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

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.

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.

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 Columnar epithelium The mucous blanket Various proteins Nasal pH Cilla Vascularity
Mucociliary blanket

Airway

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 inhalers

Pressure resistant container

Liquid solution or suspension

Metering chamber

Valve stem Actuator Mouthpiece Spray jet

Air inlet

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 (1520%) evaporated and droplets are broken up by the violent evaporation generating droplets with wide distribution (1-5m). 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 cosolvents 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

Its 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 (< 5m) Blended with large lactose particles PulmoSphere

Manufacturing Process
single 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 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.

PRESSURIZED SYSTEM
Consists of five basic components :
Drug concentrate Liquefied propellant Container Metering valve Actuator

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

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.

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

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

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

Metering Valves
Function Complex assembly The valve for suspension products The typical metering valve

At rest

During Actuation Discharging

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

Unscrambler

Hot Air

II

III

(1) Cold Filling

The cold filling method is restricted to nonaqueous 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.

Cold Filling
Chilled Product Concentrate Chilled Propellant Valve

IV

VI

(2) Pressure Filling

Low boiling propellant under pressure Product concentrate Valve

IV

VI

(3) Under Cap Filling

Propellant filling

Product concentrate

IV

VI

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.

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.

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

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 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.

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 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.

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 microprocessorcontrolled 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 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.

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 DPI Pulmonary insulin delivery requires a particle diameter of 3.3 m 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 MEDICATION

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

Market formulations
Drug Salbutamol Brand name Asthalin inhaler(200MD, 400 MD) Vent Easecaps (dry powder inhalant) Terbutaline Fluticasone propionate Bricanyl inhaler/ misthaler Seretide Accuhaler Company Cipla Kresp Astra zeneca Glaxo

Isoprenaline
Salmeterol Salbutamol+Becometha sone dipropionate

Autohaler
Salmeter inhaler Aerocort inhaler

Cipla
Dr.Reddy Cipla

Beclomethasone Dipropionate
Budesonide

Beclate inhaler (200MD,400MD)

Budecort inhaler

Cipla
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