METERED DOSE INHALER

1
METERED DOSE INHALER
Presented by Aarohi Shah M.Pharam
Department of Pharmaceutics and Pharmaceutical
Technology L.M. College of Pharmacy
2
We shall discuss

• Advantages of Nasal Route as systemic delivery
• Limitations
• Anatomy of respiratory tract
• Metered Dose inhalers design
• NONPRESSURIZED SYSTEM
• PRESSURIZED SYSTEM
• Manufacturing of Inhalers
• Novel Excipients for Inhalation Drug Delivery
• Evaluation of MDI as per FDA
• Recent innovation in MDI Technology
• Application of MDI in Systemic Medication
• Market formulations
• References

3
Introduction

• The first nasal administration of drugs was
  primarily employed for local drug effects.
• The potential nasal route for systemic delivery
  was discovered after the observation that nasally
  administered sympathomimetic and antihistaminic
  drug for local action has significant systemic
  effects.
• Nasally administered small dose display a rapid
  absorption that is comparable to intravenously
  administered drugs.

4
Advantages of Nasal Route as systemic delivery
are

• A non-invasive route
• Convenience of administration and amenable to
  chronic self administration
• Avoids first pass metabolism or gastro intestinal
  tract destruction
• A large permeable surface area and rich
  vasculature availability
• Plasma concentration time profile is comparable
  to intravenous administration
• Macromolecules like proteins and peptides can be
  successfully administered.

5
Limitations

• Rapid mucociliary clearance
• Chances of immunogenic reaction
• Inadequate availability of toxicity data for
  penetration enhancement
• Nasal pathology may adversely affect product
  effectiveness

6
Anatomy of respiratory tract

• This must be understood as a tool for formulating
  a potential dosage form as an alternative for
  parenteral route.
• Upper and lower respiratory tract with portals of
  entry being either nose or mouth.
• Airway epithelium
• The mucous blanket
• Various proteins
• Nasal pH
• Vascularity

7
Metered Dose inhalers

• It is composed of four essential components the
  base formulation (Drug, propellant, excipients,
  etc.), the container, the metering valve and the
  actuator (or mouth piece)
• The drug is delivered through a valve in a
  metered volume from a volatile propellant,
  pressurized container.

8
Metered Dose inhalers
9
Mainly two types of systems are available

• NONPRESSURIZED SYSTEM
• (B) PRESSURIZED SYSTEM

10
NONPRESSURIZED SYSTEM

• Micronised drug is dissolved or dispersed in
  liquefied propellant (CFC). Before the propellant
  exits from the atomized nozzle, it is partially
  (15-20) evaporated and droplets are broken up by
  the violent evaporation generating droplets with
  wide distribution (1-5µm).
• But due to alarms raised for stratospheric ozone
  depletion, a more environment friendly
  substitutes like Hydrofluoroalkane (HFA) came in
  light. They have the limitation of poor solvency
  which can be overcome by addition of co-solvents
  like ethanol.
• Some patients cannot fulfill the co-ordination
  requirements which is essential for maximum
  therapeutic benefits, breath actuated powder
  inhalers are developed.

11
Powder Delivery System

• Its a versatile system require some degree of
  dexterity.
• It is ozone friendly system requires no CFC to
  disperse the drug.

12
A. Unit Dose Device

• SPINHALER
• ROTAHALER

SPINHALER
ROTAHALER
13
B. Multiple Dose device

• TURBOHALER

14
B. Multiple Dose device
DISCHALER
15
Formulation

• Particle size (lt 5µm)
• Blended with large lactose particles
• PulmoSphere

16
Manufacturing Process

• single dose devices
• Multi dose dispense discs

17
Nebulized Drug delivery Systems

• For acute care of nonambulatory, hospitalized
  patients particularly with co-ordination
  difficulties.
• Not conveniently portable
• Solutions or suspensions

18
Ultrasonic devices

• Ultrasound waves - a ceramic piezoelectric
  crystal

19
Air jet nebulizer
20
Nebulizer formulation

• The pharmaceutical solution technology -
  parenteral products
• Formulated in water
• Co-solvents
• pH above 5

21
PRESSURIZED SYSTEM

• Compact pressurized dispensers designed for oral
  use, which deliver discrete doses of aerosolized
  medicament by inhalation to the lungs.
• The discharged spray undergoes flash evaporation
  of propellant liquid to produce a finely
  dispersed aerosol.
• The deposition, dependent on the mass of inhaled
  drug particles which have a suitably small
  aerodynamic size to be deposited in the required
  regions of the lungs.
• MDIs are apparently simple delivery dosage
  devices, but in practice very complex.

22
PRESSURIZED SYSTEM

• Consists of five basic components
• Drug concentrate
• Liquefied propellant
• Container
• Metering valve
• Actuator

23
Drug Concentrate

• Drug powders
• Usually suspension, occasionally solution.
• Particle size - below 10 ?m in diameter and
  mostly below 5 ?m.
• The particle size distribution

24
Drug Concentrate

• Drug Suspension
• Aggregate irreversibly and deposit on pack
  surface
• The liquid and solid-phase densities
• Low solubility in the propellant
• Physical stability of the suspension assessed
• Surfactants
• Presence of minute amount of water.

25
Drug Concentrate

• Drug Solution
• When the drug is too soluble in propellant.
• A co solvent is required and it is usually
  ethanol.
• ethanol concentration (30-50 by wt.) - some
  disadvantages
• Retard evaporation of the spray, which
  increases oropharyngeal drug deposition and
  reduce respirable aerosol fraction.
• Chemical instability of drug
• Extraction from valve rubber seal

26
Propellants

• Mainly two types
• Liquefied Compressed gases
• e.g. CFC (chlorofluorocarbons),
  
• HCFC(Hydrochlorofluorocarbons),
• HFA(hydrofluoroalkanes)
• Non Liquefied Compressed gases
• e.g. N2, CO2
• Liquefied compressed gases are preferred over the
  other one because
• Flash evaporation to give aerosol of fine
  particle size.
• Spray particle size remains constant during pack
  emptying as inhaler vapor pressure is maintained
  at constant level. While compressed gas aerosol
  performance coarsens due to decrease in gas
  pressure with increase in head space volume.

27
Propellants

• Currently only three propellants are approved
  worldwide for MDI products CFCs 11, 12, and 114
• Now a days, study of propellants of low or zero
  ozone depletion potential (ODP) is increasing.
• e.g., HCFCs 22,142b, and 152a
• Hydrofluroalkanes (HFA) are
  chlorine-free and are judged to have zero ODP.
  HFA-134a is an important promising replacent for
  CFC-12

28
Containers

• Aluminum containers
• They are light, strong, break resistant, compact
  and light proof and significantly inert.
• It is prepared by 2 methods
• (1) Rapid impact slugging
• (2) Precision deep-drawing Uniform
  wall thickness, greater strength.
• The cans should be capable of withstanding
  internal pressure of at least 1000kPa (150 psig)
  without evident distortion.
• Glass bottles
• Plasticized PVC non bonded coating

29
Metering Valves

• Function
• Complex assembly
• The valve for suspension products
• The typical metering valve

30
Actuators (Adapter)

• Discharge orifice (spray nozzle) and a socket to
  engage and form a seal with metering valve stem.
• A remarkable variety of actuator designs. But,
  original band tube arrangement with a separate
  mouthpiece cap remains predominant.
• Spacer
• The problem of poor patient co-ordination may
  also be reduced by using breath actuated
  inhalers, which are activated by the vacuum
  induced in the inhaler by an adequate inhalation
  flow rate.

31
Manufacturing of Inhalers

• Mainly 3 methods
• (1) Cold Filling
• (2) Pressure Filling
• (3) Under Cup Filling
• Low atmospheric relative humidity should be
  maintained in filing area in all the methods.

32
The primary steps for all the methods
33
(1) Cold Filling

• The cold filling method is restricted to
  non-aqueous products and to those products which
  are not adversely affected by low temperatures in
  the range of -40F.
• Potential disadvantage include high propellant
  vapor loss, high cost of refrigerator and
  humidity control equipment, a possible induction
  of nonreversible induction of physical changes in
  formulation.

34
Cold Filling
35
(2) Pressure Filling
36
(3) Under Cap Filling
37
The Terminal Procedure

• The containers pass through heated water bath
  heated at 130F to test for leak and strength of
  container.
• The containers are then air dried, capped and
  labeled.

38
Novel Excipients for Inhalation Drug Delivery

• Goals
• To expand the range of compound
• To increase the clinical benefits obtained from
  MDI by providing new capabilities like sustained
  release or greater respirability.
• Three primary Application
• (1) Suspension aids to increase the
  number of compounds that can be prepared as high
  quality suspensions.
• (2) Solubilizers to enable solution
  formation at high doses.
• (3) Sustained release agents to
  enhance lung residence time of the compound.

39
Evaluation of MDI as per FDA

• Appearance of container and closure system
• Microbial Limits
• Water or Moisture Content
• Dehydrated Alcohol Content
• Net Content (Fill) Weight
• Drug Content (Assay)
• Impurities and Degradation Products
• Dose Content Uniformity
• Particle Size Distribution
• Spray Pattern
• Plume Geometry
• Leak Rate
• Pressure Testing
• Valve Delivery (Shot Weight)
• Leachables

40
Particle droplet size analysis

• Influence on
• High speed flash photography and halography
• Laser diffraction size analysis
• Phase Droplet Anemometer.
• Microscopic analysis with an image analyzer
• Cascade Impactor

41
Particle droplet size analysis

• Single Particle Optical Sizers (SPOS)
• Disadvantages
• Drug particles are not distinguished from
  excipients.
• Sampling may not be representative of the whole
  sample.
• Assumption the particles are spherical and of
  equal density.
• Light Scattering Counters

42
Spray pattern

• Allows the cross sectional uniformity of the
  spray to be determined at specified distances
  away from the pump orifice tip.
• In past FDA recommended with impaction on TLC
  plates and manual interpretation of spray
  pattern.
• FDA2003 draft non impaction method based on
  laser sheet and digital camera using electronic
  images and automated analysis.

43
Plume Geometry

• Side view parallel to the axis of the plume of
  the spray or aerosol cloud to be determined.
• In the past, the FDA recommended that plume
  geometry could be characterized in terms of plume
  angle, plume width, and plume height using
  high-speed flash photography.
• FDAs 2003 draft laser sheet and high-speed
  digital camera with electronic images.
• ImageTherm Developed a SprayVIEW system to
  simplify the spray and plume geometry.
• Plume geometry and spray pattern measurement
  using SprayVIEW for an aqueous nasal spray.

44
Reproducibility of Valves

• 5 cans are selected from 100 cans supplied.
• Actuator is kept in place and container is
  weighed accurately to 0.5 mg.
• The valve is actuated once, container is
  reweighed and weight loss is recorded.
• Single actuations are repeated and weight loss is
  measured each time. The time interval between
  each individual actuation is recorded.
• The regions required to be evaluated are of
  initial actuations and actuations when aerosol
  container was approximately 10, 30, 50, 70, 95
  empty.
• All actuations are performed with cans in
  inverted position.

45
Loss of prime

• It is defined as valve delivery 15 below the
  mean.
• Onset of loss of prime is shown to be dependent
  on valve design as well as storage position.
• Aerosol is weighed to the nearest milligram
  before actuation.
• Aerosol can is placed in inverted position and
  press the actuator button for 3 seconds to ensure
  delivery of full dose.
• Let the unit stand at room temperature for 1
  minute to allow complete evaporation of
  propellant and the can is reweighed.
• Valve delivery for actuation number 5 is
  considered as representative of the delivery from
  a fully primed metered dose valve.

46
Recent innovation in MDI Technology

• Research on area of formulations, valves,
  canisters, elastomers, mouthpieces, etc.
• Other Improvements includes,
• Breathe-actuation technology
• Ability to deliver therapeutic proteins and
  peptides
• Sustained drug delivery
• Improved shelf life

47
AERx SYSTEM

• Sophisticated technology in order to provide
  precise dosing which includes,
• Controlled dose expression
• Control of aerosol particle size
• Management of the inhalation and delivery
• Inhalation and delivery coordination is optimized
  through a microprocessor-controlled flow sensing
  system that actuates delivery only at the
  beginning of the inspiration and within the
  correct inspiratory flow rate.

48
AERx SYSTEM
49
ADAPTIVE AEROSOL DELIVERY TECHNOLOGY

• Adapts to the patients breathing and ensures
  accurate drug delivery. Detects pressure changes
  during breathing and constantly adapt to the
  inspiratory and expiratory flow pattern of the
  patient.
• AAD systems deliver drug until all the
  preprogrammed dose has been received and gives
  audible feedback at the completion of treatment,
  irrespective of the time taken.

50
ADAPTIVE AEROSOL DELIVERY TECHNOLOGY
51
SPIROS INHALER TECHNOLOGY (DURA PHARMA)

• Small handheld, breath-actuated, battery operated
  system.
• The high speed rotating impeller provides
  mechanical energy for dispensing.
• The Spiros DPI blisterdisk powder storage system
  designed for potentially moisture sensitive
  substance,(protein.peptides)
• Clinical trials through phase-3 has been
  completed for Albuterol sulfate and
  Beclomethasone diproprionate.
• Next generation model of this system is Spiros S2
  which is motorless, cost effective, easy to use
  and for both unit dose and multidose system

52
RESPIMAT A NEW SOFT MIST INHALER

• Patented mechanism of generating a soft fine mist
  from dosed volume of drug solution
• It uses simply mechanical energy
• Delivers multiple doses without propellants

53
ELECTRONIC DPI FOR INSULIN

• 1st completely electronic DPI
• Pulmonary insulin delivery requires a particle
  diameter of 3.3 µm or less. This is achieved by
  spray drying process.
• Here in first step, the drug is aggeregated in
  aluminum blister and then in 2nd step, high
  frequency piezo vibrator deaggregates the powder
  in primary particles but still in blister and
  then in 3rd step, deaggregated particles
  circulates the top of blister which is then
  forced through pierced hole to air stream.

54
ELECTRONIC DPI FOR INSULIN
55
APPLICATION OF MDI IN SYSTEMIC MEDICATION

• Analgesics
• Butorphenol
• Enkephalins
• Buprenorphine
• Cardiovascular drugs
• Dobutamine
• Angiotensin II antagonist
• Endocrine Hormones
• Human Growth Hormones
• Calcitonin
• Luteinizing Hormone-Releasing Hormone
• Insulin

56
APPLICATION OF MDI IN SYSTEMIC MEDICATION

• ß2- Adrenoreceptor Agonist
• Salbutamol
• Buxaterol
• Soterenol
• Fenoterol
• Isoprenalin
• Anticholinergic drugs
• Atropin
• Ipratropium bromide
• Antihistaminics
• Astemizol
• Cetirizin
• Levocarbastin

57
Market formulations
58
References

• Controlled Drug Delivery Concept and Advances by
  S.P. Vyas and Roop K. Khar Pg. 315 382.
• Drugs and the Pharmaceutical Sciences Nasal
  Systemic Drug Delivery, Volume 39 by Chien, Su
  and Chang.
• Encyclopedia of Pharmaceutical Technology Volume
  9 Metered dose Inhalers Non pressurized
  systems pg. 287 298
• Encyclopedia of Pharmaceutical Technology Volume
  9 Metered dose Inhalers Pressurized systems
  pg. 299-329
• The theory and practice of Industrial Pharmacy
  Leon Lachman Third edition Pg. 589 618.
• Remington The science and Pharmaceutical
  Pharmacy 20th Edition volume I pg. 963-979.

59
References

• Test for reproducibility for metered dose aerosol
  valves for Pharmaceutical solutions A. Cutie, J.
  Burger, C. Clawns Journal of Pharmaceutical
  Science Volume 70 No. 9 September 1981, pg.
  1085-1087.
• Test method for evaluation of loss of prime in
  metered dose aerosol Eugene F., William G.
  journal of Pharmaceutical Science Volume 77 No.
  1 January 1988, pg. 90-93.
• www.fda.gov/cdere/guidance/2180dft.htm
• Encyclopedia of Pharmaceutical Technology Volume
  8 Intranasal Drug Delivery pg.175-201.
• Encyclopedia of Pharmaceutical Technology Volume
  7 Hydrocarbons, pharmaceutical uses pg 161-180.

60
References

• www.disprod.co.za
• www.astrazeneca.no
• www.zaversky.at
• www.training.seer.cancer.gov
• www.pharmatech.com

61
Thanks for listening