Respiratory Drug Delivery Quiz

Pulmonary Drug Delivery

• Pulmonary drug delivery is a method of administering drugs to the lungs.
• This method allows drugs to act quickly, minimize the required dose, and be non-invasive.
• Scientifically, inhaled drugs go directly to the lungs, minimizing side effects and avoiding hepatic first-pass metabolism.
• Inhaled drugs are systemically absorbed.

Objectives

• Understand how droplet size and settling velocity affect drug disposition.
• Understand the key differences in components of metered-dose inhalers (MDIs) and dry-powder inhalers (DPIs).
• Understand the guidelines provided by the 3 USP sections.
• Understand patient factors affecting droplet deposition.
• Understand how viscosity and surface tension affect ophthalmic and intranasal products' residence and absorption.
• Know acceptable pH, isotonicity ranges of ophthalmic and intranasal products (if mentioned) and how they relate to dosage forms.
• Know advantages, disadvantages, and characteristics of MDIs, DPIs, nebulizers, and spacers

Rationale

• Ancient civilizations understood the speed and efficiency of inhaled drugs.
• Scientists and physicians later recognized the direct delivery to the lungs and systemic absorption, reducing side effects.

Advantages of Local Respiratory Drug Delivery

• Delivery to the site of action (where a local effect is required)
• Lower doses needed (due to increased local effect)
• Reduction of systemic side effects
• Large surface area for absorption
• Rapid onset (for some asthma medications)
• Avoidance of gastrointestinal (GI) upset
• Avoidance of hepatic first-pass metabolism
• Lung environment is less hostile to many drugs (including proteins and peptides)

Disadvantages of Local Respiratory Drug Delivery

• Difficulty in dose estimation and reproducibility due to various factors
• Proper use technique is critical
• Mucus and infection can impede drug deposition in the lower airways
• Physical stability of pharmaceutical aerosols can be problematic.
• Systemic absorption can occur if the effect is systemic, including limited absorption by the mucous layer and mucociliary clearance

Respiratory Tract

• The lower respiratory tract consists of:
  • Trachea (divides into)
  • Bronchi (divide into)
  • Bronchioles (divide into)
  • Alveoli (for gas exchange)

Factors Affecting Drug Deposition in the Lung

• Physicochemical properties of the aerosolized droplets/particles
• Physiological and anatomical considerations
• The delivery device

Physicochemical Factors

• Inhaled particles need to settle on lung tissues for proper delivery.
• Both diameter and density of inhaled particles are crucial for deposition.
• Mean Aerodynamic Diameter (MAD) is the diameter of a sphere with a density of 1 g/cm³ that has the same settling velocity as a given particle.
• Stokes diameter is the spherical diameter of a particle that has the same density and settling velocity as the given particle.

Aerosol Size and Work Region

• Aerosol size correlates to the target region in the respiratory tract.
• Different-sized aerosols are used for targeting different regions of the respiratory system.
• The chart in the presentation (Slide 11) maps the sizes with intended delivery regions.

Settling Velocity Equation

• Adapted from Stokes' equation.

• Given by Dae = D x (ρp/ρa) ^0.5

  • Dae = Aerodynamic diameter
  • Dv = Volume equivalent diameter
  • ρp = Density of the particle
  • ρa = Density of the air

Additional Formulation Factors

• Humidity in the respiratory tract (99.5% at 37°C) can impact particle size and deposition.
• Lipophilic particles aren't as affected by humidity as hydrophilic ones, which experience an increased Mean Aerodynamic Diameter (MAD)
• Particle size less than 1 micron: Brownian motion
• Temperature
• Stability concerns (prevent degradation before reaching the target)
• Penetration
• Electrostatic charge
• Inertial impact (affecting deposition in the upper airway due to the higher velocity of the airstream)

MDI Inhalers

• Advantages:*

• Reliable and consistent drug dose delivery to the site of action.

• Quicker onset of action compared to oral bronchodilators.

• Fewer side effects.

• Convenient form for many medications.

• Economical/low cost.

• Disadvantages:*

• Requires coordination in actuation and inhalation.

• Not the most efficient delivery method.

• Can be uncertain when the drug cartridge is empty.

MDI Composition

• Containers
• Metering valves (release a fixed volume)
• Elastomer seals (prevent propellant leakage)
• Actuators (permit easy actuation and spray discharge)
• Propellants and/or a solvent/suspension in propellant/solvent mixture
• Drug (suspension or dissolved)
• Other excipients

How MDIs Work

• Pressing the canister activates the metering valve.
• The drug/propellant mixture is discharged under pressure.
• Expansion and vaporization of the propellant create an aerosol.

MDI Examples

• Albuterol
• Ipratropium
• Fluticasone
• Levabuterol Tartrate
• Pirbuterol

MDI's

• The drug is dissolved or suspended in liquid propellant (with/without cosolvent).
• Surfactants are included to prevent settling and lubricate the valve.
• Typical MAD: 3–6 µm (affected by technique and initial velocity)

CFC vs HFA

• In the 1980s, the Montreal Protocol mandated phasing out chlorofluorocarbons (CFCs) as propellants.
• Hydrofluorocarbons (HFA) propellants are now a more common alternative, exhibiting better lung deposition.

Dry Powdered Inhalers (DPIs)

• Advantages:*

• Automatic dose delivery and inhalation coordination.

• No propellants required.

• Potential for better drug stability.

• High dose capacity.

• Disadvantages:*

• Require a high inspiratory flow rate.

• Can be susceptible to errors in administration procedure.

DPI Function

• Micronized drug particles (1-5 µm diameter) are dispersed.
• Aerosol is generated by drawing air into a dose of powder.
• A carrier often aids in dose metering uniformity and stability.

Nebulizers

• Machines that convert liquid medication into a fine mist (inhaled droplets).
• Droplet size depends on many factors (e.g., orifice size, pressure, concentration).
• Surfactants help reduce surface tension for fine droplet formation.
• Compressed air, oxygen, or ultrasonic power can power nebulizers.

Nebulized Solutions (Examples)

• Albuterol sulfate Inhalation Solution
• Ipratropium bromide solution
• Budesonide (Pulmicort Respules)
• Albuterol/Ipratropium (Duoneb)
• Levalbuterol (Xopenex)

Nebulizers: Advantages

• Passive breathing.
• Suitable for pediatric patients.
• Suitable for liquid medications
• Minimal procedure required.
• Dose adjustment possible.

Nebulizers Disadvantages

• Time consuming.
• Require external power source (or expensive rechargeable option).
• Require cleaning.
• Inefficient (low percentage of delivered drug).
• Cumbersome

Nebulizers Components

• Air compressor (jet nebulizers)
• Nebulizer cup
• Mask or mouthpiece
• Medication (unit dose vials or bottles)
• Compressor tubing
• Baffle (decreases MAD, for ultrasonic nebulizers only)

Concerns with Nebulizers

• Contaminated multi-dose vials
• Caregiver hygiene (hand washing)
• Inadequate nebulizer cleaning

Drug Concentration Concerns

• During nebulization, drug solutions can evaporate and heat
• Resulting in higher drug concentrations, increasing exposure over time

Spacers/Holding Chambers

• Purpose:*

• Deliver medication to the lungs.

• Improve medication delivery by reducing particle size.

• Advantages:*

• Easier delivery/use, including for pediatric patients.

• Can reduce oropharyngeal deposition of medication.

• Disadvantages:*

• More cumbersome than an MDI alone.

• Requires cleaning.

Cascade Impactor

• Device used to measure aerosol size.
• Useful in determining particle size distribution during delivery and deposition.

Nasal Drug Delivery

• The nasal cavity has a large surface area.
• Appropriate dosing volume ranges should be less than 1 ml.
• Nasal tissues/mucus have a pH range of 7 to 7.5.

Nasal Anatomy and Physiology

• Total surface area of the nasal cavities is 160 cm².
• The cavity is approximately 16–19 ml volume
• Vestibule contains hairs that filter out particles greater than 10 µm.
• Nasal cavity pH is approximately 7.4, with mucus pH at 5.5–6.5.
• Larger surface area and microvilli facilitate absorption.

Nasal Structure

• Nasal vestibule (first, narrowest region): Hairs filter larger particles.
• Turbinates (bony structures): Highly vascular mucosa, pseudostratified columnar epithelium with mucus-secreting, ciliated, non-ciliated, and basal cells.
• Olfactory region: Neuroepithelium and olfactory sensory neurons (~8% of nasal surface area).

Nasal Medication Administration

• Medications can be administered for localized or systemic effects, emergencies, or vaccines.
• Examples: Flonase (allergic rhinitis), Mupirocin (antibacterial), Azelastine HCL (antihistamine), Sumatriptan (migraine), Salmon Calcitonin (osteoporosis), Fentanyl Citrate (pain), and Influenza vaccine.

Nasal Drug Delivery: Advantages

• No need to swallow; easy to administer.
• High patient compliance.
• Avoids GI and hepatic metabolism (although some enzymatic activity can occur in the nasal cavity).
• Does not need sterilization.
• Can be used for chronic condition treatment.
• Higher bioavailability (potentially compared to oral delivery).
• Faster drug delivery.

Nasal Drug Delivery: Disadvantages

• Limited number of medications for intranasal delivery.
• Difficulty and/or risks in concentrating/formulating medication.
• Limited dosing volume capacity
• Variability in nasal mucosa.
• Enzymatic activity (e.g., cytochrome P450s).

Nasal Systemic Delivery advantages

• Enhanced surface area for absorption
• Good blood supply for absorption

Nasal Systemic Delivery disadvantages

• Limited to smaller volumes (~25-200 μL).
• Mucus barrier and mucociliary clearance.
• Enzymatic activity.
• Low epithelial permeability (for hydrophilic drugs).

Systemic Delivery and Drug Absorption

• Drug absorption through nasal epithelium (transcellular and/or paracellular routes).
• Transcellular: for lipophilic/hydrophilic molecules.
• Paracellular: for small hydrophobic molecules (through tight junctions).

Physicochemical Properties and Intranasal Delivery

• Solubility of the drug.
• Lipophilicity/hydrophilicity and molecular size (lipophilic drugs absorb better).
• Degree of ionization (unionized drugs absorb better).

Formulation Factors Affecting Intranasal Delivery

• Low aqueous solubility.
• Rapid and extensive enzymatic degradation in the nasal cavity.
• Short contact time between the drug and epithelium.
• Poor permeability of the drug.

Potential Improvements to Intranasal Formulation

• Increasing aqueous solubility.
• Increasing viscosity.
• Using prodrugs.

Patient Factors Affecting Intranasal Delivery

• Patient compliance.
• Nasal pathology (e.g., common cold).
• Nasal structure (surgery, cocaine abuse).
• Discharge, congestion, or bloody nose.

Other Intranasal Information

• Intranasal solutions should be isotonic.
• Pediatric strengths often half of adult strengths.
• Dosing volumes should be less than 1 ml per nostril (unless for systemic use).
• Packaging (must be tightly closed).
• Avoid use if precipitate matter is present.
• Ideal pH: 5.0 to 8.0

Warnings/Precautions for Intranasal Delivery

• Hypo- and hyperosmotic solutions can cause bronchoconstriction.
• Safety of excipients for respiratory epithelia must be confirmed.
• Certain antioxidants may cause bronchospasm.

Ocular Drug Delivery

• Medications (topical, systemic, intraocular/periocular) are used to treat various ocular conditions.
• Routes of drug delivery include topical administration, systemic administration (oral/injection), intraocular injection, or periocular injection/implantation
• Solutions, suspesnsions, ointments, gels, and emulsions are administered as ocular formulations.

Ocular Routes and Barriers

• The cornea is the primary route for topical drug administration
• Intravitreal injection delivers drugs to the back of the eye
• The blood-retina barrier restricts drug entry into the eye

Topical Ophthalmic Preparations

• Includes solutions, suspensions, ointments, and gels.
• Used to treat infections, inflammation, and other eye conditions (including diagnostics and anesthetics).
• Overcoming protective mechanisms (like blinking, tears) is a critical factor affecting drug absorption.

Additional Ophthalmic Preparation Information

• Eye that doesn't blink can hold 30 µL fluid.
• Blinking time = ~10 μL
• Eye drops spaced several minutes apart (~50 µL/drop).
• Tear fluid is more acidic in contact lens wearers.

Ophthalmic Formulation Factors

• Relative short residence time affecting systemic effects.
• Formulation's softening point.
• Sterile environment.
• Low amount of preservatives/preservative-free.
• Isotonic formulation (~0.6%–1.8% NaCl).
• Ideal isotonic solution composition (0.9% NaCl).
• Low tear buffer capacity.
• pH within the range of 6.9 to 7.5.

Ophthalmic Formulation Factors: Considerations for improvement

• Increasing aqueous solubility.
• Adjusting viscosity and residence time.
• Designing prodrugs.

Ophthalmic Patient Factors to consider

• Patient compliance.
• Nasal pathology/disease.
• Nasal structure or surgery.
• Bloody nose, congestion, discharge

Types of Plastic Containers (for ophthalmic, nasal, and/or respiratory medication formulations)

• Polyethylene
• Polypropylene
• Polyvinyl Chloride
• Polystyrene
• Polycarbonate
• Properties/Uses* (Detailed information on properties is on previous slide)

Ophthalmic Solutions

• Advantages:*

• Easy to manufacture.

• Easy to administer.

• Rapid onset.

• No dissolution required.

• Disadvantages:*

• Drain out of the eye rapidly.

Ophthalmic Suspensions

• Used for sparingly water-soluble drugs or prolonged release.
• Need to be shaken before use.
• More susceptible to stability issues (e.g., cake formation).

Sub-micron Emulsions

• Common for drugs with poor aqueous solubility.
• Restasis(TM) is an example of an oil-in-water emulsion.

Ophthalmic Ointments

• Reduced drug drainage, improving residence time.
• Allows sustained release (~2–4 hours).
• High bioavailability compared to solutions.
• Difficult to administer (blurs vision, reduced patient compliance).

Ophthalmic Gels

• Semisolid systems.
• Consist of water-soluble bases.
• Activated by ions, pH, and temperature.
• Can be used for incorporating water-soluble drugs.

What is safe to use on the eyes?

• Plant-based makeup remover wipes (are generally acceptable to use).
• Antibacterial wipes are not recommended for eye use.

Systemic Ophthalmic Drug Delivery

• Drugs must cross the blood-retina barrier for systemic effect.
• High systemic doses are often required.
• Examples: Photodynamic therapy (using agents such as Visudyne) for treating macular degeneration

Intravtireal Injections

• Most effective route to deliver drugs to the back of the eye.
• Bypasses the blood-retina barrier.
• Systemic side effects minimized.
• Better for low molecular weight drugs.
• Often require repeated injections.
• Examples include Lucentis (used for wet macular degeneration) and Triamcinolone acetonide (steroid-use for inflammation).

Intraocular Implants

• Classified based on biodegradability (non- or bio-).
• Drug release determined by polymer and physicochemical properties.
• Biocompatible, and does not elicit an immune response.
• Example: Vitrasert (treats CMV) and Retisert (treats chronic uveitis).

Biodegradable Implants

• Composed of metabolized polymers (e.g., by enzymatic or non-enzymatic reactions).
• Ideal since no removal is required.
• Example: Ozurdex (intravitreal steroid implant).

Counseling Points (for ophthalmic medication)

• Ointments may cause temporary blurry vision (better applied at night)
• May need to forgo contact lenses during/after ophthalmic medication use.
• Ophthalmic medication doses (eye drops) should be administered several minutes apart.
• Many ophthalmic products have a short shelf-life; do not reuse outdated medication.

USP Guidelines and Sections

• USP 797: Pharmaceutical compounding for sterile preparations
• USP 795: Pharmaceutical compounding for non-sterile preparations
• USP 800: Guideline for handling hazardous drugs.

Types of Plastic Containers

• Polyethylene
• Polypropylene
• Polyvinyl Chloride
• Polystyrene
• Polycarbonate

Properties/Uses (of Plastic Containers)

(Detailed information on properties is displayed on an associated slide)

Test your knowledge on respiratory drug delivery and its advantages, challenges, and mechanisms of action. This quiz covers essential concepts related to inhaled medications and their effects on local treatment. Dive into the intricacies of pulmonary pharmacotherapy and assess your understanding.