Overview Of Pharmaceutical Inhalation Drug

The inhalation route of drug administration consists of administration of a substance in the form of a gas, aerosol, or fine powder via the respiratory tract, usually by oral or nasal inhalation, for local or systemic effect. It is an effective technique for local and systemic drug delivery for pulmonary and non-pulmonary diseases. The purpose of this route of drug administration is to target particular cells or areas of the lung, bypassing the lung clearance system, thus providing high retention of the drug over a long period.

Inhalation drug

Inhalation drugs require devices for administration. The drug formulation and the device must work hand in hand to achieve the right amount of drug delivered to the oropharyngeal route. In some cases, the patient 's ability to use the device also plays a crucial role in inhalation drugs.

Techniques Of Making Particulate Matter For Inhalation

Particles for inhalation need to be in the range 1-5mcm in order to target the appropriate area of the lung. For a solution-based product, the input particle size distribution (PSD) of the input active pharmaceutical ingredient (API) is less critical, since the aerosolization of the drug is determined by other parameters. If an MDI is formulated as a suspension, the particle size distribution (PSD) of the API is a key performance driver.

Many conventional techniques have been reported to produce DPI formulations. However, these methods have a number of limitations, such as particle size, size distribution, shape and poor control over powder crystallinity. These problems can be rectified by specialized milling techniques. Jet-milling of drug under nitrogen gas with a new nanojet milling instrument is the most suitable method for creating nanoparticles meant for pulmonary drug delivery. Others are;

1. Solvent precipitation method

2. Supercritical fluid technology

3. Spray freeze drying method

4. Spray drying technique

5. Particle replication in nonwetting templates

6. Double emulsion/solvent evaporation technique

Devices Use For Inhalation Drug

Devices used to deliver therapeutic agents as aerosols are based on one of the three platforms: pressurized metered-dose inhaler (pMDI), nebulizers and dry powder inhalers (DPIs).

Metered-dose Inhalers (MDIs)

For MDIs, there are essentially two main methods of filling employed globally today: cold filling and pressure filling.

Cold Filling

In cold filling, a concentrate of drug and excipients are mixed with the liquefied propellant at low temperature within the batching vessel. The formulation is then dispensed directly in a single filling step into the empty pMDI canister and the metering valve is then crimped into place.

Pressure Filling

In pressure filling, a concentrate of drug and excipients is mixed with the volatile propellant under pressure within the batching vessel at near ambient temperature. The whole formulation is then injected through a pre-crimped metering valve and canister. As pressure filling relies on filling the formulation backwards through the valve at high pressure, as opposed to the normal patient-use operation in which the valve opens to allow formulation out of the canister, metering valves have to be designed with this in mind.

Structural Components Of pMDIs

The structural components of the conventional pMDI are the canister, metering valve, actuator, and a mouth piece. Canisters are made of inert materials capable of enduring the high pressures required to keep the propellant gas in liquid state.

pMDIs drug formulations can be solutions or suspensions in a single propellant or propellant mixture and may include excipients such as ethanol or surfactants to solubilize the drug or stabilize a drug suspension. Recently, the use of pMDIs has extended beyond bronchodilators and corticosteroids to deliver proteins, plasmid DNA, and live attenuated virus vaccines or bacteriophages.

Ideally, propellants should be nontoxic, non-flammable, and compatible with the formulation and provide consistent vapor pressure during the entire life of the product.

Advantages Of MDIs

1. Portability

2. Multidose delivery capability

3. Lower risk of bacterial contamination

Disadvantages Of MDIs

1. Need for correct actuation and inhalation coordination

2. Oropharyngeal drug deposition

Inhalation Aids

Spacers and valved holding chambers (VHCs) are used with pMDIs to increase the efficiency of aerosol delivery. A spacer is a tube or extension device that is placed at the interface between the patient and the pMDI.

Advantages Of IADs

1. Enhanced drug delivery

2. Compensation for poor technique/coordination with MDI

3. Reduced oropharyngeal deposition

Disadvantages Of IADs

1. Large size and volume of device

2. Bacterial contamination is possible; device needs to be cleaned periodically

3. Electrostatic charges may reduce drug delivery to the lungs

Nebulizer

There are two types of nebulizers, jet and ultrasonic, that differ in the force used to generate the aerosol from the respective liquid. Depending on the model and the manufacturer, nebulizers generate 1–5 μm droplets. Nebulizers do not require patient coordination between inhalation and actuation, thus they are useful for pediatric, elderly, ventilated, non-conscious patients, or those who are unable to use pMDIs or DPIs.

Nebulizers have the capability of delivering larger doses compared to the other aerosol devices even though this will require longer administration times. They use oxygen, compressed air or ultrasonic power to break up solutions and suspensions into small aerosol droplets that are inhaled from the mouthpiece of the device. An aerosol is a mixture of gas and solid or liquid particles.

Jet Nebulizers

In these nebulizers, air stream moves through a small capillary tube at high velocity creating a low pressure that drives the liquid to be aerosolized up the capillary tube. The high velocity blast of air carrying the droplets will bump into baffles placed in different numbers and positions depending on the design of the jet nebulizer. The impaction of large droplets on these baffles either break them into smaller sized droplets that will leave the nebulizer or will retain them in the device to be re-nebulized until their size is small enough to leave the nebulizer. Baffles also reduce the velocity of the aerosol cloud emitted from the nebulizer. This protects the oropharyngeal route.

Advantage Of Jet Nebulizer

1. Cheap

2. Enhanced designs have improved performance and reduced aerosol waste during the exhalation phase

Disadvantage Of Jet Nebulizer

1. Requirement for a sometimes cumbersome compressor to generate the aerosol

2. The noise that some of them generate

3. The temperature drop of the liquid in the nebulizer chamber due to liquid evaporation in the nebulized droplets

Ultrasonic Nebulizer

In ultrasonic nebulizers, sound waves are created due to the vibration of piezoelectric crystals at high frequency, creating crests that break the liquid into small droplets. Ultrasonic nebulizers are not completely portable because they still need an electric supply for charging.

Advantage Of Ultrasonic Nebulizer

1. Do not require a source of driving gas

2. Can nebulize large volumes of liquid

3. Shorter delivery time than jet nebulizers

Disadvantage Of Ultrasonic Nebulizer

1. Ultrasonic nebulizers are more expensive

2. Tend to increase the temperature of the nebulized drug solution; thus they are considered inappropriate to nebulize thermolabile peptides or DNA

3. They are also less efficient in nebulizing viscous liquids and suspensions than jet nebulizers, probably because of the reduced force that is used to atomize a liquid

4. Cumbersome

Other Nebulizer are;

1. Vibrating mesh technology

2. Soft mist inhaler

Advantages Of Nebulizers

1. Provide therapy for patients who cannot use other inhalation modalities (e.g. MDI, DPI)

2. Allow administration of large doses of medicine

3. Patient coordination not required

Disadvantages Of Nebulizers

1. Decreased portability

2. Longer set-up and administration time

3. Higher cost

4. May need source of compressed air or oxygen (jet nebulizer)

Multi-dose Liquid Inhalers

The Respimat® inhaler combines the advantages of pMDIs and nebulizers. It is a small, portable, hand-held inhaler with no need for power supply (like pMDIs) that slowly aerosolized propellant free-drug solutions as a soft mist (like nebulizers), thus decreasing the chance for oropharyngeal deposition.

Dry Powder Inhalers (DPI)

A dry-powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. The medication is commonly held either in a capsule for manual loading or in a proprietary form inside the inhaler. Once loaded or actuated, the operator puts the mouthpiece of the inhaler into their mouth and takes a sharp, deep inhalation (ensuring that the medication reaches the lower parts of the lungs), 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 particles that are small enough to reach the lungs.

Some powder inhalers use lactose to:

1. Carry the fine particles of the active pharmaceutical ingredient (which must be fine to reach its target)

2. Improve the flow-ability of the powder during manufacturing and to aid handling

3. Act as a bulking agent

4. Aid in powder uptake from the device during inhalation and aerosolization

By the number of doses, DPIs can be classified as single-unit dose, multi-unit dose, and multi-dose reservoirs. Single-dose DPIs can further be classified as disposable or reusable. Based on the mechanism for powder aerosolization, DPIs can be classified as passively- or actively-actuated devices.

Thermal Vaporization Aerosol Devices

The STACCATO® is a novel breath-actuated inhalation delivery system, which uses heat to vaporize a thin film of the drug, which later condenses in the lungs into droplets or particles depending on the nature of the drug. In that case, the drug is dissolved in a volatile solvent/solvent mixture which is sprayed over a metal substrate such as zinc halides. The best drug candidates for such systems are those which are thermally stable and with low-melting points. The STACCATO® system can deliver the condensed aerosol deeply into the lungs with a fast onset of action making it suitable for systemic delivery.

Advantages Of DPIs

1. Breath-actuated

2. Spacer not necessary

3. No need to hold breath after inhalation

4. Portable

5. No propellant

Disadvantages Of DPIs

1. Adequate inspiratory flow required for medication delivery

2. May result in high pharyngeal deposition

3. Humidity potentially causes powder clumping and reduced dispersal of fine particle mass