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Drug Delivery > Inhalers > Flashcards

Inhalers Flashcards

1
Q

What is the main deposition mechanism of aerosol particles within the respiratory tract?

A

Within the oro-pharyngeal and upper airways: inertial impaction which is dominated by mass and airflow velocity. (d2v)
Others: gravitational sedimentation. Diffusion. Interception and electrostatically induced image changes.

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2
Q

What is gravitational sedimentation dominated by?

A

The residence time in the lower airways. (d2t). The longer the residence the more sedimentation.

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3
Q

Where may diffusion dominate in terms of aerosol particle deposition?

A

The peripheral airways.

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4
Q

Describe a solution based formulation for pMDI. Include excipients. critical attributes and challenges.

A

Ethanol = major excipient. (Non-volatile = ethanol and glycerol)
Critical key attribute is the diameter of the actuator orifice, which determines the Mass mean aerodynamic diameter.
The amount of dose emitted is directly related to the solubility.
Freely soluble drugs have the ability to crystallize out during shelf-life, especially with changing temperature.

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5
Q

Describe a suspension based formulation for pMDI. Include excipients. critical attributes and challenges.

A

E: ethanol and a range of different surfactants like SPAN 85, oleic acid and soya lecithins to maintain suspension stability.
The jet diameter and actuator orifice play a key role in the plume geometry and the velocity of the aerosol cloud.
Suspensions are generally preferred as they are often more chemically stable.
The can may need to be coated with an inert, low surface energy polymer for low dose systems.

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6
Q

What problems are commonly faced by suspension based pMDIs?

A

Vigorous shaking is required to ensure re-dispersion and formulation homogeneity.
Physical instability can occur depending on the propellant, drug and adjuvants used: rapid flocculation, bulk separation, irreversible aggregation, crystal structure instability.

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7
Q

What problems are commonly faced by solution based pMDIs?

A

Polar co-colvent can case corrosion of an aluminium canister so plastic coated glass vials are needed.
Drugs can be relatively unstable.
The relatively non-volatile co-solvent can lower the internal propellant pressure, thus, atomisation is less effective.

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8
Q

Why are DPI > pMDIs?

A

Propellant use: greenhouse gases, Montreal Protocol meant reformulation from CFCs to HFAs had to occur: expensive, difficult, issues arose.

DPI offer IP protection.

Compliance issues with pMDIs, as DPIs are automatically breath actuated, the whole process of delivering the drug is driven only when the patient inhales through the device.

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9
Q

What are the three physical forces that determine the force of adhesion of respirable size particles?

A

vdW forces, Capillary forces and Electrostatic forces.

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10
Q

What does the aerosol dispersion performance of a carrier based DPI formulation depend upon?

A

The forces required to deaggregate and disperse the drug particles from the carrier surface. For example, strong adhesive forces may result in rapid and uniform mixing but may also prevent the release of the respirable drug particles from the carrier during inhalation.

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11
Q

What is the van der Waals force?

A

Ever-present and finite. It is attractive between interacting particles in the air. The vdW force is a short-acting force, 10-100nm.
The vdW force dominates at low humidity in the absence of any contact or triboelectrification induced forces.
Magnitude of vdW depends on surface energy and contact geometry of interacting surfaces.
Changes in shape and geometry can modify magnitude greatly. 10nN-100nN.

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12
Q

What is the triboelectric effect?

A

The triboelectric effect (also known as triboelectric charging) is a type of contact electrification in which certain materials become electrically charged after they come into frictional contact with a different material.

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13
Q

When does the vdW force dominate particle adhesion/dispersion mechanics?

A

At low humidity and in the absence of any contact or triboelectric effects.

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14
Q

What does the magnitude of the vdW force depend on?

A

The surface energy of the two material and the contact geometry of the interacting surfaces.

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15
Q

Why does higher relative humidity require higher de-aggregation energy to remove particles from a lactose surface in a DPI carrier formulation?

A

As RH increases, the condensation of water vapour between two surfaces influences the surface tension and, at a critical relative humidity, may lead to the creation of a meniscus bridge between two contacting surfaces. The water acts as a glue leading to a greater inter-particle force, requiring greater de-aggregation energy.

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16
Q

What is the critical attribute of a solution based pMDI?

A

Diameter of the actuator orifice, which determines MMAD.

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17
Q

The amount of dose emitted from a solution based pMDI is directly related to what?

A

The solubility of the drug.

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18
Q

Why are suspension based pMDI often preferred?

A

More chemically stable.

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19
Q

What is the key attribute of suspension based pMDIs?

A

The jet diameter and actuator orifice play a key role in plume geometry.

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20
Q

In what type of pMDI formulation would SPAN 85 be found?

A

Suspension based. Surfactant. oleic acid and soya lecithins to maintain suspension stability.

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21
Q

Why do plastic coated glass vials often need to be used for solution based pMDI?

A

The polar co-solvent can cause corrosion of aluminum can.

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22
Q

What are the key differences in excipients between solution and suspension based pMDIs?

A

Solution: ethanol (Non-volatile: ethanol and glycerol)
Suspension: ethanol and a range of different surfactants (SPAN85), Oleic acid, soya lecithins.

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23
Q

What effect can the co-solvent have on a solution based formulation?

A

Co-solvent: relatively non-volatile and hence lowers the internal propellant pressure, this atomisation is less effective.

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24
Q

Why are fewer and fewer pharmaceutical companies formulating NCEs in pMDIs? [3]

A
  1. CFC –> HFA difficulties in formulation.
  2. Less IP protection, generics are common.
  3. More patient compliance issues vs DPIs.
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25
Q

The magnitude of the vdW force is dependent upon: [2]

A

The surface energy of the two materials + the contact geometry of the interacting surfaces.

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26
Q

Within what distances and at what force does the vdW interaction act?

A

10-100nm.

10nN-100nN.

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27
Q

What are electrostatic forces? [4]

A
  1. long-range
  2. either attractive or repulsive.
  3. charge can build up and dominate particle interactions for for highly insulate materials.
  4. Once formulated, charged materials generally lose charge over days, weeks or even months.
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28
Q

What is the key physical property that can be modified to influence the resulting force of interaction between particles?

A

The geometry between contiguous surfaces. As vdW is short range, increasing the distances between two surfaces to >200nm results in significantly reduced vdW force.

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29
Q

The fine particle delivery of a therapeutic drug can be manipulated by modifying the properties of the carrier, lactose. Discuss two possible ways in which lactose can be modified to increase the fine particle delivery of a drug.

A
  1. Lactose fines: Similar in size to micronised particles, shown to fill the active sites only: allowing the drug to occupy passive sites. The active sites are areas where particle adhesion is high and the probability of removing particles is low.
  2. Changing the surface roughness in order to manipulate the forces.
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30
Q

What is the purpose of an inertial impactor?

A

Allows in-vitro testing/estimation of the fine particle dose of an orally inhaled product.

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31
Q

When are intertial impactors typically used?

A

During product development, they are the main quality control test for the release of orally inhaled drug products.

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32
Q

What types of inertial impactors exist?

A
  1. Multi-Stage Liquid Impinger (MSLI).
  2. Andersen cascade impactor (ACI)
  3. Next Generation Impactor (NGI): specifically designed for pharma industry.
33
Q

Inertial impactors are typically arranged in a cascade (multi-staged) and range from a minimum of 2 stages up to 8 stages. Each stage separates particles according to what?

A

Each stage separates particles according to their aerodynamic particle cut-off diameter.

34
Q

How does direct quantification of the fine particle mass, mass median aerodynamic diameter and the geometric standard deviation of the particle distribution occur?

A

Upon collection of the aerosol particles onto the relevant stages of an inertial impactor, chemical analysis of the appropriate mass of the drug material is quantified on each stage.

35
Q

What is the normal flow rate range of an inertial impactor?

A

30-90L/min

36
Q

What types of particles have high inertia and will continue to move in the same direction, impacting the impacting surface?

A

The higher the mass the higher the inertia. The lower the mass, the lower the inertia.

37
Q

What influence does the narrow jet diameters found in inertial impactors have on the innate inertial properties of particles?

A

Aerosol laden air is directed towards a series of jets which increases the inertial properties of the aerosol particles as they exit the narrow jet diameter.

38
Q

How can we use an inertial impactor to determine ranges of cut-off diameters?

A

We can change the number of jets (n), the jet diameter (W) and the impactor stage separation (S).

39
Q

What are the main patient usability issues associated with pMDIs? [8]

A
  1. Failure to remove cap
  2. Failure to shake prior to use.
  3. Breathing out during actuation.
  4. Incorrect position in mouth.
  5. Slow inhalation
  6. Forgetting to continue to inhale.
  7. Forgetting to hold breath for ~5s
  8. Failure to exhale slowly.
40
Q

How can the patient usability issues associated with pMDIs be overcome? [3]

A
  1. Improved patient counselling by GPs and Pharmacists on how to correctly use each inhaler.
  2. spacer devices.
  3. Breath actuated inhalers.
41
Q

What are the main issues associated with the re-formulation of CFC driven pMDIs to HFA pMDIs? [5]

A
  1. Polarity of HFAs is lower than that of CFCs.
  2. Conventional surfactants are insoluble in HFAs.
  3. HFAs affect conventional valve elastomers.
  4. The design of the actuator is more critical with HFAs.
  5. Different HFAs have different physiochemical properties.
42
Q

What are some of the different physiochemical properties of different HFAs? [5]

A
  1. Hygroscopic differences.
  2. Differences in density.
  3. Higher vapour pressure
  4. Solubility differences.
  5. Volatility difference.
43
Q

What is the mode of action of a liquefied propellant in a pressured metered dose inhaler?

A

Unlike compressed gas propellant, liquefied propellants maintain the same equilibrium pressure after some of the liquid propellant has expired. Compressed gas have a gradual drop in atomisation efficacy.

44
Q

How is the spray formed from a typical pMDI? [5]

A
  1. Patient presses down can, which opens a channel between the metering chamber and atmosphere.
  2. Propellant starts to boil in the expansion chamber.
  3. Shearing forces produce ligaments.
  4. Propellant droplets form at actuator nozzle: ‘2-phase gas-liquid air-blast’.
  5. Propellant droplets are expelled, evaporate and cool.
45
Q

What are the major advantages in the use of pMDIs for inhalation therapy? [6]

A
  1. Consistent delivery of aerosol dose.
  2. Relatively cheap.
  3. Moisture resistant.
  4. Compact.
  5. Available for all drugs.
  6. Capital cost for market entry is lower than multi-dose DPIs.
46
Q

What are the major disadvantages in the use of pMDIs for inhalation therapy? [7]

A
  1. Patient co-ordination and force is required to actuate.
  2. Cold Freon effect.
  3. Tail off of effectivness towards end of a can.
  4. Varying deposition in the airways.
  5. Force of aerosol spray varies.
  6. Large amount of deposition in the throat.
  7. Minimum amounts of IP protection.
47
Q

What is the cold freon effect?

A

The “cold freon” effect (the initial reaction to the cold blast of MDI propellant on the back of the throat) can often result in the patient aborting the inhalation process and hence receiving inconsistent delivery to the lungs

48
Q

What are the major advantages in the use of passive dry powder inhaler devices (DPI)? [6]

A
  1. Inspirationally flow driven inhalers.
  2. Automatically breath-actuated.
  3. Relatively easy to use.
  4. Patient and environmentally friendly.
  5. Long-term replacement of pMDIs.
  6. Better IP protection for products.
49
Q

To target the bronchioles a particle should be what size?

A

5um

50
Q

To target the alveoli a particle should be what size?

A

2um

51
Q

What are the free forms of inhaler device?

A

pMDI
DPI
Nebuliser

52
Q

What are the two types of nebuliser available?

A

Pneumatic

Ultrasonic

53
Q

What is a spacer?

A

The spacer adds space in the form of a tube or “chamber” between the canister of medication and the patient’s mouth, allowing the patient to inhale the medication by breathing in slowly and deeply for five to 10 breaths.

54
Q

What are the issues with Nebulisers?

A

Up to 2/3 drug left in the device, 2/3 lost during expiration, many particles too large/small.

Many nebs deliver as little as 10% of the target dose.

55
Q

What are pneumatic nebulisers?

A

Dominant system pre 2000
Two fluid nozzle
Components: disposable unit, compressor, interfaces, valves/holding chamber.

56
Q

What are the pros of pneumatic nebulisers?

A

Cheap

Small particle sizes

57
Q

What are the cons of pneumatic nebulisers?

A

Variable performance: between and within devices.
Dead volume
Lower output
Not portable

58
Q

What is a nebuliser?

A

A nebuliser is a machine to deliver asthma medication by turning it into a mist to be inhaled through a face mask or mouthpiece. A nebuliser may be used for high doses of asthma reliever medicines in an emergency.

59
Q

How does a pneumatic nebuliser work?

A

Therefore, a pneumatic nebulizer is literally an instrument for converting a liquid into a fine spray that uses a gas as the driving force.

60
Q

What is an ultrasonic nebuliser?

A

Sound can be used instead of a gas as the energy source for converting a liquid to a mist. These nebulizers use an ultrasonic generator at a frequency of between 200 kHz and 10 MHz to drive a piezoelectric crystal. A pressure is produced that breaks the surface of the liquid - air interface. Ultrasonic nebulizers are more expensive and difficult to use but they will improve (lower) detection limits by about a factor of 10.

61
Q

What are the two theories behind how aerosol droplets are produced in ultrasonic nebulisers?

A

Taylor instability: capillary standing wave crest breaks from the surface of the solution

Cavitation: hydraulic shock of imploding cavitation bubbles.

62
Q

What are the pros of an ultrasonic nebuliser? [5]

A 
Reproducible
Small particle size: 1-6 microns
High output
Small and quiet 
Low aerosol inertia
63
Q

What are the cons of an ultrasonic nebuliser? [4]

A

Size increase of particles at end of device life/fill volume dependence.
Expensive
Heats the solution to ~40*C
Not good for suspensions

64
Q

What are some examples of modern nebulisers?

A

eflow
i-neb
aeroneb
micro-air

65
Q

What are SMIs/LDIs?

A

Smart Mist Inhalers/ Liquid Dose Inhalers
Emerging class of inhalers that are based on the drug being dissolved in a non-volatile liquid (usually water).
Volumetric dosing - comparable to pMDIs
Aerosolized in a single breath actuation
Requires tight control of droplet size via a mechanism within the device.
Aerosol is emitted as a slow moving cloud.

66
Q

From what type of device is the aerosol emitted as a slow moving cloud?

A

Smart Mist Inhaler/ Liquid Dose Inhaler

67
Q

What is an emerging class of inhalers that are based on the drug being dissolved in a non-volatile liquid (usually water)?

A

Smart Mist Inhalers/ Liquid Dose Inhalers
Emerging class of inhalers that are based on the drug being dissolved in a non-volatile liquid (usually water).
Volumetric dosing - comparable to pMDIs
Aerosolized in a single breath actuation
Requires tight control of droplet size via a mechanism within the device.
Aerosol is emitted as a slow moving cloud.

68
Q

What is AERx LDI?

A

Novel, handheld, air-jet driven neb system.
Utilises an electromechanical actuator to extrude drug, contained in unit dose liquid blisters of 50micoL, through an array of small micron sized holes.
It produces a uniformly fine aerosol for inhalation.
It uses microelectronics to guide the patient into the optimum inspiratory flow rate for actuation and delivery.

69
Q

What is the Respimat system?

A

The drug solution is forced through a micro nozzle assembly as the patient inhales.

70
Q

In what device is an electromechanical actuator utilised to extrude the drug, which is contained in unit dose liquid blisters, through an array of micron sized holes?

A

The AERx LDI.
Novel, handheld, air-jet driven neb system.
Utilises an electromechanical actuator to extrude drug, contained in unit dose liquid blisters of 50micoL, through an array of small micron sized holes.
It produces a uniformly fine aerosol for inhalation.
It uses microelectronics to guide the patient into the optimum inspiratory flow rate for actuation and delivery.

71
Q

For DPI, what is the inter-relationship between device and airflow?

A

The internal resistance of the device affects the speed and acceleration of airflow through the device.

The acceleration of the airflow affects the DPI device efficacy.

The speed of inhalation affects how much drug is deposited in the lungs,

72
Q

The delivery of respirable doses from DPI is dependant on what three interdependent factors?

A
  1. Powder formulation
  2. Inhalation device
  3. Patient’s inspiratory flow
73
Q

Particle interactions are primarily dictated by what?

A

van der Waals Forces
Electrostatic Forces
Capillary forces

74
Q

What types of interactions do we need to control and modify?

A

Cohesion: Drug - Drug interactions
Adhesion: Drug - Excipient interactions
Segregation: Drug - Device interactions

75
Q

What are the two main formulation strategies for dry powder aerosols?

A 
Carrier-based systems (adhesive bonds)
Agglomerated systems (cohesive bonds)
76
Q

What are the advantages of blending a drug with a carrier?

A
  1. Allows accurate metering of small quantities of potent drug
  2. Improves handling and processing of the formulation.

We can influence the fine particle free fraction size by changing the following carrier properties:
Particle size distribution
Particle habit/shape
Surface morphology

77
Q

How can we influence the fine particle free fraction size?

A

We can influence the fine particle free fraction size by changing the following carrier properties:
Particle size distribution
Particle habit/shape
Surface morphology

78
Q

How do we make sure the drug does not become bound to the active sites? (on the carrier)

A

Use of Fine lactose.
Fine particle lactose (FPL) blending:
Coarse lactose: %FPF = 17.0%
Blend coarse lactose with fine lactose, then blend with the drug: %FPF = 36.4%

Drug particles only become located in low energy sites where they are easily released from.

79
Q

When are agglomerated powder systems used?

A

High dose drugs whereby formulation as carrier-based systems is not feasible.

“free flowing” macroscopic agglomerates can be produced via cohesive bond formation.

Efficient deaggregation of agglomerates is required so that the drug is presented to the lungs as discrete particles.

Drug Delivery (11 decks)

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