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7.1
Medicine delivery mechanisms
See Background Chapter 7.1
Medicines have to be administered to the patient via different medicine delivery
mechanisms in order to achieve maximum clinical benefit. The most common delivery
mechanisms are tablets or capsules for oral delivery, suppositories for rectal delivery,
and injections if the parenteral route is chosen. Over recent decades, the biomedical
industry has developed a range of sustained release devices (such as patches for
transdermal drug delivery and intranasal formulations), many of which rely on
medicines diffusing or dissolving from a matrix or other structure that contains the
medication. 1 However, constraints on both private and public sector funding have
limited further development of such technologies for diseases of public health
importance.
A review of the existing state of the art of medicine delivery mechanisms leads to two
main conclusions.
Firstly, there is a wide range of existing evidence-based, very often off-patent,
technologies that are heavily underutilized. Such technologies could be used to
improve the “patient-friendly” performance of a number of existing medicines, the use
of medicines in paediatrics and geriatrics, and other areas where individualized timedosing of medicines is required, e.g., patients with impaired liver or kidney functions,
or patients with compromised immune systems. Safety concerns increasingly drive the
need for targeting potent, but very toxic, medicines (e.g., cytostatics, antivirals and
certain antifungals) to their site of action in the body, instead of exposing the whole
body to the medicine.
It is recommended that the EU invest in translational research programmes to bring
proven medicine delivery technologies to those areas where currently available
systems fail (e.g., HIV therapies for children; medicine targeting in cancer therapy;
and therapies for chronic diseases in the elderly).
Secondly, the advent of new biotechnology-derived protein/DNA-based medicines and
existing proteins, such as insulin or oxytocin, have created a need for investments in
better delivery technologies.2 New stabilization concepts (e.g., heat-resistant insulin or
oxytocin) and other “all-weather” drug delivery mechanisms are a major need.
Moreover, most current protein/DNA-based medicines need to be administered to the
patient via the parenteral route (i.e., injection, infusion). There is also a great need to
develop alternative, needle-free delivery mechanisms that are better adapted to patient
needs. Finally, many therapies based on biologicals, including gene therapies and
vaccines, need targeted delivery mechanisms to reach specific sites on the cell, inside
the cell or inside the cell nucleus. The biotechnology industry is making impressive
progress in these areas and public funding should be directed to maintaining academic
and basic research and training of future scientists (see Background Chapter 7.1).
A key example of the first conclusion, i.e., the need to stimulate translational research
in order to develop proven medicine delivery technologies to meet patient needs, are
FDCs. FDCs can be defined as two or more medicines in a single formulation, each
drug having an independent mode of action, the combination of which creates a
synergistic, additive or complementary effect. “Free” combinations can be defined as
two or more drugs in separate formulations, each usually taken at the same time.
Indeed, combination therapy, in whatever form, may be essential in the treatment of
hypertension and other cardiovascular conditions, 3 as well as for major infectious
diseases such as HIV/AIDS, TB and malaria, and for the prevention of antibacterial
resistance.
FDCs have the potential to simplify treatment regimens and improve compliance in
patients using polypharmacy. However, with few exceptions, the pharmaceutical
industry has generally been wary of FDCs as an innovative delivery mechanism,
particularly for antibacterials, following the extensive review of combination products
as part of a study carried out by the Food and Drug Administration in the USA in the
1960s and beyond.4 For decades, virtually all clinical guidelines, the teaching of health
professionals, and the regulatory environment have been resolutely opposed to the
concept of combining multiple biologically active compounds into a single tablet or
capsule. The only exception to this stance has been for proven combinations (e.g.,
contraceptives based on estrogen-prostagen combinations; combinations of enzyme
inhibitors with antibiotics or Parkinson therapies; and combined potassium-sparing
diuretics). This opposition to the use of FDCs has been largely fuelled by the fear of
overuse of medicines and the limited possibilities for patient-specific individualization
of therapy. However, there are some indications that the pendulum is now starting to
swing back towards more support for the use of FDCs.
A recent meeting at WHO (see Background Chapter 7.1) addressed the main issues
related to FDCs for the treatment of HIV/AIDS,TB and malaria. Another sign is the
recent paper by Wald et al. (see Background Chapter 6.3), proposing the widespread
use of a cardiovascular "polypill." In this Report, Chapter 6.3 recommends the
evaluation of two different FDCs for the secondary prevention of heart attack and
stroke respectively. However, the use of such FDCs for primary prevention of heart
attack and stroke is not endorsed.
Specially designed clinical trials and epidemiological, social and behavioural studies
can test the potential for FDCs to inhibit or even prevent antibacterial resistance, to
secondarily prevent cardiovascular disease, and to improve patient compliance for a
variety of medication taken over prolonged periods.
Although there are pharmacological, regulatory and intellectual property/legal barriers
to the widespread use of FDCs, these barriers can be overcome with a comprehensive
strategy and cooperation between and among the private and public sectors.
It is recommended that an FDC research agenda should be established to answer the
following questions:

In view of the clear public health need for FDCs, what are the clinically
desirable combinations?

What is the actual evidence to support the rationales for use of FDCs? For
instance, while decreasing overall antibiotic use may reverse bacterial resistance
in human populations, the use of combination therapy may not necessarily
have the same effect. It is thus critical to know whether the use of FDCs will
prevent the appearance of drug resistance and/or reverse existing rates of drug
resistance at both the individual and population levels. Although it is likely to
be difficult to measure changes in ongoing antibacterial resistance in field
situations, well thought out epidemiological studies should be undertaken to
provide evidence as to whether FDCs slow or eliminate antibacterial resistance.

Are the legal and intellectual property barriers to increased FDC access more
apparent than real? Research should be directed to finding creative ways of
managing multiple ownership issues of FDCs and increasing access for both
research and clinical purposes.5

What are the “real world” formulation and quality assurance issues?

Can there be standardized regulatory requirements for “combination” products?
Should synergy be required for combinations or is this too high a hurdle?
It is recommended that the European Union should sponsor one or more FDC Centres
of Excellence which would act as “clearing houses” for information about FDC therapy,
coordinate field studies of FDCs and assemble and maintain the best evidence on their
development, as well as on regulatory and legal issues.
1
Urquhart J. Controlled drug delivery: therapeutic and pharmacological aspects. J Intern
Med 2000;248(5):357-376.
2
Crommelin DJA, Storm G, Verrijk R, de Leede L, Jiskoot W, Hennink WE. Shifting
paradigms: biopharmaceuticals versus low molecular weight drugs. Int J Pharmaceutics
2003, 266;(1-2):3-16.
3
Wald N, Law M. A strategy to reduce cardiovascular disease by more than 80%. BMJ
2003;326:1419-1425.
4
Bazell RJ. Drug efficacy study: FDA yields on fixed combinations. Science
1971;172(987):1013-1015.
5
Clark J, Piccolo J, Stanton B, Tyson K. Patents pools: a solution to the problem of access
in biotechnology patents? Available from:
http://www.uspto.gov/web/offices/pac/dapp/opla/patentpool.pdf (accessed 10 January
2002.