Development of more effective technologies for oral delivery of drugs via improved understanding of the physiological features of the gastrointestinal tract
Submitting InstitutionUniversity College London
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences, Pharmacology and Pharmaceutical Sciences
Summary of the impact
Research by Professor Abdul Basit's group at the UCL School of Pharmacy
is leading to improved treatments for ulcerative colitis and other
conditions through increased knowledge of the complex physiology of the
gastrointestinal tract. Improved understanding of in vivo drug
release and uptake has allowed development of three patent-protected
technologies for improved drug delivery: PHLORALTM, for release
of drugs in the colon, and DuoCoatTM and ProReleaseTM
formulations designed to allow intact transit through the stomach followed
by immediate release upon gastric emptying. These technologies are the
subject of licences and ongoing development programmes, with PHLORALTM
currently in phase III clinical trials. The impact is therefore
the introduction of enabling technologies that have positively influenced
the drug development programmes of pharmaceutical companies.
The research, which underpins the innovations described below, centres on
understanding the chemistry and physiology of the digestive tract in
relation to delivery and uptake of drugs through the oral route, which is
by far the most common means to introduce drugs into the body. Our group
has made a major contribution to understanding the factors (and interplay
between factors) that lead to product failure or sub-optimal therapeutic
effects. For example, we have identified and studied numerous intestinal
parameters that can influence drug behaviour in the gastrointestinal
tract, including intestinal pH, fluid volumes and composition, intestinal
transit times and microbiota. These characteristics can be highly variable
between individuals and within the same individual tested on different
days [1, 2, 3].
Overall, therefore, our work on gut physiology in relation to drug
delivery has provided a knowledge base that facilitates the performance
understanding and hence improvement of pharmaceutical products. More
specifically, our understanding of pertinent physiological issues has led
to identification of transit features that may lead to product failure or
sub-optimal performance. For example, we have shown that, contrary to
accepted belief, the small intestinal transit time is affected by meal
intake. Food consumption was shown to significantly shorten transit time
from 200 minutes to 100 minutes . This in itself facilitates
the provision of patient advice for those medications where such transit
behaviour may be critical. In addition, we have established that
intestinal pH is subject to marked intra- and inter-subject variability .
This in turn informs the development of pH-dependent drug delivery systems
as we are now more aware of the range of gut conditions within the patient
This knowledge has therefore enabled us to develop delivery approaches
that optimise drug release, based on a more thorough understanding of how
drugs transit through the gastrointestinal tract. The key research
findings that relate to the development of our new technologies include:
- Improved understanding of the factors influencing residence time (and
variations thereof) in the different compartments of the gut [1-3],
in turn allowing us to develop delivery systems which exploit the
respective time windows more effectively and realistically.
- Improved understanding of the pH environment of the stomach and small
intestine [1-6], in turn allowing us to develop release systems
that may be more effectively and efficiently triggered by changes in pH.
- Improved understanding of the nature and behaviour of the microbiota
of the colon [1, 7-9], in turn allowing us to develop colonic
delivery systems with more specific and effective triggers for release.
For drugs that would otherwise be inactivated in the stomach, we have
developed two novel enteric technologies that exit the stomach rapidly and
thereafter release rapidly (ProReleaseTM and DuoCoatTM).
ProReleaseTM, a microparticulate drug formulation, is designed
to allow rapid transit through the stomach (via control of size) followed
by immediate release at higher pH . Drugs incorporated into
ProReleaseTM are released much more rapidly in the intestine
than standard drug formulations . DuoCoatTM, a
multiple-layer enteric coating technology, dissolves at a faster rate than
industry-standard enteric coatings  due to our appreciation
that the pH is lower in the proximal intestine than is commonly believed.
In a clinical study, the mean release time of the DuoCoatTM
technology, post gastric-emptying, was 28 minutes. This compared
favourably with a mean time of 66 minutes for the conventional enteric
Enteric-coated products are also used to deliver drugs to the large
intestine or colon for the treatment of diseases including ulcerative
colitis. However, in our studies, such coated tablets or pellets often
fail to release in the colon, either failing to disintegrate at all or
prematurely releasing their drug load [3, 7]. Further, it was
shown that contrary to accepted opinion, intestinal pH alone was a poor
indicator of successful tablet disintegration, with intestinal residence
times and fluid volumes also playing key roles . Observed
variability in drug release using conventional carriers has led the group
to develop new technologies with more reliable release characteristics.
For example, research into alternative means to achieve colonic release of
drugs led to recognition of the role of bacteria in degrading starch
coatings and therefore enabling release in the colon [7, 8]. Our
group identified this process, whereby the incorporation of starch into
traditional film coatings leads to its degradation exclusively by colonic
bacteria. This led to the development of PHLORALTM, a
dual-trigger colonic delivery system, which exploits both the pH change
and increase in bacterial numbers along the gastrointestinal tract, with
each component acting as a failsafe to guarantee reliable and consistent
targeted delivery . Overall, therefore, our fundamental work on
the effects of physiology on drug transport has led to findings which
allowed us to rationally design new delivery approaches, the impact of
which is described below.
References to the research
 Ibekwe, VC, Fadda, HM, McConnell, EL Khela, MK, Evans, DF Basit, AW.
Interplay between intestinal pH, transit time and feed status on the in
vivo performance of pH-responsive ileo-colonic release systems.
Pharm. Res. 2008 Aug;25(8):1828-35. http://dx.doi.org/10.1007/s11095-008-9580-9
 Kendall, RA, Alhnan MA, Nilkumhang S, Murdan S, Basit AW. Fabrication
and in vivo evaluation of highly pH-responsive acrylic microparticles for
targeted gastrointestinal delivery. Eur J Pharm Sci. 2009 Jun
 Liu F, Lizio R, Meier C, Petereit HU, Blakey P, Basit AW. A novel
concept in enteric coating: a double-coating system providing rapid drug
release in the proximal small intestine. J Control Release. 2009 Jan
 McConnell EL, Short MD, Basit AW. An in vivo comparison of intestinal
pH and bacteria as physiological trigger mechanisms for colonic targeting
in man. J Control Release. 2008 Sep 10;130(2):154-60.
 Ibekwe VC, Khela MK, Evans DF, Basit AW. A new concept in colonic
drug targeting: a combined pH and bacteria drug delivery technology.
Alimentary pharmacology and therapeutics. 2008 Oct 1;28(7):911-916.
Details of the impact
Improved understanding of drug release and uptake has allowed development
of three patent-protected technologies for improved drug delivery: PHLORALTM,
for release of drugs in the colon, and DuoCoatTM and ProReleaseTM,
formulations designed to allow transit through the stomach and immediate
release upon gastric emptying.
PHLORALTM arose as a result of earlier studies
on a product trademarked as COLAL-PREDTM .
COLAL-PREDTM was developed with over £1m in research and
licensing funding provided by Alizyme [a]. This technology
progressed into phase III clinical trials for a product containing
prednisolone metasulphobenzoate. The knowledge gained from this study led
to the development of PHLORALTM which is the world's first dual
trigger colonic coating technology. The coating exploits both the pH
change and increase in bacterial numbers along the gastrointestinal tract,
with each component acting as a failsafe to guarantee reliable and
consistent targeted delivery . The corresponding product, which
contains mesalazine as the active therapeutic ingredient, is currently in
phase III trials as a treatment for ulcerative colitis. It was the subject
of a patent application in 2007, which has since been granted in many
territories worldwide [b] and has been the subject of licenses,
options and contracts. The coating allows precise and consistent release
of material in the colon, and may be used for the treatment of localised
as well as systemic diseases (PHLORALTM has been licensed for
both purposes). In particular, a licence has been granted to Tillotts
Pharma AG for treatment of ulcerative colitis using mesalazine, as the
next generation of their current product AsacolTM, the
market-leading product for treatment of ulcerative colitis with an annual
global market in excess of $600m [c]. Ulcerative colitis, a form
of inflammatory bowel disease, affects 120,000 people in the UK, and is
conventionally treated with anti-inflammatory drugs, immunosuppressants
and biological therapeutics. Without successful drug delivery, surgical
removal of parts of the intestine can be the only remaining option, and
25-40% of sufferers currently have all or part of their colon removed.
This can also necessitate the use of stoma bags, which negatively impact
quality of life. The PHLORALTM product has entered a phase III
clinical trial which will report late in 2014 [d]. The project has
to date generated £0.75m in funding for research at the UCL School of
Pharmacy and from licensing [e]. PHLORALTM has
additionally been licensed to Oxford Pharmascience for the delivery of
statins to the colon [f]. This has generated more than £200,000 in
research and licence revenue [e]. Their product (SafestatTM)
is designed to reduce the amount of statin that needs to be administered
to the patient, thereby increasing safety as well as reducing cost [g].
The product is undergoing clinical development, with human trials expected
late in 2013.
ProReleaseTM is a microparticulate drug
formulation designed to allow rapid transit through the acidic stomach
environment, followed by immediate release at higher pH. Drugs
incorporated into ProReleaseTM are released far more rapidly
than standard drug formulations. A patent was filed covering this
methodology in 2004 [h], and in 2009, the technology was licensed
into a UK company, Kuecept Limited [i]. Kuecept was initially set
up as a spin-out from the UCL School of Pharmacy in 2007, and currently
has an annual turnover in excess of £1m, having worked on over 600 client
projects since incorporation [j]. The license, which is restricted
to provision of services to third-party clients, has resulted in early
development projects for a number of drugs and generated significant
income to the UCL School of Pharmacy [e].
DuoCoatTM is a multi-layer coating technology
designed to rapidly dissolve in the upper small intestine. In 2007, a
patent was filled in collaboration with Evonik industries [k]. The
technology is offered for licensing through Evonik and Kuecept Limited and
to date, positive proof-of-concept data has been generated with different
In summary, this family of products has had a significant impact on the
development of formulations within the pharmaceutical industry, providing
a clear route to much greater impact should the products be marketed for
patient use. Companies have invested heavily in the development of
products relating to these technologies and, in a competitive environment,
have included these products in the development of their business
strategies. We estimate that in total 15 pharmaceutical companies have
accessed the technologies either through licensing, options or contracts
Sources to corroborate the impact
[a] US 2003/0220861 Colonic release composition. R.M.J. Palmer, M.
Newton, A. Basit, J. Bloor ("COLAL-PRED™). COLAL-PRED™ licensed to
Alizyme. See press coverage:
COLAL-PRED™ licensed to Norgine in 2008. See press coverage:
[b] Patent no US 2007/0243253 Colonic drug delivery formulation. A.W.
Basit, V.C. Ibekwe ("PHLORAL™"):
[c] PHLORAL™ licensed to Tillotts Pharma AG. See press coverage:
[d] PHLORAL™ Phase III clinical trial 2013:
[e] Confirmation of licence agreements and income available from Senior
Business Manager, Biomedical Science, UCL Business PLC. Contact details
[f] PHLORAL™ licensed to Oxford Pharmascience Group PLC. See press
[h] Patent no US 2013/101646 Method of producing microparticles. A.W.
Basit, S. Murdan, R.A. Kendall ("ProReleaseTM") https://www.google.com/patents/US20130101646
[i] ProReleaseTM licensed to Kuecept Limited. See company
[j] Confirmation of company establishment, turnover and project numbers
available from CEO, Kuecept Limited.
[k] PCT/EP/2007/054398, Solid dosage forms comprising an enteric coating
with accelerated drug release, F. Liu, A. Basit. R Lizio, HU Peterit, C
Meier, M Damm http://www.google.com/patents/WO2008135090A8