7) Rapid response to the medication.

8) Controlled and uniform dosage produced by metered valves.

9) A fine mist is easily formed for inhalation purpose.

10) The sterility of sterile products is maintained since no organism can enter the valve is opened.

Disadvantages ^{(2, 8)}

1) Cost.

2) Disposal may be difficult.

3) The toxicity of propellant.

4) Exposed to heat may be dangerous.

There are several different types of inhalers. The most common is the pressurized metered dose inhaler (MDI). In MDI s , medication is most commonly stored in solution in a pressurized canister that contains a propellant, although it may also be a suspension. The metered dose inhaler MDI canister is attached to a plastic, hand-operated actuator. On activation, the releases a fixed dose of medication in aerosol form. The correct procedure for using an MDI is to first fully exhale, place the mouth-piece end of the pump into the mouth, and having just started to inhale at a moderate rate, depress the canister to release the medicine. The aerosolized medication is drawn into the lungs by continuing to inhale deeply before holding the breath for 10 seconds to allow the aerosol to settle onto the walls of the bronchial and other airways of the lung.

Besides the MDI, other types of inhalers include dry powder inhaler (DPIs), which release a dose of medicine as a powder aerosol that is inhaled by the patient, and nebulizers, which instead supply the aerosol as a mist created from an aqueous formulation.

The largest manufacturers of inhalers are GlaxoSmithKline(makers of the Advair Discus (a DPI), Merck, AstraZeneca (makers of Pulmicort makers of Atrovent, Combivent, and Spiriva). BI, GSK, Merck, and AstraZeneca manufacture the medication being delivered via inhaler. However, 3M Drug Delivery Systems does some of the finished product manufacturing, as they are one of the leaders of MDI canisters, metering valves and other components.

Recently, the FDA banned the use of inhalers that utilize CFCs (Chlorofluorocarbons) as propellants for the more the environmentally friendly HFA inhalers. While some asthma suffers and advocacy groups contend that these environmentally friendly inhalers are not as effective, published clinical studies indicate equivalent control of asthma is achieved with use of HFA inhalers. Patients also are concerned with the high price of the HFA inhalers as there is no generic version, which was available in the CFC inhalers for many years.

History:

Before the invention of the MDI asthma medication was delivered using a squeeze bulb nebulizer which was fragile and unreliable. The relatively crude nature of these devices also meant that the particles that they generated were relatively large, too large for effective drug delivery to the lungs. None the less these nebulisers paved the way for inhalation drug delivery providing the inspiration for the MDI.

Preparations for administration to body cavities:

1) Ear:

2) Nose

3) Oral

4) Vaginal

5) Rectal

Dry powder inhaler ^(1,13)

A Dry powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. DPIs are commonly used to treat respiratory disease such as asthma, bronchitis, emphysema and chronic obstructive pulmonary disease (COPD), lungs cancer, diabetes insipidus. although DPIs have also been used in the treatment of diabetes mellitus.

DPIs are an alternative to the aerosol based inhalers commonly called metered dose inhaler (or MDI). The DPIs may require some procedure to allow a measured dose of powder to be ready for the patient to take. The medication is commonly held either in a capsule for manual loading or a proprietary form from inside the inhaler. Once loaded or actuated, the operator puts the mouthpiece of the inhaler into their mouth and takes a deep inhalation, holding their breath for 5-10 seconds. There are a variety of such devices. The dose that can be delivered is typically less than a few tens of milligrams in a single breath since larger powder doses may lead to provocation of cough. Most DPIs rely on the force of patient inhalation to entrain powder from the device and subsequently break-up the powder into aerosol particles that are small enough to reach the lungs. For this reason, insufficient patient inhalation flow rates may lead to reduced dose delivery and incomplete deaggregation of the powder, leading to unsatisfactory device performance. Thus, most DPIs have a minimum inspiratory effort that is needed for proper use and it is for this reason that such DPIs are normally used only in older children and adults.

Theory:⁽¹²⁾

Particle size is most important factor related to the effect of drug action so; different ways are followed to maintain uniformity of particle size.

The mass mean diameter (MMD) is the most common descriptor of primary particle size, and may determined by sieving or centrifugal sedimentation .the volume mean diameter as determined by laser diffraction , may be used as an approximate MMD.

The MMD of powder can be used as a predictor of aerodynamic diameter.

MMAD = (MMD) (P⁽^1/2))

Where,

MMDA=mass median aerodynamic diameter.

And (P⁽^1/2))= true density of particle.

Values of MMDA less than 5 micrometer are considered necessary to facilitate airborne particles to past the larynx and disposition in lung. Particle of MMDA less than 0.5 micrometer are likely to be exhaled.

Surface area is a bulk powder characteristic directly depends upon particle size distribution, porosity and morphology .commonly determine by nitrogen adsorption.

Bulk powder, density, porosity, consolidation, rate are used as characteristics of powder structure and ease of flow.

Carrier based powder formulation are designed in part to overcome the inherent cohesion of micron sized particles in this formulations, the micro fine drug adhere to large sized carrier particles improving powder flow & metering capability.

Pelletization is often employed to improve the flow Pelletization converts an ensemble of single particles in to large sized agglomerates through the formulation of weak solid bridges between particles this process also results in increased bulk powder density. The solid bridge formed during Pelletization may aid powder flow & metering but must be over come during aerosolization.

Formulation:⁽¹²⁾

Formulation of dry powders for inhalation must rely on a very short list of excipient to fulfill the customary roles of diluent, stabilizer, solubilizer, processing aid & property modifier (eg. flow enhancer ) in U.S. only a few materials are approved for use in inhalation products, & of this (eg. Propellants, surfactants) many are of little help in dry powder formulation where dose requirements & drug properties allow, drug may be processed in the absence of any excipient. Most DPIS marked as well as under development, however rely on lactose, as filter & flow enhancer.

a) Controlled crystallization or precipitation- crystallization is a process by which particles are produced by precipitation of the material in suitable solvent. The level of control over these processes determines the physical nature and size of the finished particles.

b) Micronization- is the high energy particle size reduction processes. That can convert coarse particles into particles of less than 5 micrometer in diameter. different equipment are available for this process

Eg.1) Ball mill, 2) Jet or fluid energy mill.

c) Blending-The most common method for improving flowability, fillibility and dispersibility of small cohesive particles is blending the drug with excipient particles, usually lactose of considerably larger particle size, typically greater than 60 micrometer, where as the particles are less than 5 micrometer .the objective of mixing processes is to produce an ordered powder in which the small particles attaché themselves to the surface of larger carrier particles.

Secondary processing-⁽¹²⁾

1) Milling –process through which particles of larger size are broken to produce uniform micron size particles.

The mass and size of particles and time in the milling affect the milling rate. It has been reported that batch milling of brittle materials in small mills follow a first order kinetics. Different types of mills are used to for milling-

A) Cutter.

b) Fluid energy

c) Hammer

d) Roller.

2) Spray drying –spray drying finds great utility in the pharmaceutical industry because of the rapidity o drying and the unique form of the final product. There are major uses of spray drying process,

a) Drying heat sensitive materials.

b) Encapsulation solid and liquid particles.

Spray drying can be used to dry materials that are sensitive to heat and or oxidation without depredating them. Even when high temperature air is applied. The liquid feed is dispersed into droplets, which are dried in seconds because of their high surface area and intimate contact with the drying air.

3) Lyophilization –Lyophilization is the processes by which a solution of a drug is frozen to a solid and the solvent, usually water, removed by sublimation on exposure to vacuum. The process has been studied intensively because it can be applied to the preservation of liable drugs or materials such as proteins which would otherwise be adversely affected by the solvent over a period of time. In practice the entire process required to be carried out under aseptic condition, including operating in an atmosphere of filtered sterile air.

Energy sources-

Energy input is required to extract the powder from its packaging, generate the fine particles cloud, and dilute it with air; historically this energy comes from the particles inhalation effect. in some cases the energy for extracting and metering the powder comes from the mechanical manipulation of the devices by the patient.

Energy source for drug delivery:

Mechanism:

A) Patients inhalation:

Advantages:

-No need to coordinate aerosol generation with patient’s inhalation.

-Device is generally very simple in many cases no moving parts are involved in powder deagglomeration.

Disadvantage:

-Delivery, dispersion, performance and hence dose is affected by patients ability to inhale at a suitable high flow rate.

B) Other (e.g. air pump, metered propellant, electrical etc.)

Advantages:

-Decouples aerosols generation from patient’s ability.

-Allow the extraction and deagglomeration of more cohesive powders, as additional energy can be applied in the process.

Disadvantage:

-Adds complexity and cost of device by increasing number of subsystems.

Contents: ⁽³⁾

Lactose

Some powder inhalers use lactose as bulking agent and to aid in powder uptake from the device during inhalation. While some have suggested that lactose such may be harmful to lactose intolerance people the lactose dose delivered by dry powder inhalers is typically less than a few milligrams and such doses do not lead to clinically relevant concerns of adverse effects in lactose intolerant patients.

Standards:^{( 4}⁾

Identification tests:

1) To 5ml of saturated solution add 5ml of 1M sodium hydroxide solution and gently warm the mixture the liquid become yellow and then brownish red, cool to room temperature and add 0.2ml of potassium cupric tartarate solution, a red precipitate is formed.

2) Heat 5ml of 5% w/v solution with 5 ml of 10 M ammonium in water bath at 80⁰ C, for 10 min. a red color is developed

Storage :⁽²⁾

DPI medication must be stored in a dry place or sealed packaging, since exposure of the powder to moisture degrades the ability of the device to disperse its medication as an aerosol upon inhalation.

Before the invention of the MDI asthma medication was delivered using a squeeze bulb nebulizer which was fragile and unreliable. The relatively crude nature of these devices

also meant that the particles that they generated were relatively large, too large for effective drug delivery to the lungs. None the less these nebulizers paved the way for inhalation drug delivery providing the inspiration for the MDI.

Aerosol container and valve assembly.⁽²⁾

The effectiveness of a pharmaceutical aerosol depends on achieving the proper combination of formulation, container, and the valve assembly .The formulation must not chemically interact with the container or valve components so as to interfere with the stability of the formulation or with the integrity and operation of the container and the valve assembly .The container and valve must be capable of withstanding the pressure required by the product ,it must be corrosive –resistant, and the valve must contribute to the form of the product to be emitted.

Containers and storage:

Various materials have been used in the manufacture of aerosol containers, including,

1) Glass, uncoated or plastic coated;

2) Metal, including tin plated steel, aluminum, and stainless steel

3) Plastic.

The selection of the container for an aerosol product is based on its adaptability to production methods , compatibility with formulation components, ability to sustain the pressure intended for product, the interest in design and aesthetic appeal on the part of the manufacturer and cost.

Plastic coating are commonly applied to the outer surface of glass container to render them more resistance to accidental breakage, and in the event of breaking the plastic coating prevents the scattering of glass fragments.

At the present time, tin plated steel containers are the most widely used metal containers for aerosols. when required special protective coating are employed within the container to prevent corrosion and interaction between the container and formulation .Most aluminum containers are manufactured by extrusion or by other methods that make them seamless. They have the advantage over seam type of container in that there is a greater safety against leakage, incompatibility, and corrosion.

Packaging, Labeling and storage.^(2,18)

A unique aspect of pharmaceutical aerosols compared to other dosage forms is that the product is actually packaged as part of the manufacturing processes .With most other dosage forms, the product is completely manufactured and then placed in the appropriate container.

Most aerosol products have protective caps or cover that fits snugly over the valve and mounting cup .This protect the valve against the contamination with dust and dirt. The cap, which is generally made of plastic or metal, also serves as decorative function.

Medicinal aerosols that are to be dispensed only upon prescription usually may be labeled by the manufacturer with plastic peel away labels or easily removed paper label so that the pharmacist may easily replace the manufacturers label with his label containing the directions for use specified by the prescribing practitioner .Most other types of aerosols have the manufactures label printed directly on the container or on firmly affixed paper.

In addition to the usual labeling requirements for pharmaceutical products, aerosols have specific requirements related to their use and storage. For example, for safety, labels must warn users not to puncture pressurized containers , not to use or store them near heat or an open flame , and not to incinerate .Exposure to temperatures above 120 degree farad may cause an aerosol container to burst. Most medications in aerosol containers are intended for use at ambient temperatures. When the canisters are cold, less than the usual spray may result. This may be particularly important to users of metered dose inhalation sprays. These products are generally recommended for storage between 15 and 30 degree celsius. Pharmaceutical aerosols are labeled with regard to shaking before use, holding at the proper angle and distance from the target; there are special detailed instructions for inhaler devices.

Aerosols should be maintained with the protective caps in place to prevent accidental activation of the valve assembly or its contamination by dust and other foreign materials.

Categories:⁽⁸⁾

1) Topical Preparation:

This are intended for application to the external surface of the body.

2) Local analgesics:

The refrigerant effect of the evaporating propellant is used to produce surface analgesic. Ex. Ethyl chloride.

3) Local anesthetics:

These usually contain benzocaine or xylocaine.

4) Antiseptic and skin sterilizers:

Chlorohexidine, benzalkonium chloride, surgical spirit etc. may be used for pre operative skin sterilization and in the treatment of burns where swabbing with antiseptic is minimized or obviated.

5) Skin dressing:

Based on polymer these may be spread on the serve as surgical dressing. They provide a flexible water resistant and micro organism proof barrier applied with less comfort, more easily and quickly than traditional dressing.

6) Fungicidal agents:

Undecylenic acid derivatives is used for the treatment of such condition as Athlets foot.

7) Anti inflammatory agents:

e.g . Hydro cortisone and its derivative.

8) Bronchodilator Inhalers: Short-Acting Beta-2 Adrenergic Bronchodilator Inhalers

9) Daily Inhalers: Long-Acting Adrenergic Bronchodilator Inhalers

10) Daily Inhalers: Anticholinergic Bronchodilators in COPD

11) Daily Inhalers: Corticosteroids

12) Combination Inhalers: Corticosteroid with Long Acting Beta-2 Adrenergic Agonist

13) Combination Inhaler: Anticholinergics with Short- Acting Beta-2 Adrenergic Agonists.

14) Combination Inhalers: Corticosteroid with Long Acting Beta-2 Adrenergic Agonist

15) Combination Inhaler: Anticholinergics with Short- Acting Beta-2 Adrenergic Agonists.

Metered-dose inhaler ^{(2, 20)}

A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is inhaled by the patient. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for the treatment of asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as (cromoglicate or nedocromil).

Metering valve are employed when the formulation is a potent medication ,as in inhalation therapy .in this metered valve system, the amount of material discharged is regulated by an auxiliary valve chamber by virtue of its capacity or dimensions. A single depression of the actuator causes the evacuation of thus chamber and the delivery of its contents. The integrity of the chamber is controlled by a dual valving mechanism. When the actuator valve is in closed position, a seal is affected between the chamber and the atmosphere. However, in this position the chamber is permitted to fill the contents of the container to which it is open. Depression of the actuator causes a simultaneous reversal of position sealed; the chamber becomes opened to atmosphere, releasing its contents, and at the same time becomes sealed from the contents of the container. Upon release of the actuator, the system is restored for the next dose.

The effectiveness in delivering medication to the lower reaches the lungs for local and systemic effects depends in part on the particle size of the inhaled drug. Breathing patterns and the depth of respiration also play an important role in the deposition of inhaled aerosols into the lungs. Analysis of dose uniformity, particle size distribution patterns and the respirable fractions of aerosol delivered particles, are the areas of current research interest in developing aerosol products for optimal oral inhalation therapy.

A unique translingual aerosol formulation of nitroglycerin has been developed (nitroglycerin spray, Rhon- poulenc Rorer) that permits a patient to spray droplets of nitroglycerin onto or under the tongue for acute relief of an attack, or for prophylaxis, of angina pectoris due to coronary artery disease. The product is not to be inhaled. At the onset of an attack, two metered spray emissions, each containing 0.4 mg of nitroglycerin, are administered. The product contains 200 doses of nitroglycerin in a propellant mixture of History dichlorodifluomethane and dichlorotetraflurodifluoroethane.

Characterization of Liposomal Dry Powder Inhaler Formulations ^(2,4,8)

a)Angle of Repose:

The pile of powder was carefully built up by dropping the powder material through a funnel tip from height of 2 cm.^(2,4) The angle of repose was calculated by inverting tangentially the ratio of height and radius of the formed pile.

b) Angle of Spatula:

The pile of 10-g formulation was built on a flat surface and a flat spatula was placed into the bottom of the mass, and then the spatula was lifted straight up and out of the material. The angle of new surface on the spatula to the horizontal was measured immediately and again after gentle tapping of the spatula. The average of 2 measurements was taken as the value of angle of the spatula.^(2,4)

c) Compressibility Index:

The compressibility index was determined by tapping the formulation for 500 taps to reach plateau condition.^(2,4)

d) Dispersibility Index:

Formulation (10 g) was dropped through a cylinder (length 16.5 cm, internal diameter 5 cm) held 5 cm above a watch glass of 2.5-cm diameter. The dropping point was 7.6 cm above the cylinder from a funnel tip. Dispersibility index was calculated as the relative proportion of material lost to the material dropped.^(2,4)

e)Water Content Determination:

Water content of the liposomal dry powder inhaler (LDPI) formulations (1 g) was determined in triplicate on 2 consecutive days by Karl Fischer Titration.

f) Testing of filled containers:

After filling by either the cold method or the pressure method, the aerosol container is tested under various environmental conditions for leaks or weakness in the valve assembly or containers.

g) Valve discharge rate:

Filled aerosol containers are also tested for the proper function of the valve. The valve discharge rate is determined by discharging a portion of the container of a previously weighted aerosol during a given period of time, and calculating, by difference in weight, the gram of contents discharged per unit of time.

DISCUSSION:

Energy sources-^{( 9}⁾

Energy input is required to extract the powder from its packaging, generate the fine particles cloud, and dilute it with air, Historically this energy comes from the particles inhalation effect, now a days a new modified flexible plastic containers are being used to avoid some side effects, or disadvantages

To enhance drug action-

Lyophilization, powder coating, and micronization, is done to produce quicker effect. And the processes must be carried out in hygienic condition to avoid cross contamination, & spoilage of drug.

Packaging modifications:

Also for packaging modified glass container coated with the plastic, or rubber are used to improve its flexibility and also to avoid breakage of container.

To develop new propellant:

As we know that the use of propellant (e.g. Chlorofluorocarbon, diChloro- difluorocarbon, diChloro tetra fluorocarbon etc.)Are mainly carcinogenic and un hygienic to environment so, new propellants are should be replaced with this.

Development of newer adsorbent:

In case of DPI only the lactose is chief ingredient used as an adsorbent, as far as action is concerned newer adsorbent should be developed of having higher surface area and lesser density so they can easily inhaled.

REFERENCES:

1) N.K. Jain, Pharmaceutical product development, 1^st edition, 2006.

2) Ansel’s pharmaceutical dosage forms and drug delivery system, 8^th edition.

3) Handbook of pharmaceutical excepients 5^th edition, by Raymond C Rowe, Paul J Sheskey and Sian C Owen.

4) Indian pharmacopia1996 volume-1.

5) Textbook of pathology 4th edition by Harsh Mohan, Jaypee medical publication New Delhi.

6) The theory and principle of industrial pharmacy, Warghese publishing house 3d edition.

7) Martins physical pharmacy and pharmaceutical sciences 5^th edition Lipincott Williams and Wilkins publication.

8) Bentleys Text book of pharmaceutics, 8^th edition, edited by E. A .Rawlins.

9) Pharmaceutical inhalation aerosol technology, ed. A. J. Hickey, 2nd edition, Marcel Dekker Inc., NY, 2004.

10) Finlay, W. H., The mechanism of inhaled pharmaceutical aerosols: An introduction, Academic Press, 2001.

11) "Inhalation Aerosols: Physical and Biological Basis for Therapy", ed. A. J. Hickey, 2nd edition, Informa Healthcare, NY, 2007.

12) Encyclopedia of pharmaceutical technique, vol-20, pg 93, James swarbrick, James C. Boylon-medial-2001.

13) Aerosols in medicine; principles, diagnosis and therapy, by Folk morein, Michael T. Newhouse, Myma B.dolovich, 1985.

15) Equipment theory for respiratory care; by Gary.C.White -2004.

16) The mechanism of inhaled pharmaceutical aerosols; an introduction, by Warren H.Finley-2001.

17) Physiological pharmaceutics; barrier to drug absorption, by Nina Washington, Clive Washington, Clive Wilson, 2000.

18) Particle particle adhesion in pharmaceutical powder handeling, by Fridrun Podczeck.

19) Textbook of physical pharmaceutics, by C.V.S. Subramanyam Vallabh Prakashan Delhi, 2ndedition, 2005.

20) Drug targeting organ specific strategies, by Grietje Molema, D.K.F. Meijer- 2001.

Received on 07.04.2011

Accepted on 14.04.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(3): May-June 2011, 87-92

Metered-dose inhaler (2, 20)

Metered-dose inhaler ^{(2, 20)}