METERED DOSE INHALER

Presented by:

Aarohi Shah

M.Pharam

Department of Pharmaceutics and Pharmaceutical Technology

L.M. College of Pharmacy

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

IntroductionThe 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.

Advantages of Nasal Route as systemic delivery are:

A non-invasive routeConvenience of administration and amenable to chronic self administrationAvoids first pass metabolism or gastro intestinal tract destruction A large permeable surface area and rich vasculature availabilityPlasma concentration time profile is comparable to intravenous administrationMacromolecules like proteins and peptides can be successfully administered.

Limitations:

Rapid mucociliary clearance

Chances of immunogenic reaction

Inadequate availability of toxicity data for penetration enhancement

Nasal pathology may adversely affect product effectiveness

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 proteinsNasal pH Vascularity Cilla

Mucociliary blanket

AirwayColumnar epithelium

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.

Metered Dose inhalersPressure resistant container

Liquid solution or suspension

Metering chamber

Valve stem

Air inlet

Spray jet

Actuator Mouthpiece

Mainly two types of systems are available

(A)NONPRESSURIZED SYSTEM

(B) PRESSURIZED SYSTEM

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.

Powder Delivery System

It’s a versatile system require some degree of dexterity.

It is ozone friendly system requires no CFC to disperse the drug.

A. Unit Dose Device

SPINHALER

ROTAHALER

SPINHALER ROTAHALER

B. Multiple Dose device

TURBOHALER

B. Multiple Dose device

DISCHALER

Formulation

Particle size (< 5µm)

Blended with large lactose particles

PulmoSphere

Manufacturing Processsingle dose devices Multi dose dispense discs

Nebulized Drug delivery Systems

For acute care of nonambulatory, hospitalized patients particularly with co-ordination difficulties.

Not conveniently portable

Solutions or suspensions

Ultrasonic devices

Ultrasound waves - a ceramic piezoelectric crystal

Air jet nebulizer

Nebulizer formulation:

The pharmaceutical solution technology - parenteral products

Formulated in water

Co-solvents

pH above 5

PRESSURIZED SYSTEMCompact 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.

PRESSURIZED SYSTEM

Consists of five basic components :– Drug

concentrate– Liquefied

propellant– Container– Metering valve– Actuator

Drug Concentrate

Drug powdersUsually suspension, occasionally solution.

Particle size - below 10 m in diameter and mostly below 5 m.

The particle size distribution

Drug ConcentrateDrug 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.

Drug Concentrate

Drug SolutionWhen 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

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.

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

ContainersAluminum containersThey 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

Metering ValvesFunction

Complex assembly

The valve for suspension products

The typical metering valve

At rest During ActuationDischarging

During release

Chamber refilling

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.

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.

The primary steps for all the methods

Hot Air

I II III

Unscrambler

(1) Cold FillingThe 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 -40°F.

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.

Cold FillingChilled Product Concentrate

Chilled PropellantValve

IV V VI

(2) Pressure Filling

Product concentrateValve

Low boiling propellant under pressure

IV V VI

(3) Under Cap Filling

Propellant filling

Product concentrate

IV V VI

The Terminal Procedure

The containers pass through heated water bath heated at 130°F to test for leak and strength of container.

The containers are then air dried, capped and labeled.

Novel Excipients for Inhalation Drug Delivery

Goals :To expand the range of compoundTo 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.

Evaluation of MDI as per FDA

Appearance of container and closure systemMicrobial LimitsWater or Moisture ContentDehydrated Alcohol ContentNet Content (Fill) WeightDrug Content (Assay)Impurities and Degradation ProductsDose Content UniformityParticle Size DistributionSpray PatternPlume GeometryLeak RatePressure TestingValve Delivery (Shot Weight)Leachables

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

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

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.

FDA`2003 draft : non impaction method based on laser sheet and digital camera using electronic images and automated analysis.

Plume GeometrySide 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.FDA’s 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.

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.

Loss of primeIt 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.

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

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.

AERx® SYSTEM :

ADAPTIVE AEROSOL DELIVERY TECHNOLOGY

Adapts to the patient’s 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.

ADAPTIVE AEROSOL DELIVERY TECHNOLOGY

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

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

ELECTRONIC DPI FOR INSULIN :

1st completely electronic DPIPulmonary 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.

ELECTRONIC DPI FOR INSULIN :

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

APPLICATION OF MDI IN SYSTEMIC MEDICATIONβ2- Adrenoreceptor Agonist• Salbutamol• Buxaterol• Soterenol• Fenoterol• Isoprenalin

Anticholinergic drugs• Atropin• Ipratropium bromide

Antihistaminics• Astemizol• Cetirizin• Levocarbastin

Market formulationsDrug Brand name Company

Salbutamol Asthalin inhaler(200MD, 400 MD)

Cipla

  Vent Easecaps(dry powder inhalant)

Kresp

Terbutaline Bricanyl inhaler/ misthaler Astra zeneca

Fluticasone propionate Seretide Accuhaler Glaxo

Isoprenaline Autohaler Cipla

Salmeterol Salmeter inhaler Dr.Reddy

Salbutamol+Becomethasone dipropionate

Aerocort inhaler Cipla

Beclomethasone Dipropionate

Beclate inhaler (200MD,400MD)

Cipla

Budesonide Budecort inhaler Cipla

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.

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.

References:

• www.disprod.co.za

• www.astrazeneca.no

• www.zaversky.at

• www.training.seer.cancer.gov

• www.pharmatech.com