pulmonary delivery 2011lect4

8/13/2019 Pulmonary Delivery 2011Lect4

1/40

Respiratory Drug Delivery:

respiratory tract andparticle deposition

Dr Ali Nokhodchi, PharmD, PhDMedway School of Pharmacy


2/40

Why Inhalation?

Deliver drugs to the site of actionwithin the lung to exert localisedeffects, e.g. antiasthmatic drugs,leading to fast act

Minimise dose required, leading tomaximal therapeutic effects withminimal side effects

Avoid metabolism by GI tract and theliver: Inhaled drug can be adsorbeddirectly into the systemic circulation.

Act as the portal for systemicdelivery of drugs


3/40

Anatomy of Respiratory Tract

Upper respiratorytractLower respiratorytract

ConductingzoneRespiratoryzone


4/40

Lower Respiratory Tract

Larynx: maintains an openairway, routes for food andair appropriately, assists insound production

Trachea: transports air toand from lungsBronchi: branch into lungsLungs: transport air to

alveoli for gas exchange


5/40

The Respiratory Tree

A symmetrical, dichotomouslybranching network of cylindricaltubesBronchi split (bifurcate) repeatedlyinto two smaller passages calledbronchioles.

Divided into 24 generations fromtrachea to alveolar sacsThe conducting zone provideshumidification, gas buffering, gastransference and air warming.Succeeding the conducting zoneis the respiratory zone and this isthe site where gas exchangetakes place.


6/40

The Fate of Inhaled Corticosteroids

60 - 90 % Swallowed(reduced by spacer

or mouth rinsing)

Mouth and pharynx

GI tract

10 - 40 %Deposited in lung

Lung

Complete absorptionfrom the lung

SystemicCirculation

Systemicside effects

Liver

Orally bioavailablefraction

Absorptionfrom gut

First-passinactivation

Amount reaching systemic circulation=Absorption via the lung +

Absorption via GI tract


7/40


8/40


9/40

Impaction


10/40

Deposition by SedimentationSedimentation occurs when particles settle out

of the airflow due to gravity.Sedimentation is dominant in the smallerairways and alveolar region , where flowvelocities are low and airway dimensions aresmall.

Aerosol particles tend to settle onto airwaysurfaces most efficiently either during slow,steady breathing or during breath-holding.These breathing manoeuvres allow a sufficientlylong residence time of particles within the lungsfor sedimentation to occur.


11/40

Sedimentation


12/40

Deposition by DiffusionParticles < 1 m will undergo a random motion, the Brownianmotion , in the air stream due to the bombardment of the gasmolecules.Net transport of particles from a region of higher to lowerconcentration due to Brownian motion.Primary mechanism of deposition for particles


13/40

Diffusion


14/40

Deposition by Interception and ElectrostaticPrecipitation

InterceptionOccurs when a particle contacts an airway surface due to itsphysical size or shape .Most likely to occur in small airways or when the air streamline isclose to an airway wall.Interception is most significant for fibres , which easily contactairway surfaces due to their length.

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


15/40

Interception


16/40

Airway Physiological Changes and ParticleDeposition

The airway diameter decreases with increasing generations whereasthe number of airways for each generation increases at a muchhigher rate (double the previous generation). Thus, whilst thecalibre for the individual airway decreases the total area for thatgeneration increases drastically.

Whilst moving through the upper respiratory tract, the air stream issubject to a sharp change in direction especially from pharynx tolarynx, inducing instability of the air stream and substantiallyincreasing the chances of deposition by impaction.Particles deposited in the tracheobronchial region will be rapidlyremoved by mucociliary escalator. Deposition in the region is not

uniform with most drug particles being deposited at thebifurcations and on the bulged cartilagenous rings.In the lower airways, the air stream becomes more stable and themajority of the remaining air-borne particles will deposit mainly bysedimentation and diffusion mechanisms.


17/40

Factors Affecting Lung Delivery

The patient(Patho) physiology of the respiratory tractPatients inspiratory maneuvers

The delivery devicePressurised metered dose inhalers, drypowder inhalers and nebulisers

The drug substance and/or formulations

Particle size, density, shape, static electricity, etc.Inter-dependence of all these factors


18/40

Relationship between Drug ParticleSize and Deposition Sites

Particles larger than 10 mare most likely to deposit inthe mouth and throat.Between the sizes of 5 and10 m, a deposition from

mouth to airways occurs.Particles smaller than 5 mdeposit more frequently inthe lower airways.Particles smaller than 0.5m are most probablyexhaled.Drug particle should bebetween 1-5 m.


19/40

New molecules under development

Proteins and peptidesInsulin, Alpha-1 antitrypsin, calcitonin, desmopressin Anti-infectives

tobramycin, gentamicin, cyclosporin

Pain managementmorphine, fentanylVaccinesHormones

Gene therapiesImmunoglobulinsSoft steroid


20/40

Existing Delivery Platforms

Pressurised metered doseinhalers (pMDI)

Dry powder inhalers (DPI)Nebulisers


21/40

Pressurised metered dose inhalers (pMDI)

In a pMDI, the drug is eithersuspended or dissolved in a liquefiedgas called the propellant. The act ofpressing down the canister leads to apre-metered dose being released fromthe mouthpiece.

Pressurised system containing liquefiedgasFormulation either suspension orsolutionDispense micrograms to milligrams drugper actuationSmall precise volume delivered (25 -100 l)


22/40

How pMDI works


23/40

Propellants

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

Destructive to atmospheric ozone layer and contributing

to greenhouse effectTo be phased out shortlyHydrofluoroalkanes (HFAs)

Not ozone- depleting but still with greenhouse effect1,1,1,2,3,3,3 Heptafluoropropane (HFA-134a) (CF3-

CFH-CF3)1,1,1,2 Tetrafluoroethane (HFA-227) (CF3-CFH2)


24/40

Important physical properties of CFCsand HFAs

Chlorofluorocarbons (CFCs) Hydrofluoroalkanes (HFAs)

CFC-11 CFC-12 CFC-114 HFA-134a HFA-227

Formula C Cl3

F C Cl2

F2

C2

Cl2

F4

CF3-CFH-CF3 CF3-CFH2

Boiling point ( C) 23.8 -29.8 -3.8 - 26.1 -16.5

Vapor pressureat 25 C (psi)

15.3 94.5 31.0 5.72 3.90

Liquid densityat 25 C (g/ml)

1.48 1.31 1.46 1.23 1.42

ODP / GWP* 1.00/1.00 1.00/2.99 1.00/4.19 0/Low 0/Low

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


25/40

Nomenclature:

Numbering system to identify CFCs

This system consists of three digits

114 Number of carbon

atoms - 1 Number of

hydrogen atoms + 1 Number of

fluorine atoms

Number of chlorinetotal number of atoms required to saturate the compound (fluorine + hydrogen atoms)

C 2Cl 2F 4

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


26/40

Surfactants

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

FunctionsLubricate valve

Aid drug dispersion inpropellantsIncrease drug solubility


27/40

pMDIs: Advantages & Disadvantages

Needs propellants, which causes environmentalconcernsRequires co-ordination between inhalation andactuation10-15% delivered dose reaching the lung

Needs add-on devices to reduce oropharyngealdepositionsEnvironmental humidity has moderate effectsDrug delivery independent of inspiratory flow ratesTime-dependent dose variation

Difficult to use in small children and elderlypatients, unless attached to a spacer No dose indicator Portable and durable

Most drug inthe stomach


28/40

Dry powder inhalers (DPIs)DPIs are devices that do not contain propellants. Drugdelivery is achieved by either patients inhalation or anexternal energy such as compressed air . In a DPI, themicronized 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 toimprove its flowability, reduce cohesiveness and enhancedispersion, it iseither made into loose agglomerates (similar to

granulation before tableting)or blended with a coarse , inert carrier, normally lactosemonohydrate, such that the drug particles are adheredonto the surface of the carrier


29/40

Basic principle of formulationsusing carrier particles

+

20 m

5 m 5 m

(SEM images from Gilani et al. Eur. J Pharm. Biopharm., (2004) 58, 595-606)Lactose carrier Micronized drug Ordered mix


30/40

Drug and carrier deposition

60- 90 m: Deposition in the

mouth and throat

3-5 m: Followsairstream into the

lower respiratory tract


31/40


32/40

Flakes

Porous

Partially crystalline Monodisperse

Smooth dimpled


33/40

Lessons from nature

Perfect aerosol particles?

Fungal spore Small porous particles

r


34/40

-Rotahaler (GSK)-Aeroliser (Novartis)

- H a n d i h a l e r ( B o e h r i n g e r

I n g e l h e i m )

-Diskhaler (GSK) -Accuhaler (GSK) T u r b o h a l e r ( A s t r a Z e n e c a )

Novoliser (Viatris

A i r m a x ( I V a x )

Different DPI idevice in the market


35/40

DPIs: Advantages & disadvantages

No propellantsNo co-ordination requiredLung deposition varies with devices but can match pMDIVariable oropharyngeal depositions. No add-on devicesMany devices sensitive to humidity

Drug delivery dependent on inspiratory flow ratesReservoir devices generally more variable than premetereddevicesExpensiveRelatively easy to useNewer Multi-dose DPIs have dose indicator Portable and durable


36/40

Nebulisers

Solution of drug passedthrough pump compressorproducing mist of druginhaled through a mask.

Antibiotics, bronchodilatorsand corticosteroidsMay be used at home orhospitalTwo types:

Air jetUltrasonic


37/40

Definitions of common terms

Metered doseFor a device-metered inhaler, it is the dose released from the drugreservoir into the metering chamber each time the inhaler isactuated.For pre-metered device, it is the dose contained in a capsule orblister.

Delivered dose or emitted doseThis is the dose released or emitted or delivered from themouthpiece of the inhaler. Delivered dose equals to metered doseminus device retention.

Fine particle doseThis is the mass of drug particles that have aerodynamic particle sizeless than 5 m

Fine particle fractionIt is the fine particle dose expressed as the percentage of thedelivered dose.


38/40

Twin stage liquid impinger

Operated at 60 L/min.

7 ml and 30 ml suitablesolvent introduced to theupper and lower stage,respectively.

Upper stage cut-offdiameter: 6.4 m


39/40

Andersen cascade impactor

Operated at 28.3 L/min for pMDIand Q for DPI.

For DPI testing, each stage shouldbe coated with a sticky materialsuch 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=0.4m


40/40

Other criteria

Water contentImpurities and degradation productsMicrobial limitsLeachables and extractablesLeak rate

pulmonary delivery 2011lect4

Documents