FORMULATION AND PRODUCT DEVLOPMENT OF PRESSURISED METERED DOSE INHALER: AN OVERVIEW

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ABOUT AUTHORS:
*S R Thorat1, S M Meshram2
1Lupin Research Park, Hinjewadi, Pune, Maharashtra
2TATA Consultancy Services, Hinjewadi, Pune, Maharashtra
santoshthorat345@gmail.com

ABSTRACT
Pressurized metered dose inhalers (MDIs) are widely used dosage form for treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease. The metered dose inhaler (MDI) contains the active pharmaceutical ingredient dispersed or solubilised in a high vapour pressure propellant and metered accurately in tens to hundreds of micrograms and administered directly to the lungs. The most dominant characteristics of MDI include their portability, convenience of use and quick effect. MDI comprises of drug formulation, propellant, metering valve, actuator, and container. This review contains overview of excipient selection, primary packaging material, propellant selection and formulation development of pMDI. Two of the most commonly used methods for the manufacturings of MDIs are cold filling method and pressure filling method.This review demonstrates different analytical techniques for characterization of pMDI’s like uniformity of delivered dose, water content, spray pattern and plume geometry were discussed. This review also presents in-vitro characterization, pharmacokinetic and pharamcodynamic study of MDI.

REFERENCE ID: PHARMATUTOR-ART-2361

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 3, Issue 9

Received On: 17/05/2015; Accepted On: 22/05/2015; Published On: 01/09/2015

How to cite this article: SR Thorat, SM Meshram; Formulation and product development of pressurised metered dose inhaler: An overview; PharmaTutor; 2015; 3(9); 53-64

INTRODUCTION
Pulmonary delivery is used from ancient times in the delivery of drug for both local and systemic drug delivery. The inhaled therapies started since 4000 years ago in India, from that time leaves of the atropa belladonna plant smoke, aromatic plants are used to treat cough and other respiratory disorders. Pulmonary drug delivery is mainly used in the treatment of asthma, cystic fibrosis and COPD. It minimizes systemic side effects, required small dose and provides fast response.[1]

The inhalation therapies involved the use of leaves from plants, vapours from aromatic plants and balsams. Around the turn of the 19th century, the invention of liquid nebulizers as a newer treatment developed into valid pharmaceutical therapies. In 1920 adrenaline was introduced as a nebulizer solution, in 1925 nebulizer porcine insulin was used in investigational studies in diabetes, in 1945 pulmonary delivery of the newly revealed penicillin was investigated. Steroids had been introduced in 1950 in the form of nebulizers for the treatment of asthma. In 1956 the pressured metered dose inhaler (pMDI) was introduced and become the major stay for the asthma treatment. It may found that certain drugs taken by pulmonary route are readily absorbed by the alveolar region direct in to blood circulation because of the some unique physiological characteristics of the respiratory route of drug administration.

Advantages
1. Pulmonary drug delivery requires small fraction of oral dose. (i.e. drug content of one 4 mg tablet of salbutamol equals to 40 doses of meter doses.)
2. It delivers drug locally at low concentration that reaches systemic circulation thus reducing systemic side-effects.
3. Onset of action is very quick with pulmonary drug delivery.
4. It avoid first pass metabolism. (e.g. Budesonide almost completely absorbed from the gastrointestinal tract but its bioavailability is low i.e. about 10% due to extensive first-pass metabolism in the liver).
5. Large surface area around 100 m2 and thin 0.1 to 0.2 µm thickness of pulmonary epithelium increase the permeation of the drug.
6. Bioavailability of larger drug molecules can be improved by means of absorption enhancer.[2]

Disadvantages
1. Oropharyngeal deposition causes local side effect.
2. Patient faces difficulty in using the pulmonary drug devices correctly.
3. The total amount of drug per puff delivered to the lung is too less than 1000 mcg.

Devices for Pulmonary Drug Delivery
There are three main methods of delivering respiratory drugs for most of the asthma patients metered dose inhaler (MDI), dry powder inhaler (DPI) and nebulizers. In case of dry powder inhalers (DPI) active pharmaceutical ingredient (API) powder with or without carrier (e.g. lactose) fine micronized particles are inhaled. The aggregates are converted into an aerosol by inspiratory airflow and this minimizes the problem of coordination between the delivery of the drug and the initiation of inspiration. But it is unsuitable for patients who are unable to generate high inspiratory flow rates. Active drug particles have a typical length-scale of 5 µm, while the carrier particles (usually a form of lactose) have a much wider size distribution. The most common carrier blend, a-lactose monohydrate, has particles ranging between order of magnitude larger and smaller than the active drug particles. This powder is stored within the device in different ways depending on the design.[3]

Nebulizer is a devices used to administer aerosolized medication in the form of a mist inhaled into the lungs. Nebulizer uses oxygen, compressed air or ultrasonic powder to break up medical solutions and suspensions into small aerosol droplet called mists that can be directly inhaled from the mouthpiece of the device. Nebulizers have also many disadvantages such as operation noise especially with jet nebulizers, bulky design, long administration period, unportable, variable performance because of gas flow for jet nebulizers, reservoir volume and drug physicochemical properties such as viscosity for ultrasonic nebulizers. [4]

In the metered dose inhaler (MDI) the API dispersed or solubilised in a high vapour pressure propellant and metered accurately in tens to hundreds of micrograms and administered directly to the lungs. pMDIs are most widely used device for drug delivery to the lungs. With this method, a medication is mixed in a canister with a propellant, and the preformed mixture is expelled in precise measured amounts upon actuation of the device.

Figure 1. Pressurized metered dose inhaler[5]

History:

Table 1. History of Metered dose Inhaler

1956
First MDI “Medihaler” by Riker Laboratories now owned by 3M Healthcare Ltd.
1974
This year saw the publication of the 'ozone depletion theory', put forward by two American scientists, Rowland and Molina.
1987
“Montreal protocol” This agreement set target dates for significant reductions in the use of CFCs. The protocol was revised in 1990, in order to phase out the use of CFCs by the year 2000. CFC propellants are now only used in certain 'exempt' products.
1995
First HFA MDI. “Airomir”

Advantages
1. It delivers specified amount of dose.
2. It is small in size, portable and convenient for use.
3. It is usually less expensive as compare to dry powder inhalers and nebulizers.
4. Quick to use.
5. The contents are protected from contamination by pathogens.
6. It is having multi dose capability more than 100 doses available.

Disadvantages
1. It is difficult to deliver high doses through pMDI.
2. Accurate co-ordination between actuation of a dose and inhalation is required.
3. Drug delivery is dependent on patient technique.

Components
The key components of pMDI are drug formulation, propellant, metering valve, actuator, and container. All play an importent role in the formation of aerosol plume and in determining amount of drug to the lung.

1. Canister
The pMDI container should be able to withstand the high pressure generated by the propellant and it should be made of inert materials. Aluminium container is nowadays preferred because it is lighter, more compact, less fragile and light proof. Coatings on the internal surfaces of canister may be useful to prevent drug adsorption, corrosion and drug degradation. Common coatings include epoxy resins, anodized aluminium, epoxy-phenol and perfluoroalkoxyalkane. [6]

Ideal properties
1. Material used for canister should be compatible with formulation.
2. It should have ability to withstand pressure up to 1500 kPa.
3. It should have light weight.
4. It should be break resistant.
5. It should protect concentrate from sunlight.

2. Metering Valve
The metering valve of a pMDI is critical component in the effectiveness of the delivery system. The function of the metering valve is to deliver dose accurately and reproducibly. The volume measured by it ranges from 20-100 μL and form a propellant-tight seal for high pressure in the canister. The elastomeric seals and the gaskets are important components of the metering valve. The valves must be constructed from a variety of inert materials to ensure the compatibility of the formulation with the valve components. They form the barrier to the external environment and prevent the leakage of the product. The solvency properties of the propellant and storage temperature can affect the degree of swelling of valve elastomer. The valve regulates the flow of the content from the container and determines the spray characteristics of the aerosol.[7]

3. Actuator
The actuator which is fitted to the aerosol valve stem is a device which on depression or any other required movement opens the valve and directs the spray to the desired area. The actuator of a pMDI is generally made from polyethylene or polypropylene materials. The design of actuator is important for the production of appropriate aerosols including the particle size, droplet size and the characteristics of the aerosol plume emitted from a pMDI. The design of an actuator which incorporates an orifice of varying size, shape and expansion chamber are crucial factors in influencing the physical characteristics of the spray particularly in the case of inhalation aerosols, where the active ingredient must be delivered in the proper particle size range. A proportion of the active ingredient is usually deposited on the inner surface of the actuator, the amount available is therefore less than the amount released by actuation of the valve.[8]

4. Formulation
There are two types of MDI formulations: i) Suspension formulations, in which micronized drug are dispersed in a propellant or combination of propellants; and ii) Solution formulations, in which the drug is dissolved in either the propellant or a combination of propellant and co-solvent.[9]

Suspension formulations are the more common dosage form, when used alongwith with the hydrofluoroalkane propellants such as HFA-134a. However, propellants like HFA-227ea have poor solvency characteristics there for the use of co-solvents has become more common. Some of the products of suspension and solution are given in table 2.

Table 2. Solution and suspension formulations of pMDI

Sr. No.

Brand Name

Active Ingredient

Dose

Type of Formulation

1

Serovent

Salmeterol

25μg/dose

Suspension

2

Ventoline

Albuterol sulfate

100 μg/dose

Suspension

3

Qvar

Beclomethasone

Dipropionate

50 μg/dose Solution

100 μg/dose

Solution

4

Fluvent HFA

Fluticasone Propionate

50 μg/dose

125 μg/dose

250 μg/dose

Suspension

5

Atrovent

Ipratropium Bromide

20 μg/dose

Solution

A) Solution Formulation
Drug is completely dissolved in HFA propellant and appropriate co-solvent (e.g. Ethanol) is added to produce the solution. This is a two phase system of gas and liquid.[10]

Advantages
1. Homogeneous and uniform drug delivery.
2. Enhance efficiency of aerosolization and increase lung deposition.
3. No issue of particle growth and aggregation.
4. Very less drug particle deposition on component.

Disadvantages
1. Sufficient solubility is required in vehicle.
2. Possible reduction in chemical stability.
3. Few options of co-solvent for inhalation formulation.
4. Co-solvent decreases vapor pressure which is required for automation.

B) Suspension Formulation
Micronized drug is suspended in propellant or combination of propellant. Drug should be insoluble in propellant. This is a three phase system consisting of gas, liquid and solid.

Advantages
1. Formulation resulting good chemical stability.
2. No additional excipients need to add which may be toxic.

Disadvantages
1. The density difference between propellant and drug affect dose uniformity.
2. Difference in hydrophilicity and hydrophobicity cause flocculation.

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