Pulmonary Drug Delivery PDF

PHARMACEUTICS I Pulmonary Drug Delivery Jose Rocca, Ph.D.  Outline Introduction Overview of Pulmonary Drug Delivery The Lung Physiology Mechanisms Involved in Pulmonary Delivery Formulation Attributes Forms of Pulmonary Delivery – Meter...

PHARMACEUTICS I Pulmonary Drug Delivery Jose Rocca, Ph.D.  Outline Introduction Overview of Pulmonary Drug Delivery The Lung Physiology Mechanisms Involved in Pulmonary Delivery Formulation Attributes Forms of Pulmonary Delivery – Metered Dose Inhaler – Dry Powder Inhaler – Nebulizer – Other devices Pulmonary Drug Delivery Injection Alternative Local and Systemic Effect Pulmonary delivery is a non-invasive method of delivering drugs into the lungs through inhalation  Perceived as:  Complex  Difficult  Expensive Source: What is the future of inhalation delivery? By: Simon Moore BSC (Hons), PhD, MRSC, WHITE PAPER MAY 2016 Director of Inhalation Science and Engineering, Envigo  Pulmonary Drug Delivery Market The global market for pulmonary drug delivery devices and systems is projected to reach USD 55.1 billion by 2025, according to a new report from Grand View Research, Inc. The metered-dose inhaler (MDI) segment currently holds the largest market share, driven by its affordability and widespread adoption following its early introduction. Other alternatives, such as dry powder inhalers (DPIs) and nebulizers, are also experiencing significant growth, with the market expected to expand at an approximate compound annual growth rate (CAGR) of 12.5%. Regionally, North America leads the respiratory drug delivery market, followed by Europe and the Asia-Pacific. This growth is attributed to advancements in digital inhaler technology by various companies and supportive reimbursement policies, including Medicare and Medicaid. Key players in the respiratory drug delivery market include GlaxoSmithKline, Boehringer Ingelheim GmbH, 3M, AstraZeneca plc, Merck & Co., Inc., Novartis AG, Omron Corporation, and Sunovion Pharmaceuticals Inc.  Projected Market for Inhaled Drugs The asthma segment accounts for the major share in the market due to increasing prevalence of asthma across the globe*  Pulmonary Drug Delivery It is estimated that almost 53 million people suffer from asthma in the United States (Over 300 MM Worldwide) - Estimated that an additional 100 million people with asthma by the year 2025 Increases in incidences and diagnosis of asthma and Chronic obstructive pulmonary disease (COPD) – Market expected to increase significantly in the coming years (High number of patients affected by asthma in developing and developed regions) – Specially in Asia Pacific – Over 210 MM people suffer COPD Worldwide – Could become 3rd leading cause of death – Chronic Obstructive Pulmonary Diseases (COPD) segment is anticipated to grow at a lucrative CAGR due to the presence of favorable reimbursement policies for treatment of COPD – More amenable for Home care segment can exhibit exponential growth due technologically advanced, portable, and small-sized devices – The market is progressing due to the rising demand for better treatment options, efficient drug delivery, and rapid treatment of local respiratory disorders  Why Pulmonary Delivery? Rich blood supply and enormous surface area The surface area of human adult lungs is about 1,100 square feet (i.e., larger than the size of a tennis court) Primary role of lung is to exchange oxygen and carbon dioxide Gas exchange occurs in roughly 300 million alveoli Provide the most direct route of entry for medications into bloodstream For psychoactive substances such as nicotine, pulmonary delivery has long been recognized as the most efficient route of delivery Pulmonary drug delivery has been limited to this point, due to an absence of technology that allows this route to be utilized.  Pulmonary Drug Delivery Used for decades to deliver drugs for the treatment of respiratory disorders It is also being used for the delivery of antibiotics, such as tobramycin, to patients suffering from cystic fibrosis (i.e. TOBI®) There still an ongoing pandemic with SARS-CoV- 2 which has affected all countries around the world Pulmonary infectious diseases have long been a major category of diseases severely threatening human life and global health.  Pulmonary Drug Delivery According to WHO statistics, pneumonia is the leading cause of death among children. In 2017 alone, it claimed the lives of approximately 808,694 children under the age of five worldwide, accounting for 15% of all deaths in this age group. Tuberculosis (TB) continues to be among the top 10 causes of death globally. In 2017, it resulted in 1.6 million deaths, with over 10 million people living with the disease. Pulmonary infectious diseases have a significant global impact, imposing severe social and economic challenges. Despite ongoing efforts, the development of effective and safe treatment options for these diseases remains a major challenge. Reference: He, S., Gui, J., Xiong, K. et al. A roadmap to pulmonary delivery strategies for the treatment of infectious lung diseases. J Nanobiotechnol 20, 101 (2022).  Pulmonary Drug Delivery Symptomatic relief and treatment of asthma and chronic obstructive pulmonary disease (COPD) – Inhaled corticosteroids approved in 1970s – There is no cure, treatments can help manage symptoms – Non-reversal – must have continuity of treatment Early counseling and effective management of asthma and COPD can help slow their progression and enhance quality of life Evolution of Pulmonary Delivery Devices  Pulmonary Drug Delivery The principal behind pulmonary drug delivery is aerosolization of drug compounds to be delivered to bronchioles and alveoli. http://www.youtube.com/watch?v=yU8jJ0HPhys  The Lung Lung is a robust organ – Handles millions of particulates daily – Has complex airway geometry – Humidity – Mucociliary clearance: Upper portions of pulmonary tract are coated with thick, mucus covered cells with cilia (hair like projections) => Trap and filter out particles – Alveolar macrophages Lung Physiology  Lung Physiology (Two Main Regions) Conductive Airway Respiratory Region (where gas exchange takes place) 1. Nose 1. Respiratory 2. Pharynx bronchioles 3. Larynx 2. Alveolar ducts 4. Trachea 3. Alveoli (or alveolar 5. Bronchial tubes sacs) 6. Bronchioles  The Lung Alveoli are thin-walled, take oxygen from the air into the blood and pass back CO2 Intimate connection between alveoli and capillaries – Can deliver large molecular weight proteins Liquid solutions or microparticles – Can get immediate uptake of blood into capillaries  Pulmonary Drug Delivery Advantages: Easy to titrate dose – Titration by therapy – Titration by Patient High efficiency and rapid onset of action For local effect, maximize benefit/minimize side effects Avoidance of degradation in GI Tract and first pass effect Lower dose levels with potentially fewer side-effects Drugs that are not absorbed orally can be delivered via the lung Pain Free Non-Invasive Lower degree of product contamination  Pulmonary Drug Delivery (added advantages) Utilization of huge surface area of lungs to deliver drugs into the blood circulation transforming into reality Lungs best alternative for drugs needing to bypass the gastrointestinal tract, such as proteins, peptides and other macromolecules. Pulmonary delivery is independent of dietary complications, extracellular enzymes and interpatient metabolic differences that affect gastrointestinal absorption  Pulmonary Drug Delivery Disadvantages: Takes significant degree of coordination Patients with lung disease may not be able to inhale adequately Variability in delivery High cost of manufacturing Most macromolecules cannot be administered orally because proteins are digested before they are absorbed into the bloodstream. Also, their large size prevents them from naturally passing through the skin or nasal membrane, and therefore they cannot be administered intranasally or transdermally without the use of penetration enhancers. Thus, the easiest route of administration for proteins has been through intravenous or intramuscular/subcutaneous injection. It has been known for many years that proteins can be absorbed from the lung, as demonstrated with insulin in 1925 Macromolecules 5–6 nm in diameter) are slowly absorbed over many hours; inhaled albumin (68 kDa) and α1-antitrypsin (45–51 kDa) have a Tmax of 20 h and between 12 and 48 h, respectively  The Fate of Inhaled Corticosteroids 10 - 40 % Deposited in lung Complete absorption from the lung Lung Systemic Mouth and pharynx Circulation Orally bioavailable fraction Absorption from gut Liver Systemic 60 - 90 % Swallowed Side Effects (reduced by spacer or mouth rinsing) First-pass GI tract inactivation  Pulmonary Delivery (Important points) Immediate uptake of drug into bloodstream Rapid absorption – Lower bioavailability can result due to clearance of foreign bodies through phagocytosis and metabolic degradation (exopeptidases) To reach alveoli, particles less than 5 microns – Larger particles will stick to upper portions of the airways, trachea, nasal or oral cavity http://www.youtube.com/watch?v=I5tdi4QmUcg Site of Delivery Particle Size in Pulmonary Delivery  Factors and Challenges that Influence Deposition of Particles in the Lung Physicochemical properties – Too small – can be exhaled – Too large – deposited oropharynx and larynx Formulation – Type od carrier and stability (some are very moisture sensitive, different crystals, agglomeration) – Very low dose per actuation Technique – Depth of inspiration, pause prior to exhalation, coordination of inhalation – Inspiratory flow rate, flow pattern, respiratory rate, inhaled volume, ratio of inspiratory time to expiratory time (I:E ratio), and breath-holding – Not too practical on usage to children and elderly  Factors affecting deposition Physiological – Pulmonary disease Worsening conditions Airway obstruction Device usage and maintenance – Malfunctioning and valve obstruction Inhale - Peptide Delivery  Key Attributes for Pulmonary Delivery Formulation particle size