Opportunities in Drug Delivery

Identifying hot technologies, companies and markets

Brian Minter PhD

Published and Distributed by

Urch Publishing Ltd
PO Box 27554
London SE4 2GZ
United Kingdom
email: info@urchpublishing.com
web: http://www.urchpublishing.com
Executive Summary

Of the leading 150 pharmaceutical products (in terms of sales), almost all orally
administered drugs are now available in formulations enabling once-daily dosing.
Opportunities for development of future formulations of top-selling drugs will probably be
focused on sustained oral release to reduce frequency of dosing to less than once-daily
for products that need to be taken for long periods of time on a regular basis, such as
antihypertensive drugs and lipid-lowering drugs and quick-dissolving tablets enabling the
rapid absorption of drug.

Drug-delivery companies have targeted approximately 80 drugs to develop alternative

formulations. The highest number of new formulations has been focused on morphine,
fentanyl, tramadol, oxybutynin, paclitaxel, sumatriptan and zolpidem – drugs that have
been administered sub-optimally in terms of patient convenience. There are currently
more than 20 different formulations of morphine in development, at least six novel
formulations of tramadol in development and no fewer versions of paclitaxel. Many of the
formulations are similar to each other and will compete directly for market share. Most of
these product variations, if they reach the market at all, are unlikely to have annual sales
exceeding $10–50m.

With most of the top-selling drugs already having been targeted for a wide range of
delivery systems, drug-delivery companies will need to focus their technology
increasingly on new chemical entities in research and development (R&D). They will
have to compete with the in-house expertise of the pharmaceutical companies
themselves or focus their alliances with the smaller and considerably more numerous
small (biotech) companies.

Advances in drug-delivery technology have contributed to a revival in the development

of peptides as therapeutic agents. Sales of short-chain peptides were approximately
$6bn in 2001; at least 80 products are in various stages of clinical trials for a wide range
of indications and a further 60 candidates are in late-stage pre-clinical trials. Around 50
companies have peptides in clinical trials and a further 25–30 companies have peptides
in late pre-clinical evaluation. Most of the peptides in clinical trials are administered by
injection but a number of companies have been reported to be investigating alternative,
more patient-friendly, ways of administering their products. There appears to be
considerable opportunity for drug-delivery companies to collaborate with companies
developing peptides.

Excluding monoclonal antibodies (not covered in this report), sales of therapeutic

polypeptides and proteins reached $12.5bn in 2001. Of the major drug-delivery
companies profiled in this report, some 25 have developed novel technologies for the
delivery of peptides, polypeptides and proteins. There has been a crowding of
companies developing novel formulations of the top-selling therapeutic proteins. Nine
companies are developing new formulations of growth hormone (sales of $1.06bn in
2001), 13 companies are developing a range of formulations for insulin (sales of
$3.75bn in 2001), of which five are inhaled versions, one a buccal formulation, one a
lingual spray, one a transdermal version and one an oral formulation. Fourteen
companies are developing novel formulations of interferon alfa (sales of $1.62bn in
2001) and eight companies are investigating new formulations of interferon beta (sales
of $2.2bn in 2002). The launch of sustained-release versions of erythropoietin and
filgrastim (G-CSF) appears to have deterred companies from developing or continuing
to develop alternative formulations, probably owing to their available technology not
being able to optimise the dosing protocols further. There are currently some 20 novel
proteins in research and development (excluding vaccines and monoclonal antibodies)
and around 350 monoclonal antibodies. With opportunities for improved delivery of the
top-selling proteins/polypeptides having been exhausted, new opportunities for

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OPPORTUNITIES IN DRUG DELIVERY

improved drug delivery will need to be focused on products currently in research and
development.

Oligonucleotides are finally emerging as viable drugs and at present 22 companies are
investigating oligonucleotides. Twenty-three oligonucleotides are undergoing clinical
trials, of which four are in phase III clinical trials. Many more are in pre-clinical stages of
development. Cancer therapy is currently the most important application, with 12
products in clinical trials, each product aiming at a different molecular target. Other
applications include macular degeneration, restenosis, arterial graft surgery, HIV, and
inflammatory diseases including Crohn’s disease, psoriasis and asthma. The next 5
years should witness the launches of Genasense (from Genta) and Affinitak (from Isis)
for the treatment of cancer, Alicaforsen (from Isis) for Crohn’s disease and E2F decoy
from Corgentech for arterial graft survival. More products will follow for cancer and
inflammatory disorders within the next decade. Oligonucleotides are now beginning to
establish themselves as viable therapeutic options, and oral and liposomal inhaled
formulations have been developed and used in the clinic. With their relatively short
history as drugs, oligonucleotides offer interesting opportunities to drug companies able
to stabilise them sufficiently for oral formulation and to improve their uptake in specific
types of cells and microorganisms. At least 11 companies have developed expertise for
the delivery of oligonucleotides.

Inhalation is an important mode of drug delivery, and sales of products in 2001 using
pulmonary delivery systems were approximately $8bn. Fuelled by the anticipated launch
of inhaled insulin, sales should increase to around $15bn by 2006. Almost all of the
products in research and development relying on inhalation-delivery devices are for the
treatment of lung diseases. Of the 40 products in clinical trials, using inhaled delivery, 13
represent improvements in patient convenience with improved or novel devices for drugs
already licensed for the treatment of asthma: salbutamol (four products), budesonide
(four products), formoterol (three products) and cromoglycate (one product). Despite
much publicity as to the advantages of pulmonary delivery, R&D-based pharmaceutical
companies still regard inhalation as a mode for systemic delivery of drugs with a high
degree of scepticism. This will probably change if inhaled formulations of insulin become
successful and more commercially approved devices become available. There is no
shortage of commitment in the pulmonary-delivery segment. If we include the companies
with proprietary devices on the market, there are at least 25 companies involved with
developing and/or marketing inhalation devices and probably close to 30 different
devices commercially available. With technologies now available for the production and
stabilisation of powders, dry powder inhalers appear to have become the major focus for
new types of inhalers in development.

At least eight companies have focused on technologies for the nasal delivery of (ethical)
drugs. New nasal formulations are focusing on the treatment of pain with formulations of
ketamine, morphine, propranolol and sumatriptan in clinical trials for various pain
indications. Systems for the nasal delivery of peptides and proteins including interferon
alfa, interferon beta and parathyroid hormone are also undergoing clinical trials.

The buccal form of delivery based on adhesive tablets and patches has attracted
relatively little attention, with only six companies reporting activities in the segment. Two
companies, Generex and NovaDel Pharmaceuticals, have products in clinical trials using
buccal delivery.

At least 17 companies are engaged in investigating systems for transdermal delivery,

the majority of which are based either on patches or gels. There has been an
overcrowding of commitment to developing transmucosal formulations of testosterone
and oestrogen and oestrogen/progestogen combinations for hormone replacement
therapy, a segment where there is unlikely to be any growth in the use of oestrogen-
based drugs until a number of safety issues have been resolved. To overcome the
limitations of transdermal drug delivery, there is a focus on development of formulations
and technologies to improve the bioavailability of both small molecules and

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 EXECUTIVE SUMMARY

macromolecules by the use of substances that increase the passage of drugs through
the skin. There are 10 transdermal formulations in clinical trials for drug active
substances other than oestrogens or testosterone, including six in phase III clinical trials:
buprenorphine (from Teijin), diltiazem (from SLA Pharma), fentanyl (from Alza),
ketoprofen (from Zambon), nicotine (from Stowic) and rotigotine (a new drug active
substance (from Schwartz Pharma) for the treatment of Parkinson’s disease).

PEGylation remains a key technology for stabilisation and sustained release of

macromolecules in the circulation. Seven companies have developed expertise in
PEGylation technology, of which the most experienced are Alza, Enzon, Nektar
Therapeutics and Valentis. There are at least 14 PEGylated drugs in clinical trials, of
which PEG-hirudin (from Abbott for treatment of thrombosis), pegaptomib (a PEGylated
oligonucleotide from Eyetech for the treatment of macular degeneration), CDP870 (a
PEGylated monoclonal antibody fragment from Pharmacia for rheumatoid arthritis) and
Axokine (from Regeneron for treatment of gross obesity) are in phase III clinical trials.

There are 17 liposomal and lipid formulations of drug active substances in clinical trials,
of which 12 are under development for cancer; of these, three products are based on
paclitaxel (from Munich Biotechnology, NeoPharm and Sonus), and two are based on
cisplatin (from Alza and Ethypharm). Of products in clinical development for other
indications, there are two formulations for insulin (from Provalis and IDEA), one inhaled
liposomal corticosteroid formulation from AstraZeneca for asthma and two liposomal
formulations of prostaglandins (from Endovasc in phase III) and Taisho (in registration in
Japan) for the treatment of ischaemia due to the narrowing of peripheral arteries.

Oral formulations continue to occupy the greatest share of drug-delivery programmes

and at least 28 speciality drug-delivery companies are profiled in this report (there will be
many more smaller companies) as having active programmes. Novel formulations
capable of delivering peptides and macromolecules orally have assumed increasing
importance, as have sustained-release oral formulations that act by adhering to the
lining of the stomach or colon. Nanoparticle and amorphous powder technology is being
employed to improve bioavailability of poorly soluble drugs and is succeeding in
increasing the chances of poorly soluble drugs reaching the market. At least six
companies now have technology for the manufacture of fast-melt tablets, a delivery
protocol that is also gaining popularity.

During the last decade the parenteral or injectable delivery of drugs has focused on
controlled- and sustained-release depot formulations, a number of which can deliver
drugs for a period of 12 months. Controlled release has been achieved by the use of
polymeric coating technologies or attachment to or entrapment within polymers and
proteins. Technologies have also been developed for improvement of bioavailability of
poorly soluble drugs, mostly by using nanoparticles and lipid formulations.

© 2003 URCH PUBLISHING LTD 3