Formulations Administered Through The Pulmonary Route Biology Essay

Published:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

A comparison of the formulations administered through the pulmonary route has been discussed in this report. Metered dose inhalers, breathe actuated inhalers, dry powder inhalers and nebulizers have been discussed as possible formulations for the deposition of drugs into the lungs. The most popularly prescribed and used method for the delivery of drugs into the lungs is the metered dose inhalation due to portability and potential of multidose. Whereas the DPIs are also popularly used due no requirement of coordination technique and nebulizers are not preferred by patients that much.

The pulmonary route of drug delivery has been used for thousands of years for the treatment of lung diseases such as asthma and COPD via drugs such as salbutamol (Ventolin®) and ipratropium (Atrovent®). However, a more innovative approach towards pulmonary drug delivery for the treatment of systemic diseases such as diabetes mellitus is being investigated; this has been a major challenge since the 1924, when the German researchers first introduced the idea of inhalable insulin (Gillis, 2006). This idea just shows the importance of innovation in industry and thus innovation has guided the industries towards the formulation of new inhalation devices which make it possible to deliver larger doses of drugs i.e. delivery of milligrams in comparison to micrograms to the airways of the lungs for the achievement of greater drug deposition in the airways (Labiris and Dolovich 2003). The older generation of inhalation devices such as metered dose inhalers only provided lung deposition of 20% drug, whereas the newer inhalation therapies such as nebulisation provide up to or greater than 50% drug deposition in the airways of the lungs (Dolovich 1999, Labiris and Dolovich 2003).

The lungs are an excellent source for the delivery of drugs through the inhalation route because they have a very large surface area for the absorption of drugs and drug deposition. The presence of alveoli increases the surface area of the lungs massively and the rich network of capillaries acts as an excellent absorbing surface for the administration, deposition and absorption of drugs.

The primary principle of pulmonary drug delivery is the reduction of particle size of drug compound so that it may be delivered in to the bronchioles and the alveoli via inhalation. The most important physicochemical property of a drug when being prepared for use through the inhalation route is the particle size of the drug due to its ability to make it to the bronchioles or the alveoli (Aulton, 2008). The ability of inhalers to deliver drugs to the lungs is an excellent approach for the treatment of asthma and COPD, but one of the major disadvantages of using the lungs as a delivery system is that they have a very efficient clearing mechanism whereby the mucous lining of the pulmonary airways clear away any deposited particles towards the throat thus reducing the bioavailability of the drug (Drug delivery system).

Figure 1 illustrates the anatomy of the lungs; the lungs consist of branches of the trachea broken further down in to the bronchus and then the bronchioles. The bronchioles consist of the alveoli, where gas exchange takes place and probably is the best place for the absorption of drugs from the pulmonary route. Figure 1 also illustrates the rich network of capillaries surrounding the alveoli for the exchange of oxygen and carbon dioxide.http://www.daviddarling.info/images/lungs_how_they_work.gif

Image taken from http://sites.google.com/site/nursing211fall09/wk-2-lung-surgery-pleural-effusion-resp-failure-ards-chest-trauma/211b-group-3.

From Figure 1 it may also be noted that as the trachea breaks down into smaller branches of bronchus, then the bronchioles and then alveoli the size gets smaller and smaller, therefore the particle size required to deposit a drug into the alveoli requires a size of between 1 and 3µm (Patton et al 2004).

Thus the therapeutic effect of aerosolized therapy depends on the amount of dose deposited and its distribution within the lungs (Labiris and Dolovich 2003). Ruffin et al (1978) showed that a small dose of aerosolized histamine would mainly deposit in the central airways and increase airway obstruction by 11-fold than histamine which diffused into the airway, this suggests that surface concentration of a drug has affect on response and that the histamine receptors are mainly based in the centre of the lungs (Ruffin et al 1978, Labiris and Dolovich 2003). Therefore one of the major advantages of pulmonary drug delivery is that the drug may be delivered at high concentrations directly to the site of the disease; which minimizes side effects and provides a rapid clinical response (Labiris and Dolovich 2003).

Another major advantage of the pulmonary route is that the drug is able to bypass the first-pass metabolism in comparison to the oral route where majority of the drug is lost due to poor gastrointestinal absorption and first pass metabolism in the liver. Therefore pulmonary inhalation is able to achieve a much higher therapeutic effect at just a fraction of the oral route e.g. oral salbutamol 2-4mg is therapeutically equivalent to 100-200micrograms by the inhalation (MDI) route (Labiris and Dolovich 2003).

Discussion

Inhalation delivery devices

The development of devices for inhalation is illustrated in an excellent manner in Figure 2 and thus the devices can be divided in to three categories; nebulizers, metered dose inhalers (MDI) and dry powder inhalers (DPI).

Image taken from Labiris and Dolovich, 2003.

Figure 2. Illustration of the evolution of inhalation delivery devices.

Nebulizers

Nebulizers have been used for many years for the treatment of asthma and other respiratory diseases such as COPD and cystic fibrosis. Nebulizers are a very effective tool of administration of the drug to the lungs because they deliver a large volume of the drug and are also convenient for the formulation of drugs which cannot be formulated into MDI's or DPI's or where the therapeutic dose is too large to be delivered through MDI's or DPI's, thus nebulizers can aerosolize most drug solutions (Aulton, 2008). One of the major advantages of using nebulizers over MDI's is that there is no requirement of any specific technique or co-ordination in order to use it, whereas the MDI's require a specific technique or co-ordination in order for them to be therapeutically effective and therefore nebulizers are very convenient for infants, children, the elderly and patients with arthritis (Labiris and Dolovich 2003, Aulton, 2008).

There are two main types of nebulizers, jet and ultrasonic nebulizers, as illustrated in Figure 2. The jet nebulizer functions by the Bernoulli principle, whereby compressed gas (air and oxygen) is passed through a narrow tube called the Venturi nozzle into an area of negative pressure where the air jet appears and causes liquid to be drawn up a feed tube from the reservoir, as seen in Figure 3 (Aulton, 2008, Labiris and Dolovich 2003). As the drug is inhaled, the liquid emerges as fine filaments collapsed in droplets, which appears to be a mist or steam (Aulton, 2008).

Jet nebulizers can aerosolize most of the drug solutions and can provide large doses with very little patient co-ordination or skill in comparison to MDI's. However, treatment using these nebulizers can be very time consuming and they are also associated with large amounts of drug wastage because they have to be operated continuously and thus due to this reason a loss of 50% can take place (Labiris and Dolovich 2003, O'Callaghan and Barry 1997). A major disadvantage of using nebulizers is that most of the drug actually never reaches the lungs, majority of the drug is either retained within the nebulizer, referred to as dead volume, or is released into the environment during expiration (Labiris and Dolovich 2003). On average, about 10% of the dose placed in the nebulizer is actually deposited in the lungs (Labiris and Dolovich 2003 O'Callaghan and Barry 1997). Figure 3. Illustration of the mechanism of function of a jet nebulizer.

Image taken from Aulton, 2008

Some other disadvantages of nebulizers are that it is quite bulky and therefore cannot be easily carried around by patients, which reduces compliance within some patients. In comparison to MDI's and DPI's, which are very easily carried anywhere. Even though the nebulizers themselves are quite cheap, the gas compressors are relatively expensive (Labiris and Dolovich 2003).

Ultrasonic nebulizers such as the Pari e-Flow and MicroAir use a rapidly vibrating piezoelectric crystal to produce aerosol particles which appears like a fountain of liquid in the nebulizer chamber, as seen in Figure 4.

Image taken from Aulton, 2008

Figure 4. Illustration of an ultrasonic nebulizer. The piezoelectric crystal vibrates at such a high frequency that the solution is turned into a fog of drug particles ready to be inhaled, in some ultrasonic nebulizers there is a fan to blow the therapeutic mist of drug upwards and then the patient inhales the drug (Aulton, 2008).

Formulation of Nebulizer Fluids

The nebulizer fluids are generally formulated in water. However, sometimes they are formulated with the addition of co-solvents such as ethanol or propylene glycol (Aulton, 2008). Nebulizer solutions with a pH of greater than 5 (iso-osmotic) are used because if the pH is too low or if the solution is hyper- or hypo- tonic then the aerosol may induce bronchoconstriction, coughing and irritation of the lung mucosa (Weber et al 1997, Eschenbacher et al 1984). Other excipients such as antioxidants and preservatives can also be used in the nebulizer fluids and they also have the capacity to cause bronchospasm, thus antioxidants are not routinely added into nebulizer fluids (Aulton, 2008). Some of the physical properties of the drug to be nebulized are also important, such as the particle size because this will influence the nebulization rate (Labiris and Dolovich 2003).

Metered Dose Inhalers (MDI)

Metered dose inhalers (MDI's) such as Ventolin® were introduced in the mid 1950s and are still the most widely used and prescribed inhalation delivery device in the world, as seen in Figure 4 (Pederson 1996, Keller 1999, Aulton, 2008). The principle behind MDIs is that the drug suspension is in a canister with a fitted valve and is emitted as an aerosol through a nozzle at high velocity (>30m s-1), the drug emitted is driven by propellants such as chlorofluorocarbons (CFC) or the replacement of CFC, hydrofluoroalkanes (HFAs) (Labiris and Dolovich 2003, Aulton, 2008).

Figure 4. Illustration of MDI

Image taken from Aulton, 2008

The MDIs deliver a very small fraction of the drug to the lungs; usually about 10-20% of the emitted dose is deposited into the lungs (Labiris and Dolovich 2003, Newman and Clark 1993). A high volume of the drug (50-80%) is lost in the oropharyngeal region due to the high velocity of drug release from the inhaler and the large particle size (Labiris and Dolovich 2003). A major problem with using MDIs in comparison to the nebulizers or DPIs is the hand to mouth discoordination whilst trying to inhale the drug into the lungs for the optimal use of the MDI. A study by Crompton et al (1982) found that 51% of the patients did not know how to inhale the drug from the MDIs properly; they did not have the required coordination to operate the inhaler efficiently. From the same study 24% of the patients stopped breathing in when the inhaler was fired for actuation into the mouth and 12% inspired through their nose instead of the mouth when the aerosol was actuated into the mouth (Labiris and Dolovich 2003). Thus an education of how to use the inhaler is very important in order to use the MDI efficiently.

With patients who have a poor MDI technique, breath actuated MDIs such as salbutamol easyhaler (Salamol) and Autohaler have been developed to eliminate coordination difficulties by firing in response to the patients' inspiratory effect (Labiris and Dolovich 2003). The Autohaler increases the lung deposition of the drug from 7.2% with a conventional MDI to 20.8% (Labiris and Dolovich 2003, Newman et al 1991).

However, despite the disadvantages and development of newer inhalation therapies since the introduction of MDIs, i.e. the dry powder inhalers (DPIs) and the nebulizers, the MDIs still remain choice of inhalation therapy for the treatment of asthma by far (Keller 1999). This is because of the devices portability, durability, reliability, long shelf life, microbial robustness, cost effectiveness and ease of use in critical situation (Keller et al 1999, Aulton, 2008).

Formulating metered dose inhalers

The drug in the MDIs can either be in the form of solutions or suspensions in the liquefied propellant; the solutions are two-phase systems. The propellants are poor solvents and therefore co-solvents such as ethanol and isopropanol are used. The propellants CFCs have been banned from being used in inhalation devices due to detrimental effects on the ozone layer and thus now HFAs have replaced their use as suitable substitutes. Due to the replacement of propellants, the jetting force and velocity of the spray are reduced, which may decrease he oropharyngeal dose (Labiris and Dolovich 2003). A fundamental property of the drug in pressurized MDI is the particle size; the drug normally has to be micronized to a size of 2-5micrometers.

Dry powder inhalers

The dry powder inhalers (DPIs) such as the Accuhaler work by the drug being inhaled as a cloud of fine particles, the drug can be preloaded in an inhalation device or can be filled into hard gelatin capsules or foil blister discs which can be loaded into a device before use (Aulton, 2008). The aerosol is produced by air being drawn from the aggregates of micronized particles present in the powder, the micronized particles are either loose aggregates or they can be bound to larger carrier particles such as lactose or glucose (Dhand 2005). The drug, aerodynamic and flow properties of the inhaler device are very important for effective performance and generation of aerosols, in most DPIs the aerosol is produced from the energy generated from inhalation (Dhand 2005). Excellent powder flow properties are fundamental for accurate and reproducible dosing.

The DPIs are better than MDIs to a certain extent because the DPI formulations are CFC free and contain the minimal amount of exciepients i.e. the carrier, which most commonly is lactose. The DPIs also don't require any coordination whilst being used, whereas the MDIs do require a good coordination for an effective dose to be deposited into the lungs, thus the DPIs are simpler and easier to use and therefore are a suitable formulation choice for young children and patients with poor actuation coordination (Aulton, 2008 2008, Labiris and Dolovich 2003). The DPIs are also able to deliver a much greater dose than the MDIs. The MDIs are limited due to the volume of metering valve and the maximum suspension concentration that can be employed without causing the valve to clog up (Aulton, 2008). Thus due to a wide range of advantages of the DPIs over MDIs, there are now a variety of DPIs available on the market; i.e. single dose devices loaded by patients such as the Rotahaler, multiple dose devices provided in a blister pack such as the Diskhaler, multiple unit doses sealed in a blister on a strip which moves through the inhaler such as the Diskus and reservoir type systems such as the Turbohaler, as seen in Figure 5 below (Labiris and Dolovich, Aulton, 2008).

Figure 5. An illustration of the different DPIs available.

Picture taken from Aulton, 2008 2008.

Among the different DPI devices, the lung deposition of the drug varies. Approximately 12-40% of the drug dose emitted is delivered to the lungs with 20-25% of the drug being retained within the device (Labiris and Dolovich 2003, Pedersen 1996, Dolovich 1999, Newman et al 1989).

As mentioned earlier, the drug aerosol is produced by the energy driven from inhalation by the air going through the loose powder, most particles are too large to penetrate into the lungs due agglomeration of the particles or presence of large carrier particles such as lactose (Labiris and Dolovich 2003). Therefore the production of turbulent airflow in the system is necessary to break up the particles so that they are small enough to be carried into the lower respiratory airways (Concessio et al 1999). Each DPI has a different airflow resistance, the higher the resistance of the device, the more difficult it is to generate an inspiratory flow required to achieve the maximum dose from the inhaler (Labiris and Dolovich 2003). Figure 6 shows the effect of specific resistance on percentage drug deposition in the lungs.

Poor drug deposition is associated with insufficient disaggregation of the drug particles from the carriers e.g. lactose or drug pellets which could possibly be related to insufficient airflow whilst inhaling i.e. slow inspiratory flow rate (IFR) (Labiris and Dolovich 2003). Other factors influencing the deaggregation of the drug particles are high humidity due to the storage of inhalers at ambient temperatures, rapid or large changes in temperature also affect the deaggregation and stability of the powders in DPIs. In DPIs the drug delivery to the lungs is increased by fast inhalation, e.g. increasing the IFR from 35 l min-1 to 60 l min-1 increases the total drug deposition of terbutaline from 14.8% to 27.7% via the Turbohaler (Borgstrom et al 1994). In contrast with MDIs, which require slow inhalation and breathe holding to enhance lung deposition of the drug (Labiris and Dolovich 2003).

Picture taken from Labiris and Dolovich 2003.

Figure 6. An illustration of the % lung deposition of the drug via different DPIs at specific DPI resistance (cmH2O/lpm). From Figure 6 it can be seen that the Turbohaler achieves the highest lung deposition of the drug at around 20%, hence being the most efficacious. On the other hand, the Rotahaler achieves the lowest lung deposition at just over 5% and thus is the least efficacious.

Poor drug deposition is associated with insufficient disaggregation of the drug particles from the carriers e.g. lactose or drug pellets which could possibly be related to insufficient airflow whilst inhaling i.e. slow inspiratory flow rate (IFR) (Labiris and Dolovich 2003). Other factors influencing the deaggregation of the drug particles are high humidity due to the storage of inhalers at ambient temperatures, rapid or large changes in temperature also affect the deaggregation and stability of the powders in DPIs. In DPIs the drug delivery to the lungs is increased by fast inhalation, e.g. increasing the IFR from 35 l min-1 to 60 l min-1 increases the total drug deposition of terbutaline from 14.8% to 27.7% via the Turbohaler (Borgstrom et al 1994). In contrast with MDIs, which require slow inhalation and breathe holding to enhance lung deposition of the drug (Labiris and Dolovich 2003).

Formulating dry powder inhalers

The formulation of dry powders for DPIs involves micronization of the drug particles and excipients via jet milling, precipitation, freeze-drying or spray drying (Labiris and Dolovich 2003). Particle size is the primary factor which influences the lung deposition of the drug and thus majority of the DPIs consist of drug particles with a size of less than 5 micrometers, blended with larger (approximately 30-90micrometers) inert carrier particles (Usually lactose) (Concessio et al 1999). The smaller particles in the range of micrometers display forces of attraction dictated by Van der Waals, electrostatic and capillary forces (Visser 1989, Hickey et al 1994). These forces are affected by the particle size, shape and chemical composition of the particle and thus these forces also contribute towards particle-particle and particle-surface interactions (Concessio et al 1999). Therefore due to cohesive forces, the powder flow property is reduced and to overcome the problem, the drug has to be blended with a coarse carrier system such as lactose (Labiris and Dolovich 2003).

The blending of the drug with carrier system such as lactose improves the release of the drug from the inhalation device due to improved powder flow properties and improvement in the uniformity (Aulton, 2008). Upon release from the inhaler, the turbulent air produced in the system is sufficient for the deaggregation of the particles blended in the carrier system, the large particles in the carrier system collide in the throat and the smaller drug particles are carried forward deeper into the respiratory tract to the site of action (Aulton, 2008). The deposition of the drug into the lungs is less from a DPI in comparison to the MDIs because usually twice the amount of dose is needed from a DPI to deliver the same amount of dose as MDI (Melchor et al 1993).

Conclusion

It can be concluded that the lungs are an excellent source for the delivery of drugs through the inhalation route for the treatment of respiratory diseases such as asthma, COPD and possibly in the future vascular diseases such as diabetes.

It has been discussed that the MDIs are the most popularly prescribed and accepted choice of formulation for the inhalation of drugs despite the problem with inhaler technique faced by patients and the poor deposition of approximately 20% of the drug into the lungs. However, the problem of poor actuation technique has been overcome by the development of breathe actuated inhalers such as salbutamol easy breathe (Salamol). The MDIs are ideal due to portability.

The DPIs are CFC free and contain the minimal amount of exciepients i.e. the carrier, which most commonly is lactose. The DPIs also don't require any coordination whilst being used, whereas the MDIs do require a good coordination for an effective dose to be deposited into the lungs, thus the DPIs are simpler and easier to use and therefore are a suitable formulation choice for young children and patients with poor actuation coordination.

There are two main types of nebulizers, jet and ultrasonic nebulizers and there there is no requirement of any specific technique or co-ordination in order to use them, whereas the MDI's require a specific technique or co-ordination in order for them to be therapeutically effective and therefore nebulizers are very convenient for infants, children, the elderly and patients with arthritis.

Writing Services

Essay Writing
Service

Find out how the very best essay writing service can help you accomplish more and achieve higher marks today.

Assignment Writing Service

From complicated assignments to tricky tasks, our experts can tackle virtually any question thrown at them.

Dissertation Writing Service

A dissertation (also known as a thesis or research project) is probably the most important piece of work for any student! From full dissertations to individual chapters, we’re on hand to support you.

Coursework Writing Service

Our expert qualified writers can help you get your coursework right first time, every time.

Dissertation Proposal Service

The first step to completing a dissertation is to create a proposal that talks about what you wish to do. Our experts can design suitable methodologies - perfect to help you get started with a dissertation.

Report Writing
Service

Reports for any audience. Perfectly structured, professionally written, and tailored to suit your exact requirements.

Essay Skeleton Answer Service

If you’re just looking for some help to get started on an essay, our outline service provides you with a perfect essay plan.

Marking & Proofreading Service

Not sure if your work is hitting the mark? Struggling to get feedback from your lecturer? Our premium marking service was created just for you - get the feedback you deserve now.

Exam Revision
Service

Exams can be one of the most stressful experiences you’ll ever have! Revision is key, and we’re here to help. With custom created revision notes and exam answers, you’ll never feel underprepared again.