Table Of ContentPhys. Technol. 16 (1985). Printed in Northern Ireland
DRUG DELIVERY AND TARGETING
A T Florence and G W Halbert
Conventional forms of drugs normally the gastro-intestinal tract and absorbed into the
medicate the whole body, reaching circulation, from which it diffuses into surrounding
healthy areas as well as diseased. tissues.
The active principle may be required only in one
However techniques are now available
particular organ or indeed in a few cells but the
which are better at restricting drug action
drug is free to range more expansively in the body,
to the sites where it is needed.
medicating cells, tissues and organs which are in no
need of the drug. In most cases drug toxicity is
Since the development of compressed tablets and sufficiently low for this inefficiency to be of little
hard and soft gelatin capsules (the successors to clinical significance, but where highly toxic drugs
moulded pills, which were often prepared extem- are used there is a need to direct the drug more
poraneously), patients have taken most of their specifically to target organs to minimise systemic
medications in these cmvenient units or ‘dosage toxicity, or to control drug release from the dosage
forms’ in which the dose of drug is carefully form to reduce the fluctuations in plasma drug
controlled. Disintegrants such as starch cause levels that occur with conventional tablets or
tablets to break up following contact with the capsules. Sometimes it may be desirable to reduce
contents of the gastro-intestinal tract while gelatin local high concentrations of a drug which may
capsules dissolve more gradually in the stomach irritate or damage, say, the membranes of the
and intestine. In both cases the drug is released into gastro-intestinal tract. There has thus been
considerable research effort directed in the last
decade to the design of controlled release systems
and to the exploration of drug targeting. This has
been aided by our increasing understanding of
pharmacokinetics (the kinetics of drug absorption
and elimination in the body) and the application of
modern materials, particularly polymers, to phar-
maceutical formulation. New dosage delivery
systems have been developed which have the ability
to maximise the therapeutic effects of a drug whilst
minimising the possibility of toxic effects.
The relationship between the concentration of a
drug in the body that causes toxic effects (CBTox)
and the concentration producing a minimal
beneficial therapeutic effect (G ,nerap) can be
represented graphically (figure la). The ideal
plasma drug concentration-time profile is shown to
be one which remains above C B Tan~d b~elo~w ~ ~
CBTox for the optimal time. Unfortunately the body
does not handle drugs in a way which allows this
164 0305-4624/85/040164+08$02.25@ 1985 The Institute of Physics
b A
- - - - - - - - - - - - - - TOXICle vel,
CBTOX
toncentmtion required for desired effect
-r _ _- - _-_-_- -1-M inimum therapeutic
CE level, tElhemp CB
c
Figure 1. a, Theoretical ideal profile for drug action; b, concentration of a drug in the body, CB, following oral
administration (A, single dose; B, repeated dose).
profile to be attained easily. Not unnaturally the It is evident that to maintain CB at a constant
body always tries to remove foreign substances level and approach the idealised therapeutic
including drugs; the elimination of drugs can be profile, a drug should be administered in very small
adequately described mathematically using the quantities at very short time intervals so that
first-order rate equation variations in CB are minimised. The easiest way to
achieve this is to administer the drug continually to
CB(t) = C,(t -At)exp(-k,,At). (1)
the body in such a way that the rate of
The drug concentration can be related to an administration is equal to the rate of elimination of
elimination rate constant (k,,) and time (t), so the the drug. Using pharmacokinetics it is possible to
equation allows us to predict the variation in CB quantify the rate of elimination from the body:
with time. The oral administration of a convention-
al dosage form such as a tablet produces the type of rate of drug elimination = CB x kel (3)
drug profile represented in figure lb, which again and this allows the pharmaceutical formulator to
can be described mathematically using the equation modify the rate of drug release appropriately to
above and allowing for an absorption phase of the maintain CB above C Bbut b~elow C~BT~~T~hi.s ~ ~
drug from the gastro-intestinal tract. The concen- forms the basis for the use of drug delivery systems
tration of the drug in the body at any time after that administer the drug to the body at a
administration of a single dose is represented by predetermined rate.
This method of alteration of drug administration
will only be effective if there is a well characterised
difference between C B Tan~d C~B~T~~In~ ~.s om e
when F is the fraction of the given dose D absorbed cases these concentrations may be very close, if not
and kab is the first-order absorption rate constant equal. Anticancer drugs, for example, act by killing
for that dosage form. This profile has obvious living cells, but they do not have the ability to
drawbacks in that CB may not be maintained above discriminate very effectively between normal and
C Bfor ve~ry lon~g. How~ever, ~the adm~inistr ation malignant cells. Therefore whatever the rate of
of another tablet before all of the drug from the administration of these drugs they will always
first tablet has been completely eliminated will produce some form of toxic effect. The sites in the
result in the accumulation of the drug in the body. body which are responsible for the toxic effects
Eventually after several tablets have been taken at (e.g. the bone marrow and gastro-intestinal tract)
regular intervals CB will reach a steady state level may be anatomically separate from the desired site
(figure lb), hopefully greater than C B Tbu~t le~ss ~ ~of ~act ion of the drug, and if it were possible to
than CBT~Th~e. c oncentration though will rise after target the drug exclusively to the site of the tumour
each dose is given and fall progressively until the the systemic toxic side-effects would be reduced.
next dose, so that CB will vary, sometimes quite The administration of the anticancer drug attached
markedly, during one ‘dosing interval’. This may inactively to some form of carrier which targets the
result in swings of CB above CBT~or~ below drug to the site of action will reduce toxicity and
C B so t~hat th~e dru~g the~rapy p~rovide d is result in an improved therapy. In some cases as
sub-optimal. drug action is dependent on cellular kinetics
165
Table 1. Depot forms employing waxes or polymeric films and matrices?.
Type Materials Diagrammatic representation: Mechanism
1. Barrier coating Beeswax, glyceryl monostearate, Diffusion
ethylcellulose, nylon
(Ultramid IC) acrylic resins
(Eudragit retard) coating
2. Fat embedment Glycerol palmitostearate drug Erosion, hydrolysis of
(Precitrol), beeswax, fat, dissolution
glycowax, castorwax,
aluminium monostearate, fot
carnauba wax,
glyceryl monostearate
stearyl alcohol
3. Plastic matrix Polethylene . . Leaching, diffusion
Polyvinylacetate . . .. ..
Polymethacrylate
polymer
Polyvinylchloride
Ethylcellulose
4. Repeat action Cellulose acetylphthalate Dissolution of enteric
5. Ion exchange Amberlite Dissociation of drug-
Dowex resin complex
6. Hydrophilic matrix Carboxymethylcellulose
Sodium carboxymethylcellulose
Hydroxypropylmethylcellulose
I. Epoxy resin beads Epoxy resins
swelling, diffusion
9-
8. Microcapsules Polyamides, gelatin . . (-)
9. Soft gelatin depot Shellac-PEG epoxy resin bead Diffusion
capsules Polyvinylacetate-PEG
or microcapsule
t After Ritschel (1974). $Not to scale.
selective drug targeting as well as controlled rates throughout their lifetime. This means that varying
of delivery are desirable: this is a huge challenge to amounts of drug are released during the lifetime of
the designer of the system. Tentative approaches the preparation and this is especially marked during
have been made towards the design of such the beginning and end of the drug release
systems, but so far both targeting and control of process - a feature which is not conducive to
drug release are less than perfect. adequate drug therapy. Some of the techniques are
shown in table 1.
Controlled release preparations
Polymeric rate-controlling membranes form the
Site-specific releasing systems have been available basis for many controlled release devices. Control
since the latter part of the last century using enteric is achieved both by appropriate choice of polymer
coatings which dissolve not in the stomach but in or copolymers, membrane thickness, use of
the intestine or in the colon. Control of the rate of diluents and plasticisers, fillers, the degree of
drug release in oral medications may be achieved crystallinity and extent of cross-linking in the
most commonly by using non-disintegrating tablet polymer, and by the solubility of the drug in the
formulations. The drug may be dispersed in a polymer. Fick’s first law describes the flux of drug,
water-insoluble waxy or polymeric matrix from J, in terms of its diffusion coefficient, D, and the
which it is slowly leached, or incorporated into a concentration gradient across the membrane,
hydrophilic polymer (generally a methylcellulose dcidr :
derivative) which swells, forming a gel-like viscous J = -D(dddr).
layer through which the drug must diffuse. Drugs
might also be dispensed in microcapsules which If the membrane has a thickness 1 and if the
have a polymeric outer layer which acts as a barrier difference in concentration of drug on either side of
to release. A wide variety of release profiles can be the membrane is Ac then
achieved but few dosage forms so far devised
produce a constant zero-order release of drug J = DKAcll
166
where K is the distribution coefficient of the drug showing how the properties of the membranes can
towards the polymer. The permeation, P, of drug be altered.
molecules through the solid polymer, which may be The natural permeabilities of polymers vary over
acting as a drug depot, is a function of the solubility a wide range and this widens the choice, provided
of the drug in the polymer as P = DK. one can select a polymer which is compatible with
Alteration of polymerimembrane thickness, cou- the tissues with which it comes into contact. Having
pled with appropriate choice of polymer, can give chosen a polymer which gives a flux of drug
rise to the desired flux. Within a given polymer, sufficient to provide adequate circulating levels of
permeability is a function of the degree of drug, use of fillers and plasticisers can give fine
crystallinity, which itself is a function of polymer control of permeability.
molecular weight. If P is the permeability of the
Recent developments
drug in a partially crystalline polymer, the volume
fraction of the crystalline regions being &, and Pa Some recent products of research, principally by
is the permeability in an amorphous sample then the Alza Corporation in the USA, which have now
reached the market are discussed below. The
PIP, = (1 - &)2. majority of these products have rate-controlling
The addition of inorganic fillers in which the drug is membranes.
insoluble alters the overall solubility of the drug in The Ocusert (figure 2a) system is designed for
the polymer and hence alters the permeation placement in the lower conjunctival sac of the eye
characteristics. The overall solubility, S, is for the treatment of glaucoma. It comprises a
reservoir in which the active pilocarpine is
S = SfGf + SpGp embedded in an alginic acid matrix sandwiched
where f refers to filler and p to polymer. Thus when between two rate-controlling membranes of a vinyl
Sf= 0, as happens when inorganic fillers such as acetate copolymer. These membranes are subject
zinc oxide are employed, an obstruction type of to strict quality control during manufacture and the
equation may be written: thickness and the copolymer ratio adjusted to give
a flux of either 20 or 40pghh-', the difference in
sisp = (1 - @f), rate being achieved by controlling the amount of
Figure 2. a, Ocusert; b, Transiderm; e, Progestasert; d, Oros.
b
10-14 mm
Backing membrane
Me
v \ m
0.17 mm
Rateiontrolling layer
+ /,CL--- -7 $>" Contact adhesive
k+ectives trippoble
-
Osmotic delivery
C -3cm d
O r i f Y
Rate control membrane
Progesterone in reservoir
(microcrystalsi n Liquid)
Retrieval filament Semi -p&neable Osmotic core
membrane containing drug
167
plasticiser (di-2-ethyl hexyl phthalate) in the maintained at saturation. The drawback with this
polymer. Increasing the plasticiser concentration system is that individual variability in transit times
increases the permeability to the pilocarpine. The can lead to marked differences in the availability of
unit is designed to release drug over a period of the drug for absorption; so far we have not
seven days, thus avoiding the repeated administra- achieved the appropriate physiological control of
tion of eye drops several times a day and also the patient to fully utilise this technology by the
minimising the initial rapid absorption of the drug oral route. Man is a complex animal and an
across the cornea which gives rise to visual additional problem in a few patients has been the
disturbances. release of drug from the delivery portal at the
Not all drugs can be administered by way of the mucosal surface leading to a high drug concentra-
skin, but for those which can (e.g. nitroglycerine, tion at the intestinal wall, sometimes resulting in
hyoscyamine and clonidine) rate control of the very membrane damage that the device was
penetration can be important. The transdermal designed to avoid.
therapeutic system Transiderm (figure 2b) was A further development of osmotic pumps has led
designed to control penetration of such drugs to a variety of experimental designs, some with
across the skin for systemic medication. The interior compartments (figure 3). Miniaturisation of
permeability of the skin is variable from site to site the osmotic ‘cells’ leads to a monolithic device in
and patient to patient, hence the need for a which drug is released by penetration of water into
controlled release system which is of course only the cells or microcompartments until the pressure
properly effective in highly permeable skin when rises sufficiently to burst the cell wall leaving the
the polymeric membrane assumes the rate-limiting next layer of osmotic cells exposed to the aqueous
role. front.
Longer-term drug delivery was achieved by the One of the characteristics of the systems
Progestasert system (figure 2c), designed for discussed so far is that the polymer membranes or
implantation into the uterine cavity to release 65 pg matrices provide constant or decreasing release
progesterone per day providing contraceptive cover rates with increasing time. There is no control on
for one year. The progesterone crystals were the release once begun, but a pulsed release rate
dispersed in a silicone oil liquid reservoir which is might be appropriate. One experimental approach
surrounded by a rate-controlling membrane; the to temporal control of release characteristics is to
body of the system is fabricated from an embed small (1.4pm) magnetic beads in an
ethylene-vinyl acetate copolymer. ethylene-vinyl acetate copolymer matrix along with
For oral use, such long-term control of drug the drug. Release rates can be increased by as
release is not possible. Gastro-intestinal transit much as 100% on oscillating an external bar
times are such that release from an oral dosage magnet. It has been postulated that the oscillating
form must be complete in under 10-12h. An magnetic field, by causing the magnetic particles to
elegant application of physical chemistry is seen in
the OrosR osmotic pump, no larger than a tablet,
Figure 3. Osmotic cell delivery system with pulsed
fabricated to release the drug over a 10 h period
release.
following administration by mouth (see figure 2d).
Water from the gastro-intestinal tract penetrates Drug capsule System+ e dge
c
the semi-permeable membrane and mixes with the
~ 0 0 0 1
drug in a soluble salt form and with a salt or water-
......... ..... . . . . . . .
soluble polymer used as an osmotic agent. The
osmotic pressure drives the core contents at a
controlled rate out of the laser-drilled delivery
orifice. The rate of release of the drug (dmidt),
which is independent of orifice diameter if the
orifice is less than about 150pm, is controlled by
varying the area of membrane, A, the membrane
thickness, h, and its permeability to water, k. The
concentration, Sd,o f drug in the compartment, and
the osmotic pressure of the drug formulation, q,
contribute directly to the release rate as
O W
..........
nf remains constant as long as the inner solution is
168
however, are believed to allow only small
molecules and particles less than 100nm diameter
to escape and the larger colloidal carriers will
remain trapped in the circulatory system. Other
limitations are imposed by the diameter of the
blood vessels. Red blood cells have an average
diameter of approximately 7 pm and in the smallest
vessels or capillary beds of an organ they travel in
single file, so that any inflexible carrier that is
greater than 7 pdi ameter will be trapped in the
capillary network of an organ by simple filtration.
Lastly the body very efficiently eliminates foreign
colloidal particles that find their way into the
Figure 4. Scanning electron micrograph of albumin circulation; therefore any injected colloidal carrier
microspheres. is removed by the reticulo-endothelial system,
which is situated mainly in the liver and spleen.
reorientate, alternately compresses and expands This system is so efficient that approximately
pores containing the drugs and thus accelerates 80-90% of any injected colloidal material will
release. Electro-osmotic systems for the actuation eventually be sequestered by the liver and spleen.
of implantable pumps for insulin delivery have All these difficulties are outweighed, however, by
been designed and tested. the potential improvements that drug targeting may
bring, and much effort is currently being applied in
Drug targeting
this research field.
Limiting the activity of drugs to a specific site of The targeting of drugs may be viewed on two
action is the aim of drug targeting. It implies that levels: (a) organ targeting and (b) cellular
the drugs must be carried to the site of action in targeting; the former is actually dependent on the
some inactive form. This can be achieved in part by size, shape and material properties of the carrier
attaching or entrapping the drug within a carrier employed whereas the latter depends upon a more
that masks its action until the carrier reaches the specific interaction at a molecular level between the
target site and there releases the drug. These carrier and the cellular target.
carriers are normally, small colloidal particles
(0.1-300~) manufactured from a variety of Organ targeting
materials. The most common type of carrier under If we consider the case of an intravenously injected
investigation (along with other carriers such as lipo- carrier which has a mean particle size greater than
somes which consist of spherical bilayers of phos- 7 pm diameter, after intravenous injection this
pholipids) is the protein microsphere 0.2-300 pm in carrier will target selectively to the lungs. This
diameter and consisting, for example, of albumin, effect is simply due to mechanical filtering of the
produced by forming a water-in-oil emulsion of an carrier from the blood by the capillary beds of the
aqueous solution of the protein and drug in oil and lung which are the first that the carrier will
then denaturing the protein either by heat or by encounter after injection (figure 5). This allows
chemical means to form small spherical particles
(figure 4). A subset of smaller particles, termed
Figure 5. Transmission electron photomicrograph of rat
nanoparticlesw ith diameters in the range 100-500 nm lung after injection of microspheres, showing microsphere
have also been used and also may be composed (centre) located in capillary next to alveolar space.
of proteins. Alternative materials are constantly
being sought with which to fabricate these carriers,
and biodegradable cyanoacrylate polymers have
been used to form either nanoparticles or
microcapsules.
The only method available for transporting these
drug carrier complexes around the body is to use
the bloodstream and this immediately imposes
restrictions on the applications of drug targeting by
this route. The circulatory system of the body is a
virtual closed loop so that the target must be in
contact with the blood to interact with the carrier
system. The cells lining the vascular system,
169
selective targeting of anticancer drugs for the
treatment of lung cancer and, although the carrier
may not be able to leave the capillary beds, the
drug will only be released in the lung. The rate of
drug release from the carrier should be controlled
so that a negligible concentration of drug is found
in the systemic circulation whilst a high localised
concentration is maintained in the lungs. This will
facilitate the diffusion of the drug out of the
capillaries and into the surrounding tissues to act
locally on the tumour without causing systemic
toxicity.
Reynolds number
Carrier systems which have a mean particle size
Figure 6. Retention of microcapsules flowing in physio-
below 7pm will not become trapped in capillary
logical saline with 6% Dextran 70 in various magnetic
systems and will remain circulating in the fields: 0,2800 G; A, 2020 G; 0,1500 G; 0,840 G.
bloodstream. Under these conditions the reticulo- (Redrawn from Ishii et a1 1984 Chem. Pharm. Bull. 32
endothelial system in the liver and spleen 678.)
selectively accumulates the carrier particles and
facilitates targeting to these organs. This is of value in-oil or water-in-oil-in-water - so called multiple
in the treatment of visceral leishmaniasis, a emulsions, which all have potential as carriers when
parasitic disease which is characterised by the administered to the site of tumour growth.
presence of the parasite in the cells of the liver and
Magnetic microspheres
spleen. The use of carriers under these circum-
stances provides selective targeting to the cells External control over the eventual targeting site of
carrying the parasites and a reduction in the carriers smaller than 7pm diameter can be
systemic side-effects associated with the drugs used exercised if the microspheres are produced
to kill the parasite. containing magnetite (Fe3O4>.T hese microspheres
Targeting to other organs in the body requires respond to an applied magnetic field and by
some form of intervention to allow successful aim carefully controlling the content of magnetite and
to take place. This interaction can either be the applied magnetic field strength it is possible to
external or internal - in the latter case, for selectively locate the microspheres in the capillary
example, the carrier may be injected directly into bed of an organ to which the magnetic field is
the artery supplying a specified organ. The carrier applied. This location is due to the difference in the
used must of course be greater than 7pm in rates of blood flow between arteries and capillaries,
diameter and, depending on the number of carrier which require different strengths of field and
particles injected, either all or some of the magnetite content to trap the microspheres (figure
capillaries may be blocked. Usually only partial 6). This level of location is essential as the released
blockage of the capillary beds is attempted, but in drug will be maximally effective if it is released only
certain cases total blockage has been employed in the capillaries, as again the slow blood flow will
with the camer loaded with cytotoxic drug. This facilitate diffusion of the released drug into the
latter technique - chemoembolisation - attacks the surrounding tissue. In larger vessels the greater
tumour by depriving it of oxygen and nutrients blood flow will inhibit diffusion of the drug out of
whilst at the same time it is also attacked by the the vessel and probably result in a greater systemic
released cytotoxic drug. Although this technique level of the drug and therefore higher incidence of
will also damage the organ involved (it is usually side-effects. This technique which shows great
only applied to the treatment of kidney where there promise has so far only been applied in
is still one viable kidney in operation), it normally experimental animal tumour models, but the results
allows the satisfactory removal of the tumour with a achieved have been startling, with a tumour
reduced incidence of metastatic spread of the remission rate of up to 70% in some experiments.
tumour.
Cellular targeting
Metastasis of tumours from their site of primary
growth is usually due to the passive migration of Targeting to various organs in the body is
detached tumour cells along the lymph glands, therefore possible by simple alterations of the
which remove extracellular fluids from the tissue material and physical properties of the carrier
surrounding the tumour. Targeting to lymph glands vehicle, but targeting to individual cells is not so
in the tumour area can be performed by using simple.
emulsions, for example oil-in-water, microsphere- continued on p 176
170
the dangers of supporting a broad research front ment officials interviewed during the research is
at several laboratories with limited resources (with gratefully acknowledged.
one stroke, the Japanese government provided
more funds than CVD provided over ten years); References and further reading
the ineffectiveness of relying on information
Burggraaf P 1981 ‘Ion implantation in wafer fabrication’
dissemination alone as a means of encouraging
Semicond. Int. (November 1981) pp39-62
industrial take-up.
Dearnaley G 1983 ‘The modification of materials by ion
Clearly, the UK has failed to extract sufficient implantation’ Phys. Technol. 14 225-32
commercial advantage from semiconductor ion Dearnaley G and Freeman J 1969 ‘Doping solids with
implantation research in relation to the effort ions’ New Scientist 6 February p282
expended over the last 20 years. Dickson K 1983 ‘The influence of Ministry of Defence
More recently, workers at AERE have also funding on semiconductor research and development in
pioneered the application of ion implantation to the UK’ Research Policy U 2 113-20.
surface treatment (Dearnaley 1983). However the New Scientist 1982 ‘Chips are down for ion company’ 2
December p566
group’s research leader has been quoted (Technolo-
Ryssel H and Glawischnig (ed.) 1982 Ion Implantation
gy 1984) to the effect that AERE’s world lead in
Techniques (Berlin: Springer)
this field is becoming harder to maintain in the face
Science Research Council 1970 Ion Implantation Panel
of US competition where much more resources are Report Report by Physics Committee to SRC, February
being directed to the technology: ‘they are now 1970
cashing in on it - after we removed the risk’. Will Science Research Council 1974 Ion Implantation Panel
history repeat itself? Report Report by Physics Committee to SRC, January
1974
Acknowledgments Stephen J 1972 ‘Ion implantation in semiconductor device
technology’ Radio Electron. Engr 42 265-83
This paper arose from research funded by the
Technology 1984 ‘Getting ions of wear’ 18 June, pp20, 22
SERC/ESRC Joint Committee and The
Wegmann L 1981 ‘Historical perspective and future
Leverhulme Trust. Their support and the assistance trends for ion implantation systems’ Nucl. Instrum.
of the industrial managers, academics and govern- Meth. 189 1-6
~ ~ ~ ~ ~ ~~~~
continued from p I70 boration, too, between scientists of many
Cellular targeting implies that the carrier has the disciplines as the problems to be overcome are
ability to discriminate between different cells - a many. While many of tomorrow’s drugs with short
process which will have to occur at the molecular biological half-lives will need this new technology,
level rather than the more microscopic levels it is true that most drugs will continue to be taken
required in organ targeting. The carrier therefore by tablet and capsule, the products of a more
has to be designed with this ability in mind, but the empirical art.
protein microspheres and nanocapsules have no
Acknowledgment
cell-selective capability of their own. Cellular
selectivity, however, can be conferred on these We thank Dr Neville Willmott for the photographs
particles by attaching a molecule that can provide of albumin microspheres used in this paper.
cellular recognition; usually this is an antibody
which is specific for an antigen on the surface of the
tumour cells. This approach has been very
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