Aerosol Drug Delivery Systems PDF

PHARM 131: LOREM IPSUM AEROSOL DRUG DELIVERY SYSTEMS Czarina Dominique R. Rodrguez, RPh M Eng | Reviewed: Dec 12, 2024 | Last Edited: ○​ Patient parameters ​ D...

PHARM 131: LOREM IPSUM AEROSOL DRUG DELIVERY SYSTEMS Czarina Dominique R. Rodrguez, RPh M Eng | Reviewed: Dec 12, 2024 | Last Edited: ○​ Patient parameters ​ Deposition of product in the respiratory tract (dependent OUTLINE on particle size): ○​ Inertial impaction ​ The main mechanism for particle size greater AEROSOLS than 5 micrometers INHALATION AEROSOLS ​ Since the particle size is relatively large, there is COMPONENTS OF AN AEROSOL SYSTEM greater momentum upon release which will VALVE ASSEMBLY impact the air wall (e.g. trachea) instead of ACTUATORS following the air stream (due to weight) TYPES OF INHALATION AEROSOLS ​ Branching of airways (e.g. bronchi, METERED-DOSE INHALERS (MDIs) bronchioles) decreases the velocity of air MANUFACTURE/FILLING stream—Inertial impaction becomes a less significant mechanism in aerosol deposition SPACERS ○​ Gravitational sedimentation BREATH-ACTUATED MDIs ​ Main mechanism of ‘medium-sized’ particles (1 DRY POWDER INHALERS (DPIs) micrometer to 5 micrometers) FORMULATION/MANUFACTURE ​ Movement according to Stoke’s Law; Particles NEBULIZERS that have escaped inertial impaction JET NEBULIZER ​ Through gravity, ‘sedimentation’ happens in ULTRASONIC NEBULIZER the lower parts of the respiratory tract QUALITY CONTROL ○​ Brownian diffusion ​ Main mechanism of ‘small’ particles (less than 1 micrometer) ​ Dependent on the collision and movement of the AEROSOLS particles ​ Products that are packaged under pressure and contain ​ Particles, upon reaching the smaller airways, will therapeutic APIs that are released upon the activation begin to diffuse to an area from a higher of an appropriate valve system concentration to a lower concentration ○​ You have to “press something” to release the API ​ The rate of diffusion is inversely proportional to ​ Colloidal dispersions of liquids or solids in gases particle size ​ Application: ○​ Topical COMPONENTS OF AN AEROSOL SYSTEM ​ NSAIDs (Freeze spray) ​ Propellant ○​ Local application to nose (nasal aerosols) ○​ Supplies the necessary pressure to expel material ○​ Mouth (lingual aerosols) from the container ○​ Lungs (Inhalation aerosols; most common) ○​ Selection depends on the desired vapor pressure, ​ Metered-dose inhalers solubility, and particle size ​ Dry powder inhalers ○​ Common propellants: ​ Nebulizers ​ Fluorinated hydrocarbons ​ Typically implemented if we want the drug to ​ Propane have a systemic effect due to, excellent surface ​ Butane area and good blood supply ​ Isobutane ​ Compressed gases: INHALATION AEROSOLS ​ Nitrogen ​ The dispersion of the product upon release is the most ​ Carbon dioxide important since we need to ensure that it reaches the ​ Nitrous oxide lungs, specifically the alveoli, where systemic effect ​ It is not necessary to utilize only one propellant; through absorption will take place typically, multiple gases are used to achieve the ​ Dispersion of product to airways depend on: desired vapor pressure ○​ Physicochemical properties of the drug (e.g. particle ​ Relate to Dalton’s Law: total pressure of a size) mixture of gases is equal to the sum of the ​ Utilization of polydispersion partial pressures of the individual ○​ Humidity component gases ​ A bigger problem in hydrophilic aerosols due to ​ Container further solubilization (generation of ‘solution’ ○​ Must withstand pressures as high as 140 to 180 psig coating) which may cause swelling, affecting the (pound per square inch gauge) at 130OC particle size of the API ○​ Composition: Metal (steel, aluminum), glass ○​ Formulation ○​ Device DATOON​ 1  ​ Glass not really that common in modern market ​ The high-velocity gas aids in breaking up the due to practicality and risk of damage liquid into fine particles/droplets ​ Valve and Actuator ○​ Need to coordinate with deep inhalation of the patient ○​ Valve: Regulates the flow of material from the in order to successfully deliver the required dose container ○​ Drug typically in suspension form (solid dispersion) ​ Can have different shapes and sized ○​ Actuator: Fitting attached to the valve system, which when depressed or moved, opens the valve ​ Product concentrate ○​ API + solvents, antioxidants, surfactants VALVE ASSEMBLY ​ Ferrule or Mounting Cup (A) ○​ Attaches the valve to the container ​ Stem (B) ​ Valve Seat (C) ○​ Where the valve is actually connected ​ Valve Body (D) Figure 3. Parts of a Metered-Dose Inhaler ○​ Contains an opening that attaches to the dip tube ​ Mounting Gasket (E) ​ Important parameters: ○​ A rubber that secures the connection of the dip tube ○​ Particle size of the solid and valve body to avoid leaking ○​ Valve clogging ​ Dip Tube (F) ○​ Relative density of propellant and drug ○​ Rigid plastic tubing made of polyethylene or ○​ Solubility of API in propellant polypropylene where the product travels and is ○​ Boiling point and vapor pressure of propellant released ○​ Use of surfactants MANUFACTURE/FILLING ​ Liquefying the propellant at reduced temperature or elevated pressure ​ Methods ○​ Cold filling (More common) 1.​ API, excipients and propellant are chilled and filled at about -30OC 2.​ Additional propellant is added at the same temperature 3.​ Sealing of canister with the valve ○​ Pressure filling 1.​ A drug/propellant concentrate is produced at Figure 1. Parts of a Valve Assembly room temperature (or slightly chilled) and pressure, then filled into the canister ACTUATORS 2.​ Valve is crimped into the canister ​ Can have different shapes and sizes to ensure that 3.​ Additional propellant (not necessarily liquid) is product is released on its intended form filled at elevated pressure through the valve (gassing) SPACERS ​ Function: aids in the delivery of metered-dose inhaler ​ Mechanism ○​ Additional length decreases the initial velocity of the dosage form which minimizes the amount of product that hits the upper air wall (more product gets deposited on the lower airway) ○​ Permit efficient propellant evaporation that leads to Figure 2. Different Shapes of Actuator finer particles ​ Result: Coordinated patient deep breathing is minimized TYPES OF INHALATION AEROSOLS which can improve medication adherence METERED-DOSE INHALERS (MDIs) ​ Drug is dissolved or dispersed in a liquid propellant mixture together with the excipients ​ Predetermined dose is released as a spray on the actuation of the metering valve ○​ Upon activation, the solution will undergo volume expansion which results in a mixture of liquid and gas DATOON​ 2  FORMULATION/MANUFACTURE ​ Principle of micronization or decreasing the particle size to less than 5 micrometers with the addition of carrier particles (e.g. lactose, 30-60 micrometers) leading to ordered mixing ○​ Function of carrier particles is to avoid agglomeration of fine particles due to high surface area and inter particulate attraction ○​ Addition will result in an increased particle size HOWEVER not an issue as this is only a form of Figure 4. Parts of a Spacer weak attraction (van der Waals forces) in which the velocity of the air or particles can remove the API BREATH-ACTUATED MDIs from the coarse particles ​ Dependent on the patient’s breathing pattern to release the product ​ Mechanism/Process: ○​ Flick the priming mechanism to release the product downwards (see gray knob at the top of diagram) ○​ Upon inhalation, flaps will open to release the product (see yellow part at the bottom of the diagram) ​ Advantage: ○​ Minimizes the need for proper coordinated patient deep breathing technique ​ Disadvantage/Concern: ○​ Patient must have necessary inhalation flow rate to open the flap to release product Figure 7. Principle of Ordered Mixing ​ Important formulation factors: ○​ Adhesion of drug and carrier during mixing and filling ○​ Ability of drug to desorb from carrier during inhalation NEBULIZERS ​ Convert liquids into a fine droplet mist Figure 5. Mechanism of Breath-Actuated MDIs ​ Advantages ○​ Possibility of high-volume output DRY POWDER INHALERS (DPIs) ○​ Utilization of normal tidal breathing ​ Drug is inhaled as a cloud of fine particles ​ Formulations available as solutions or suspensions ​ Drug is either pre-loaded in an inhalation device or filled (prepared as discussed in previous topics) into hard shell capsules or foil blister discs which are ○​ Parameters to consider: loaded into the device prior to use ​ Viscosity ​ Propellant-free, excipient-free, breath-actuated ​ Surface tensions ○​ Or most of the time, minimal excipient (only diluents) ​ Disadvantages/Concerns JET NEBULIZER ○​ Similar to Breath Actuated MDIs, patient must have ​ Mechanism: Utilization of compressed gas necessary inhalation flow rate to properly administer ​ Compressed gas enters the Venturi nozzle where there is dose an area negative pressure ○​ Since solid, less stable because it is prone to caking ​ Liquid stored in the reservoir will be drawn upwards until or reaction with moisture released to the outlet ○​ As it passes through the negative pressure area with compressed air, it is dispersed as a mist ​ Determinant of particle size: Compressed gas flow Figure 6. Sample Dry Powder Inhaler DATOON​ 3  Figure 8. Parts and Mechanism of a Jet Nebulizer ULTRASONIC NEBULIZER ​ Mechanism: Mechanical vibration ​ Piezoelectric crystal provides energy to atomize the droplets in conjunction with a high frequency source Figure 9. Parts and Mechanism of an Ultrasonic Nebulizer QUALITY CONTROL ​ USP Chapter ○​ Delivery rate and delivered amount ○​ Leakage ​ Measured in years ○​ Minimum fill ○​ Number of Discharges per Container (MDIs) ○​ Delivered-dose Uniformity (MDIs, PDIs) ○​ Delivered-dose Uniformity over the Entire Contents (aerosols with multiple doses) ○​ Particle Size (aerodynamic diameter) ​ Uses cascaders or impingers ​ Aerodynamic diameter: physical diameter of a unit density sphere which settles through air with a velocity equal to the particle in question DATOON​ 4