Pulmonary Drug Delivery (3/6/26) - Pharmaceutics II

Give the anatomical division order of the Respiratory System from top to bottom.

Trachea

Primary Bronchus

Primary Bronchiole

Secondary Bronchiole

Terminal Bronchiole

Respiratory Bronchiole

Alveolar Duct

Alveoli

From the top to bottom of the Anatomical Divisions in the Respiratory System, how do directional changes occur?

Top --> Very Abrupt

Middle --> Less Abrupt

Bottom --> Mild

From the top to bottom of the Anatomical Divisions in the Respiratory System, how does air velocity change?

During Inertial Impaction --> ++++

Trachea to Bronchial --> +++

In Bronchiolar Region --> ++

During Sedimentation --> +

In Alveolar Region --> 0

What is the Drug Dissolution for the Nasopharyngeal Region?

Bronchiolar Region?

Alveolar Region?

Nasopharyngeal --> 10-30 micrometers

Bronchiolar --> 5-10 micrometers

Alveolar --> 1-5 micrometers

What process occurs in the Nasopharyngeal Region?

Alveolar Region?

Nasopharyngeal --> INERTIAL IMPACTION

Alveolar --> DIFFUSION

What is an Aerosol?

Dispersion of particles or droplets suspended in a gas or vapor

What is the rationale behind using Inhalation Aerosols for Local Delivery?

Used for Asthma and COPD

Avoids systemic effects (Corticosteroids)

Has rapid onset (Beta-Adrenergic Agonists in Acute Asthma)

Acceptability (Compared to Injections)

What is the rationale behind using Inhalation Aerosols for Systemic Delivery?

Large surface area (120-160 m2; around tennis court size)

No degradation by Stomach and Enzymes, which allows for it to avoid First-Pass Metabolism in Liver

What are the main limitations of Inhalation Aerosols?

Lungs are generally designed to prevent inhalation of Exogenous compounds / particulates

SOME devices only deliver ~10% of the dose to the lungs

Oropharyngeal Irritation and Taste of Medication

What is Aerodynamic Diameter?

What is a simpler way of saying this?

Diameter of a hypothetical sphere with Density = 1 g/cm3, which has the same terminal settling velocity in calm air as the particle in question, REGARDLESS of its geometric size, shape, and true density

Essentially, how well the droplet or particle can fly in a stream of air

What are some examples of mechanisms for Aerosol Deposition?

Gravitational Settling (Sedimentation; between Bronchiolar and Alveolar Regions)

Impaction (>5 micrometers)

Brownian Diffusion (<5 micrometers)

What are the four main factors influencing Deposition?

1. Particle Size AND Distribution

2. Particle Size

3. Density (Particle / Droplet)

4. Solubility / Hygroscopicity (Particles / Droplets)

Which factor that influences Deposition plays the most significant role in Aerosol Deposition as a whole?

Particle Size AND Distribution

What Distribution value type is preferred for Aerosol Deposition?

Geometric Standard Deviation (GSD) that is LESS THAN 2 is preferred

How does Density influence Aerosol Deposition?

Give the equation for Density in use for Aerosol Deposition.

Density (Particle / Droplet) contributes to Inertia

dae = dg * p^(1/2), where:

dae - Aerodynamic Diameter

dg - Geometric Diameter

p - Density

Given two particles that have the same density of 0.03 g/mL, how does an increase in Geometric Diameter (dg) from 3 to 17 micrometers change the Aerodynamic Diameters (dae)?

Increase in dg from 3 micrometers to 17 micrometers with INCREASE Aerodynamic Diameter from 0.52 micrometer to 3 micrometer

How does Solubility / Hygroscopicity influence Aerosol Deposition?

Influences the deposition in the lungs that are at high humidity

Hygroscopic Particle --> Water / Humidity in Respiratory Tract --> makes a conglomerate or something

What are some examples of Conventional Devices used for Pulmonary Drug Delivery?

Metered Dose Inhaler (MDI) - ex. typical Albuterol inhaler you see

Nebulizer

Dry Powder Inhaler (DPI) - ex. Advair Diskus

What compounds are administered to the lungs via a Nebulizer for Cystic Fibrosis?

For Emphysema?

Cystic Fibrosis --> rhDNAse (cleaves leukocyte DNA), Tobramycin (treats Pseudomonas aeruginosa infections)

Emphysema --> alpha1-antitrypsin

What are the oldest aerosol generating devices?

What classifications can they be classified into?

How are these classifications determined?

Nebulizers

Classifications include Air-Jet and Ultrasonic

Classifications are determined by the mechanism of Aerosol production

What are some advantages to using Nebulizers for Pulmonary Drug Delivery?

Long treatment times

Aqueous Solutions

- Ease of Manufacture

- No Environmental Concerns

- Good for Biotech Companies

Does not depend on patient inspiratory force

What are some disadvantages to using Nebulizers for Pulmonary Drug Delivery?

Bulky / Not Portable

Expensive

Poorly Optimized

- Devices designed independently of drug

- Wastage (delivers when patients exhale)

Contamination

What is the general mechanism of Aerosol Generation in Nebulizers?

1. Compressed air enters Nebulizer by a designed channel

2. Solution is contained in side channels

3. Air + Solution mix rapidly, creating liquid droplets

4. Biggest droplets impact into the baffle / impinger, and are then retained in the nebulizer cup

5. Smaller droplets enter air stream, forming a liquid Aerosol

6. Aerosol leaves nebulizer through the tubing to get to the mask

What factors are Droplet Sizes dependent on when looking at emitted doses using Nebulizers?

Volume of the Solution

Surface Tension

Density AND Viscosity

Nebulizer Make / Model

What are some limitations to Ultrasonic Nebulizers?

Not recommended for drugs that are degraded by heat

May require higher degree of sterility due to Piezoelectric Transducer

Can produce smaller droplets, but are less efficient

- Less aerosol produced per liquid loaded

What was the first formulation developed for Nebulization?

TOBI

What types of solutions are typically used for Nebulization?

Typically solutions used for injection

What characteristics should a solution being used for inhalation through a Nebulizer have?

1. Sterile and Non-Pyrogenic

2. Chemically Stable

3. Free of Preservatives + Toxic Material

4. pH of 4.5-8.7

5. Osmolality of 150-550 mOsm/kg (Cl- conc. of 31-300 mM; ISOTONIC)

6. Enhances patient acceptance; tasteless or pleasant taste

Describe Inhaled Tobramycin as a medication.

Branded TOBI is used for Inhalation

Sterile, Clear, Slightly Yellow, Non-Pyrogenic, Aqueous Solution

pH and Salinity adjusted for administration through COMPRESSED AIR DRIVEN REUSABLE NEBULIZER

Each single-use 5 mL Ampule contains:

- 300 mg Tobramycin

- 11.25 mg NaCl (for isotonicity and osmolality) in Sterile Water

- If pH needs adjusted to 6.0, Sulfuric Acid and NaOH can be added

- NO PRESERVATIVES

Describe Injectable Tobramycin as a medication.

Clear, Colorless, Sterile, Aqueous Solution for Parenteral administration

Each mL contains:

- Tobramycin Sulfate = 40 mg Tobramycin

- Phenol preservative (5 mg, multi-dose)

- Sodium Metabisulfite (3.2 mg, multi-dose)

- Edetate Disodium (0.1 mg)

- Water for injection

- If pH needs adjusted to 3.0-6.5, qs. Sulfuric Acid and / or NaOH

What conditions do we typically see treated with Pressurized Metered Dose Inhalers (pMDIs)?

What types of compounds are administered for treating these conditions?

Asthma and COPD

Compounds include:

- Beta2-Adrenergic Agonists

- Glucocorticoids

- Mast Cell Stabilizer

What are Metered Dose Inhalers (MDI or pMDI)

Devices that contain a pressurized formulation that is aerosolized through an atomization nozzle and produces a METERED dose of the aerosolized drug for inhalation by the patient

What are some advantages of MDIs?

Portable

Perceived as easy to use and convenient

Stability (protection from Light, Oxygen, and Water)

Tamper-proof

What are some disadvantages of MDIs?

Expensive

Prone to Incorrect Use

Pressurized Contents pose safety issues

What are the various components of a pMDI?

Canister

Valve

Actuator

Formulation Ingredients (Propellants, Solvents, APIs + other Additives)

What types of materials can the Canisters of pMDIs be made of?

What types of Valves can be part of a pMDI?

Canisters --> Aluminum or Glass-Coated

Valves --> Metered (25-100 microliters) or Continuous

What are the functions of Actuators?

Allow release of formulation from valve in pMDIs

Generate aerosol through the orifice

Directs the aerosol

What are examples of Auxiliary Systems used with APIs?

Baffles

Spacer Devices

What are some issues that occur using Spacer Devices with MDIs?

Evaporation of Aerosol

Loss of Inertia

Large particle Sedimentation

What factors impact the particle size emitted from an MDI?

Formulation

Valve Design

Actuator

Propellant

What is the general mechanism of Aerosol Generation in pMDIs?

1. Canister is pressed against Actuator, causing

2. Actuator seat moves the nozzle in the metering valve (PRIME STEP)

3. Metering Valve opens to the canister

4. Dose of drug and propellant fill the chamber in the valve

5. Second actuation releases the aerosol through mouth piece of the actuator (for patient to inhale)

6. If spacer is used, larger droplets will settle at bottom of spacer and respirable droplets can be inhaled by the patient

What are the three main formulation ingredients included in pMDIs?

1. Propellants

2. Solvents

3. APIs + Other Additives

What are the main functions of Propellants in the formulation of pMDIs?

Provide pressure to expel the product

Act as a dispersion medium

Sometimes exhibit solvent properties

What are the main functions of Solvents in the formulation of pMDIs?

Bring the API into solution

Act as a Co-Solvent for Immiscible liquids

Influence Particle Size

Reduce Vapor Pressure

Why are Propellants banned?

Due to their effect on the Ozone Layer (global warming potential)

What are the two most common Propellant Types?

Which one has less Global Warming Potential (GWP)?

Describe both in terms of (a) Toxicity, (b) Stability, (c) Solvents, and (d) Effect on the Ozone

1. Chlorofluorocarbons (CFCs)

- LOW Toxicity

- HIGH Stability

- GOOD Solvents

- DESTROYS Ozone (ODP)

2. Hydrofluoroalkanes (HFAs)

- LOW Toxicity

- HIGH Stability

- POOR Solvents

- NON-OZONE DEPLETING

HFAs have six times less GWP

What was the Montreal Protocol?

Protocol built to phase out Chlorofluorocarbons (CFCs) by 2000, with a complete transition by 2005

What are the five main factors that influence formulation performance of pMDIs?

1. DRUG SOLUBILITY (soluble or insoluble, not in between; solution or suspension)

2. VAPOR PRESSURE (particle size, droplet evaporation, velocity)

3. SURFACE TENSION (droplet formation)

4. SOLUBILITY OF OXYGEN / HYGROSCOPICITY (stability of drug)

5. DENSITY (stability of suspension)

What developments led to the increased used of Dry Powder Inhalers (DPIs)?

Response to the phasing out of CFCs and other propellants from the Montreal Protocol

What are the main reasons for the increase in development of Dry Powder Inhalers (DPIs)?

Phasing out of Propellants, including CFCs

Ease of Use (no coordination with actuation required)

Stability Advantages (most notably with Biotech Compounds)

Can be used for Small or Large doses

What are some examples of Dry Powder Inhalers (DPIs)?

Turbuhaler (Budesonide or Budesonide / Formoterol)

Handihaler (Tiotropium)

Cyclohaler (Aerolizer / Formoterol)

Diskus (Salmeterol / Fluticasone)

What are some advantages to DPIs?

Portable and Convenient

Can deliver much higher drug doses than nebulizers and MDIs

Ease of Use (dependent on design)

No Coordination with Actuation Required

Stability

Tamper-Proof

What are some examples of Compounds we administer to the lungs using DPIs?

Asthma / COPD Compounds

Insulin (for Diabetes)

Antibiotics (via Tobi-Podhaler)

What are some disadvantages to DPIs?

Efficiency is heavily dependent on the formulation and design of the device

Strength of the patient's airflow determines the dose that is administered

Not recommended for children or elderly patients

What are Passive DPIs?

What is the main determining factor on their efficiency?

How does this affect who can use them?

DPIs that depend on patient's inhalation to provide the energy needed for dispersing the powder

Main determining factor on their efficiency is if the patient can inhale at a maximum rate

Because of this, the inhaler is dependent on the strength of the patient's airflow to work properly and give the proper dose

- This is problematic for Children and Elderly patients whose airflow is not as strong as most normal adults

What are the three general parts of a DPI?

How do certain parts differ between DPI types?

1. Powder Reservoir

- Capsule (Spinhaler, Aerolizer)

- Blister (Diskus)

2. Mechanism of Powder Release and Fluidization

- Rotating Impeller / Chamber (Spinhaler)

- Piercing Pins / Capsule (Aerolizer)

- Foil Sprocket / Chamber (Diskus)

3. Mouth Piece

What is required of the Aerosol Powder before it is delivered to patient airflow when using DPIs?

Powder dose must be fluidized before it can be transformed into an Aerosol and delivered to patient airflow

What is the general mechanism of Aerosol Generation using DPIs?

1. Patient inhales at max force

2. Powder Bed fluidizes

3. Fluidize Powder bed separates into small aggregates of Drug and Carrier (Dilated Powder)

4. As patient continues inhaling, powder is completely Aerosolized

5. Drug is stripped from carrier particles (>40 micrometers)

6. Carrier particles are retained either (a) in the device or (b) in the patient's mouth, while Drug Particles (<5 micrometers) are deposited in the small airways or Alveoli based on drug particle size

What are the two main factors affecting DPI performance?

1. Complex Physics Behind Powder Fluidization

- Particle Size

- Attractive Forces between Particles

2. Forces Between Particles less than 5 Microns often prevents Fluidization

- Inter-Particulate Forces

- Carrier Particles (40-60 micrometers)

What equation is used to calculate Porosity?

ln(p / p0) = -2Mγ / rRT,

where:

p / p0 - relative pressure

p0 - saturation vapor pressure

M - molar volume of gas or fluid

γ - surface tension

r - radius of the pore

R - universal gas constant

T - temperature

What other application does Porosity have in pharmaceutical powders?

Adsorption of Flavoring Agents and Perfumes into Films, Containers, or Polymeric Materials

What two groups of formulation ingredients are included in DPIs?

Describe what ingredients are included in these groups.

1. Powder Blends

- Drug (usually <5 micrometers)

- Carrier (Lactose*, Trehalose, Mannitol, Leucine)

2. Engineered Particles

- Solid Lipid Nanoparticles

- Proprietary Technologies (Pulmospheres, Technospheres, ProMaxx, etc.)

- Experimental Approaches (Biodegradable Polymers, PLGA, Chitosan, etc.)

What is the only FDA approved carrier for DPIs?

Lactose