Chiesi Farmaceutici, S.p.A. - Commercialisation of Modulite® technology for pressurised metered dose inhalers
Submitting InstitutionUniversity of Bath
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Engineering: Interdisciplinary Engineering
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Pharmacology and Pharmaceutical Sciences
Summary of the impact
The transition, at the end of the 20th century, from
ozone-depleting chlorofluorocarbons (CFCs) to hydrofluoralkane (HFA)
propellants in metered dose inhalers (MDIs), for drug delivery to the
upper airways in the lungs, taxed the ingenuity of formulation scientists
and device design engineers. The regulatory requirement for clinical
equivalence between the CFC and HFA products demanded an unchanged drug
dosing regimen and identical lung deposition profiles.
Research funded by Chiesi Farmaceutici (Parma, Italy) in the Centre of
Drug Formulation Studies (CDFS) at the University of Bath led to
development of the Modulite® technology which met the
challenges posed and mimicked the performance of CFC MDI using HFA
propellants. The proprietary technology enabled Chiesi to re-formulate and
commercialise a number of products, which now represent mainstay therapies
in the treatment of asthma and chronic obstructive pulmonary disease
The Modulite® technology has provided the greatest
contribution to both the turnover and the global development of the Chiesi
group, via several successful in-house developmements and collaboration
agreements with leading pharmaceutical companies. Global sales of Chiesi's
Atimos Modulite®, Fostair/Foster (25% of sales) and Clenil
Modulite® (14.4% of sales) MDI products produced revenue of in
excess of $450 Million in 2012.
Metered dose inhalers (MDIs) are one of the main treatments for asthma
and chronic obstructive pulmonary disease (COPD). For decades, CFCs were
the most suitable propellant for use in MDIs, but were subsequently
identified as contributing to ozone destruction and damage to the Earth's
ozone layer. Although CFC MDIs were granted a temporary "essential use"
status under the Montreal Protocol on substances that deplete the ozone
layer, they were required to be phased out when alternative technologies
and regulatory approval of CFC-free MDIs could be obtained.
The switch from 40 years of research and technical understanding with CFC
metered dose inhalers to HFAs was simple in principle but scientifically
very challenging. Differences in the physical and chemical properties of
CFCs and HFAs created significant problems in the reformulation of
existing suspension-based MDI products. For example, conventional
surfactants used in CFCs were not soluble in HFA liquefied propellants.
The gasket seal materials used in CFC valves were not compatible with
HFAs, and the differences in the thermodynamic properties of the liquefied
propellants required a new actuator design to obtain correct particle size
and plume geometry.
With the need to develop pharmaceutical and therapeutically equivalent
products, researchers at the University of Bath developed in collaboration
with, and funded by, Chiesi Farmaceutici S.p.A., a novel solution-based
technology that enabled a simple yet elegant approach to mimicking the
performance characteristics of the existing CFC products [1,2]. A team of
three scientists was led by David Lewis, an aerosol scientist at CDFS
(1996 - 1999), and supervised by Brian Meakin, Senior Lecturer in the
Department of Pharmacy & Pharmacology, and Director of its Centre for
Drug Formulation Studies (1960 - 1997). The platform technology allowed
the manipulation of HFA-based systems by permuting two inter-dependent
variables: the addition of a non-volatile component to the formulation and
the geometry of the actuator orifice. Together with two minor variables
(quantity of co-solvent and metering volume) to further refine
performance, the Modulite® technology enabled modulation of
aerosol cloud formation with well-defined aerodynamic particle sizes and
plume speeds .
The addition of an inert, non-volatile additive provided a means of
controlling particle size, as the final particle size distribution of a
dry droplet will depend on the concentration of drug within the droplet
and any other non-volatile component that has been added. With the
addition of glycerol and polyethylene glycol, the aerodynamic particle
size distribution of an aerosol cloud, the mass median aerodynamic
diameter (MMAD), can be altered by controlling the volumetric contribution
of the non-volatile component using a relatively simple formula [4,5].
Assuming that the aerosol cloud particles approximate to a spherical
geometry, the particle diameter (d), is related to the cube root of the
volume. For a given combination of drug, non-volatile additive and
propellant, and assuming that the spray pattern is maintained, and that
density changes are small as composition varies, the increase in the MMAD
from a baseline value of MMAD0 to MMAD1 can be
theoretically be determined by: MMAD1 = MMAD0·(m1/m0)¾
, where mo is the mass of drug in the propellant and m1
is the mass of drug plus non-volatile additive.
With the Modulite® approach, it is possible to develop
HFA-based solution formulations where the cloud characteristics can be
tailored to meet specific needs, allowing various drugs such as short-and
long-acting beta agonists, corticosteroids and anti-cholinergics to be
readily re-formulated in HFA MDIs [4,5]. The outstanding achievement and
contribution that Modulite® technology made at a time when the
European Union ended the use of CFC-based inhalers was highly significant.
Modulite® was awarded the 2006 Frost & Sullivan Technology
Innovation Award for demonstration of technological superiority within the
References to the research
1. Brambilla, G., Ganderton, D, Garzia, R., Lewis, D., Meakin, B.J. and
Ventura, P. Modulation of aerosol clouds produced by pressurised
inhalation aerosols. Int. J. Pharm., 186 (1999) 53-61. DOI:
2. Meakin, B., Lewis, D., Ganderton D. and Brambilla, G. Countering
challenges posed by mimicry of CFC performance using HFA systems.
Respiratory Drug Delivery VII, (2000) 99-107. Available on request
from the HEI.
3. Ganderton, D., Lewis, D., Davies, R., Meakin, B., Brambilla, G. and
Church, T., Modulite®: a means of designing the aerosols
generated by pressuized metered dose inhalers. Respir. Med. 96 (2002)
4. Ganderton, D., Lewis, D., Meakin, B., Brambilla, G., Garzia, R. and
Ventura, P. Pharmaceutical aerosol composition. (1997) UK Patent
Application Number 9712434.1. Patent published in 2008 (WO1998/056349). http://www.google.com/patents/WO1998056349A1?cl=en
5. Lewis, D., Ganderton, D., Meakin, B., Brambilla, G., Garzia, R. and
Ventura, P. Pressurised metered dose inhalers (MDI). US Patent filling in
1999. Patent granted in 2008 (US7347199).
Details of the impact
The technology, which was invented and developed at the University of
Bath, was patented in 1997 and eventually transferred to a purpose-built
MDI filling line at Chiesi Farmaceutici S.p.A., Parma, Italy [4,5]. All
research and development activities relating to the Modulite®
technology remained within the Centre of Drug Formulation Studies (CDFS)
at the University of Bath until 2000. For several years thereafter, Chiesi
then sponsored further fee-for-service development work employing 17
members of staff before, in 2010, the Italian parent company opened its
own purpose-built laboratories in Chippenham. The original University of
Bath employees, who had conceived the Modulite® technology, and
had been working on the Chiesi-sponsored research and development, formed
the core of this new structure (Chiesi UK, Ltd.). The laboratory at
Chippenham (which now employs 13 full-time staff) is tasked with producing
new formulations having improved drug delivery efficiency resulting in
enhanced absorption and therapeutic efficacy of the Modulite®
The Drug Delivery Technologies Director of Chiesi has stated that, "The
team at Bath... showed that addition of a low volatility component to a
propellant containing HFA and a co-solvent to solubilise the drug could
controllably increase the aerodynamic diameter of the aerosol particles
on actuation from a metered dose inhaler (MDI). Their input led to [the]
patent application on the addition of a low voltaility component in
modulating an MDI having HFAs as propellant that was pharmaceutically
and clinically equivalent to our exisiting MDIs which used CFCs. This
technology was [named] Modulite®."
The Modulite® technology currently generates for the Chiesi
group revenues of around $450M per annum .
The impact of the Modulite® technology has been widely
recognised by the pharmaceutical industry through successful partnership
and collaboration agreements with leading pharmaceutical companies,
including GlaxoSmithKline (GSK), Novartis and AstraZeneca.
Specific examples include:
- GSK has a semi-exclusive international license and supply agreement
for Modulite® beclomethasone dipropionate for treatment of
asthma in a number of European and non-European countries.
- Novartis has a semi-exclusive international license and supply
agreement for a Modulite® formoterol product for the
treatment of asthma in a number of European and non-European countries.
Chiesi's leading marketed product is Modulite® Fostair/Foster,
which is a fixed combination of beclometasone dipropionate
(corticosteroid) and formoterol fumarate (long-acting 03b22-agonist) with
rapid onset of its therapeutic effect.
Chiesi's Drug Delivery Technologies Director affirms that, "As a
result of [the Bath] invention, Chiesi has successfully developed and
launched three products (Atimos Modulite ® —
Formoterol Fumarate Dihydrate (FFD), Clenil Modulite® —
Beclomethasone dipropionate (BDP) and Foster Modulite® — a
fixed combination of FFD and BDP) across European and other territories.
For certain territories, Chiesi has also licensed the distribution and
sales of the Modulite ® products through GSK,
Novartis and other primary pharmaceutical companies. Foster Modulite
® has become Chiesi's top selling product, with sales in
2012 in excess of $300,000,000 and is now being sold in over 35 counties
worldwide; further launches are planned throughout 2013-2014."
In 2010, Foster became Chiesi's top selling product  and in the 2012
Chiesi Group annual report, the company's chairman announced that market
figures have indicated that: "Foster is the biggest-selling product
resulting from Italian [sponsored] research in the world" .
The Foster/Fostair product was further approved in November 2012 as a
maintenance and reliever therapy in 35 European countries thus confirming
its efficacy both for maintenance and "as- needed" therapy. Furthermore, a
Foster MDI COPD clinical programme was successfully complet- ed in 2013,
which will result in a marketing application for this new indication.
The Drug Delivery Technologies Director of Chiesi concludes, "The 10+
year collaboration between Chiesi and CDFS at the University of Bath has
led to Chiesi's most successful product development programs and
Modulite® continues to be at the forefront of our
R&D programs involving new chemical entities for asthma and COPD."
In sum, the reach of the impact of the Bath-based research described here
is evident from the increasing use of the Modulite® technology
in products used across the globe; the significance lies not only in the
technical success of the science driven by an environmental imperative,
but also the key achievement of assuring the efficacy of potent drugs by
their effective delivery using formulation skill combined with clever
Sources to corroborate the impact
- Letter from the Drug Delivery Technologies Director, Chiesi
Farmaceutici, S.p.A., Parma, Italy.
- 2010 Chiesi Annual report, page 6.
- 2012 Chiesi Annual report, page 4.