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The pulmonary route of drug delivery has been used for thousands of years for the treatment of lung diseases such as asthma and COPD. 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.
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 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
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).
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 (Reference). 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). 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 was deposited mainly in the central airways and it increased airway obstruction by 11-fold than histamine which diffused into the airway, this suggests that surface concentration of a drug has affect on response (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 effectsand 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).
Inhalation delivery devices
The development of devices for inhalation can be divided in to three categories; nebulizers, metered dose inhalers (MDI) and dry powder inhalers (DPI), this is illustrated very well in Figure 2.
Figure 2. Illustration of the evolution of inhalation delivery devices.
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). One of the major advantages of using nebulizers over MDI's or DPI's is that there is no requirement of any specific technique or co-ordination in order to use it, whereas the MDI's and DPIs 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).
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, 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).
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 or DPI'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.
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).
The ultrasonic nebulizer uses 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.
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).
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). 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 (Aulton, Labiris and Dolovich 2003, 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). 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) 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). 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).
Figure 4. Illustration of MDI
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 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).
Formulating metered dose inhalers
Pressurized aerosols may be formulated as either solutions or suspensions of drug in the liquefied
propellant. Solution preparations are two-phase systems. However, the propellants are poor solvents
for most drugs. Cosolvents such as ethanol or isopropanol may be used, although their low volatility
retards propellant evaporation. In practice, pressurized inhaler formulations have, until recently, been
almost exclusively suspensions. These three-phase systems are harder to formulate and all the problems
of conventional suspension formulation, such as caking, agglomeration, particle growth etc. must be
considered. Careful consideration must be given to the particle size of the solid (usually micronized to
between 2 and 5 /mi), valve clogging, moisture content, the solubility of active compound in propellant
(a salt may be desirable), the relative density of propellant and drug, and the use of surfactants as
suspending agents, e.g. lecithin, oleic acid and sorbitan trioleate (usually included at concentrations
between 0.1 and 2.0% w/w). These surfactants are very poorly soluble (« 0.02% w/w) in HFAs, and
so either ethanol must be used as a cosolvent or
alternative surfactants such as fluorinated polymers
must be developed (Byron et al 1994). Recently
solution formulations of beclomethasone dipropionate
have been marketed. Evaporation of HFA propellant
following actuation of these formulations
results in smaller particle sizes than with conventional
suspension formulations of the same drug,
with consequent changes in its pulmonary distribution
Justin Gillis (January 28, 2006). "Inhaled Form of Insulin Is Approved". The Washington Post. http://pqasb.pqarchiver.com/washingtonpost/access/977402861.html?dids=977402861:977402861&FMT=ABS&FMTS=ABS:FT&fmac=&date=Jan+28%2C+2006&author=Justin+Gillis&desc=Inhaled+Form+of+Insulin+Is+Approved. Retrieved 2007-10-21.
Insulin was introduced by Banting and Best from the University of Toronto in 1921 as an injectable agent. German researchers first introduced the idea of inhalable insulin in 1924. Years of failure followed until scientists realized they might be able to use new technologies to turn insulin into a concentrated powder with particles sized for inhalation.
This technology was developed so that the inhaled insulin can effectively reach the lung capillaries where it is absorbed. Nektar Therapeutics of San Carlos, California developed this technology that paved the way for pharmaceutical companies to begin testing and formulating inhalable insulin. Once concrete methods were developed, human tests began in the late 1990s. In January 2006, the U.S. Food and Drug Administration (FDA) approved the use of Exubera which is a form of inhalable insulin developed by Pfizer