Page 1: Introduction to Pulmonary Drug Delivery Systems

Overview

• Instructor: Joe Su, PhD

• Course: PHRM 604

• Source: climate.nasa.gov

Page 2: Learning Objectives

Key Learning Points

1. Physiology of the lung.

2. Changes in lung epithelium from upper airways to peripheral lung.

3. Impact of mucociliary clearance on drug absorption from pulmonary drug delivery systems (DDS).

4. Ideal physicochemical properties of drugs for pulmonary DDS.

5. Formulation factors important for pulmonary DDS.

6. Comparison of major device types for pulmonary DDS.

Page 3: Advantages and Disadvantages of Pulmonary Drug Delivery

Advantages

• Local and systemic efficacy.

• Non-invasive and rapid absorption.

• High bioavailability with a wide variety of drug sizes.

• Large surface area for absorption.

• Avoids hepatic first pass metabolism.

• Convenient alternative to oral delivery, potential for long-term use.

Disadvantages

• Use of penetration enhancers can be problematic.

• Smaller absorption surface area than the gastrointestinal (GI) tract.

• Irreversibility of drug once administered.

• Possible irritation can affect patient compliance.

Page 4: Local vs. Systemic Drug Delivery

Local Delivery Applications

• Conditions affecting the lung:

  • Asthma

  • Emphysema

  • Chronic Obstructive Pulmonary Disease (COPD)

  • Cystic fibrosis

  • Primary pulmonary hypertension

  • Lung cancer

Systemic Delivery Applications

• Used for:

  • Acute and chronic therapies (e.g., diabetes insulin delivery, osteoporosis calcitonin, venous thromboembolism heparin).

Page 5: Physiology of the Lung

Structure Overview

• Divided into three main sections:

  1. Upper airways

  2. Conducting airways

  3. Peripheral airways

Page 6: Lung Epithelia

Characteristics

• Highly permeable and absorptive.

• Essential in delivering inhaled medications.

Page 7: Physiological Barriers to Drug Absorption (1/3)

Factors Affecting Absorption

• Lung Morphology: Short average path length allows for greater peripheral drug deposition; altered morphology can affect drug sedimentation.

• Oral Breathing: Inhalation of aerosol via mouth can influence deposition.

• Tidal Volume: Higher volume leads to better alveolar region deposition.

• Bronchial Blood Circulation: High circulation in alveolar and respiratory bronchioles facilitates absorption.

Page 8: Physiological Barriers to Drug Absorption (2/3)

Lung Clearance Mechanisms

• Mucociliary Clearance (MCC): Ciliated epithelium removing insoluble particles.

• Absorption Pathways:

  • Lipophilic molecules via passive transport.

  • Hydrophilic molecules through various methods (tight junctions, active transport, endocytosis).

• Phagocytosis and Enzymatic Clearance: Same enzymes as liver but in lesser amounts; lower degradation of proteins and peptides compared to the GI tract.

Page 9: Physiological Barriers to Drug Absorption (3/3)

Membrane Permeability and Transport Mechanisms

• Main barrier is lung epithelium.

• Transport Mechanisms:

  • Small molecules: Diffusion or carrier-mediated transport.

  • Macromolecules: Various transport methods based on size and structure (e.g., transcytosis, receptor-mediated).

Page 10: Physicochemical Factors Impacting Pulmonary Function (1/2)

Key Particle Characteristics

• Location of Deposition and Particle Size:

  • Size > 10 μm: Impacted in upper airways.

  • Size 1-5 μm: Optimal for lung periphery.

  • Size < 1 μm: Typically exhaled.

Page 11: Physicochemical Factors Impacting Pulmonary Function (2/2)

Additional Considerations

• Molecular Weight: Less than 1,000 Da allows for fast absorption; over 150 kDa limits systemic absorption.

• Lipophilicity: More lipophilic drugs have faster absorption rates.

• Particle Stability and Density: Stability is important for reducing enzymatic degradation, particularly of proteins.

Page 12: Pulmonary Devices

Overview and Efficiency

• Generally, less than 20% of drug delivered via inhalers reaches the lower airways.

• Characterization Parameters:

  1. Output rate of drug mass.

  2. Size distribution of aerosol.

  3. Consistency within and between devices.

Page 13: Albuterol Device Comparison

Summary of Albuterol Delivery Profiles

• Devices: DPI, pMDI, pMDI with holding chamber (MDI/HC), nebulizer (NEB).

• Highlights:

  • Significant differences in dosage optimization and deposition outcomes.

Page 14: Nebulizers

Types and Usability

• Jet Nebulizer: Patient-driven.

• Ultrasonic Nebulizer: Power-assisted, easier for children and elderly.

• Basic operation: Requires some device preparation but allows simple tidal breathing.

Page 15: Pressurized Metered-Dose Inhaler (pMDI)

Operational Insights

• Delivers 10-20% of dose to lungs; coordination needed for effective use.

• Commonly used for asthma and COPD; portable and easy to use but requires practice for efficient dosing.

Page 16: Dry Powdered Inhaler (DPI)

Characteristics and Limitations

• Higher delivery rates (12-40%) to lungs; however, requires good inspiratory flow which can be challenging for younger and older patients.

Page 17: Formulation Factors Affecting Pulmonary Function

Important Factors

• Dissolution Rates: Affects systemic absorption vs. local activity.

• Aerosol Velocity: Influenced by inspiration and device characteristics.

• Stability of Formulations: Physically unstable systems can lead to aggregation and poor dosing accuracy.

• Role of Excipients: Fewer excipients limit interactions but can enhance bioavailability, with safety concerns.

Page 18: Dosage Forms in Pulmonary DDS (1/2)

Common Formulations

• Solutions: Most common, involving drug in equilibrium between vapor and liquid.

• Emulsions: Dispersal of drug in propellants, stability concerns with surfactants.

Page 19: Dosage Forms in Pulmonary DDS (2/2)

Other Formulations

• Suspensions: Require stabilizing agents and face challenges with dosing consistency.

• Dry Powders: High volume per puff and lower microbial risks but complex formulation strategies needed.

Page 20: How to Use a Metered-Dose Inhaler

Step-by-Step Instructions

1. Shake the inhaler.

2. Position correctly while exhaling.

3. Press and inhale deeply; hold breath to ensure full uptake.

Page 21: How to Use a Dry Powdered Inhaler (DPI)

Step-by-Step Instructions

1. Prepare device and load dose.

2. Breathe out, place mouthpiece, inhale deeply.

3. Check dose counter and reload if necessary.

Page 22: Lecture Quiz

Review Questions

1. Identify the major drug absorption site in the lung.

2. Required particle size for effective deposition in lung periphery and consequences of size variance.

3. Identify pulmonary drug delivery devices suitable for children.

Page 23: Learning Objectives (Final Review)

Recap of Course Goals

1. Anatomy and physiology of the respiratory system.

2. Changes in lung epithelium from upper airways to the peripheral lung.

3. Influence of mucociliary clearance on drug absorption from pulmonary DDS.

4. Ideal physicochemical properties for pulmonary DDS.

5. Formulation factors affecting pulmonary DDS.

6. Comparison of major types of devices for pulmonary DDS.