Respiratory Drug Delivery: respiratory tract and particle deposition

Dr Ali Nokhodchi, PharmD, PhD Medway School of Pharmacy

Why Inhalation?

Deliver drugs to the site of action within the lung to exert localised effects, e.g. antiasthmatic drugs, leading to fast act Minimise dose required, leading to maximal therapeutic effects with minimal side effects Avoid metabolism by GI tract and the liver: Inhaled drug can be adsorbed directly into the systemic circulation. Act as the portal for systemic delivery of drugs

Anatomy of Respiratory Tract

Upper respiratory tract Lower respiratory tract Conducting zone Respiratory zone

Lower Respiratory Tract

Larynx: maintains an open airway, routes for food and air appropriately, assists in sound production Trachea: transports air to and from lungs Bronchi: branch into lungs Lungs: transport air to alveoli for gas exchange

The Respiratory Tree

A symmetrical, dichotomously branching network of cylindrical tubes Bronchi split (bifurcate) repeatedly into two smaller passages called bronchioles. Divided into 24 generations from trachea to alveolar sacs The conducting zone provides humidification, gas buffering, gas transference and air warming. Succeeding the conducting zone is the respiratory zone and this is the site where gas exchange takes place.

The Fate of Inhaled Corticosteroids

10 - 40 % Deposited in lung Complete absorption from the lung

Lung Mouth and pharynx

Orally bioavailable fraction Absorption from gut 60 - 90 % Swallowed (reduced by spacer or mouth rinsing)

Systemic Circulation

Liver
Systemic side effects

GI tract

First-pass inactivation

Amount reaching systemic circulation=Absorption via the lung + Absorption via GI tract

Particle Deposition in the Lung

Deposition is a process by which inhaled particles separate from the flow streamlines and contact a respiratory surface from which there is no rebound or resuspension.

Deposition by Inertial Impaction

Each time the air stream changes direction, the airborne particles tend to maintain their established trajectories. If the particles possess sufficient momentum, they will not follow the gas streamlines and will impact on any obstacles in their trajectories. Occurs mostly for larger particles that are very close to airway walls, near the first airway bifurcations. Therefore, deposition by impaction is greatest in the bronchial region. Impaction accounts for the majority of particle deposition on a mass basis.

Impaction

Deposition by Sedimentation

Sedimentation occurs when particles settle out of the airflow due to gravity. Sedimentation is dominant in the smaller airways and alveolar region, where flow velocities are low and airway dimensions are small. Aerosol particles tend to settle onto airway surfaces most efficiently either during slow, steady breathing or during breath-holding. These breathing manoeuvres allow a sufficiently long residence time of particles within the lungs for sedimentation to occur.

Sedimentation

Deposition by Diffusion

Particles < 1 m will undergo a random motion, the Brownian motion, in the air stream due to the bombardment of the gas molecules. Net transport of particles from a region of higher to lower concentration due to Brownian motion. Primary mechanism of deposition for particles <0.5 m Occurs mostly when particles have just entered the nasopharynx Also most likely to occur in the smaller airways of the pulmonary (alveolar) region, where air flow is low

Diffusion

Deposition by Interception and Electrostatic Precipitation

Interception Occurs when a particle contacts an airway surface due to its physical size or shape. Most likely to occur in small airways or when the air streamline is close to an airway wall. Interception is most significant for fibres, which easily contact airway surfaces due to their length.

Electrostatic precipitation

A charged particle may induce an image charge on the surfaces of the airways and subsequently deposit by electrostatic precipitation. The repulsion between like-charged inhaled particles may also direct the particles toward airway walls, resulting in deposition in those regions.

Interception

Airway Physiological Changes and Particle Deposition

The airway diameter decreases with increasing generations whereas the number of airways for each generation increases at a much higher rate (double the previous generation). Thus, whilst the calibre for the individual airway decreases the total area for that generation increases drastically. Whilst moving through the upper respiratory tract, the air stream is subject to a sharp change in direction especially from pharynx to larynx, inducing instability of the air stream and substantially increasing the chances of deposition by impaction. Particles deposited in the tracheobronchial region will be rapidly removed by mucociliary escalator. Deposition in the region is not uniform with most drug particles being deposited at the bifurcations and on the bulged cartilagenous rings. In the lower airways, the air stream becomes more stable and the majority of the remaining air-borne particles will deposit mainly by sedimentation and diffusion mechanisms.

Factors Affecting Lung Delivery

The patient

(Patho) physiology of the respiratory tract Patients inspiratory maneuvers Pressurised metered dose inhalers, dry powder inhalers and nebulisers

The delivery device

The drug substance and/or formulations

Particle size, density, shape, static electricity, etc.

Inter-dependence of all these factors

Relationship between Drug Particle Size and Deposition Sites

Particles larger than 10 m are most likely to deposit in the mouth and throat. Between the sizes of 5 and 10 m, a deposition from mouth to airways occurs. Particles smaller than 5 m deposit more frequently in the lower airways. Particles smaller than 0.5 m are most probably exhaled. Drug particle should be between 1-5 m.

New molecules under development

Proteins and peptides

Insulin, Alpha-1 antitrypsin, calcitonin, desmopressin tobramycin, gentamicin, cyclosporin morphine, fentanyl

Anti-infectives

Pain management

Vaccines Hormones Gene therapies Immunoglobulins Soft steroid

Existing Delivery Platforms

Pressurised metered dose inhalers (pMDI) Dry powder inhalers (DPI) Nebulisers

Pressurised metered dose inhalers (pMDI)

In a pMDI, the drug is either suspended or dissolved in a liquefied gas called the propellant. The act of pressing down the canister leads to a pre-metered dose being released from the mouthpiece.

Pressurised system containing liquefied gas Formulation either suspension or solution Dispense micrograms to milligrams drug per actuation Small precise volume delivered (25 100 l)

How pMDI works

Propellants

Propellants provide the medium and driving force to expel drug from its container. Chlorofluorocarbons (CFCs)

Destructive to atmospheric ozone layer and contributing to greenhouse effect To be phased out shortly Not ozone-depleting but still with greenhouse effect 1,1,1,2,3,3,3 Heptafluoropropane (HFA-134a) (CF3CFH-CF3) 1,1,1,2 Tetrafluoroethane (HFA-227) (CF3-CFH2)

Hydrofluoroalkanes (HFAs)

Important physical properties of CFCs and HFAs

Chlorofluorocarbons (CFCs) CFC-11 Formula Boiling point (C) Vapor pressure at 25C (psi) Liquid density at 25C (g/ml) ODP / GWP* C Cl3 F 23.8 15.3 1.48 1.00/1.00 CFC-12 C Cl2 F2 -29.8 94.5 1.31 1.00/2.99 CFC-114 C2 Cl2 F4 -3.8 31.0 1.46 1.00/4.19 Hydrofluoroalkanes (HFAs) HFA-134a CF3-CFH-CF3 - 26.1 5.72 1.23 0/Low HFA-227 CF3-CFH2 -16.5 3.90 1.42 0/Low

*Ozone Depletion Potential / Global Warming Potential relative to CFC-11

Nomenclature:
Numbering system to identify CFCs This system consists of three digits

C2Cl2F4

114
Number of carbon atoms - 1 Number of hydrogen atoms + 1 Number of fluorine atoms

Number of chlorine
total number of atoms required to saturate the compound (fluorine + hydrogen atoms) Isomers: the most symmetrical compound is given the designated number, all other isomers are assigned a letter, e.g. a, b, c, in descending order of symmetry

Surfactants

Types

Anionic (oleic acid) Zwitterionic (lecithin) Non-ionic (sorbitan trioleate)

Lubricate valve Aid drug dispersion in propellants Increase drug solubility

Functions

pMDIs: Advantages & Disadvantages

Needs propellants, which causes environmental concerns Requires co-ordination between inhalation and actuation 10-15% delivered dose reaching the lung Needs add-on devices to reduce oropharyngeal depositions Environmental humidity has moderate effects Drug delivery independent of inspiratory flow rates Time-dependent dose variation Difficult to use in small children and elderly patients, unless attached to a spacer No dose indicator Portable and durable

Most drug in the stomach

Dry powder inhalers (DPIs)

DPIs are devices that do not contain propellants. Drug delivery is achieved by either patients inhalation or an external energy such as compressed air. In a DPI, the micronized drug is kept in a solid state.

Micronised drug (1-5 m) has very poor flowability, is highly cohesive and difficult to disperse. In order to improve its flowability, reduce cohesiveness and enhance dispersion, it is either made into loose agglomerates (similar to granulation before tableting) or blended with a coarse, inert carrier, normally lactose monohydrate, such that the drug particles are adhered onto the surface of the carrier

Basic principle of formulations using carrier particles

+
20 m

Lactose carrier

5 m Micronized drug

5 m Ordered mix

(SEM images from Gilani et al. Eur. J Pharm. Biopharm., (2004) 58, 595-606)

Drug and carrier deposition

3-5 m: Follows airstream into the lower respiratory tract

60-90 m: Deposition in the mouth and throat

Flakes

Partially crystalline

Monodisperse

Smooth dimpled

Porous

Lessons from nature

Perfect aerosol particles?

erosols

Fungal spore

Small porous particles

-Rotahaler (GSK)
-Aeroliser (Novartis)
Turbohaler (AstraZeneca)

-Diskhaler (GSK)
Airmax (IVax )

-Accuhaler (GSK)

Novoliser (Viatris )

Different DPI idevice in the market

-Handihaler (Boehringer Ingelheim)

DPIs: Advantages & disadvantages

No propellants No co-ordination required Lung deposition varies with devices but can match pMDI Variable oropharyngeal depositions. No add-on devices Many devices sensitive to humidity Drug delivery dependent on inspiratory flow rates Reservoir devices generally more variable than premetered devices Expensive Relatively easy to use Newer Multi-dose DPIs have dose indicator Portable and durable

Nebulisers

Solution of drug passed through pump compressor producing mist of drug inhaled through a mask. Antibiotics, bronchodilators and corticosteroids May be used at home or hospital Two types: Air jet Ultrasonic

Definitions of common terms

Metered dose

For a device-metered inhaler, it is the dose released from the drug reservoir into the metering chamber each time the inhaler is actuated. For pre-metered device, it is the dose contained in a capsule or blister. This is the dose released or emitted or delivered from the mouthpiece of the inhaler. Delivered dose equals to metered dose minus device retention. This is the mass of drug particles that have aerodynamic particle size less than 5 m It is the fine particle dose expressed as the percentage of the delivered dose.

Delivered dose or emitted dose

Fine particle dose

Fine particle fraction

Twin stage liquid impinger

Operated at 60 L/min. 7 ml and 30 ml suitable solvent introduced to the upper and lower stage, respectively. Upper stage cut-off diameter: 6.4 m

Andersen cascade impactor

Operated at 28.3 L/min for pMDI and Q for DPI. For DPI testing, each stage should be coated with a sticky material such as silicone oil. Cut-off diameter at 28.3 L/min: S0=9.0; S1=5.8; S2=4.7; S3=3.3; S4=2.1; S5=1.1; S6=0.7; S7=0.4 m

Other criteria

Water content Impurities and degradation products Microbial limits Leachables and extractables Leak rate