INHALATIONDRUG DELIVERY SYSTEM

Why pulmonary drug administration?and where?

1. Local therapy (in the airways) :– Asthma, COPD, Cystic Fibrosis, HIV, influenza– Advantages:

• High dose at the site of action• Increased efficacy• Rapid onset of action• Reduced side-effects

2. Systemic therapy (airways but often alveoli) :• The lung as a “port of entry” for the systemic

administration of drug• Peptides and proteins (insulin, interferon-)• Morfine, Ergotamine, 9-tetrahydrocannabinol

Advantages of the Inhalation Route of Administration With Aerosolized Drugs in Treating Pulmonary Diseases:1. Aerosol doses are generally smaller than systemic doses. For example, the oral dose of albuterol is 2 - 4 mg, whereas the inhaled dose is 0.2 mg (via MDI) to 2.5 mg (via SVN).2. Onset of effect is faster with inhalation than with oral administration. For example, the onset of effect with oral albuterol is about 30 min, whereas inhaled albuterol takes effect within about 5.3. The drug is delivered directly to the target organ (lung), withminimized systemic exposure.4. Systemic adverse effects are less severe and less frequent withinhalation than with systemic drug delivery (injection or oral) (eg, less muscle tremor and tachycardia with β-2 agonists; lesshypothalamic pituitary adrenal suppression with corticosteroids). 5. Inhaled drug therapy is painless and relatively comfortable.MDI metered dose inhaleiSVN small volume nebulizerCOPD chionic obstiuctive pulmonaiy Gisease

Structure of the lung• The airways:

– 23 bifurcations through which the air flows

– Covered with mucus– Mucus is moved to the pharynx by cilia– Air flow rate is decreasing

turbulent laminar• Alveoli:

– No mucus, no movement– Alveolar lining fluid (dipalmitoyl

phosphatidylcholine)– Thin membrane

The lung model of Weibelgeneration diameter

(cm)length(cm) number

total crosssectional

area (cm2)trachea 0 1.80 12.0 1 2.54

1 1.22 4.8 2 2.332 0.83 1.9 4 2.13

bronchi

3 0.56 0.8 8 2.004 0.45 1.3 16 2.48co

nduc

ting

zone

bronchioles

terminal bronchioles

5

16

0.35

0.06

1.07

0.17

32

6·104

3.11

180.01718respiratory

bronchioles19 0.05 0.10 5·105 103

2021alveolar ducts22

tran

sitio

nal a

ndre

spira

tory

zon

es

alveolar sacs 23 0.04 0.05 8·106 104

Cross sectional area of the airways available for air flow

Conducting zonegeneration 1-11

Transitional zonegeneration 12-16

Respiratory zonegeneration 17-23

Structure of the alveoli– Large surface area: 43-102 m2

– high degree of vascularization– Thin membrane– Covered with a thin layer of

fluid (ALF: alveolar lining fluid, dipalmitoyl-phosphatidylcholine)

– Limited amount of proteolitic enzymes

– No mucus, nocilia, nomovement

– Clearance of insoluble particles: macrophages (weeks-years)

– Clearance of low molecular weight soluble substances: transepithelial transport

Another Physiological Adventage of Alveoli

• No 1st Pass Metabolism• Small efflux transporter activity• Rich in protease inhibitor• Small volume of fluid (10 – 20 ml)• Prolonged residence time

No non invasive route of delivery provide the speed of action that an inhaled drug can provide

structure of the alveolar membrane• Thin type I alveolar cells (0.05-0.1 µm) with a

relatively large surface (6000 µm2) cover 93 % of alveolar surface

• Tight junctions space ±5 nm– accessible for proteins up to 40 kD

• Capilary endothelial pores: 10-15 nm

Caveolae

• Transport through the epithelial cells• Non coated vesicles• Up to 1.7 x 106 caveolae per type I cell• 40- 100 nm (up to 400 kDa)

Absorption over the alveolar endothelium

• What is rate limiting? – Dissolution– transport over the alveolar-capillary

membrane– Others ?

• Possible routes:» Passive transport through

hydrophilic pores (tight junctions» Passive transport through lipophilic

pathways (cell membranes?)» facilitated passive transport» active transport (caveolae)

Route of Absorbstion

• Macromoleculules, throught tight junction and endocytic veicles

• Endogenous molecules (albumin, immunoglobulin, transferrin) have spesific receptor-mediated transport

• Disodium cromoglikat and cycloleucyn transported by carier mediated transport

Inhaled Peptides and Protein

• Biasanya diberikan secara suntikan• Tidak nyaman, kepatahan kurang terutama

jika harus obat jalan• Route non invasive memberikan

bioavailabilitas jelek• Dikembangkan inhalasi• Contoh: insulin, LHRH• Peptida mudah terhidrolisis, protein sulit

karena ujungnya menekuk (globuler)

Factors affecting protein pulmonary absorption

• Size and volume:– proteins < 20 kDa are absorbed with near IV like

kinetics– Proteins > 20 kDa slow release pattern:

• lung acts as a depot• Risk of depot formation or sequestering:

– stimulation of defence mechanisms (housekeeper cells, metabolising enzymes)

– Immune respons or inflamatory reactions– Morphological changes in tissue

(irreversible!)– changes in gas permeability– reduced resistance against (pathogenic)

micro-organisms

Why inhalation delivery of peptides and proteins ?

• Poor oral bioavailability:– G-I tract environment:

• pH (secondary and tertiary structure)• enzymatic activity in the G-I lumen

– membrane transport (tight junctions size limitation)

– first pass metabolism• Mucosal (e.g. nasal, sublingual, buccal or rectal)

transport only feasible for smaller peptides (up to 10-18 amino acids)

• Parenteral administration is uncomfortable for the patient

Molecular weight : effect on bioavailability

Peptide Mw (Da) Tmax (hr) r.B.A.(%)LHRH analog 1,067 1.0 4.6 - 95 DDAVP 1,209 0.5 84Insulin 5,700 0.25 15-25 PTH 9,418 0.5 >20GCSF 18,600 1.5 45Glycos. Interferon 19,000 6.0 <5Human growth horm. 22,000 0.75 9 - 36DNase 32,000 <2Albumin 68,000 20.0 4-5IgG 150,000 16.0 1.5-1.8

Enam peptida pertama memberikan bioavailabilitas yang bagus karena tahan terhadap peptidase

• Terjadi modifikasi pada ujung C atau N, atau• Terikat dengan cincin seperti siklosporin

Natural peptida (somastatin, VIP, Glucagon)Terdegradasi di paru

Peptide and protein absorbtion

• Siklosporin, kelarutan dalam air rendahdissolution rate limiting step?

T maks Insulin reguler (60 – 180 menit)>insulin inhalasi (5 – 60 menit)

GCSF = granulocyte colony-stimulating factor; hGH = human growth hormone.

Inhalation Technology

The behaviour of an aerosol particle in the airways

• Determined by the physical interaction between the particle and the airflow– The inhalation airflow generated by patients

shows large variations– Particles: manipulation of behaviour through

change of physical properties• Mass (size)• Density• Shape• Velocity

Forces acting on aerosol particles in a bent airway duct

FC is the centrifugal force

FC = m.UT2/R

FD is the drag force

FD = 3...UPA.D/CC

FG is the force of gravity

FG = m.g

M= /6 . D3 . P

Deposition mechanisms in the respiratory tract

Inertial impaction

Sedimentation

Diffusion

Particle size, penetration and deposition in the lung

>5 minertial impactionin oropharnyx

1- 5 m sedimentation indeeper airways

< 1 m diffusion andexhalation

0

20

40

60

80

100(%)

Deposition

Penetrationin target area

Particle diameter (m)

Per

cent

age

pene

tratio

n /de

posi

tion

Preferredparticle size

0.1 0.5 1 2 4 6 8 10

How can we combine high penetration changes with high deposition changes??

Different groups (principles)

of aerosolisation devices for pulmonary drug delivery

Group 1: dry powder inhalers (dpi’s)

Group 2: metered dose inhalers (mdi’s)

Group 3: classic jet and ultrasonic nebulisers

Group 4: soft mist inhalers

Criteria for selection

of aerosolisation devices for pulmonary drug delivery

The target area for the drug (local or systemic delivery)

Patient factors

The therapeutic dose (range) for the drug

Stability of the drug (in aqueous solution or suspension)

The quantity of drug being available

particle size distribution in relation to the inhalation manoeuvre

inhaler handling and lung physiological parameters

microgram or milligram range

dry powder formulations may guarantee a greater stability

e.g. testing of small unformulated samples: preformulation phase

The most fundamental differencesbetween the four groups of inhalation devices

are: the mode and rate with which the entire dose is aerosolised the inhalation manoeuvre with which the aerosol is inhaled

This may have consequences for the deposition efficiency and patient compliance

Example dry powder inhalers: aerosolisation of the entire dose is in (split) seconds using the energy within the generated air flow for dispersion* the fine particle fraction may vary with the inspiratory flow rate administration is in one single inhalation instructions are to inhale deeply and forcefully (high flow rate?)

* With a few exeptions, e.g. Exubera

The most fundamental differencesbetween the four groups of inhalation devices

Metered dose inhalers: instantaneous firing of the entire dose propellant delivers the energy for aerosolisation high plume velocity (CFC >> HFA) co-ordination between firing of a dose and inhalation is required

Classic (jet) nebulisers: the aerosolisation process requires several minutes preparation and cleaning (disinfection) increase total nebulisation time aerosolisation is continuous; inhalation is intermittent patient can exercise a normal breathing pattern

Soft mist inhalers: aerosolisation of the entire dose varies from seconds to minutes production of a dense aerosol with low velocity claims include monodisperse droplets

NEBULIZERAerosolization of solution or suspension done by:1. Jet Nebulizer (umum)

Aliran gas dihasilkan oleh kompresor atau gas yang dimampatkan

2. Ultrasonic nebulizerTenaga listrik menggetarkan lempengan sehingga permukaan cairan bergetar dan jadilah kabut.

The volume at the surface of a liquid is dispersed in

the airflow

1. Through momentum transfer from air to fluid:

Jet nebulizer

2. High frequency sound waves: Ultrasonic

nebulizer

Disadventage:

Long administration times (30 minutes)

Only about 10% lung deposition (highly variable)

The working principleof jet and ultrasonic nebulisers

Jet nebulisers (basically two fluid atomisers): droplet

formation is by a combination of ligament stripping and turbulent

rupture, resulting in a wide droplet size distribution

Ultrasonic nebulisers: droplet formation occurs on the tops of standing waves created by high

frequency vibration imposed (directly or indirectly)upon the liquid surface

JET NEBULIZER DIAGRAM

Jet nebulisers: two examples

Exhaled airAir valve (inlet)

Pressurized air

Baffle

Maximum level for drug solution

Medic-Aide Sidestream (open vent)

Pari LC Plus (breath assisted open vent)

Classical nebulizers

Modern nebulizers:Adaptive aerosol delivery

• Registration of the inhalation flow profile of the three preceding breath cycles

• Aerosol (ultrasonic) released only during inspiration

600

300

0

300

600

Flow

ml/s

inspiration

expiration

time

aerosol release

mouthpiece

bafflemedication

chamber

selectionbuttons

electronics

How to use Jet Nebulizer

Nebulizers are used to treat asthma, Chronic Obstructive Pulmonary Disease (COPD), and other conditions where inhaled medicines are indicated. Nebulizers deliver a stream of medicated air to the lungs over a period of time.

Assemble the nebulizer according to its instructions. Connect the hose to an air compressor.

Fill the medicine cup with your prescription, according to the instructions.

Attach the hose and mouthpiece to the medicine cup.

Place the mouthpiece in your mouth. Breathe through your mouth until all the medicine is used, about 10-15 minutes. Some people use a nose clip to help them breathe only through the mouth.Some people prefer to use a mask.Wash the medicine cup and mouthpiece with water, and air-dry until your next treatment.

Wash the medicine cup and mouthpiece with water, and air-dry until your next treatment.

Presurized Metered Dose Inhaler

The aerosol generation• Liquefied propellant

How the spray from a pressurized metered-dose inhaler is formed.

The pressurized metered dose inhaler (pMDI)• Drugs in propellant:

– Dissolved– Suspension (stability)

• CFC’s (Freon) banned and replaced by HFA’s: Tetrafluoro ethane (HFA134a) or Hepta Fluoro propana (HFA 227)

• Good hand-lung co-ordination required– Spacers– Autohaler

• High speed of the droplets– Lung-deposition: 10-20%– Throat deposition: 70-90%

Lung deposition and actuator retention with a hydrofluoroalkane (HFA) solution formulation of fenoterol and ipratropium bromide delivered through actuator nozzles with diameters of 0.2 mm, 0.25 mm, and 0.3 mm. The data are compared with values from a chlorofluorocarbon (CFC) formulation containing the same drugs. * indicates a statistically significant difference compared with HFA 0.3 mm.

Adventage of pMDI• Practical benefit: Small size, portability,

convenience, relatively unexpensive• The Multi Dose capability• Deliver of drug in few second, unlike nebulizer

Limitation of pMDI Misuse, failure to coordinate actuation and

inhalation Some patien suffer from cold propellant

(esspecially freon), cause stop inhaling

result in supoptimal dosing

Solution of disadventage- Breath-Actuated pMDIs:

sense the patient’s inhalation through the actuator and fire the inhaler automatically in synchrony.ex: Autohaler (3M Pharmaceutical USA), Easibreate (Norton Healtcare UK), K-Haler (Aldsworth UK), MD Turbo (Respiric, USA), Xcelovent (Meridika, UK)

- Breath-coordinated Devicesex: Easidose (Bespak, UK), BCI (Aeropharm, USA)

- Novel Devices: placing baffles near the actuator nozzleSpacehaler (Celtech Medeva, USA), Tempo (Map Pharm, USA), Bronchoair (Ger)

- Spacer Design

SPACER DEVICE

• The larger the spacer better the dose available• However, increasing the spacer volume to 1 L

would probably be counterproductive, because the spacer would no longer be easilyportable, and because it would be more difficult for the patient to inhale the complete contents.

LINK Video

• How to use jet/classic nebulizer:• http://www.youtube.com/watch?

v=A7DhGX0p1KY• How to use metered dose inhalers:• http://www.youtube.com/watch?

v=A7DhGX0p1KY&feature=channel

Dry powder inhaler (DPI)• “Breath-controlled, “breath-actuated”• 40 to 60 % lung deposition possible• No propellant• Stable formulations possible• For processing agglomerated particles required• In the aerosol de-agglomerated particles

required• Formulation

difficult

Functional parts of a DPI

Mouthpiece

Powder disperser (disintegration principle)

Powder formulation

Dose measuring system

Or preloaded cartidges

The design of DPI’s

DPI performancedose entrainmentpowder disintegrationlung deposition

DPI designpowder formulationdose systemdisintegration principle

Patientinstructionclinical pictureage and gendertrainingsmoker/non smoker

Patient’s effort

DPI air flow resistance Flow parameterspeak flow rate (PIFR)flow increase rate (FIR)inhalation time

Variables and interactionsin the use of dry powder inhalers

From design

Powder formulations for particles of 2 - 5 m

• Soft spherical pellets– Micronized drug– cohesive forces– instable– good de-agglomeration

• adhesive mixtures– Micronized drug with

(larger) carrier crystals– adhesive and cohesive

forces– stable systems– Difficult de-agglomeration

Fine particle fractionsfrom different DPI’s

TH: Turbuhaler

AH: Diskus

FDH: Flixotide Diskhaler

BDH: Beclometasone Diskhaler

SH: Spinhaler

CH: Cyclohaler

The relative lungdose decreases when the inhalation flow rate increases

In order to compensate for the relatively decreased lung penetration the absolute fine particle dose must increase to keep the lung dose at the same level.

Oropharyngeal deposition increases, when the inhalation flow rate increases

(FC = m.UT2/R)

Carrier related variables

Size and size distributionImpurities

storage and conditioning

Inhaler and inhalation

Bulk propertiesSurface properties

Example 1: Interpretations and understanding• Budesonide versus salbutamol fine particle fractions

from mixtures with different Respitose carriers% fpf (stage 4+3+filter)

0

10

20

30

40

50

60

70

SV007 SV003 ML001

1% 2% 2% 0.5%

C N D H C N D H C N D H

C: Cyclohaler

N: Novolizer

D: Diskus

H: HandiHaler

budesonide

salbutamol

Dat

a sh

own

by c

ourt

esy

of D

MV-

Font

erra

, The

Net

herla

nds

Obvious conclusion: budesonide particles attach to the carrier surface

with higher force than salbutamol particles

–4 kPa or 100 l/min

The effect of the carrier surface properties is determined by:

• The particle size of the carrier

• The payload of the drug on the carrier

• The bulk properties and mixing of the powder mixture

Additives• Additives (force control agents) mentioned in

literature:– Lactose fines– Magnesium stearate– L-leucine

• Effects of additives:– “Competition” for active sites– Change the payload of a mixture– Reduce press-on forces during mixing– Agglomeration of additives and drug

Powder formulation

Desintegration principe

poor

moderate good

Generation of the aerosol in a DPI: a balance between binding forces and de-agglomereation forces

Binding forces:v.d. Waals forcessurface irregularitiesimpuritiescapillaire forceselectrostatic forces

De-agglomeration forces:shear and friction forcesDrag and lift forcesImpaction forces

The powder formulation

Nucleus agglommerateAdhesive mixture Spherical pellets

Drug concentration up to 10%Mechanically stableDifficult to break upLow risk of inhaler pollution

Drug concentration up to 50% (or more)InstableEasy to break upLow risk of inhaler pollution

Drug concentration up to 100%Highly instableEasy to break upHigh risk of inhaler pollutionBatch variability

Effective dry powder inhalation

requires good control of a series of processes that are dominated by various forces, e.g.:

inertial and frictional forces during mixing

interparticulate forces in the powder blend

drag forces during dose entrainment

dispersion forces during inhalation

deposition forces in the respiratory tract

AHB01

formulation

DPI design

and

patient factors