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To maintain a maximum use of pressurized metered - dose inhalers, the device must be shaken vigorously before each inhalation, doing so help in preventing variation doses that reaches tha patient's lung and extend the life span of the device (D.Lucini et al,2005). The medication in metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of those two, and mainly designed for a limited number of usages that can be clearly printed on the canister, it is advisable to follow the instructions because the inhaler may continue to work beyond the labelled number of uses in spite of the amount of medication delivered may not be correct, therefore it can be replaced after its recommended number of uses.
A deep and slow, rather than quick, inhalation followed by a breath -holding for at least 4 seconds before the exhalation can significantly maximize the deposition of aerosol in the lower respiratory tract (Pavia et al, 1977). However, holding the breath for 10 seconds after inhalation enables particle to be deposited in the peripheral areas and improve pulmonary bioavailability compared to not holding breath (Newton et al, 1993). Moreover, Breath holding enhances deposition by facilitating sedimentation and diffusion ( Dolovich et al, 2000 ).
The most widely used inhalation devices are the pressurized metered-dose inhalers (pMDIs) because of their effectiveness, low cost, and relative simplicity of use. However, many patients are unable to coordinate inspiration with pMDI activation, which may lead to failure of therapy. To overcome this, the use of dry-powder inhalers (DPIs) or spacer devices attached to the pMDI has been proposed. (Ref)
On the other hand, according to previous study conducted by Newman, only about (10% to 15%) from dose inhaled expected to reach the lung, the reason attributed to the time delays between aerosol actuation and inhalation (Newman et al, 1984). Another previous study demonstrated that less than 30% of the inhaled drug has been reached to the lung and 38% of incorrect user have been reported (MC fadden, 1995) and most of the remainder impacts on the oro-pharynx (Hickey and Dunbar, 1997) However, according to a review of previous studies (21 studies), the pMDI misusers ranges from 14-90% with an estimated average of 50% misuse decreases lung deposition from 20% to 7% (N.Roche and V. Giraud,2002).
Table 1: incidence of patient's misuse of pMDIs
Incorrect use (%)
Position in mouth
Actuated at start
Continue to inhale
Adapted from Respiratory Medicine 13-16 ( D.GANDERTON,1997)
Shim and Williams reported that 47% of experienced pMDI users used an incorrect technique the most common mistake was to actuate the inhaler too late in the inspiration cycle. So the question of increased incorrect use remains amajor problem, to overcome this problem spacer devices attached to the pMDI has been suggested. Correct and safe performance of metered dose inhalers is essential for efficient treatment of asthma under all climatic conditions.
1.12. Pros and Cons of meter dose inhalers
The (pMDI) is a portable multi dose inhaler, convenient and easy to use by patients due to its portability, durability, reliability, and longer shelf life and less expensive than other respiratory delivery systems and safe method for delivering bronchodilator aerosols. About 80% of inhalation therapies in the world's largest world patient populations are delivered by MDI (International Pharmaceutical Aerosol Consertium, 1997).
1.12.1 The drawbacks of the MDIs
First, an optimum drug delivery may not be achieved due to the poor synchronisation between actuation and inhalation during inspiration, the so called "hand-lung" co-ordination is often found difficult to perform in children or severely ill patients (Coady et al.1976; Orehek et al; 1976).
Second, because a high velocity and large size of the inhaled particles a major portion of the aerosol is impact in the oro-pharyngal region by inertial impaction (Kim et al, 1989). The excessive oro-pharynx deposition often can be undesirable and induces local and systemic side effects (kim and Luis, 1993).The other drawbacks are :
Droplet leaving the actuator orifice can be too large (Moren F, 1981) and have an extremely high velocity (Race, 1974) resulting in extensive oro-pharyngeal deposition.
The output of the MDIs and the synchronise of the aerosol discharge with inspiration.
The dimension of the metering valve and the actuator orifice limits the maximum amount of dose delivered to about 1mg (Ganderton and Kassem, 1992)
The inconsistent dosing towards the end of the canister life dependant on shaking, priming, actuation time and can content.
Cold feeling "Freon effect" (early breath cut off) after actuation due to the immediate evaporation of the propellant.
High oropharyngeal deposition due the ballistic component of the aerosol.
Lack of clear indication of remaining number of dose in the canister.
Highly variable and low deposition the peripheral regions of the lung (5-25%) of the labelled dose depend on the inhalation technique.
1.14. Generation of aerosol particles
The redesign of valve and actuator HFA may produce "softer puff than from traditional CFC inhalers. The new generation of CFC- free MDIs provide significant improvements in dose reproducibility (J.Gabrio et al 1999). CFC have been the customary propellants used in MDIs (Hoye;et al,2005).The switch from chlorofluorocarbon (CFC) to hydrofluoroalkane (HFA), resulted in characteristic changes in plume properties and particle size distributions in the aerosol, the two major replacement of reformulated product (HFA),which has become mandatory in the new pMDIs(Tansey,1997),includes,1,1,1,2-tetraflouroethane (C2H2F4,HFA134a),and 1,1,1,2,3,3,3,- heptafluoropropane (C3 H F7,HF A227) (ZongTzoux et al,1997). These compounds comprise C-F bonds, which are the strongest single bonds in organic chemistry, and chlorine free (N.Butz et al,2002). Hydroflouroalkane (HFA) are more popular than CFCs and have poorly characterised solvency properties than CFC (Byron et al;1994).
The most common three CFCs are:
1,2 dicholurotetrafluromethane CFC 114.
1.15. Physical properties of the propellants
The vapour pressure of the pMDI determines the speed and rate of evaporation which in turn will influence the aerosol droplets size and the efficiency deposition within the lung. High vapour pressure will provide small droplets due to rapid propellant evaporation (Moren F., 1981).
Only CFC12 exhibits a boiling point below 0Co (MC Donald and Martin, 2000). Also CFC12 have a high vapour pressure of 350-450 kPa at room temperature and is highly volatile. The propellant blends with other CFC used pMDIs in order to reduce the final vapour pressure within the can. In contrast to CFCs, propellant, HFA 134a and HFA227 differ significantly in vapour pressure; 570 and 390kPa at 20Co, respectively. Addition of co-solvent and non-volatile additive lower the propellant vapour pressures, although for HFA134a systems remain higher than for equivalent HFA227systems.The HFA 134a and HFA227, both have boiling points of less than -15Co. The similarity of their boiling points means that HFAs cannot be blended in order to reduce their volatility (Zong Tzoux et al, 1997).
The replacement of CFC propellants with reformulating products of Metered Dose Inhalers resulted in the manufacturers having had to consider whether their objective therapeutically equivalent to the original CFC containing products or to improve the performance of new products. Some reformulated Metered Dose Inhalers have been designed to improve the amount of drug delivered into the lungs with consequent dose reduction compared to earlier products containing CFC propellants (Leach.1998). The vapour pressure, density and viscosity of the propellants are critical physico-chemical properties that influences the physical stability and the performance of pMDIs ( Philip p.Thompason,1999), such as the aerosol droplet velocity increased with increasing vapour pressure (Rance,1974) results in a finer droplet size causing inertial impaction in the oropharyngeal ( Gonda, 1992;Newman et al.,1982; Harnor et al.,1993). Smaller metering volumes may also produce a finer aerosol with higher respirable fractions and more peripheral lung deposition. Respirable fractions may decline with increasing volume of the metering chamber as well as increasing drug concentration per shot (Dolovich,1995).
Table 2: Physico-chemical and atmospheric properties of propellants used in (pMDIs)
Density (g/ml)at 20Â°C
Boiling point Â°C at
C2 H2 F4
C3 H F7
C F Cl3
C Cl2 F2
C2 Cl2 F4
Adapted from respiratory care 2000,vol 45 No6,page 623-35
From the table above we can see the propellant HFA-134a has extents higher vapour pressure at room temperature. Temperature control is critical because of the strong dependence of propellant vapour pressure on temperature; the most common transport regulation IATA specified that the pressure should not exceed15.00 kpa at 55Â°C(REF) and most licences specified storage temperature at 25Â°C or less which is require during storage, transit, and handling(royal socity.2004).
The transition to the new environmentally acceptable HFA propellants has been difficult, due to the poor solvency properties of the HFA, which limits the solubility of surfactants (i.e. oleic acid, lecithin and sorbitan trioleate) (Byron et al.,1994). The potential problems associated with the use of co-solvents such as ethanol to increase the solubility of these surfactants include, chemical instability of the drug substance, extraction of elastomeric components from the valve, enhanced Ostwald ripening and alcohol taste not to the liking of some patients (Ref).
1.16. Inhalation Mechanism
The respiratory tract consists of multiple branching airways (pharynx, larynx, trachea, bronchioles and alveoli). Deposition in the respiratory tract take place by a combination of three physical mechanisms; namely:
1.16.1 Inertial impaction
This deposition mechanism, mainly in the larger airways, (particles >5 Âµm) is highly dependent on the mass and velocity of the particles and the effect of high momentum of certain particles in an aerosol cloud. A particle with high momentum is less able to follow changes in direction of air stream as it passes the bifurcation. As a result, the particle instead impact on airway walls. The proportion of particles deposited by inertial impaction in the airways increases with particle size and air flow rate (Lippman, 1997). Deposition is proportional to log (d2 f), where (d) is a particle diameter and (f) is inhalation flow rate. Particles with an aerodynamic Mass Median Diameter (AMMD) bigger than 10Âµm are deposited in the upper airways by impact. The AMMD is the diameter around which the mass of particles is equally divided, 50% of the mass residing in particles less than 5 Âµm and 50% in particles greater than 5 Âµm.
The distribution of the particles may be mono-disperse or hetero-disperse. Therapeutic aerosols are generally hetero-disperse. This means they have a geometric standard deviation of less than 1.2. The density of aerosol depends largely on the aerosol generator.
1.16.2. Gravitational sedimentation
The gravitational sedimentation, mainly in the smaller peripheral airways and in the alveoli, inhaled particle depend on size, density and residence time in the airways. As the particles of drug move with the air in laminar flow in the airways, they fall under the force of gravity. This deposition mechanism for particle size between 0.5Âµm to 3 Âµm, in the small airways and also applies to larger particles under low flow rate or with low density. Gravitational tends to be influenced by breath-holding.
The sedimentation that occurs in more peripheral airways is gravitational in character and allows more time for gravity to have an effect (Philip p j.Thompason, 1999). The inhalation of low flow rate enhances sedimentation and therefore increases deposition in the more distal small airways, whereas high flow rates promote impaction and increase deposition in the large airways. The bigger the aerosol containing part of the tidal volume, the bigger the lung deposition (Heinrich Mathys, 1990).
1.16.3. Brownian Diffusion:
Collision and bombardment of small particles by molecules in the respiratory tract produce Brownian motion. The effectiveness of deposition by diffusion increases as particle size reduced, which contrasts with the above particle with 0.5 Âµm in diameter. However, particle of this size have the minimum probability of deposition in the upper respiratory tract. (Attwood, 2006)
1.17. In -Vitro Characterisationof aerosol:
There are many ways in which aerosol particle size of PMDIs can be measured in vitro using microscopic method, time of flight, aero-size, sedimentation cells and light scattering, currently inertial impaction and impinger are considered as the "golden standard" for inhaler testing. Because the yield mass fractions of the drug dose that classified into tow aerodynamic size ranges that are relevant to particle deposition in human respiratory tract. Sizing data techniques are capable of chemical identification and measure the aerodynamic diameter of particles (was highlight by Edwards et al, 1997), but they are laborious, time consuming, and bulky to use (de Boer AH, 2002)