

TABLE 3.7 (Continued) Test class

Test or specification name

Oral pMDIs

DPIs

Physical characterization

F

F

Plume geometry

F

Preservative effectiveness and sterility maintenance

Inhalers spray

F

Pressure testing

F

Single-dose fine particle mass

E

Spray pattern

F

Water or moisture content

F

F

F

E

E

E

E

“F” and/or “E” denote that guidelines exist for the study/specification in an FDA (F) and/or EMA (E) guidance document. If blank, no specific guidance exists. DPI, Dry powder inhaler; pMDI, pressurized metered-dose inhaler.

an indispensable alternative for enhanced therapeutic efficacy. Besides, such formulations are not only employed for increased local targeting but also considered an attractive and promising method of drug delivery for achieving a high systemic concentration of various molecules for the treatment of diabetes, allergy, etc. Pulmonary drug delivery might become a lucrative option for delivery of protein and peptide drugs, which are highly susceptible to enzymatic degradation. This is primarily due to high surface area and permeability of lungs leading to high bioavailability and, second, low metabolic activity due to avoidance of hepatic metabolism. Undoubtedly, knowledge of diseases/disorders especially related to the respiratory system, understanding of the mechanism(s), and mode of pulmonary delivery provides a platform to develop novel formulations as well as novel devices. Moreover, encompassing the various pulmonary diseases, intense research in this area will offer more user-friendly as well as economic devices.

Abbreviations ABC API CFC CO2 COPD DDS DPI EMA EMEA FDA LDL N2O O2

ATP-binding cassette active pharmaceutical ingredients chlorofluorocarbon carbon dioxide chronic obstructive lung disease drug delivery systems dry powder inhaler European Medical Agency European Medicines Agency Food and Drug Administration low density lipids nitrous oxide oxygen

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124 OAT OCT PCP PEPT2 pMDI PRINT SCF SLC

3. Strategies for pulmonary delivery of drugs

organic anion transports organic cation transporters Pneumocystis jirovecii pneumonia peptide transporter 2 pressurized metered-dose inhaler particle replication in nonwetting templates supercritical fluids solute carrier transporters

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