Metered Dose Inhaler

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FROM AEROSOLS AND METERED DOSE INHALERS

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METERED DOSE INHALER:

METERED DOSE INHALER Presented by: Sumit kumar mittal M.Pharma(2 nd sem) Department of Quality Assurance I.S.F. College of Pharmacy(Moga)

I shall discuss::

I 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:

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::

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::

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 :

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 Cilla Mucociliary blanket Airway Columnar epithelium

Metered Dose inhalers:

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:

Metered Dose inhalers Pressure resistant container Liquid solution or suspension Metering chamber Valve stem Air inlet Spray jet Actuator Mouthpiece

Mainly two types of systems are available:

Mainly two types of systems are available NONPRESSURIZED SYSTEM (B) PRESSURIZED SYSTEM

NONPRESSURIZED 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:

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:

A. Unit Dose Device SPINHALER ROTAHALER SPINHALER ROTAHALER

B. Multiple Dose device:

B. Multiple Dose device TURBOHALER

B. Multiple Dose device :

B. Multiple Dose device DISCHALER

Formulation:

Formulation Particle size (< 5µm) Blended with large lactose particles PulmoSphere

Manufacturing Process:

Manufacturing Process single dose devices Multi dose dispense discs

Nebulized Drug delivery Systems:

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

Ultrasonic devices:

Ultrasonic devices Ultrasound waves - a ceramic piezoelectric crystal

Air jet nebulizer :

Air jet nebulizer

Nebulizer formulation::

Nebulizer formulation: The pharmaceutical solution technology - parenteral products Formulated in water Co-solvents pH above 5

PRESSURIZED SYSTEM:

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:

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

Drug Concentrate:

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 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 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::

Propellants: Mainly two types Liquefied Compressed gases e.g. CFC (chlorofluorocarbons), HCFC(Hydrochlorofluorocarbons), HFA(hydrofluoroalkanes) Non Liquefied Compressed gases e.g. N 2 , CO 2 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::

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:

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:

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):

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:

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 :

The primary steps for all the methods Hot Air I II III Unscrambler

(1) Cold Filling:

(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 -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 Filling:

Cold Filling Chilled Product Concentrate Chilled Propellant Valve IV V VI

(2) Pressure Filling:

(2) Pressure Filling Product concentrate Valve Low boiling propellant under pressure IV V VI

(3) Under Cap Filling:

(3) Under Cap Filling Propellant filling Product concentrate IV V VI

The Terminal Procedure:

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:

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 :

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:

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:

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:

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:

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. 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:

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:

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:

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 ::

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 ::

AERx® SYSTEM :

ADAPTIVE AEROSOL DELIVERY TECHNOLOGY :

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 :

ADAPTIVE AEROSOL DELIVERY TECHNOLOGY

SPIROS INHALER TECHNOLOGY : (DURA PHARMA):

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 : :

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 ::

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.

ELECTRONIC DPI FOR INSULIN ::

ELECTRONIC DPI FOR INSULIN :

APPLICATION OF MDI IN SYSTEMIC MEDICATION :

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:

APPLICATION OF MDI IN SYSTEMIC MEDICATION β 2- Adrenoreceptor Agonist Salbutamol Buxaterol Soterenol Fenoterol Isoprenalin Anticholinergic drugs Atropin Ipratropium bromide Antihistaminics Astemizol Cetirizin Levocarbastin

Market formulations:

Market formulations Drug 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

DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS:

DIFFICULTIES ASSOCIATED WITH COMPOUNDING METERED-DOSE INHALERS Difficulties in Compounding Drug Delivery System Sophisticated and complex Crucial to drug dosing accuracy and reproducibility Direct effect on potency, purity, and quality Indirectly affects safety and effectiveness

Difficulties in Compounding:

Difficulties in Compounding Testing Examples of complex tests necessary to ensure product quality: Particle size distribution Moisture content Leak rate Leachables Microbial limits

Difficulties in Compounding:

Difficulties in Compounding Testing Particle size distribution - Cascade impactor More critical for MDIs Not solely determined by initial drug substance particles Critical independent variables - complex -Formulation -Valve -Mouthpiece Inability to meet particle size distribution specifications has resulted in product recalls

Difficulties in Compounding:

Difficulties in Compounding Testing Moisture Content Most critical for MDI suspension formulations Strict limits needed to prevent changes Particle size distribution Morphic form Crystal growth and aggregation Leak Rate Affects internal canister pressure Influences performance of actuator and valve Delivery of the proper dose to the patient Leakage may influence formulation composition Change particle size distribution and/or dose content uniformity Failure to meet specifications have resulted in product recalls

Difficulties in Compounding:

Difficulties in Compounding Testing Leachables Compounds extracted into formulation from Elastomers Plastic components Requires identification and quantitation Concentration profile established Make evident undisclosed changes

Difficulties in Compounding:

Difficulties in Compounding Testing Microbial Limits Total aerobic count Total yeast and mold count Freedom from pathogens Additional testing is necessary for product development -Ensure formulation does not support microbial growth -Microbial quality is maintained throughout the expiration dating period

Conclusion:

Conclusion Because of the above complex and necessary criteria for compounding, MDI drug products present demonstrable difficulties in this endeavor. These difficulties would likely have an adverse effect on the safety and effectiveness of such drug products.

References::

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::

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::

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

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