Handbook of Lung Targeted Drug Delivery Systems

Recent Trends and Clinical Evidences

Yashwant Pathak, Nazrul Islam, Yashwant Pathak, Nazrul Islam

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000450804
• Edition: 1
• Topic: Medicina
• Subtopic: Farmacología

Handbook of Lung Targeted Drug Delivery Systems: Recent Trends and Clinical Evidences covers every aspect of the drug delivery to lungs, the physiology and pharmacology of the lung, modelling for lung delivery, drug devices focused on lung treatment, regulatory requirements, and recent trends in clinical applications. With the advent of nano sciences and significant development in the nano particulate drug delivery systems there has been a renewed interest in the lung as an absorption surface for various drugs. The emergence of the COVID-19 virus has brought lung and lung delivery systems into focus, this book covers new developments and research used to address the prevention and treatment of respiratory diseases. Written by well-known scientists with years of experience in the field this timely handbook is an excellent reference book for the scientists and industry professionals.

Key Features:

• Focuses particularly on the chemistry, clinical pharmacology, and biological developments in this field of research.
• Presents comprehensive information on emerging nanotechnology applications in diagnosing and treating pulmonary diseases
• Explores drug devices focused on lung treatment, regulatory requirements, and recent trends in clinical applications
• Examines specific formulations targeted to pulmonary systems

1

Introduction to Lung Physiology from a Drug Delivery Perspective

Aparoop Das^1,♯, Manash Pratim Pathak^1,2, Pompy Patowary^1,3, and Sanghita Das^3,4

¹Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, India

²Pratiksha Institute of Pharmaceutical Sciences, Assam, India

³Division of Pharmaceutical Technology, Defence Research Laboratory, Assam, India

⁴Pharmaceutical & Fine Chemical Division, Department of Chemical Technology, University of Calcutta, Kolkata, India

♯ First Author and Primary Contact

DOI: 10.1201/9781003046547-1

1.1 Introduction

1.1.1 Brief Introduction to Nanotechnology and Nanoparticle Mediated Drug Delivery

Nanoparticles (NPs) are nanosized materials used to embed drugs, imaging agents and genes intended for targeted drug delivery by covalent conjugation or noncovalent attachment (1). As defined by the International Organization for Standardization, NPs are those having at least one dimension less than 100 nm. The American Food and Drug Administration (FDA) has cited another broader definition of NPs as ‘engineered to exhibit properties or phenomena attributable to dimensions up to 1000 nm’, which is typically adopted in academic research (2). To deliver the appropriate amount of the desired drug precisely to the target organ without causing any side effects while also taking care of the induction of drug resistance is a daunting task; however, it is an important requirement in a targeted drug delivery system (DDS) (3). NP drug carriers can modulate drug distribution via passive and active targeting. Passive targeting is the process by which nanoscaled particles accumulate in tumors/sites of inflammation merely due to their size, whereas active targeting works through the attachment of biochemical moieties which facilitate delivery to diseased tissues expressing biomarkers distinguishing them from the surrounding healthy tissue (4). The term nanotechnology involves manipulating and controlling nanoscale (1–100 nm) objects. For over 28 years, the potential benefit of nanotechnology has been appreciated by most researchers and has revolutionized the field of drug delivery and drug targeting with the hope of transforming Ehrlich's hypothetical concept of a “magic bullet” into clinical reality.

The new interdisciplinary platform of nanotechnology-based DDS shows a great deal of promise with several advantages such as improved solubility and bioavailability of hydrophobic drugs, rendering them suitable for parenteral administration encapsulation efficacy which enhances the drug release profiles, high drug payload, extended drug half-life, improved therapeutic index of peptides, oligonucleotides, etc., controlled release along with reduced immunogenicity, and toxicity (5). They can further be used for drug delivery to the central nervous system (CNS) owing to their smaller size and higher barrier permeability.

1.1.2 The Inhalation Route

Drug delivery via the inhalation route has been known since the distant past, when the Egyptians inhaled black henbane vapour to treat various diseases (6). The lung is taken into high consideration as an attractive target among a myriad of routes of administration due to its several advantages (2) over conventional oral administration. Drug delivery to the lungs by inhalation offers a targeted drug therapy for a wide range of respiratory diseases including lung cancer, chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), tuberculosis (TB), pneumonia and pulmonary hypertension (7), among which COPD, lower respiratory infections and lung cancer are the third, fourth and sixth causes of death worldwide respectively. Other than pulmonary disease, inhaled medications are also beneficial for treatment of anxiety, hypertensive crisis, certain seizures, arrhythmias, spasms, nausea and myriad forms of pain (8).

The inhalation route has received widespread attention within the drug delivery field as it possesses many characteristics ideal for drug transportation and has many advantages over other methods, since the lungs have a large surface area (100 m²) and a very thin epithelial layer (0·2–0·7 μm) for high blood perfusion, elevated blood flow (5 L/min), extensive vascularization to promote systemic delivery, high solute permeability, avoidance of first pass metabolism, and sustained release of the drug and thus reduced dosing frequency (9, 10, 11). In addition, drug-metabolizing enzymes are present in much lower concentrations in the lungs than the gastrointestinal tract and liver, thereby limiting enzymatic and proteolytic interaction with the inhaled molecules (8). Moreover, the lung is capable of absorbing pharmaceuticals either for local deposition or for systemic delivery by targeting the drug delivery carriers to the alveolar region with uniform distribution. Additionally, in inhalation drug delivery there is no risk of needle injuries and health-care staff are not needed, resulting in better patient compliance. The pulmonary tissue has notably high levels of systemic bioavailability for macromolecules, making it the best non-invasive absorption route. Although drug molecules are absorbed more efficiently from the lung than from any other non-invasive routes, however, the therapeutic efficacy of inhaled drugs is limited by their rapid clearance in the lungs (12).

The practice of respiratory medicine has entered into a brave new era through the development of new therapeutic strategies and improvement of current therapies, with some NPs already developed into commercial products. Although inhalation devices and aerosols containing various drugs have been used since the early 19th century, currently there are three main delivery devices used for pulmonary delivery of drugs, viz. nebulizers, pressurized metered-dose inhalers and dry powder inhalers (DPIs) to deliver solutions, suspensions and dry particles respectively (13, 14) and an array of carrier systems, which hold great potential for treating diseases that require direct lung delivery. An ideal delivery device has to generate an aerosol in the range of 0.5–5 µm and provide reproducible drug dosing without affecting the physical and chemical stability of the drug formulation (15). Moreover, the ideal inhalation system must be a simple, convenient, inexpensive and portable device. Although efficient and reproducible pulmonary deposition of aerosol medicines is now possible with current technology, however, the mechanism of the action of particles after pulmonary deposition is highly complex due to the various barriers and clearance mechanisms in the respiratory tract, which pose significant challenges in formulation development (6). The fate of particle–lung interactions are still being researched and have become indispensable for pharmaceutical scientists to develop more effective inhalable formulations. Moreover, toxicity and regulatory concerns limit approval of nanotechnology-based medicinal products (16).

The primary focus of this chapter is to provide an insight into the physiological and efficacy aspects of the mechanism of pulmonary DDS with respect to the lung structure and characteristics, and also the research progress on various parameters to be considered during formulation development and how molecular properties affect rate and extent of pulmonary drug absorption, clearance and metabolic mechanisms, etc. Herein, we have also highlighted the future opportunities for nanotechnology focusing on the treatment of lung diseases.

1.2 Anatomy and Physiology of Lungs

1. Anatomy of lungs/gross tissue organization:
   1. The respiratory system:

Energy is produced in the form of adenosine triphosphate (ATP) in the body through cellular respiration. For cellular respiration, cells need oxygen (O₂) as a reactant, and carbon dioxide (CO₂) is produced as a waste product. As excessive CO₂ may become toxic, it is eliminated from the body by the joint cooperation of the respiratory and cardiovascular systems. However, intake of O₂ and expulsion of CO₂ is performed solely by the respiratory system, and the cardiovascular system supports the entire system by aiding in the transportation of blood containing the gases between the body cells and lungs. Apart from the regular gas exchange, the respiratory system also participates in a repertoire of functions like blood pH regulation, aiding in smelling, and production of the voice, and it helps the body gets rid of heat and water in exhaled air (17, 18).

Structurally, the respiratory system consists of two main parts: (a) upper respiratory system and (b) lower respiratory system. The nose, nasal cavity, and pharynx and its associated structures comprise the upper respiratory system and the larynx, trachea, bronchi and bronchioles comprise the lower respiratory system (17). Functionally, also, the respiratory system is divided into two parts, i.e. the conducting zone and the respiratory zone. The conducting zone is not directly involved in gas exchange which includesthe nose, nasal cavity, pharynx, larynx, trachea, bronchi, bronchioles and terminal bronchioles. These components filter, moisten or warm the air and facilitate conduction of the air. The respiratory zone is the site where gaseous exchange takes place and this zone includes respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli, and here the gaseous exchange takes place between air and blood (18).

2. Upper respiratory system:
   1. Nose and nasal cavity:

The nose is the external and visible component of the respiratory system and is followed by the internal component inside the skull called the nasal cavity or internal nose. The nose is made up of bone and hyaline cartilage which is covered by muscle and skin and is lined by mucous-secreting cells called goblet cells. The nasal cavity is a two-way irregular passage for the entry of air and is divided by a septum. The posterior part of the septum is made up of ethmoid bone and vomer, and anteriorly made up of hyaline cartilage. The nasal cavity is lined up with the vascular ciliated columnar epithelium containing goblet cells that secretes mucous which coats the nasal hairs and make them sticky. Bones in the face and cranium that are filled with air are called paranasal sinuses and are present in the nasal cavity. Some of the sinuses are maxillary sinuses in the lateral wall, frontal and sphenoidal sinuses in the roof and ethmoidal sinuses in the upper portion of the lateral wall of the nasal cavity (17, 19).

Inspired air passes through the nose, which is the first respiratory passage, and then the air enters the nasal cavity where air is filtered, moistened or humidified, and warmed. Sticky hairs in the nares of the nasal cavity filter the air from any particles or microbes from the external environment. As the filtered air passes through the mucosa, which are in moist condition, the air becomes moistened. There is a huge vascularity surrounding the mucosa that makes the passing ai...