Research Article: Asthma pressurised metered dose inhaler performance: propellant effect studies in delivery systems

Date Published: June 29, 2017

Publisher: BioMed Central

Author(s): William F. S. Sellers.


Current pressurised metered dose asthma inhaler (pMDI) propellants are not inert pharmacologically as were previous chlorofluorocarbons, have smooth muscle relaxant‚ partial pressure effects in the lungs and inhaled hydrofluoroalkane 134a (norflurane) has anaesthetic effects. Volumes of propellant gas per actuation have never been measured.

In-vitro studies measured gas volumes produced by pMDIs on air oxygen (O2) levels in valved holding chambers (VHC) and the falls in O2% following actuation into lung ventilator delivery devices.

Volumes of propellant gas hydrofluoroalkane (HFA) 134a and 227ea and redundant chlorofluorocarbons (CFC) varied from 7 ml per actuation from a small salbutamol HFA inhaler to 16 ml from the larger. Similar-sized CFC pMDI volumes were 15.6 and 20.4 ml. Each HFA salbutamol inhaler has 220 full volume discharges; total volume of gas from a small 134a pMDI was 1640 ml, and large 3885 ml. Sensing the presence of liquid propellant by shaking was felt at the 220th discharge in both large and small inhalers. Because of a partial pressure effect, VHC O2% in air was reduced to 11% in the smallest 127 ml volume VHC following 10 actuations of a large 134a salbutamol inhaler. The four ventilator delivery devices studied lowered 100% oxygen levels to a range of 93 to 81% after five actuations, depending on the device and type of pMDI used.

Pressurised inhaler propellants require further study to assess smooth muscle relaxing properties.

Partial Text

Inhaled therapy delivery devices for asthma and chronic lung disease such as oxygen driven jet nebulisers, pressurised metered dose inhalers (pMDI), and valved holding chambers (VHC) have little evidence or research to support their efficacy [1, 2]; historical use determines current practice. The amounts of drugs deposited, and in which part of the respiratory tract absorption occurs, is based on intuition rather than research. Inhaled asthma drugs are erroneously considered to act directly through local absorption into receptors, and not systemically. The physical and pharmacological properties of the propellant and drugs in pMDIs gives a scientific explanation and reason for the increasing use of pMDIs and VHCs to manage acute severe asthma in place of evidence-baseless jet nebulisation of beta2-agonists in saline. Inhaled anaesthetic agents and stupefants (glue, butane) descend deep into the lung architecture where bronchial and alveolar absorption into blood is followed by vascular delivery to the whole body. Beta2-agonists in respiratory disease arrive at bronchial smooth muscle receptors from bronchial arteries, and one cardiac cycle later by pulmonary arteries. Inhaled terbutaline has been studied for uterine tocolysis. Upper respiratory tract and oral absorption also play an unknown-percentage part in the delivery of inhaled drugs to target organs. There are corticosteroid receptors in the bronchial epithelial lining cells, which may account for the thought that inhaled drugs act locally and remain in the lungs. The propellants of pMDIs have had little scrutiny, either of previous chlorofluorocarbon (CFC) di-chlorodi-fluoro and tri-chlorofluoro methanes, current hydrofluoroalkanes (HFA) 134a and 227ea. HFA (hydrofluorocarbon) inhaler propellants replaced chlorofluorocarbons in the late 1990s, but propellant toxicological research was incomplete and an anaesthetic effect of HFA134a was missed. Asthma inhaler actuation produces a measurable volume of propellant gases, CFCs, HFA134a, HFA227ea, and as per John Dalton’s Law of partial pressures, oxygen and nitrogen in air are reduced in the lungs during inhalation. Inhaler abuse for recreational purposes occurs and Olympic endurance athletes with asthma have out-performed their healthy rivals since the year 2000 [3, 4], interestingly mirroring replacement of inert CFCs by the improved delivery effects of pharmacologically active HFA propellants.

In vitro experiments were performed using anaesthetic equipment and oxygen monitors; pMDIs were well shaken prior to actuation.

No research has been performed to quantify the bronchodilating actions of HFA134a and 227ea. Delivery from pressurised metered dose inhalers (pMDIs) relies on these two fluorinated hydrocarbon propellants with low boiling points. The majority of pMDIs use hydrofluoroalkane (HFA) 134a, norflurane, formula CF3CFH2, an anaesthetic agent of intermediate potency, described in 1967. The gas was studied in dogs, cats and monkeys, and required 50% in oxygen to anaesthetise dogs: “Action was rapid and readily reversible, overdosage is difficult and vital functions appear to be protected even at very high concentrations”. No human studies were performed on anaesthetic effects. This publication is not cited in any toxicology study of the propellants, possibly because the Shulman and Sadove [12] publication title used the alternative name for HFA134a of 1,1,1,2-tetrafluoroethane (TFE). This has a similar chemical structure to the inhalational anaesthetic agent halothane; a bromine and chlorine is replaced by an additional fluorine and hydrogen. Halothane and all other hydrofluorocarbon (hydrofluoroalkane) anaesthetic agents are potent smooth muscle relaxants of gut, vasculature, uterus and bronchi. HFA 227ea, apaflurane, CF3CFHCF3, the other pMDI propellant, is chemically similar to the inhalational anaesthetic agent isoflurane but has no anaesthetic activity. Both propellants are refrigerants, the boiling point of HFA 134a is minus 26.3 °C, and of HFA227ea is minus 17.3 °C. Corticosteroid pMDIs contain 13% ethanol to improve solubility, one salbutamol pMDI (Respigen™, Mylan, Auckland, NZ) has 7% ethanol; all other salbutamol HFA MDIs have 1% ethanol added. The high percentage of ethanol is the likely reason for cough following inhalation of corticosteroid.

A greater volume of HFA134a propellant per actuation is produced by large salbutamol metered dose inhalers, 16 ml versus 7 ml for the smaller. If this propellant on its own relaxes bronchial smooth muscle and the gas aids drug delivery (including corticosteroid), then large metered dose inhaler actuation gives maximum bronchodilation for patients and athletes (and huffers). Exhaustion of pMDIs can be sensed by shaking, inhalers are now produced using a mechanical system with a numbered dial to count down each actuation. Further research on bronchial smooth muscle effects of HFAs may be performed with available propellant—only pressurised metered dose inhalers which are used to assess efficiency of inhalation by patients.