Pulmonary Drug Delivery PDF

Pulmonary Drug Delivery A. Introduction a. Purposes of delivery drugs to the lungs i. To achieve a local e9ect 1. Examples: a. Asthma i. Beta-2 agonists, glucocorticoids, ant...

Pulmonary Drug Delivery A. Introduction a. Purposes of delivery drugs to the lungs i. To achieve a local e9ect 1. Examples: a. Asthma i. Beta-2 agonists, glucocorticoids, antimuscarinics, mast cell stabilizers b. Infections i. P. carinii – e.g., pentamidine ii. Respiratory Syncitial Virus – e.g., ribavirin c. Mucolytics i. e.g., n-acetylcysteine d. Cystic Fibrosis i. e.g., deoxyribonuclease e. Respiratory Distress Syndrome i. e.g., pulmonary surfactant ii. To achieve a systemic e9ect 1. Promising, but not common (1. Large surface area, 2. no hepatic first pass) 2. Examples: a. Insulin (Afrezza – a DPI of recombivant human insulin) b. Loxapine (Adasuve – a DPI used in schizophrenia) c. Levodopa (Inbrija – a DPI used in Parkinson’s disease) b. Methods of pulmonary drug delivery i. Two main methods: 1. Intratracheal instillation a. A drug liquid is instilled into the trachea for distribution deeper into the lung i. e.g., surfactant therapy for neonatal RDS 2. Aerosol inhalation a. Aerosols may be delivered intratracheally and via oral inhalation b. We will focus on oral aerosols c. Types of Oral Aerosols i. Inhalers: Propellant-driven liquid, mechanical energy-driven liquid, and dry powder ii. Nebulizers: Air-jet and ultrasonic B. The Respiratory Tract a. Regions of the respiratory tract i. Upper airway 1. The nose and nasal cavity ii. The trachea-bronchial tree 1. From the beginning, at the branching of the trachea, the airways progressively decrease in caliber (diameter) and primarily function to conduct air to the respiratory region, where the function becomes gas exchange a. Segmental bronchi b. Nonrespiratory bronchioles c. Respiratory bronchioles d. Alveolar ducts e. Alveoli b. Pulmonary epithelia i. Upper airway and Tracheobronchial tree 1. Ciliated epithelia a. The nasal cavity, nasopharynx, larynx, trachea, and bronchi are lined with pseudostratified ciliated columnar epithelia cells along with goblet cells 2. Mucus a. Mucus in the lungs has a similar composition and function to that in the nasal cavity (1. Prevents epithelial dehydration, 2. Traps foreign particles) b. It covers the epithelia from the trachea to the terminal bronchioles and is moved upwards by the cilia towards the pharynx, from which it is swallowed c. This process provides an important cleaning mechanism, the mucociliary escalator, which moves particles upwards ii. Alveoli  1. At the alveolar level, surface area increases dramatically and the distance to the circulation is very short 2. Macrophages roam freely (Engulf particulates, e.g., bacteria and undissolved drug) 3. The surface lining layer (SLL) covers the epithelium with an amorphous hypophase and alveolar surfactants C. Disposition of Aerosols in the Lungs a. Overview i. The di9erent oral inhalation devices will produce a respirable cloud of particles that – in varying amounts – will be inhaled through the mouth, into the lungs ii. The drug will either be the aerosolized particles themselves or will be contained within droplet particles iii. Depending on several properties (discussed later), the aerosolized particles will deposit at di9erent locations – from the point of inhalation to the alveoli iv. At each point of deposition, a di9erent fate may be met b. Fate of the drug at deposition sites i. Oropharynx 1. Some absorption is possible, but drug deposited here will likely pass into the GI tract (Where it may be absorbed and it subject to intestinal & hepatic first-pass) ii. Tracheobronchial region 1. Drug is deposited in the layer of mucus, where it can meet di9erent fates: a. Removal by the mucociliary escalator (To pharynx, then GI) b. Permeation of the epithelium (Primarily by passive di9usion, but transporters are present) c. Systemically absorbed (No hepatic first-pass) iii. Alveoli 1. Drug is deposited in the SLL, where it can meet di9erent fates: a. Some of the high MW drugs & particles will be engulfed by macrophages (Migrate to M.E.) b. Some drug will be systemically absorbed (With no hepatic first-pass) c. Mechanisms of aerosol deposition i. Depending on aerosol properties, di9erent mechanisms dictate the fate of the inhaled particles: 1. Inertial impaction: Caused by the tendency of particles to move in a straight direction, instead of following bends in the moving airstream 2. Sedimentation: Where particles deposit under the force of gravity (i.e., they fall out of the moving airstream) 3. Di9usion: Where particles di9use to the deposition sites (A random process) d. Aerosol-related factors a9ecting particle deposition in the lungs i. The primary aerosol-related factors a9ecting particle deposition are the size and speed of the particles 1. Particle size a. Aerosol particles are measured by their aerodynamic diameter, which takes into consideration: i. Particle size ii. Particle shape iii. Particle density b. Generally, the smaller the aerodynamic diameter, the further into the lung the particle will go: i. >10 = Extrathoracic (Particles are too big and many impact in the oropharynx or upper airways) ii. 5-10 = Upper tracheobronchial (Impact & settle in upper airways) iii. >1-5 = Bronchioles, alveolar ducts, alveoli (1. Settle & di9use as the airstream slows down, 2. Most important size range for deeper penetration) iv. Submicron = Alveolar or exhalation of particle (Di9usion dominates) 2. Particle velocity a. Increased particle velocity favors deposition by impaction (The particle can’t stay with the bending airstream) e. Patient- related factors a9ecting particle deposition in the lungs i. Several patient-related factors, including breathing pattern and disease state, will a9ect the fate of the aerosol cloud 1. Breathing pattern a. Both the rate and depth of patient breathing can a9ect particle deposition:  i. Example: For small respirable (1-5 micrometer) particles: 1. Rapid/shallow breathing favors tracheobronchial deposition 2. Slow/deep breathing favors deeper penetration b. Holding the breath favors deposition by sedimentation & di9usion (1. Allows time for sedimentation, 2. Minimizes exhalation of particles) 2. Disease state a. Example: Diseases that can a9ect the caliber or tortuosity of the airways can a9ect aerosol flow through the lungs (May a9ect aerosol flow and turbulence) f. E9icacy of pulmonary drug delivery i. Pulmonary drug delivery is noted for its poor e9iciency (e.g., varying amounts can end up in the GI tract). Why? 1. Suboptimal aerosol generation: a. Aerosol particles are in a size distribution, with a significant fraction of large particles (impact in the back of the throat) b. Rapid aerosol release – favors impaction in the back of the mouth 2. Suboptimal inhalation technique: a. e.g., Rapid inhalation favors impaction in the back of the mouth D. Oral Pulmonary Inhalation Devices a. Pressurized Metered-Dose Inhalers (pMDIs): The pMDI is the most commonly prescribed pulmonary aerosol device. It is a pressurized canister containing a mixture of drug, liquified propellants, & excipients. Upon actuation, the liquid is expelled in a metered volume, which quickly becomes a mist of quickly evaporating fine droplets. i. Description of MDIs: 1. Four essential components to an MDI delivery system: 1. The container, 2. The metering valve, 3. The actuator (or mouthpiece), 4. The propellant. They all work in concert to produce a respirable aerosol of the drug product. a. The container i. Must be strong enough to hold the contents under pressure ii. Most are aluminum, 15 to 30mL b. Metering valves i. Is attached to the actuator via the valve stem ii. Essentially designed to work in the inverted (stem-down) position iii. Has a metering-chamber of a specified volume, that empties upon actuation, & refills thereafter (Delivers a very accurate volume) c. Actuator i. Serves to depress the valve stem and as the (mouthpiece) ii. Most commonly, it is L-shaped d. The propellants i. There are hydrocarbon-based compounds that are gases at ambient temperature & pressure, but become liquid at low temperatures & high pressures (Thus, filled under these conditions) 1. Most common propellant in inhalers: a. HFA 134 – The main CFC alternative, breaks down faster in the atmosphere (Reduces ozone depletion) b. HFA 227 – Di9erent properties, currently less used 2. Roles of the propellant a. The power source for aerosolization b. The vehicle for the drug 3. Properties of the propellant a. They are nonpolar b. They have many other important properties including boiling point, vapor pressure, density, stability, and solvent power ii. Nature of aerosol release from a pMDIs 1. The pressure in the pMDI is about 3atm 2. After depression of the valve stem, liquid aerosol is exposed to atmospheric pressure & over about a 20 msec time period, vaporization (“flashing”) occurs. A “plume” is produced (Drug is in propellant droplets) iii. Formulation of MDIs 1. Solutions  a. The drug is dissolved in the propellant b. Cosolvents may be needed (e.g., ethanol, in this case, make the solvent MORE polar) 2. Suspensions a. Drug is dispersed in the propellant b. Very common because of the relatively poor solubilizing capacity of propellants c. Major disadvantage i. Potential physical instability of the suspension (e.g., particles can aggregate, becoming too large) d. Drug i. Must be micronized ii. Must be stabilized e. Excipients i. Dispersing and suspending agents 1. Example: surfactants (e.g., oleic acid, soya lecithin) & povidone 2. Surfactants can have other functions as well (Can help the aerosol pass through the valve and can prevent particle adhesion to container) ii. Cosolvents (e.g., ethanol) iv. Important factors in storage & handling of pMDIs 1. Loss of prime a. = the loss of propellant from the metering valve (Leaks into the bulk liquid) i. Can happen over time and, with HFA inhalers, can happen when dropped ii. Can significantly reduce the dose iii. Typical recommendation: Prime the inhaler by spraying 2 to 4 sprays (to refill the metering chamber, spray into the air) under certain conditions (New use, period of non-use, after dropping, after cleaning. Read instructions) 2. Loss of dose a. = an aerosol dose that is less than the label claim i. Can result from loss of prime or phase separation in heterogenous systems ii. Typically, suspended drug will cream (rise to the top) over a fairly short time period iii. Recommendation: shake & immediately fire 3. Clogging of the actuator or the valve stem (from residue; excipient surfactants can help minimize) a. Recommendation: Periodically clean the actuator according to recommendations (Typically at least once a week; Specific instructions per product) v. Inhalation aids for MDIs 1. Problems with pMDIs a. Coordination of inhalation with actuation b. Oropharyngeal deposition problems (taste, hoarseness, thrush) c. Poor lung targeting 2. Several inhalation aids are available to help with these problems. They are mostly space devices: a. The inhaler is attached to the spacer b. Actuation occurs into the spacer, immediately followed by slow & deep inhalation 3. E9ects of using spacer devices a. They produce a more respirable cloud i. They allow time & space for evaporation (reduces particle size) ii. They reduce aerosol velocity (leaves a suspended cloud) b. They make it easier for the patient to use the pMDI (They allow for easier coordination of actuation & inhalation) c. They reduce oropharyngeal deposition & can improve lung targeting (reduces particle size, velocity, inhalation force; greater of fraction of cloud enters lungs) d. There is significant loss of aerosol product within the device 4. Key features of spacer devices: a. Presence of valves = valved holding chamber i. Inspiratory valve (Keeps the aerosol in the device until the patient inhales) ii. Expiratory valves (Directs exhalation away from the chamber & the patient) b. Flow indicator sound (Means inhalation is too fast) c. Antistatic coating (Reduces deposition in the spacer & can increase the available dose)  d. Example: AeroChamber Valved Holding Chamber (“VHC”), Nebuhaler e. Others: Vortex, Aerochamber HC-MV, Aeromask ES 5. Examples of pMDIs – See notes vi. Alternatives to traditional pMDIs 1. Breath-Actuated pMDIs a. A pressurized metered dose inhaler (pMDI) that automatically triggers the inhaler spray actuation when the patient inhales i. Eliminates the need for coordination & actuation ii. Typically actuated with a relatively low inspiratory rate iii. Spacers are not needed b. Example: QVAR Redihaler (beclomethasome dipropionate HFA) 2. Mechanical Energy-Driven Liquid Metered Dose Inhaler – Respimat (Boehringer Ingelheim) a. Respimat – A multi-dose propellant-free device, where a drug solution in a cartridge is inserted into the Respimat device (an aqueous solution, usually with benzalkonium chloride) b. Aerosol is generated when the liquid formulation is pushed through nozzles by a spring mechanism c. The resulting aerosol is soft & slower compared with that generated by pMDIs (Dose not require a valved holding chamber) d. Examples: See notes b. Dry-Powder Inhalers (DPIs) i. Description 1. These dispense a dry powder in a stream of inspired air 2. The force for powder flow comes inspiratory e9orts of the patient ii. Powder formulation 1. The drug formulation is usually the drug plus a carrier powder a. The drug i. Must be micronized to the proper size ii. Problem: When powders get this small they can become more cohesive & adhesive (They can stick to each other & to the device) b. Carrier powder i. These are larger particles that “carry” the smaller particles ii. Function to improve powder flow & dispersibility iii. Examples: Lactose & glucose iv. Since the carrier particles are larger, they will be less respirable (They will impact & be swallowed) iii. Devices & examples 1. Unit-Dose DPIs – The drug formulation is prefilled in hard gelatin capsules & loaded into the device a. Handihaler i. The capsule is punctured on the side in the device & the powder is inhaled through a screen tube b. Inbrija (levodopa inhalation powder) i. The capsule is punctured the end in the device & the powder is inhaled c. Afrezza (insulin regular adsorbed onto fumaryl diketopiperazine (FDKP) microspheres) (These are 3-5 micron particles that carry insulin deep into the lungs then dissolve to release the insulin) i. Available as 4U, 8U, and 12U dose in individual cartridges 2. Multiple Unit-Dose DPIs – These have several unit doses loaded into the device a. Diskhaler - Contains a circular disk that contains powder charges separately packed in aluminum blister packs (are pierced before inhalation of the powder) i. Relenza (Zanamivir for inhalation, with lactose) b. Diskus Powders – (Drug plus lactose) are contained within a blister strip with each blister containing a dose that is inhaled after activation by the patient i. Serevent Diskus ii. Advair Diskus iii. Flovent Diskus c. Wixela Inhub – a generic of Advair Diskus d. Ellipta  i. Pre-loaded with 1 month’s supply of pre-filled, foil-laminated, individually sealed blisters containing drug formulation ii. One option is a two-strip configuration with two 30-dose blisters (Contain separate drug formulations & delivered simultaneously during a single inhalation) iii. Example: Breo Ellipta 3. Multiple-Dose DPIs a. The container has a reservoir of drug, from which doses are metered into an inhalation chamber b. Pulmicort Flexhaler i. A metered-dose powder delivery system ii. Micronized budesonide plus micronized lactose is contained within a storage reservoir (Contains the formulation - in bulk - from which each dose is loaded) iv. Important factors a9ecting dose delivery from DPIs 1. Inspiratory flow rate a. Full & deep delivery of the dose depends on the energy of the inspiratory flow (Must be adequate to withdraw the powder from the device; Not all patients are capable of this) 2. Humidity a. Moisture sorption – Can increase particle size & can decrease the ability of the agglomerate to deagglomerate (Can reduce the dose inhaled deep into the lungs; a key reason you do not breath into the device) b. Example: Flexhaler can be more sensitive to high humidity than Diskus (Powder more exposed) c. Small Volume Nebulizers (SVN) i. Description 1. Solutions or suspensions are nebulized (production of particles, such as spray or mist, from a liquid) & administered through a mouthpiece, ventilation mask, or tracheostomy 2. Key Feature: The product is administered during a normal breathing pattern (Treatment time: about 7-10 min) ii. Types of SVN 1. Air-Jet Nebulizers a. Compressed air is forced through an orifice leading to an area of negative pressure that draws thin layers of liquid from the product b. An air-jet at the orifice then shears the liquid to produce aerosol particles c. Smaller particles will the device as an aerosolizable mist (Larger particles strike a ba9le & drop) 2. Ultrasonic Nebulizers a. Piezoelectric crystals vibrate when electrically excited, creating ultrasonic waves in the liquid that generate geysers at the surface (Geysers release aerosol particles) iii. Some important features of nebulizers 1. Aerosol particle size may di9er (Can a9ect how far they go into the lungs) 2. E9iciency of aerosol delivery is low (e.g., jet nebulizers – only about 1-10% of the dose in the nebulizer will make it into the lungs) a. Most of the dose ends up as dead volume (a lot adheres to the device) b. A significant fraction blown out with exhalations 3. There is potential for either type to denature protein drugs (e.g., due to sheer forces) 4. Both types have problems with variability of generate particle sizes both within & between brands a. Thus, in many cases it is unacceptable to switch between di9erent brands or types of nebulizers iv. Formulation of nebulizer solutions 1. Cosolvents a. e.g., glycerin, propylene glycol 2. Osmolarity a. Should be isotonic, but doesn’t have to be for smaller volumes (Spread over a large surface area in the lungs) 3. pH a. Generally, it should be above 5 (Increased risk of bronchospasm if below 5)  b. As with most drug products bu9er capacity should be limited, so as to not to overwhelm our own 4. Others a. Additives must be chosen judiciously b. Preservatives may or may not be present (Those without preservatives are for single use) 5. Sterility a. Nebulizer formulations must be sterile v. Examples of commercial nebulizer solutions 1. See Notes E. Typical Patient Populations for Oral Inhalation Devices a. MDI – Should be able to coordinate actuation/breathing (e.g., 7 years & older without spacer, 3 years & older with spacer) b. DPI – Should be capable of forceful inspiratory flow (e.g., 3-4 years & older) c. Nebulizer – For those less able to coordinate or inspire well (e.g., the very young & old)