Pulmonary Drug Delivery PDF

**Pulmonary Drug Delivery** A. Introduction a. Purposes of delivery drugs to the lungs i. To achieve a [local effect] 1. Examples: a. Asthma i. Beta-2 agonists, glucocorticoids, antimuscarinics, mast cell...

**Pulmonary Drug Delivery** A. Introduction a. Purposes of delivery drugs to the lungs i. To achieve a [local effect] 1. Examples: a. Asthma i. Beta-2 agonists, glucocorticoids, antimuscarinics, mast cell stabilizers b. Infections ii. P. carinii -- e.g., pentamidine iii. Respiratory Syncitial Virus -- e.g., ribavirin c. Mucolytics iv. e.g., n-acetylcysteine d. Cystic Fibrosis v. e.g., deoxyribonuclease e. Respiratory Distress Syndrome vi. e.g., pulmonary surfactant ii. To achieve a [systemic effect] 2. Promising, but not common (1. Large surface area, 2. no hepatic first pass) 3. Examples: f. Insulin (Afrezza -- a DPI of recombivant human insulin) g. Loxapine (Adasuve -- a DPI used in schizophrenia) h. Levodopa (Inbrija -- a DPI used in Parkinson's disease) b. Methods of pulmonary drug delivery iii. Two main methods: 4. *Intratracheal instillation* i. A drug liquid is instilled into the trachea for distribution deeper into the lung vii. e.g., surfactant therapy for neonatal RDS 5. *Aerosol inhalation* j. Aerosols may be delivered *intratracheally* and via *oral inhalation* k. We will focus on [oral aerosols] c. Types of Oral Aerosols iv. Inhalers: Propellant-driven liquid, mechanical energy-driven liquid, and dry powder v. Nebulizers: Air-jet and ultrasonic B. The Respiratory Tract d. Regions of the respiratory tract vi. Upper airway 6. The nose and nasal cavity vii. The trachea-bronchial tree 7. 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] l. Segmental bronchi m. Nonrespiratory bronchioles n. Respiratory bronchioles o. Alveolar ducts p. Alveoli e. Pulmonary epithelia viii. Upper airway and Tracheobronchial tree 8. Ciliated epithelia q. The nasal cavity, nasopharynx, larynx, trachea, and bronchi are lined with pseudostratified ciliated columnar epithelia cells along with goblet cells 9. Mucus r. Mucus in the lungs has a similar composition and function to that in the nasal cavity (1. Prevents epithelial dehydration, 2. Traps foreign particles) s. 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 t. This process provides an important cleaning mechanism, the *mucociliary escalator*, which moves particles upwards ix. Alveoli 10. At the alveolar level, surface area increases dramatically and the distance to the circulation is very short 11. Macrophages roam freely (Engulf particulates, e.g., bacteria and undissolved drug) 12. The surface lining layer (SLL) covers the epithelium with an amorphous hypophase and alveolar surfactants C. Disposition of Aerosols in the Lungs f. Overview x. The different oral inhalation devices will produce a respirable cloud of particles that -- in varying amounts -- will be inhaled through the mouth, into the lungs xi. The drug will either be the aerosolized particles themselves or will be contained within droplet particles xii. Depending on several properties (discussed later), the aerosolized particles will deposit at different locations -- from the point of inhalation to the alveoli xiii. At each point of deposition, a different fate may be met g. Fate of the drug at deposition sites xiv. Oropharynx 13. 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) xv. Tracheobronchial region 14. Drug is deposited in the layer of mucus, where it can meet different fates: u. Removal by the mucociliary escalator (To pharynx, then GI) v. Permeation of the epithelium (Primarily by passive diffusion, but transporters are present) w. Systemically absorbed (No hepatic first-pass) xvi. Alveoli 15. Drug is deposited in the SLL, where it can meet different fates: x. Some of the high MW drugs & particles will be engulfed by macrophages (Migrate to M.E.) y. Some drug will be [systemically absorbed] (With no hepatic first-pass) h. Mechanisms of aerosol deposition xvii. Depending on aerosol properties, different mechanisms dictate the fate of the inhaled particles: 16. [Inertial impaction]: Caused by the tendency of particles to move in a straight direction, instead of following bends in the moving airstream 17. [Sedimentation]: Where particles deposit under the force of [gravity] (i.e., they fall out of the moving airstream) 18. [Diffusion]: Where particles [diffuse] to the deposition sites (A random process) i. Aerosol-related factors affecting particle deposition in the lungs xviii. The primary aerosol-related factors affecting particle deposition are the size and speed of the particles 19. Particle size z. Aerosol particles are measured by their aerodynamic diameter, which takes into consideration: viii. Particle size ix. Particle shape x. Particle density a. Generally, the smaller the aerodynamic diameter, the further into the lung the particle will go: xi. \>10 = Extrathoracic (Particles are too big and many impact in the oropharynx or upper airways) xii. 5-10 = Upper tracheobronchial (Impact & settle in upper airways) xiii. \>1-5 = Bronchioles, alveolar ducts, alveoli (1. Settle & diffuse as the airstream slows down, 2. Most important size range for deeper penetration) xiv. Submicron = Alveolar or exhalation of particle (Diffusion dominates) 20. Particle velocity b. Increased particle velocity favors deposition by [impaction] (The particle can't stay with the bending airstream) j. Patient- related factors affecting particle deposition in the lungs xix. Several patient-related factors, including breathing pattern and disease state, will affect the fate of the aerosol cloud 21. Breathing pattern c. Both the [rate and depth] of patient breathing can affect particle deposition: xv. Example: For small respirable (1-5 micrometer) particles: 1. Rapid/shallow breathing favors tracheobronchial deposition 2. Slow/deep breathing favors deeper penetration d. Holding the breath favors deposition by sedimentation & diffusion (1. Allows time for sedimentation, 2. Minimizes exhalation of particles) 22. Disease state e. Example: Diseases that can affect the caliber or tortuosity of the airways can affect aerosol flow through the lungs (May affect aerosol [flow] and [turbulence]) k. Efficacy of pulmonary drug delivery xx. Pulmonary drug delivery is noted for its poor efficiency (e.g., varying amounts can end up in the GI tract). Why? 23. Suboptimal aerosol generation: f. Aerosol particles are in a size distribution, with a significant fraction of large particles (impact in the back of the throat) g. Rapid aerosol release -- favors impaction in the back of the mouth 24. Suboptimal inhalation technique: h. e.g., Rapid inhalation favors impaction in the back of the mouth D. Oral Pulmonary Inhalation Devices l. [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. xxi. Description of MDIs: 25. 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. i. The container xvi. Must be strong enough to hold the contents under pressure xvii. Most are aluminum, 15 to 30mL j. Metering valves xviii. Is attached to the actuator via the valve stem xix. Essentially designed to work in the inverted (stem-down) position xx. Has a [metering-chamber] of a specified volume, that empties upon actuation, & refills thereafter (Delivers a very accurate volume) k. Actuator xxi. Serves to depress the valve stem and as the (mouthpiece) xxii. Most commonly, it is [L-shaped] l. The propellants xxiii. 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) 3. Most common propellant in inhalers: a. HFA 134 -- The main CFC alternative, breaks down faster in the atmosphere (Reduces ozone depletion) b. HFA 227 -- Different properties, currently less used 4. Roles of the propellant c. The [power source] for aerosolization d. The [vehicle] for the drug 5. Properties of the propellant e. They are [nonpolar] f. They have many other important properties including boiling point, vapor pressure, density, stability, and solvent power xxii. Nature of aerosol release from a pMDIs 26. The pressure in the pMDI is about 3atm 27. 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) xxiii. Formulation of MDIs 28. Solutions m. The drug is [dissolved] in the propellant n. Cosolvents may be needed (e.g., ethanol, in this case, make the solvent MORE polar) 29. Suspensions o. Drug is [dispersed] in the propellant p. Very common because of the relatively poor solubilizing capacity of propellants q. Major disadvantage xxiv. Potential physical instability of the suspension (e.g., particles can aggregate, becoming too large) r. Drug xxv. Must be micronized xxvi. Must be stabilized s. Excipients xxvii. Dispersing and suspending agents 6. Example: surfactants (e.g., oleic acid, soya lecithin) & povidone 7. Surfactants can have other functions as well (Can help the aerosol pass through the valve and can prevent particle adhesion to container) xxviii. Cosolvents (e.g., ethanol) xxiv. Important factors in storage & handling of pMDIs 30. *Loss of prime* t. = the loss of propellant from the metering valve (Leaks into the bulk liquid) xxix. Can happen over time and, with HFA inhalers, can happen [when dropped] xxx. Can significantly reduce the dose xxxi. 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) 31. *Loss of dose* u. = an aerosol dose that is less than the label claim xxxii. Can result from [loss of prime] or [phase separation] in heterogenous systems xxxiii. Typically, suspended drug will cream (rise to the top) over a fairly short time period xxxiv. Recommendation: shake & immediately fire 32. Clogging of the actuator or the valve stem (from residue; excipient surfactants can help minimize) v. Recommendation: Periodically clean the actuator according to recommendations (Typically at least once a week; Specific instructions per product) xxv. Inhalation aids for MDIs 33. Problems with pMDIs w. Coordination of inhalation with actuation x. Oropharyngeal deposition problems (taste, hoarseness, thrush) y. Poor lung targeting 34. Several [inhalation aids] are available to help with these problems. They are mostly space devices: z. The inhaler is attached to the spacer a. Actuation occurs into the spacer, immediately followed by slow & deep inhalation 35. [Effects of using spacer devices] b. They produce a more respirable cloud xxxv. They allow time & space for evaporation (reduces particle size) xxxvi. They reduce aerosol velocity (leaves a suspended cloud) c. They make it easier for the patient to use the pMDI (They allow for easier coordination of actuation & inhalation) d. They reduce oropharyngeal deposition & can improve lung targeting (reduces particle size, velocity, inhalation force; greater of fraction of cloud enters lungs) e. There is significant loss of aerosol product within the device 36. Key features of spacer devices: f. Presence of valves = valved holding chamber xxxvii. Inspiratory valve (Keeps the aerosol in the device until the patient inhales) xxxviii. Expiratory valves (Directs exhalation away from the chamber & the patient) g. Flow indicator sound (Means inhalation is too fast) h. Antistatic coating (Reduces deposition in the spacer & can increase the available dose) i. Example: AeroChamber Valved Holding Chamber ("VHC"), Nebuhaler j. Others: Vortex, Aerochamber HC-MV, Aeromask ES 37. Examples of pMDIs -- See notes xxvi. Alternatives to traditional pMDIs 38. Breath-Actuated pMDIs k. A pressurized metered dose inhaler (pMDI) that automatically triggers the inhaler spray actuation when the patient inhales xxxix. Eliminates the need for coordination & actuation xl. Typically actuated with a relatively low inspiratory rate xli. Spacers are not needed l. Example: QVAR Redihaler (beclomethasome dipropionate HFA) 39. Mechanical Energy-Driven Liquid Metered Dose Inhaler -- Respimat (Boehringer Ingelheim) m. 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) n. Aerosol is generated when the liquid formulation is pushed through nozzles by a spring mechanism o. The resulting aerosol is soft & slower compared with that generated by pMDIs (Dose not require a valved holding chamber) p. Examples: See notes m. Dry-Powder Inhalers (DPIs) xxvii. Description 40. These dispense a dry powder in a stream of inspired air 41. The force for powder flow comes inspiratory efforts of the patient xxviii. Powder formulation 42. The drug formulation is [usually] the [drug plus a carrier powder] q. The drug xlii. Must be micronized to the proper size xliii. Problem: When powders get this small they can become more cohesive & adhesive (They can stick to each other & to the device) r. Carrier powder xliv. These are larger particles that "carry" the smaller particles xlv. Function to improve powder flow & dispersibility xlvi. [Examples]: Lactose & glucose xlvii. Since the carrier particles are larger, they will be less respirable (They will impact & be swallowed) xxix. Devices & examples 43. Unit-Dose DPIs -- The drug formulation is prefilled in hard gelatin capsules & loaded into the device s. Handihaler xlviii. The capsule is punctured on the side in the device & the powder is inhaled through a screen tube t. Inbrija (levodopa inhalation powder) xlix. The capsule is punctured the end in the device & the powder is inhaled u. 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) l. Available as 4U, 8U, and 12U dose in individual cartridges 44. Multiple Unit-Dose DPIs -- These have several unit doses loaded into the device v. Diskhaler - Contains a circular disk that contains powder charges separately packed in aluminum blister packs (are pierced before inhalation of the powder) li. Relenza (Zanamivir for inhalation, with lactose) w. 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 lii. Serevent Diskus liii. Advair Diskus liv. Flovent Diskus x. Wixela Inhub -- a generic of Advair Diskus y. Ellipta lv. Pre-loaded with 1 month's supply of pre-filled, foil-laminated, individually sealed blisters containing drug formulation lvi. One option is a two-strip configuration with two 30-dose blisters (Contain separate drug formulations & delivered simultaneously during a single inhalation) lvii. Example: Breo Ellipta 45. Multiple-Dose DPIs z. The container has a [reservoir] of drug, from which doses are metered into an inhalation chamber a. Pulmicort Flexhaler lviii. A metered-dose powder delivery system lix. Micronized budesonide plus micronized lactose is contained within a storage reservoir (Contains the formulation - in bulk - from which each dose is loaded) xxx. Important factors affecting dose delivery from DPIs 46. Inspiratory flow rate b. 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) 47. Humidity c. 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) d. Example: Flexhaler can be more sensitive to high humidity than Diskus (Powder more exposed) n. Small Volume Nebulizers (SVN) xxxi. Description 48. Solutions or suspensions are [nebulized] (production of particles, such as spray or mist, from a liquid) & administered through a mouthpiece, ventilation mask, or tracheostomy 49. Key Feature: The product is administered during a [normal breathing] pattern (Treatment time: about 7-10 min) xxxii. Types of SVN 50. Air-Jet Nebulizers e. Compressed air is forced through an orifice leading to an area of negative pressure that draws thin layers of liquid from the product f. An air-jet at the orifice then shears the liquid to produce aerosol particles g. Smaller particles will the device as an aerosolizable mist (Larger particles strike a baffle & drop) 51. Ultrasonic Nebulizers h. Piezoelectric crystals vibrate when electrically excited, creating ultrasonic waves in the liquid that generate geysers at the surface (Geysers release aerosol particles) xxxiii. Some important features of nebulizers 52. Aerosol particle size may differ (Can affect how far they go into the lungs) 53. Efficiency 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) i. Most of the dose ends up as dead volume (a lot adheres to the device) j. A significant fraction blown out with exhalations 54. There is potential for either type to denature protein drugs (e.g., due to sheer forces) 55. Both types have problems with variability of generate particle sizes both within & between brands k. Thus, in many cases it is unacceptable to switch between different brands or types of nebulizers xxxiv. Formulation of nebulizer solutions 56. Cosolvents l. e.g., glycerin, propylene glycol 57. Osmolarity m. Should be isotonic, but doesn't have to be for smaller volumes (Spread over a large surface area in the lungs) 58. pH n. Generally, it should be above 5 (Increased risk of bronchospasm if below 5) o. As with most drug products buffer capacity should be limited, so as to not to overwhelm our own 59. Others p. Additives must be chosen judiciously q. Preservatives may or may not be present (Those without preservatives are for single use) 60. Sterility r. Nebulizer formulations must be sterile xxxv. Examples of commercial nebulizer solutions 61. See Notes E. Typical Patient Populations for Oral Inhalation Devices o. MDI -- Should be able to coordinate actuation/breathing (e.g., 7 years & older without spacer, 3 years & older with spacer) p. DPI -- Should be capable of forceful inspiratory flow (e.g., 3-4 years & older) q. Nebulizer -- For those less able to coordinate or inspire well (e.g., the very young & old)