Pulmonary Drug Delivery Methods PDF

3.7 Reasons for Delivering Drugs to the Lungs Local Effect: The main reason for pulmonary drug delivery is to achieve a localized effect in the lungs. This is particularly relevant for conditions like asthma and COPD, where medications act directly on the airways to alleviate...

3.7 Reasons for Delivering Drugs to the Lungs Local Effect: The main reason for pulmonary drug delivery is to achieve a localized effect in the lungs. This is particularly relevant for conditions like asthma and COPD, where medications act directly on the airways to alleviate symptoms. Examples include: ○ Asthma medications: Beta-agonists (bronchodilators), glucocorticoids (anti-inflammatories), antimuscarinics (reduce secretions), and mast cell stabilizers. ○ COPD medications: Mucolytics like N-acetylcysteine and deoxyribonuclease to reduce mucus viscosity, particularly in cystic fibrosis. ○ Neonatal Respiratory Distress Syndrome: Treatment with exogenous pulmonary surfactant. ○ Infections: Medications like pentamidine for Pneumocystis jirovecii pneumonia and ribavirin for RSV. Systemic Effect: The lungs offer a promising route for systemic drug delivery due to their large surface area and the absence of hepatic first-pass metabolism. This means that drugs absorbed through the lungs bypass the liver, leading to higher bioavailability. ○ Examples of medications delivered systemically via the lungs include: Afrezza: A dry powder inhaler (DPI) of recombinant human insulin for diabetes. Adesu: A DPI of loxapine for schizophrenia. INBRIJA: A DPI of levodopa for Parkinson’s disease. Methods of Pulmonary Drug Delivery Intratracheal Instillation: This method involves directly administering the drug solution into the trachea for distribution to the lungs. It is primarily used for delivering pulmonary surfactant to neonates with respiratory distress syndrome. This method requires specific patient positioning to ensure proper drug distribution within the lungs. Aerosol Inhalation: This is the most common method, involving inhalation of aerosolized drug particles through the mouth for deep penetration into the lungs. This method is the primary focus of the source material. Aerosol inhalation can also be administered via a tracheostomy, where the device is attached to the trachea, directly delivering the drug to the lungs. Types of Oral Aerosols Propellant-driven: The most dominant type historically, these are the classic “aerosol” inhalers. They rely on a pressurized propellant to deliver the drug in a fine mist. Mechanical energy-driven: A newer type of inhaler that uses mechanical energy to generate the aerosol.  Dry powder inhalers (DPIs): DPIs deliver the drug in a dry powder form, requiring the patient to inhale with sufficient force to disperse the powder into the lungs. These became prominent due to the phasing out of CFC propellants in metered dose inhalers. Nebulizers: Nebulizers use air or ultrasonic waves to create a cloud of drug particles that is inhaled by the patient. Anatomy and Physiology of the Respiratory Tract Tracheobronchial Tree: The lungs are comprised of a branching network of airways called the tracheobronchial tree. This tree starts with the trachea, which branches into progressively smaller airways: the bronchi, bronchioles, and finally, the alveoli. Alveoli: These tiny air sacs are the primary site of gas exchange in the lungs. The alveoli have a large surface area, which is advantageous for systemic drug absorption. Pulmonary Epithelium: The cells lining the airways are called the pulmonary epithelium. The epithelium in the upper airways and tracheobronchial tree is ciliated, meaning it has tiny hair-like structures called cilia. The cilia move in a coordinated fashion to propel mucus upwards, a process known as the mucociliary escalator. Role of Mucus in the Lungs Protection: The mucus in the lungs, similar to the nasal cavity, serves as a protective barrier. It traps foreign particles like dust, bacteria, and drug crystals, preventing them from reaching the delicate lung tissue. Hydration: Mucus also helps to keep the lung lining moist, preventing dehydration of the epithelial cells. Mucociliary Escalator: The mucus layer is constantly moved upwards by the cilia, carrying trapped particles towards the pharynx, where they are swallowed. This mechanism, known as the mucociliary escalator, is crucial for clearing the lungs of debris and foreign substances. Alveolar Macrophages Defense Mechanism: The alveoli contain specialized immune cells called alveolar macrophages, which act as scavengers. They engulf and remove foreign particles that reach the alveoli, including bacteria, dust, and undissolved drug crystals. Particle Removal: Macrophages contribute to particle removal by migrating towards the mucociliary escalator, carrying engulfed particles upwards to be eliminated from the lungs. Disposition of Aerosols in the Lungs Aerosol Cloud: All pulmonary inhalation devices generate a respirable cloud of particles, either solid drug crystals or droplets containing the drug.  Deposition Sites: The location where the aerosol particles deposit in the lungs depends on several factors, including particle size, velocity, and the patient's breathing pattern. Gamma Scintigraphy: This imaging technique uses radioactive markers to visualize aerosol deposition in the lungs, illustrating the distribution of inhaled particles. A typical image will show significant deposition in the mouth, followed by the lungs, and then the stomach (due to swallowing). Fate of Deposited Drug Oropharynx (Mouth): Drug deposited in the mouth can be absorbed locally or swallowed, entering the gastrointestinal (GI) tract. Once in the GI tract, the drug is subject to intestinal and hepatic first-pass metabolism, potentially reducing its systemic availability. Tracheobronchial Region: Drug deposited in the mucus lining of the airways can be cleared by the mucociliary escalator, permeate the epithelium (mainly via passive diffusion) and be systemically absorbed, or be engulfed by macrophages. Alveoli: Drug reaching the alveoli can be absorbed systemically (bypassing hepatic first-pass metabolism), engulfed by macrophages, or exhaled. Mechanisms of Aerosol Deposition Inertial Impaction: Occurs when larger or faster-moving particles cannot follow the curves of the airways and collide with the airway walls, typically in the upper airways or mouth. Sedimentation: As airflow slows down deeper in the lungs, particles settle out of the airstream due to gravity. Diffusion: The smallest particles (< 1 micron) move randomly in the airstream and deposit on airway surfaces through diffusion. Aerosol-Related Factors Affecting Particle Deposition Particle Size: The size of aerosol particles, measured as aerodynamic diameter, is a crucial factor influencing deposition. Smaller particles generally penetrate deeper into the lungs. ○ Particles > 10 microns deposit in the oropharynx (mouth and throat). ○ Particles 5-10 microns deposit in the upper tracheobronchial tree. ○ Particles 1-5 microns are ideal for deep lung penetration, reaching the bronchioles and alveoli. ○ Submicron particles (< 1 micron) can reach the alveoli but are prone to exhalation. Particle Velocity: Higher particle velocity increases the likelihood of inertial impaction in the upper airways. Patient-Related Factors Affecting Deposition Breathing Pattern:  ○ Rapid, shallow breathing: Favors deposition in the upper tracheobronchial tree. ○ Slow, deep breathing: Promotes deeper penetration into the lungs. Breath-Holding: Holding the breath after inhalation allows time for sedimentation and diffusion, enhancing deposition and minimizing exhalation of particles. Disease State: Lung diseases like asthma, COPD, and emphysema can alter airway caliber and airflow patterns, impacting particle deposition. ○ Narrowed airways (e.g., in asthma) and altered lung architecture (e.g., in emphysema) can lead to increased turbulence and impaction. Efficiency of Pulmonary Drug Delivery Low Efficiency: Pulmonary drug delivery is generally characterized by low efficiency, with a significant portion of the inhaled dose ending up in the GI tract (estimated at 80-95% but varies depending on the product). Factors Contributing to Low Efficiency: ○ Suboptimal aerosol generation: Particles outside the ideal size range, leading to impaction in the mouth and throat. ○ Fast release velocity: Favors impaction in the upper airways. ○ Suboptimal inhalation technique: Rapid inhalation increases the likelihood of impaction. Types of Pulmonary Delivery Devices Metered Dose Inhalers (MDIs): ○ Pressurized canisters: Contain drug, liquefied propellant, and minimal excipients. ○ Metering valve: Delivers a precise dose upon actuation. ○ Actuator (mouthpiece): Depresses the valve stem and directs the aerosol into the mouth. ○ Propellants: Typically hydrocarbon-based (e.g., HFA 134a). Act as the power source for aerosol generation and the vehicle for the drug. Properties like boiling point, vapor pressure, density, stability, and solvent power are crucial for device design and performance. ○ Aerosol Release Mechanism: High pressure inside the canister forces the liquid out upon actuation. Rapid evaporation of the propellant creates a fine mist of droplets containing the drug. ○ Formulations: Solutions: Drug dissolved in the propellant, may require co-solvents (e.g., ethanol) to enhance solubility. Suspensions: Drug particles dispersed in the propellant, common due to the limited solubility of many drugs in hydrocarbon propellants. Disadvantages: Physical instability (settling, aggregation).  Excipients: Surfactants (e.g., oleic acid, soy lecithin) for dispersion, lubrication, and prevention of particle adhesion; co-solvents may be used to solubilize excipients. Dry Powder Inhalers (DPIs): ○ Rose in popularity as an alternative to MDIs with the phasing out of CFC propellants. Nebulizers: ○ Produce a cloud of drug particles via air jet or ultrasonic waves.