Delivery Systems & Formulation For Inhalation

Question 1

How do we deliver drugs to the lungs?

Answer 1

Aerosol

Dispersion of solid particles or liquid droplets in a gas

(Needs a source of energy required to form an aerosol)

Question 2

Types of inhalers

Answer 2

1) Nebulisers
2) Pressurised metered dose inhalers (pMDI) - widely used + most convienient
3) Dry powder Inhalers (DPI)

Question 3

Nebulisers

Answer 3

Aqueous drug solution/suspension aerolised onto droplets

• energy provided by compressed air or ultrasound

Question 4

pMDI

Answer 4

Drug formulated in a liquefied gas under pressure

• Aerosol formed by evaporation of the gas at atmospheric pressure

Question 5

DPI

Answer 5

Drug normally with other solid excipients in a dry powder state

• Aerosolisation by patient’s inhalation

Question 6

2 types of Nebulisers

Answer 6

Jet Nebuliser

Ultrasonic Nebuliser

Question 7

Jet Nebuliser

Answer 7

Air from a compressor forced through a narrow hole to give high velocity air stream

• High velocity air breaks drug solution/suspension into droplets for inhalation
• baffles used to remove larger particles

Question 8

Ultrasonic Nebuliser

Answer 8

• Piezoelectric (vibrating) crystal emits high frequency signal
• breaks drug solution/suspension into droplets for inhalation
• lighter + quieter than a jet nebuliser

Question 9

How to use nebulisers

Answer 9

Patient breaths normally into face mask/mouthpiece

Patient needs to wash it every time

Question 10

Advantages of Nebulisers

Answer 10

• aqueous drug solutions
• no hand-lung coordination
  
  • good for elderly + children
• no controlled inhalation manoeuvre required
  
  • useful in severe, acute asthma attacks
• large doses of drugs not normally available can be given
• low cost
• visible mist (patient reassured)

Question 11

Disadvantages of nebulisers

Answer 11

• not fully portable
• equipment not fully regulated
• lengthy nebulisation time
• low efficiency
  
  • as low as 10% of drug reaches lungs
• solution concentrates as water evaporates
• insoluble drugs require solubilisation
• some suspensions can be difficult to nebulise
• susceptible to microbiological contamination

Question 12

Name the different parts of a MDI

Answer 12

Question 13

Metered dose inhaler (Canister) container requirements

Answer 13

Must:

• withstand high pressure
• Robust
• Light in weight
• Inert
• Made of aluminium/stainless steel

Question 14

pMDI metering valve

Answer 14

Ensures accurate + reproducible volume of drug formulation is delivered

Different from continuous spray valves

volume = 25-100 microlitres

Question 15

pMDI propellant requirements

Answer 15

Must be:

• liquid under pressure
• gas at atmospheric pressure + ambient temperature
• that its vapour pressure must stay constant
• non-flammable, non-toxic
• chemically inert + compatible with drug formulation

Question 16

Types of propellants in pMDIs

Answer 16

Chlorofluorocarbons

Hydrofluoroalkanes

Question 17

CFCs

Answer 17

Ozone depleting gases

Banned

Responsible for ‘cold-freon effect’

Question 18

Hydrofluoroalkanes

Answer 18

Drugs need to be re-formulated due to different properties of HFA vs CFC

New valve materials had to be developed

Question 19

What is the dose range for each actuation in a pMDI?

Answer 19

Dose per actuation from 5 microgram to 5 milligram

Question 20

Drug formulation types for pMDIs

Answer 20

Drug is soluble in propellant

• drug solubilised in propellant
• ethanol might be added as a co-solvent

Drug is insoluble in propellant (most common)

• micronised drug particles suspended in propellant
• surfactants added to increase suspension stability

Question 21

Suspension formulation of a pMDI

Answer 21

• each volume of suspension must be homogenous
• surfactants added to formulation to
  
  • improve stability
  • aid in the formulation of a flocculated suspension
• surfactants approved in inhaled products: oleic acid, sorbitan trioleate, lechitin

Question 22

Problems with suspensions

Answer 22

Sedimentation

Flocculation (reversible aggregation by shaking)

Caking (difficult to redisperse)

Particle size growth by Ostwald ripening (deposition in lungs reduce)

Question 23

How can we minimise caking

Answer 23

Controlled flocculation

Question 24

what is the ideal suspension stability

Answer 24

Slow flocculation (>30 secs)

Slow sedimentation (>30 secs)

Easy redispersion

(still need to shake device before use to redisperse settled flocculates)

Question 25

Excipients included in pMDI drug formulation

Answer 25

**Flavours** - to mask bitter drugs **Sweeteners** - to mask bitter drugs **Lubricant** - to improve valve operation **Density modifiers** - to decrease sedimentation rate **Antioxidants** - to prevent chemical degradation

Question 26

Why use spacer devices with pMDI

Answer 26

**Increase lung deposition** * delay between actuation + inhalation * decrease velocity of the spray * more time for the propellant to evaporate However, it is **cumbersome** (have to carry around bulky device) + **decreases dose inhaled by patient** (deposition in the device as electrostatic charges cause droplets to stick to chamber)

Question 27

How to improve inhalation of pMDI

Answer 27

Spacer devices Breath-actuated pMDI

Question 28

Why does a Breath-actuated pMDI improve inhalation for the patient?

Answer 28

Inhaler is fired by the patients inhalation No coordination needed Particles still leave inhaler at a high velocity

Question 29

Advantages of pMDI

Answer 29

Compact, portable, robust, convenient Multi-dose Short treatment time Consistent format Good dose content uniformity Inexpensive Good protection against moisture + pathogen Inexpensive

Question 30

Disadvantages of pMDI

Answer 30

Usually no breath-actuation Low lung depostion No dose counter Only low doses can be delivered (\<1mg) Need priming before use Performance depends on temperature Drug formulation is challenging Not environmentally friendly - HFAs are still greenhouse gases

Question 31

What are Dry Powder Inhalers?

Answer 31

Delivers dry powder, no solvent Developed for delivery of sodium cromoglicate as large dose could not be delivered by pMDI Breath actuated (no coordination required) As a drug + excipients in a dry form tend to be more stable than drug dispersed in a solvent as in pMDI

Question 32

Components of DPI

Answer 32

Drug powder or blend of drug with excipients Drug reservoirs or pre-metered doses Body of device Cap to protect powder from dust, moisture

Question 33

Principles of DPI operation

Answer 33

Patient's inspiration flow is used to: * **fluidise** the static powder blend * **de-aggregate** particle agglomerates into inhalable particles Dose delivered + deposited into the lungs depends on the patient's inspiratory flow rate

Question 34

DPI - particle de-aggregation

Answer 34

Particles less than 5 micrometers are extremely cohesive

Question 35

Types of DPI

Answer 35

Unit dose device Multiple unit dose Reservoir devices

Question 36

DPI: Single uni dose device

Answer 36

Drug excipients In capsule

Question 37

DPI: multi-unit dose

Answer 37

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Question 38

DPI- multidose reservoir devices

Answer 38

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