| This year sees the 50th anniversary of the marketing of the
first pressurised metered dose inhaler (pMDI) for epinephrine and isoproterenol,
by Riker Laboratories. The Medihaler was developed initially by the company
as a locally administered aerosol delivery device for the treatment of
asthma but was found subsequently to have many other uses. The pMDI represented
a milestone in the development of inhaled drugs, being one of the first
and simplest examples of targeted drug delivery.
Symptomatic control of episodes of wheezing and shortness of breath is
generally achieved with fast-acting bronchodilators and such attacks can
be prevented with frequent use of corticosteroids. Typically, these are
delivered by pMDIs that comprise five parts:
• The medicine
• The propellant
• The canister
• The metering valve
• The mouthpiece
The system is inherently tamper proof and, as a sealed system, minimises
the effect of the environment on the formulation. Pressing down on the
inhaler releases a mist of medicine, which is then inhaled into the lungs.
It is most commonly used to treat asthma, chronic obstructive pulmonary
disease and other respiratory problems. Other aerosol delivery systems
include dry powder inhalers and nebulisers.
History of inhaled therapies
Inhaled therapies have been used since ancient times and may have had
their origins with the smoking of datura preparations in India 4,000
years ago. In the late 18th and in the 19th century, earthenware inhalers
were popular for the inhalation of air drawn through infusions of plants
and other ingredients.
Atomisers and nebulisers were developed in the mid-1800s in France
and were thought to be an outgrowth of the perfume industry as well
as a
response to the fashion of inhaling thermal waters at spas. Around the
turn of the 20th century, combustible powders and cigarettes containing
stramonium were popular for asthma and other lung complaints. The use
of inhaled epinephrine for relief of asthma was reported as early as
1929 in England1 and subsequently a variety of hand-bulb and early compressor
nebulisers were developed.
Inhalation became a mainstay of respiratory care in the 20th century.
Despite problems with low lung deposition with all the early devices,
evidence accumulated that supported the advantages of the inhalation
route over other drug-administration routes. Inhaled drugs are localised
to the target organ, which generally allows for a lower dose than is
necessary with systemic delivery and thus results in fewer and less severe
adverse effects.
The development of the pMDI began with the complaint of a young asthma
sufferer. The 13-year-old daughter of George Maison, president of Riker
Laboratories (acquired by 3M Pharmaceuticals in 1970), suffered from
severe asthma and took her daily medicine from the common apparatus of
the time, a squeeze-bulb glass nebuliser. The nebuliser was bulky, broke
easily and had to be freshly loaded for each dosage. Further, it could
not deliver a uniform dose, although it did deliver medicine right to
the lungs.
Dr Maison’s daughter finally asked him one day, “why can’t
they put my asthma medicine in a spray can like they do for perfume?”.
Dr Maison took this question seriously and put the idea forward to his
company’s pharmaceutical development laboratory for action. In
1956, Charles Thiel, a chemist who is credited with producing the first
MDI, began working with Irving Porush, head of Riker’s development
laboratory. Porush had developed a prototype inhaler using the most rudimentary
materials — propellant purchased from DuPont, alcohol to dissolve
the drug, an old ice-cream freezer, empty soda bottles as pressure containers
and a bottle-capper. Porush’s inhalers were filled-in perfume vials
capped with metering valves which had been invented by Philip Meshberg
and licensed to Riker Laboratories.
The first pMDIs were based on dissolving the drug in ethanol and using
liquefied compressed gases and chlorofluorocarbons (CFCs) to force the
mixture through an atomising nozzle. The research team attempted to substitute
water for alcohol to eliminate the stinging in a nasal decongestant.
Some 114 solutions were tried, nearly all of which were dismal failures.
The problem was finally solved by eliminating both water and alcohol
from the formulation.
After clinical trials had shown efficacy, a cold-fill manufacturing process
was developed. In March 1956, new drug applications were approved for
the OTC bronchodilator Medihaler-Epi (epinephrine) and the prescription
only version Medihaler-Iso (isoproterenol). Three months later, and less
than a year after the project was launched, these products were packaged
and ready for for marketing. The UK trademark for Medihaler-Iso was granted
in August 1958 and it was included in the first British National Formulary
in 1981.
Following the launch of the first pMDIs, Riker began to work on two novel
systemic applications for the new technology: the delivery of insulin
and amyl nitrate. Unfortunately these early attempts were not successful.
Insulin was incompatible with the early formulations. The amyl nitrate
inhaler Medihaler-Nitro was launched, but, although the product worked,
patients preferred the ease and discretion of a tablet under the tongue.
Subsequently, the surfactant Span 85 (sorbitan trioleate) was used to
create suspension formulations. This enabled the formulation of insulin
and animal trials were conducted. Although some effect was seen, the
response was variable and the product was not developed further.
In 1959 Riker launched Medihaler Ergotamine (ergotamine tartrate) for
migraine headaches, as an alternative to the oral route of drug delivery.
The product was successful and remained on the market until the late
1990s. Duo-Medihaler (isoproterenol and phenylephrine chloride) was the
first synergistic combination and became available in 1962.
Subsequent development of formulations with drug particles in suspension
enabled better uniformity with the dosage. The first nasal product, Medihaler-Phen
(a mixture of phenylephrine, neomycin and hydrocortisone) was launched
in March 1957, a year after the first pMDIs.
Breath-activated devices
Work proceeded to address the problems posed by poor inhalation technique
and inadequate pulmonary deposition. An early breath-activated device
was promoted in 1974. The pocket-sized inhaler was claimed to be easy
for patients to use. However, some complained that the loud “click” that
resounded when the mechanism fired was disconcerting. As a result,
the device was sidelined until the company eventually developed Aerolin
(salbutamol), the world’s first breath-actuated inhaler in 1989.
This proved popular for patients who could not co-ordinate the “press
and breathe” action of the original device.
Following the first pMDIs, dry powdered inhalers (DPIs) became available.
Early DPIs included the Spinhaler for cromolyn, introduced by Fisons
in 1971, and the Rotahaler for albuterol, introduced by Glaxo in 1977.
Because of deleterious effects that CFCs have on the ozone layer, the
Montreal Protocol was adopted by the United Nations in 1987 to ban substances
that deplete the ozone layer. Although inhalation aerosols were responsible
for less than 1 per cent of the total CFC production, the pharmaceutical
industry now faced a turning point. This ban led to the phasing out of
CFCs by 1996, although pharmaceutical companies had exemptions. The ban
posed significant technical challenges and had a large effect on the
development of inhaler technology.
Alternative to CFCs
There were two stages to the development of a suitable alternative.
First, there was the challenge of developing an appropriate formulation
to
deliver the appropriate amount of medicine to the appropriate part
of the lung. Only after this was achieved could a company move to the
second phase of development: clinical testing to prove that the product
is equivalent to the existing CFC-containing product.
Hydrofluoroalkane (HFA) propellants were found to be generally effective
substitutes but changed the properties of the pMDI spray. HFA-propelled
beclometasone required reformulation as a solution rather than as a suspension
and the resulting aerosol contained a much higher fraction of fine particles,
which exited the inhaler at a lower velocity. There was also higher lung
deposition (several CFC-based MDI formulations delivered as low as 5
per cent to 10 per cent of the total dose) and lower oropharyngeal deposition.
3M produced the first HFA pMDI system in 1995, for which the company
received a Stratospheric Ozone Protection Award from the US Environment
Protection Agency.
In some cases the CFC problems have still not been resolved. In the US
a joint meeting of the Non-Prescription Drugs and Pulmonary and Allergy
Advisory Committees was held in January 2006 to discuss the status of
OTC epinephrine MDIs that still use CFCs as the propellant.
GlaxoSmithKline has announced that it is to discontinue Becotide and
Becloforte from the third quarter of 2007, since there is now a range
of CFC-free beclometasone inhalers on the market. The company has been
unsuccessful in securing licences for dose equivalent CFC-free MDIs.
Therefore it will not be introducing CFC-free Becotide and Becloforte
MDIs in the UK.
Manufacturers of CFC-free MDIs recommend regular washing of the devices
to ensure continued, reliable performance and this information is conveyed
in the patient information leaflets supplied with these products. Anecdotal
evidence from patients suggests that some CFC-free MDI devices frequently “seize
up” or “become blocked”, despite an adequate reservoir
of drug in the pressurised cannister. These observations indicate a potential
problem with the performance and reliability of the devices.
Problems with inhalers
Poor user technique and adherence are significant problems with all
types of inhalers and there has been much development work to try and
address
them. In an Italian study Sestini et al demonstrated that inhaler misuse
was common and similar for pMDIs and DPIs. For both types of inhalers,
misuse was significantly and equally associated with age, those with
a poorer education and those who had received little instruction from
health care personnel. The “Global
burden of asthma report” (PJ,
8 May 2004, p562) stated that poor adherence to medication is one of
the key factors contributing to asthma deaths. Appropriate counselling
at the point of supply is thus vital.
A further problem is associated with continuity of supply. Patients
may run out of medicine or they may discard their device before it
is empty
to ensure that they do not run out, costing the NHS money. Considering
the sophistication of pMDI technology it is surprising that individual
patients in the UK do not currently have a reliable means of monitoring
the contents of their metered-dose inhalers. Traditional methods of guessing
at the amount of medicine remaining in each canister (weighing, floating
in water, shaking, etc) are inaccurate. 3M has said that it is working
on the development of a device with dose counting technology in the US
and expects it to be available globally in the future. Other enhancements
are being made in ergometric design, including new valves to improve
dose consistency.
Although the first inhaled macromolecule developed was in a pMDI, the
current trend is to use dry-powder or liquid-based inhalers. However
it has been demonstrated in recent years that there is no evidence to
show that these alternative inhaler devices are more effective than standard
pMDIs for delivering beta2 agonist bronchodilators in asthma. pMDIs generally
remain a cost effective delivery device although some of modern entrants
to the market may be considered expensive.
All inhalation drug delivery systems (nebulisers, DPIs and MDIs) have
progressed over the past 10 years in the areas of new device and formulation
technology. These technological advances provide exciting opportunities
for patients to improve further their quality of life. With many future
therapies likely to involve short courses of treatment, smaller pack
sizes will be required in the future. Already there is a variety of pack
sizes for pMDIs, the minimum being seven doses and, potentially, just
one for vaccines. Trials involving the administration of insulin by pulmonary
delivery systems are already in progress.
Expanding the capability
The opportunity for safe, painless drug delivery to the systemic circulation,
especially for the newer class of protein and peptide pharmaceuticals,
would be a landmark for patients who seek alternatives to injections.
Inhalation drug delivery provides the option of treating the lung
locally or using the lung as an organ for drug absorption to the systemic
circulation.
3M has been working to develop the tools required to maximise the
stability and delivery profile of protein and peptide therapeutics using
the
MDI. The company has also developed several classes of novel excipients
to increase the capability of the MDI. Its goal is to expand the
range of compounds that can be successfully formulated in the MDI and
to
increase the clinical benefits obtained from the MDI by providing
new capabilities such as sustained release or greater respirability.
Studies
have been completed in several areas, including particle size reduction,
container and closure compatibility, and formulation.
With world-wide production exceeding 500 million devices annually
and different manufacturers launching ever more sophisticated models,
the
future of the pMDI looks safe for the foreseeable future. |
The
Pharmaceutical Journal