An Examination Of The Advantages Of Inhalation Therapy Biology Essay


Inhalation Therapy is becoming an attractive route and is a highly advantageous route of medication as aerosolized drugs in the treatment of Asthma or Chronic Obstructive Air ways Disease (COPD) and other respiratory diseases (REF). The main reasons for administration of these drugs via inhalation are that the delivered drug is rapidly absorbed from the alveoli to the blood and the systemic side effects can be minimized (REF). When a drug is given by inhalation it must be aerosolized. Medication is propelled from MDIs to patient by rapid evaporation of highly volatile chlorofluorocarbon propellants. Aerosols are relatively easy to administer, effective in much lower doses than required for oral administration and are easier to use than injection (Cheng, Yazzie and Zhou 2001).

Successful inhalation therapy commonly depends on proper drug deposition in the targeted airways; this is significantly affected not only by the type of inhalation device and its proper handling, but also by the respiratory manoeuvre that consists of a deep inspiration and breath holding for a few seconds performed by the patients (Kamin, et al. 2002) and the particle size and aerosol characteristics (combination of formulation and device) (Keller et al.1999; Cripps et al 2000).

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Dosing required to achieve a therapeutic effect are normally only one tenth to one fifth compared to an oral dose (Dobrozsi, Smith b and Sakr 1999).

Three main aerosol delivery systems that produce particles in the respiratory range have been devised namely, pressurised Meter Dose Inhaler (MDI), Nebuliser and Drug Powder Inhaler (DPI). However, the efficiency of inhalation therapy is not high since only about 10%-15% of the inhaled dose of the drug reaches the alveoli, and the major part is swallowed into the gastro-intestinal tract (Newman et al, 19981a).

1.1 Metered Dose inhalers

The Metered Dose Inhaler (MDI) is the most common device that helps deliver a specific amount of medication (a "Metered Dose") to the lungs. It is commonly to treat asthma, Chronic Obstructive Pulmonary Disease (COPD) and other respiratory diseases. The device consists of five components these are; the canister, the propellant (an excipient mixture), the metering valve and the actuator, or (Mouthpiece).

The design of pMDI is significantly different from other spray delivery systems being characterised by the following:

Formulations containing high vapour pressure hydroflouroalkane (HFA) propellants;

Spray generation, using small metered volumes of pressurised propellant;

Small particle size ranges between 1-5 µm (Smyth, et al. 2006).

A therapeutic mixture of medication and propellant were stored in the canister in the form of suspension or solution, as the mixture leaving the metering valve and hydroflouroalkane were used as propellant to generate an aerosol that was characterized by large particles and a very high speed (more than 30m/sec) at the mouthpiece (Ref). The spray from a pMDI basically travels at a high speed and rapidly changes in both size and velocity. However, monitoring the spray size from MDIs can be useful in both development of new products and the quality assurance processes of routine manufacturing. (Dolovich et al, 2000).

MDIs is a pressure packed system consisting of pressurized canister containing micronized drug powder dissolved or suspended into a liquefied propellants, surfactant which keep the drug particle in suspension, preservatives, and flavouring agents, with approximately 1% of the total contents being active drug . This mixture is released from the canister through a metering valve and stem that fits into an actuator. A small change in the actuator design can change a pMDIs aerosol characteristics and output (Dolovich et al, 2000).

The volume of aerosolized material with each actuation in different MDIs formulations varies from (25-100µl). All MDIs produced before 1996 containing chlorofluorocarbon (CFCs) propellant has been banned due to their implications in the depletion of ozone (June et al, 1994). Newer MDIs product containing hydroflouroalkane (HFA) as alternative propellants has recently been introduced (June et al, 1994).

1.2. Physical nature of the drug substance

Metered dose inhalers are formulated both as suspensions or conventional solutions of drug in the propellant. Excipient mixture with varying levels of surfactant in solution aerosols and addition of co- solvent delays the evaporation and generates larger particles (Kirk, 1972, Bell et al, 1973). Large amounts of co-solvents were used in order to dissolve the drug substance in the non - polar propellants (Naser et al, 1998).

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Suspension formulation contain a mixture of micronized drug surfactant, such as olieic oil, sorbitan trioleate (span85), or lecithin and the non volatile surfactants are added in small concentrations to help disperse the drug to improve the desired physical stability of the suspension and to function as lubricants for the metering valve (Moren F., 1981).

A non-volatile co solvent, such as ethanol, helps to solubilise the surfactant and may also help to disperse the drug to facilitate manufacturing or to improve the homogeneity of the formulation (Dalby et al, 1990), and is required to form a drug /Co solvent concentrate currently used for suspension formulations (Schultz et al, 1997).

pMDIs suspension are physically more unstable, suspension instability can be identified as creaming, flocculation, sedimentation and Ostwald ripening. However, suspension with poor stability does not only determine the dosing reproducibility but also affecting the respirable dose upon actuation (pharm res 2008). Therapeutic aerosols are "unstable" in terms of their aerodynamic behaviour such as some suspension may subject some changes to physical characteristics (e.g. particle size) as a result of temperature fluctuation (John Taylor and Ian Holloway, 2007).

Suspension also has the advantages of delivery of greater mass per unit volume than solutions.

In such systems the drug must be micronized (2-8 µm in size) if it is to be inhaled into the lungs (Buckton et al, 1995).

A well formulated suspension should be stable and re-dispersible after storage for prolonged periods, as stability and uniformity are important for safety and efficacy (Robert Price et al, 2007).

1.3. HFA MDI Solution Formulation:

The homogenous nature of metered dose inhaler (MDIs) formulations in which the drug solubilised or dispersed in the propellant may offer several advantages over the traditional formulation as suspensions (Dalby and Byron, 1988).

However, previous work has shown that significantly greater lung deposition has been demonstrated using pMDI containing solution aerosol formulation compared to suspension product in both healthy and asthmatic patients (Swarbrick,2007).

Another key advantage in formulating drugs as solutions in pMDI is the reducing primary aerosol droplet size by manipulation of the actuator orifice diameter. Solution system may be fired through smaller diameter actuator orifices compared to suspension MDIs (Evans et al, 1991). An increase in the vapour pressure of the formulation due to a change in the propellant mixture or an increase in temperature produces smaller particles (Polli et al, 1969). The same effect is obtained by a decrease in the diameter of the actuator orifice. However, clogging may occur if the orifice is too small, which can be a problem with suspension aerosols in particular (Moren F.,1981) Therefore, it is necessary that suspension - type MDIs are formulated "potentially respiring" in micronized particles (median diameter approximately 3µm) and these particles should not grow during the shelf life of the product ( ref).

The problems associated with solution aerosol is the propellant leakage from an MDI which is occurs by diffusion through the valve. The leakage rate is increases with increase in environmental temperature and may shorten the product shelf- life by raising the concentration of the liquid contents, therefore increasing the metered dose actuations (Swarbrick, 2007)

1.3. Crystal growth

Crystal growth can occurs by temperature fluctuations as small micronized drug particles slowly dissolve onto large particle (Oswald ripening) and cause crystallization in rod-like structures (Martin,1993) (Tzou et al, 1997).

Crystal growth can lead to a decrease the amount of respiring drug available to the patient and could influence the deposition in the respiratory tract in addition to disrupting the operation of the metering valve. (Dalby et al, 1991).

Hygroscopic particles increase in size as they flow through a moist stream (Dolovich et al, 2000) and particles can grow up to six times their original size as they travel down the airways depending upon airway tonicity and water content, which both are related to the airways temperature and humidity (Dolovich et al, 2000).

Hygroscopic effects can also appear in the peripheral airways, where the temperature is approximately 37°C and the humidity is 44mg/cm3 (Philip p j. Thompason, 1999).

The RH within the lungs is reported to be 99.5% (Porstendorfer,1971) and the hygroscopic particles with an initial diameter of 1µm of an aerosol particle can reach in human lung within approximately 1 second which is within the best residence time (Ferron,1977) (Martin,1988).

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To achieve accurate dose metering, good flow properties are required.

1.4. Dose uniformity

Rapid physical separation of the drug and propellant may lead to a lack of dose uniformity per actuations. The phase separation of the suspension problem is addressed by vigorously shaking the pMDIs immediately prior to use. Patient compliance with even the simple task is difficult to control which can affect dose uniformity and the size distribution of the dose. However, slight delays between shaking and administration can affect dose uniformity for poorly stabilised suspensions. (Dellamary et al,2000)

HFA 134a MDI can be more uniform and less dependent in actuation number or can fill volume than corresponding CFC system (Leach,1995;Smith,1995;leach, 1996; Elvecrgo,1997).However earlier studies of the in -vitro performance of salbutamol MDIs powered by CFCs, HFA134a showed differences in dose uniformity and suspension homogeneity due to the differences in formulations( propellants), valve and mouthpiece actuators ( Keller et al.,1997a).

In the British Pharmaceutical Codex BPC the dose available to the patient is determined by subtracting the amount retained in the actuator from the amount delivered by the valve. The bioavailability is dependent on the formulation of the pressurized aerosol and the aerodynamic diameter of the aerosol particles. However, it is also influenced by the patient's particle clearance and any pathological conditions in the respiratory tract. No satisfactory in vitro model is a available to cover these parameters (Moren F., 1981).

1.5. Lung Physiology

Figure 1: Diagram of the respiratory system. (

The lung may be used as a route for delivering drugs because of its large surface area (70-80m2) which facilitates rapid absorption of the inhaled drug. The respiratory tract can be considered as conducting (central region) and respiratory (peripheral region). Insoluble particles which land on the conducting airways are cleared from the lungs by mucociliary clearance or through coughing (Hasting et al, 1992).

The respiratory tract extends from the mouth and nose to the alveoli. The right lung is divided into 3 lobes (Upper, Middle and Lower) whereas the left has only 2 lobes (Upper and Lower). The upper airways have a very high filtering capacity and removes between 70 and 90% pressurised meter dose (pMDI) particles.

The specific anatomy of the lungs requires that compounds are delivered as fine aerosols with particle a size range of ~0.5-6 µm. The small airways (i.e., .2mm) have an increased surface area relative to the larger airways and are subject to a variety of lung diseases which, unfortunately,