Implantable Drug-Delivery Systems Many therapeutic drugs are most effective when they are delivered into the bloodstream steadily. Such delivery can be accomplished by the surgical implantation ofa drug pellet, a reservoir or a pump by Perry J. Blackshear
any drugs that are administered for medical reasons work best when the drug is delivered to the bloodstream continuously at a con stant rate. A patient taking a drug in intermittent oral doses will often not achieve anything like that result. About the only way to achieve it now is through continuous intravenous infu sion, which is normally done in a hospi
M
tal with an elaborate rig involving bot tltis of fluid, connecting tubes and can nulas, or intravenous tubing; this is the procedure that goes by the familiar ab breviation "LV." (for intravenous). Sev eral groups of workers are attempting to perfect new and radically different pro cedures for delivering a drug by way of a device implanted in the body. Already the strategy serves effectively in such ap plications as contraception and the che motherapy of cancer. In the future one can see systems that do such things as release insulin in response to the body's own biochemical feedback loop and so function as a true artificial pancreas, deliver dopamine to the appropriate area of the brain to control Parkinson's disease or infuse immunosuppressive drugs to prevent the rejection of trans planted organs. As one would expect, an oral dose generally provides a high level of the drug in the blood right after the dose is taken. The drug immediately begins to disappear from the blood, however, at a different rate for each drug in each pa tient. The rate is usually expressed in terms of the half-life of the drug in the circulation, that is, the time it takes for the concentration of the drug to de crease to half its peak level. If one plots the rise and fall on a graph, a peak-and valley pattern emerges. This peak-and-valley effect can give rise to a number of problems. For ex ample, the drug procainamide, which is administered to counteract irregular rhythms of the heart, must be given to most patients every three hours in order
to provide blood levels near the thera peutic range; the reason is its brief half life. Shortly after each dose the concen tration of the drug in the blood reaches a level that for some individuals may be toxic. On the other hand, if one skips a dose, as most patients do at night, the blood level of procainamide falls below the therapeutic range, leaving the pa tient vulnerable to the underlying condi tion. A continuous infusion of the drug directly into the bloodstream, which would be achieved by an implantable system, avoids the peak-and-valley ef fect and administers a constant level of a drug to the patient. Another reason for developing im plantable drug-delivery systems is due to the fact that many drugs must be given by injection because they are inactivated in the gastrointestinal tract. If such a drug also has a short half-life in the circulation, it must be given in
.fl.
frequent uncomfortable injections or by intravenous infusions. Hence the admin istration of such drugs is limited almost exclusively to hospitalized patients. Examples of drugs that have a short half-life and must be injected are hep arin, the best available agent for pre venting the clotting of the blood, and lidocaine, probably the most effective means of suppressing life-threatening disturbances of the heart rhythm. An other substance that must commonly be injected is insulin, the pancreatic hor mone that is deficient in diabetes. It has a relatively long half-life when it is given in one of the modern long-acting prepa rations, and so in many cases it can be administered as infrequently as once a day. Because the levels of insulin in the blood after injection do not closely match the levels achieved with the in sulin secreted by the normal pancreas, however, such preparations may cause problems for some diabetics. I shall re turn to this point below. To my knowledge the concept of
66 © 1979 SCIENTIFIC AMERICAN, INC
implantable drug-delivery systems orig inated with R. Deansley· and A. S. Parkes, who in about 1937 presented at the Royal Society of Medicine in Lon don a paper describing the effects of various hormone preparations on the growth of livestock. In one experiment they compressed pure crystalline es trone into small pellets, which they im planted under the skin of brown leghorn capons. Because no blood test for estro gen was available at the time, they as sessed the effect of the hormone by shaving areas of the chicken'S breast and observing new feathers as they ap peared. To their surprise one subcutane ous estrone pellet caused female feath ers to grow on the male birds for as long as three months. In 1938 P. M. F. Bishop of Guy's Hos pital in London reported the use of sub cutaneous pellets of compressed estro gen in the treatment of a young woman suffering from premature menopause.
The effectiveness of the therapy was monitored by the number of hot flashes the woman had per day. Although this technique is hardly as precise as measur ing the serum estrogen concentration in picograms per milliliter, which is how such a therapeutic regimen would be monitored today, Bishop and his col leagues concluded that some degree of estrogen replacement continued for as long as five weeks after the implant, as judged by a decrease of 50 percent in the number of hot flashes per day. The technique of implanting solid pel lets of pure hormone quickly evolved to include other steroid hormones. Among them are testosterone for males with a deficiency of the hormone, deoxycorti costerone for the treatment of Addison's disease and estradiol for prostate can cer. The pellets are the simplest kind of implantable drug-delivery device. They release their contents into the subcuta neous tissue mainly through a process of erosion. The rate of release depends pri marily on the surface area of the im-
;������:-- RESERVOIR
PELLET
PUMP----
IMPLANTABLE DEVICES are shown in a hypothetical patient
dIe; the drug then drains into a ventricle of the brain. The pellet, which
(hypotbetical because no one person would be likely to have all three
consists of a concentrated drug, is implanted just under the skin. It
devices at the same time). The device implanted under the scalp is the
releases its drug into the subcutaneous tissue mainly through a proc
Ommaya reservoir, wbicb has tbe advantage of giving access to tbe
ess of erosion. The implanted pump has a fluorocarbon propellant
otherwise largely inaccessible cerebrospinal fluid. The bulbous part
that maintains a constant pressure on a supply of a drug, so that the
close to the scalp can be refilled repeatedly with a hypodermic nee-
pump is able to deliver drug at a constant rate to a vein or an artery.
© 1979 SCIENTIFIC AMERICAN, INC
67
plant and the solubility of the drug in the body fluids. SKIN
Over the past 15 years the concept of implantable drug-delivery systems has reached a somewhat higher level of so VENTRICLE
phistication.
In
1964 Judah Folkman
and David M. Long, working at the Na tional Naval Medical Center in Bethes da, Md., described experiments in which compounds of low molecular weight were shown to diffuse out of a small silicone-rubber capsule implanted in the heart muscle of dogs. They also found that the capsule, implanted under the skin, elicited little of the inflammation that often results from the body's defen sive mechanisms against foreign sub stances. Later studies by these investigators and others demonstrated that several classes of drugs would diffuse out of a silicone-rubber capsule at a fairly con stant
rate:
steroid
and
thyroid
hor
mones, anesthetic agents and antibiot ics. These first studies were limited to fat-soluble compounds of low molecu lar weight because large molecules such as proteins and polysaccharides will not diffuse through silicone rubber. By 1972 the development of a differ ent matrix, polyacrylamide, made possi ble the release of large molecules; the first report of success in this area, in volving the protein insulin, was pub lished by B. K. Davis of the Worcester Foundation for Experimental Biology. Further reports by Davis and Folkman extended the technique to several oth er proteins. The polymers of the time,
SPINAL CORD
however, provoked a local inflammato ry reaction when they were implanted. More recently Robert Langer and Folk man have demonstrated that the poly mers hydroxymethyl methacrylate and ethylene-vinyl acetate copolymer are as effective as polyacrylamide but cause little inflammation. Usually a polymeric device for deliv ering a drug is implanted under the skin after a small incision has been made un der local anesthesia. Some quite small capsules can be injected under the skin through a large needle. Whatever the combination of drug and polymer, the net drug-delivery effects are much the same. After an initial period of rapid release of the drug, termed the burst ef fect, the active ingredient is released at a constant rate for prolonged periods of time. Hence after a single subcutaneous implantation of a drug-polymer combi nation fairly constant levels of the drug can be maintained in the blood. he techniques of implanting cap
T sules OMMA Y A RESERVOIR is depicted as it would be utilized for the delivery of a drug such as a chemotherapeutic agent
(top)
and as it would serve for the withdrawal of a quantity of cere
brospinal fluid by means of a syringe
(bottom). In
a typical procedure the syringe would be put
aside and a second syringe containing a drug would he attached to the catheter. More cere brospinal fluid would be withdrawn to be mixed with the drug, which would then be injected through the catheter. Finally, fluid in the first syringe would be injected to flush the system.
68 © 1979 SCIENTIFIC AMERICAN, INC
containing drugs have now
reached the stage of application both in experimental and in clinical settings. Numerous devices have been developed
for the diffusion of steroid hormones through silicone rubber. For example, contraceptive devices in the form of sili-
cone-rubber capsules or rings contain ing progesterone have been implanted subcutaneously or placed in the uterus or the vagina. Hans Marberger of the University of Innsbruck has employed subcutaneous silicone-rubber capsules containing ethinyl estradiol in the treat
ment of more than 100 patients with prostate cancer. He has also shown that a single capsule of testosterone implant ed subcutaneously will release the hor mone at a low and fairly constant rate for up to 13 months and that various disorders of male reproductive function caused by a deficiency of testosterone can be treated by this means. Other devices exploit the principle of controlled drug release from a polymer ic matrix without being strictly implant able. The Alza Corporation of Palo Alto, Calif., has developed a number of such devices. They include a wafer of ethylene-vinyl acetate copolymer that releases pilocarpine onto the conjuncti va of the eye in the treatment of glau coma and a thin membrane containing scopolamine that is placed on the skin, allowing the drug to diffuse through the skin for the treatment of motion sick ness and severe nausea resulting from the chemotherapy of cancer. Alza has also developed an intrauterine device that prevents conception through the slow release of a progesterone directly into the uterine cavity. Many investigators are now applying the principles of controlled release from silicone rubber and other polymers in animal models of a variety of human conditions. Examples include systems for delivering narcotic antagonists such as nalozone in the treatment of opiate addiction, prostaglandins to induce ear ly abortion, various chemotherapeutic agents for the treatment of cancer, insu lin for diabetes and heparin in the treat ment of abnormal blood clotting. otwithstanding the advantages of the deliv ery of drugs in this way still has many limitations. For one thing, the drug is released into the subcutaneous tissue rather than directly into the blood stream. Its entry into the circulation is therefore controlled to some degree by the local blood supply, which in turn varies with the amount of fat in the sub cutaneous tissue, the activity of the pa tient and other factors. Moreover, the body sometimes surrounds an implant ed object with a dense layer of fibrous tissue, which can impede the diffusion of a drug into the circulation. Another ma jor problem is that the amount of drug delivered cannot be readily adjusted or stopped once the implant is in position. The ability to regulate the dosage is im portant with powerful drugs such as heparin and insulin, with which over treatment and undertreatment can be dangerous. Finally, only a few drugs are
UIP,I"HHAlljM
COMPRESSES PROPELLANT
N subcutaneous capsules,
IMPLANTABLE PUMP, which has the trade name Infusaid, is shown in operation during refilling
(bottom). The pump
(top)
and
consists of a disk made of titanium. Inside it is divided into
two chambers by a bellows. The bottom compartment contains a fluorocarbon propellant that at body temperature exerts a constant pressure against the bellows. Above the bellows is the drug, termed the infusate, which is pushed by the propellant into a catheter that is inserted in a vein or an artery. The infusate chamber can be refilled by means of a hypodermic syringe.
available in forms sufficiently concen trated to make small, long-term subcu taneous implants practicable. To circumvent some of these prob lems several other types of implantable drug-delivery system have been devised. The first of them to be employed clini cally was the Ommaya reservoir, devel oped in about 1963 by Ayub K. Om maya of the National Institute of Neu rological Diseases and Blindness. This simple device is a small container that is implanted under the skin of the scalp
and is connected to a cerebral ventricle by means of a short tube. On the side nearest the skin the reservoir has a self sealing membrane that can be punc tured repeatedly by hypodermic needle; hence the device gives the physician easy and repeated access to the cerebro spinal fluid, the blood-plasma filtrate that bathes the brain and the spinal cord. The Ommaya reservoir has been use ful in the treatment of certain forms of leukemia in which the malignant cells are sequestered in the subarachnoid
69 © 1979 SCIENTIFIC AMERICAN, INC
a
b
tration of the drug in the infusate. The
c YMER
change can be made during the refilling
procedure. A different drug or a placebo can be put into the pump in the same way. With an inner-chamber capacity of
about 45 milliliters of usable volume
and a delivery rate of about one millili ter per day the pump needs to be refilled in most situations about every 45 days. reliminary studies with dogs demon
P strated that the pump could infuse
heparin (or sterile water serving as an experimental control) intravenously for more than four years without blockage of the cannula or serious side effects. We then began implanting pumps for the in fusion of heparin in a series of human patients with severe clotting problems who had failed to respond to treatment with conventional measures. ( My col leagues in these studies were Buchwald, Varco, Thomas D. Rohde and Philip D. Schneider.) Most of the patients had suf
(0) con
fered from the recurrent formation of
sists of compressed drug or hormone. Tbe material enters tbe subcutaneous tissue by erosion
clots in their leg veins, with subsequent
IMPLANTABLE PELLETS include tbe tbree forms depicted here. Tbe simplest type and goes from tbere into tbe bloodstream. In anotber type of pellet
(b)
tbe drug or hormone is
put in a silicone-rubber capsule, tbrougb wbich it diffuses into tbe tissue. In tbe tbird type
(c)
tbe drug is contained in a matrix of polymer that degrades witbin tbe body, so tbat it enters tbe tissue botb by diffusion tbrougb tbe outer layer of tbe polymer and by erosion of tbe polymer.
migration of clots to the lungs, notwith standing treatment with the oral antico agulant sodium warfarin. Many of the patients had had the largest vein in the abdomen (the inferior vena cava) tied off surgically to prevent the movement
space (which is filled with cerebrospinal
improvement on the membranes has re
of clots to the lungs, a procedure tha t
fluid) and are otherwise protected from
mained essentially the same in concept,
is generally a last resort and that intro
chemotherapeutic
do not
although its design has been changed
duces many complications of its own.
cross the barrier between the brain and
several times. It is now being manufac
About a third of the patients were giv
the general circulation of the blood. The
tured under the trade name Infusaid
ing themselves heparin from four to six times per day by subcutaneous or even
drugs that
reservoir is also useful in chronic forms
by the Metal Bellows Corporation of
of fungal meningitis, when high concen
Sharon, Mass. It consists of a cylindri
intravenous injection. Heparin, as the
trations of antibiotics in the cerebrospi
cal disk about the size and shape of an
most effective anticoagulant drug avail
nal fluid are needed. The usefulness of
ice-hockey puck. The disk is made of
able, had prevented the recurrent for
the device lies in its ability to provide
the relatively light metal titanium, so
mation of clots in these patients previ
easy entrance to the otherwise fairly in
that its empty weight is only 190 grams
ously, but only at the cost of frequent
(6.7 ounces). The titanium is compatible
injections or continuous infusion, a pro
with body tissues.
cedure that requires prolonged hospital
accessible subarachnoid space. The concept of a subcutaneous drug reservoir evolved further in 1970 when Henry Buchwald,
The inside of the disk is divided into
ization.
Richard L. Varco,
two chambers by a cylindrical titanium
When these patients entered the hos
Perry L. Blackshear, lr. (my father),
bellows, which forms a barrier between
pital at the University of Minnesota,
Frank D. Dorman and I at the Universi
the compartments that is collapsible but
we first established their intravenous re
ty of Minnesota School of Medicine de
impermeable. The outer compartment
quirement for heparin by means of in
signed an implantable infusion pump
contains a fluorocarbon in a liquid-va
fusions from a pump outside the body.
and began testing it. The purpose of the
por combination; it serves as the propel
The pump was then implanted (with lo
device was to provide a means of contin
lant. The inner chamber contains the in
cal anesthesia) under the skin of the
uously delivering heparin to ambula
fusate, the drug to be delivered.
chest wall, a procedure identical with
tory patients with severe clotting prob
The principle underlying the opera
the implantation of a cardiac pacemak
Heparin can be given only by
tion of the pump is the basic physical
er. The delivery cannula was threaded
injection or infusion, and so it is admin
concept that a liquid in equilibrium with
through a tributary vein into the superi
istered almost exclusively to hospital
its vapor phase exerts a constant vapor
or vena cava. After being discharged
ized patients. Injections are impractical because they are needed every four to
pressure at a given temperature, regard
from the hospital a patient was to return
less of its volume. Hence in the relative
every week or two for blood tests and
six hours, a function of heparin's short
ly constant temperature of the body the
every four to eight weeks for refilling of
half-life in the circulation; furthermore,
fluorocarbon exerts a constant pressure
the pump.
recent studies of patients with various
on the infusate and forces it through a
We have now implanted about 20
clotting problems have shown that the
series of filters and flow-regulating re
pumps for the delivery of heparin; some
lems.
continuous infusion of heparin carries
sistance elements into a vein or an ar
of them have been in place for more
less risk of bleeding complications than periodic injections do.
tery. The infusion rate of a particular
than two years. The results of these pre
infusate is therefore constant for any
liminary trials have been encouraging.
We first tried to administer heparin by
given combination of propellant chemi
Our main objective was to prevent the
diffusion through silicone-rubber mem
cal, flow restrictor and infusate temper
recurrence of obstructing clots in the
branes; the attempts failed mainly be
ature and viscosity.
lungs and deep in the venous system.
cause of the large size of the heparin
The amount of active drug delivered
In more than 2 50 patient-months of the
molecule. The pump we designed as an
can be altered by changing the concen-
infusion of heparin through the pump
70 © 1979 SCIENTIFIC AMERICAN, INC
u
X
o I-
/
u
f=
=> w (L « a: w I I-
/
"-
"
\ r-----�/------��--------� \ I \ I \ I \ I \ I \ I \
3
o
J
9
6
12
TIME (HOURS)
375 milligrams every three hours. The concentration of procainamide
PEAK-AND-V ALLEY PATTERN of the level of a drug in the blood appears when the concentration resulting from intermittent
in the blood serum remains in the therapeutic range unless a dose is
oral doses is plotted over time. Here the drug is procainamide, which
missed
regulates abnormal rhythms of the heart, and the normal dose
ly gives rise to a drug concentration that is toxic to some patients.
80
(color) is
(broke1l colored lille).
A dose of
B
L
SK
D
SU
B
L
SK
D
SU
I
I
I
I
I
I
I
I
I
I
IN
EX
EX
EX
I
n
n
n
SLEEP
IN
EX
EX
EX
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n
n
750
milligrams
(black)
rapid
B
I IN
SLEEP
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� w I:::; :::; .J
60
� z -a:
.J w =>(L
40
�� Z
=> 0 a: u
20
� 0
Cii
400
a: w I:::; :::; 300 .J w� o (/)0 0ua: =>w .J (L (!)(/) � « a: 100 (!) :::; .J
�
0 07
13
19
01
19
13
07
01
07
13
TIME OF DAY
(EX),
(SK),
(D),
(S U)
CONTROL OF DIABETES is difficult with the conventional daily
cise
injection of insulin, as is shown in these curves reflecting the concen
unregulated insulin concentrations of diabetics do not prevent wide
tration of insulin and glucose in the hlood of three diabetics
swings in glucose. Implantable devices could provide steadier levels.
and three nondiabetics
(blac k).
day their regimen was injection
(color) 7:00 A.M. on the first (IN), breakfast (8), lunch (L), exer-
Beginning at
snack
dinner
supper
and sleep. Higher but
A different version of graph was published by others in
Mayo Clillic Proceedillgs;
G.
D. Molnar and
it appears with their permission.
71 © 1979 SCIENTIFIC AMERICAN, INC
only one clinically suggestive episode of thrombosis in a leg vein was encoun tered, and we saw no lung clots. The pump functioned accurately and reli ably, maintaining fairly constant levels of heparin in the blood. The versatility that distinguishes the pump from passive devices for diffusion
was demonstrated during the refilling procedure. At that time the rate of deliv ery of heparin could be adjusted easily by changing the concentration of the drug in the new solution of infusate. Side effects have been rare. Perhaps the best feature of the pumps is that they enable a patient to go about his daily activities with little more inconvenience than he would have with a cardiac pace maker. One patient even played a week ly game of volleyball with no ill effects, although this is not an activity we would recommend in the circumstances. second clinical application of the
A pump utilized a main advantage of
certain implantable systems, the ability to deliver a drug to a specific target area or organ. We installed the pump to pro vide an intra-arterial infusion of a che motherapeutic drug for the treatment of 100
cancers of the liver. These tumors, in cluding not only hepatoma, or primary liver cancer, but also metastatic cancers originating in the bowel or the pancreas, are in most cases rapidly fatal. Che motherapy has had little effect, notwith standing its success in the treatment of many other types of cancer. The liver is unusual in that blood flows to it not only through arteries but also through veins. Most of the organ's normal blood supply is venous, but the blood supply of a liver tumor is almost exclusively arterial. Here was an open ing for the delivery of a chemotherapeu tic agent by infusion directly into the hepatic artery, which supplies the liver with arterial blood. We knew the pump could be implanted successfully for long periods of time; what was uncertain was whether a cannula in the hepatic artery would remain open when the drug being infused was not an anticoagulant and whether the high pressure and different clotting environment of the arterial sys tem would cause problems. Studies with dogs indicated that the pump would work. Then our group (Buchwald, Varco, Rohde, Theodor B. Grage, Pericles P. Vassilopoulos and I)
implanted pumps in five patients with liver cancer. The pumps were placed un der the skin of the abdominal wall and the cannulas were threaded through a branch artery into the hepatic artery. When the incisions had healed, the pa tients received alternating infusions of 5-fluorodeoxyuridine (the chemothera peutic agent) and water (to keep the can nula open during a respite when the drug showed signs of reaching toxic lev els), each infusion continuing for sever al weeks. The pumps worked satisfactorily, and the patients were able to leave the hospi tal and resume their normal activities. The effects of the drug were less satis factory. In some patients the symptoms improved and the tumors temporarily stopped growing, but all the patients eventually died or developed more widespread tumors. This result empha sizes the need to test new drugs and dif ferent schedules of delivery for this type of cancer. We hope also to develop an implant able infusion device that would provide a total artificial replacement for the beta cells of the pancreas. These cells nor mally secrete insulin in a predictable
,-------,
75
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50
UJ ::;;
t=
25
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� UJ I:J :J ...J
.6
�
c: UJ 0.. en I-
.4
Z 2z
a:
any drugs that are administered for medical reasons work best when the drug is delivered to the bloodstream continuously at a con stant rate. A patient taking a drug in intermittent oral doses will often not achieve anything like that result. About the only way to achieve it now is through continuous intravenous infu sion, which is normally done in a hospi
M
tal with an elaborate rig involving bot tltis of fluid, connecting tubes and can nulas, or intravenous tubing; this is the procedure that goes by the familiar ab breviation "LV." (for intravenous). Sev eral groups of workers are attempting to perfect new and radically different pro cedures for delivering a drug by way of a device implanted in the body. Already the strategy serves effectively in such ap plications as contraception and the che motherapy of cancer. In the future one can see systems that do such things as release insulin in response to the body's own biochemical feedback loop and so function as a true artificial pancreas, deliver dopamine to the appropriate area of the brain to control Parkinson's disease or infuse immunosuppressive drugs to prevent the rejection of trans planted organs. As one would expect, an oral dose generally provides a high level of the drug in the blood right after the dose is taken. The drug immediately begins to disappear from the blood, however, at a different rate for each drug in each pa tient. The rate is usually expressed in terms of the half-life of the drug in the circulation, that is, the time it takes for the concentration of the drug to de crease to half its peak level. If one plots the rise and fall on a graph, a peak-and valley pattern emerges. This peak-and-valley effect can give rise to a number of problems. For ex ample, the drug procainamide, which is administered to counteract irregular rhythms of the heart, must be given to most patients every three hours in order
to provide blood levels near the thera peutic range; the reason is its brief half life. Shortly after each dose the concen tration of the drug in the blood reaches a level that for some individuals may be toxic. On the other hand, if one skips a dose, as most patients do at night, the blood level of procainamide falls below the therapeutic range, leaving the pa tient vulnerable to the underlying condi tion. A continuous infusion of the drug directly into the bloodstream, which would be achieved by an implantable system, avoids the peak-and-valley ef fect and administers a constant level of a drug to the patient. Another reason for developing im plantable drug-delivery systems is due to the fact that many drugs must be given by injection because they are inactivated in the gastrointestinal tract. If such a drug also has a short half-life in the circulation, it must be given in
.fl.
frequent uncomfortable injections or by intravenous infusions. Hence the admin istration of such drugs is limited almost exclusively to hospitalized patients. Examples of drugs that have a short half-life and must be injected are hep arin, the best available agent for pre venting the clotting of the blood, and lidocaine, probably the most effective means of suppressing life-threatening disturbances of the heart rhythm. An other substance that must commonly be injected is insulin, the pancreatic hor mone that is deficient in diabetes. It has a relatively long half-life when it is given in one of the modern long-acting prepa rations, and so in many cases it can be administered as infrequently as once a day. Because the levels of insulin in the blood after injection do not closely match the levels achieved with the in sulin secreted by the normal pancreas, however, such preparations may cause problems for some diabetics. I shall re turn to this point below. To my knowledge the concept of
66 © 1979 SCIENTIFIC AMERICAN, INC
implantable drug-delivery systems orig inated with R. Deansley· and A. S. Parkes, who in about 1937 presented at the Royal Society of Medicine in Lon don a paper describing the effects of various hormone preparations on the growth of livestock. In one experiment they compressed pure crystalline es trone into small pellets, which they im planted under the skin of brown leghorn capons. Because no blood test for estro gen was available at the time, they as sessed the effect of the hormone by shaving areas of the chicken'S breast and observing new feathers as they ap peared. To their surprise one subcutane ous estrone pellet caused female feath ers to grow on the male birds for as long as three months. In 1938 P. M. F. Bishop of Guy's Hos pital in London reported the use of sub cutaneous pellets of compressed estro gen in the treatment of a young woman suffering from premature menopause.
The effectiveness of the therapy was monitored by the number of hot flashes the woman had per day. Although this technique is hardly as precise as measur ing the serum estrogen concentration in picograms per milliliter, which is how such a therapeutic regimen would be monitored today, Bishop and his col leagues concluded that some degree of estrogen replacement continued for as long as five weeks after the implant, as judged by a decrease of 50 percent in the number of hot flashes per day. The technique of implanting solid pel lets of pure hormone quickly evolved to include other steroid hormones. Among them are testosterone for males with a deficiency of the hormone, deoxycorti costerone for the treatment of Addison's disease and estradiol for prostate can cer. The pellets are the simplest kind of implantable drug-delivery device. They release their contents into the subcuta neous tissue mainly through a process of erosion. The rate of release depends pri marily on the surface area of the im-
;������:-- RESERVOIR
PELLET
PUMP----
IMPLANTABLE DEVICES are shown in a hypothetical patient
dIe; the drug then drains into a ventricle of the brain. The pellet, which
(hypotbetical because no one person would be likely to have all three
consists of a concentrated drug, is implanted just under the skin. It
devices at the same time). The device implanted under the scalp is the
releases its drug into the subcutaneous tissue mainly through a proc
Ommaya reservoir, wbicb has tbe advantage of giving access to tbe
ess of erosion. The implanted pump has a fluorocarbon propellant
otherwise largely inaccessible cerebrospinal fluid. The bulbous part
that maintains a constant pressure on a supply of a drug, so that the
close to the scalp can be refilled repeatedly with a hypodermic nee-
pump is able to deliver drug at a constant rate to a vein or an artery.
© 1979 SCIENTIFIC AMERICAN, INC
67
plant and the solubility of the drug in the body fluids. SKIN
Over the past 15 years the concept of implantable drug-delivery systems has reached a somewhat higher level of so VENTRICLE
phistication.
In
1964 Judah Folkman
and David M. Long, working at the Na tional Naval Medical Center in Bethes da, Md., described experiments in which compounds of low molecular weight were shown to diffuse out of a small silicone-rubber capsule implanted in the heart muscle of dogs. They also found that the capsule, implanted under the skin, elicited little of the inflammation that often results from the body's defen sive mechanisms against foreign sub stances. Later studies by these investigators and others demonstrated that several classes of drugs would diffuse out of a silicone-rubber capsule at a fairly con stant
rate:
steroid
and
thyroid
hor
mones, anesthetic agents and antibiot ics. These first studies were limited to fat-soluble compounds of low molecu lar weight because large molecules such as proteins and polysaccharides will not diffuse through silicone rubber. By 1972 the development of a differ ent matrix, polyacrylamide, made possi ble the release of large molecules; the first report of success in this area, in volving the protein insulin, was pub lished by B. K. Davis of the Worcester Foundation for Experimental Biology. Further reports by Davis and Folkman extended the technique to several oth er proteins. The polymers of the time,
SPINAL CORD
however, provoked a local inflammato ry reaction when they were implanted. More recently Robert Langer and Folk man have demonstrated that the poly mers hydroxymethyl methacrylate and ethylene-vinyl acetate copolymer are as effective as polyacrylamide but cause little inflammation. Usually a polymeric device for deliv ering a drug is implanted under the skin after a small incision has been made un der local anesthesia. Some quite small capsules can be injected under the skin through a large needle. Whatever the combination of drug and polymer, the net drug-delivery effects are much the same. After an initial period of rapid release of the drug, termed the burst ef fect, the active ingredient is released at a constant rate for prolonged periods of time. Hence after a single subcutaneous implantation of a drug-polymer combi nation fairly constant levels of the drug can be maintained in the blood. he techniques of implanting cap
T sules OMMA Y A RESERVOIR is depicted as it would be utilized for the delivery of a drug such as a chemotherapeutic agent
(top)
and as it would serve for the withdrawal of a quantity of cere
brospinal fluid by means of a syringe
(bottom). In
a typical procedure the syringe would be put
aside and a second syringe containing a drug would he attached to the catheter. More cere brospinal fluid would be withdrawn to be mixed with the drug, which would then be injected through the catheter. Finally, fluid in the first syringe would be injected to flush the system.
68 © 1979 SCIENTIFIC AMERICAN, INC
containing drugs have now
reached the stage of application both in experimental and in clinical settings. Numerous devices have been developed
for the diffusion of steroid hormones through silicone rubber. For example, contraceptive devices in the form of sili-
cone-rubber capsules or rings contain ing progesterone have been implanted subcutaneously or placed in the uterus or the vagina. Hans Marberger of the University of Innsbruck has employed subcutaneous silicone-rubber capsules containing ethinyl estradiol in the treat
ment of more than 100 patients with prostate cancer. He has also shown that a single capsule of testosterone implant ed subcutaneously will release the hor mone at a low and fairly constant rate for up to 13 months and that various disorders of male reproductive function caused by a deficiency of testosterone can be treated by this means. Other devices exploit the principle of controlled drug release from a polymer ic matrix without being strictly implant able. The Alza Corporation of Palo Alto, Calif., has developed a number of such devices. They include a wafer of ethylene-vinyl acetate copolymer that releases pilocarpine onto the conjuncti va of the eye in the treatment of glau coma and a thin membrane containing scopolamine that is placed on the skin, allowing the drug to diffuse through the skin for the treatment of motion sick ness and severe nausea resulting from the chemotherapy of cancer. Alza has also developed an intrauterine device that prevents conception through the slow release of a progesterone directly into the uterine cavity. Many investigators are now applying the principles of controlled release from silicone rubber and other polymers in animal models of a variety of human conditions. Examples include systems for delivering narcotic antagonists such as nalozone in the treatment of opiate addiction, prostaglandins to induce ear ly abortion, various chemotherapeutic agents for the treatment of cancer, insu lin for diabetes and heparin in the treat ment of abnormal blood clotting. otwithstanding the advantages of the deliv ery of drugs in this way still has many limitations. For one thing, the drug is released into the subcutaneous tissue rather than directly into the blood stream. Its entry into the circulation is therefore controlled to some degree by the local blood supply, which in turn varies with the amount of fat in the sub cutaneous tissue, the activity of the pa tient and other factors. Moreover, the body sometimes surrounds an implant ed object with a dense layer of fibrous tissue, which can impede the diffusion of a drug into the circulation. Another ma jor problem is that the amount of drug delivered cannot be readily adjusted or stopped once the implant is in position. The ability to regulate the dosage is im portant with powerful drugs such as heparin and insulin, with which over treatment and undertreatment can be dangerous. Finally, only a few drugs are
UIP,I"HHAlljM
COMPRESSES PROPELLANT
N subcutaneous capsules,
IMPLANTABLE PUMP, which has the trade name Infusaid, is shown in operation during refilling
(bottom). The pump
(top)
and
consists of a disk made of titanium. Inside it is divided into
two chambers by a bellows. The bottom compartment contains a fluorocarbon propellant that at body temperature exerts a constant pressure against the bellows. Above the bellows is the drug, termed the infusate, which is pushed by the propellant into a catheter that is inserted in a vein or an artery. The infusate chamber can be refilled by means of a hypodermic syringe.
available in forms sufficiently concen trated to make small, long-term subcu taneous implants practicable. To circumvent some of these prob lems several other types of implantable drug-delivery system have been devised. The first of them to be employed clini cally was the Ommaya reservoir, devel oped in about 1963 by Ayub K. Om maya of the National Institute of Neu rological Diseases and Blindness. This simple device is a small container that is implanted under the skin of the scalp
and is connected to a cerebral ventricle by means of a short tube. On the side nearest the skin the reservoir has a self sealing membrane that can be punc tured repeatedly by hypodermic needle; hence the device gives the physician easy and repeated access to the cerebro spinal fluid, the blood-plasma filtrate that bathes the brain and the spinal cord. The Ommaya reservoir has been use ful in the treatment of certain forms of leukemia in which the malignant cells are sequestered in the subarachnoid
69 © 1979 SCIENTIFIC AMERICAN, INC
a
b
tration of the drug in the infusate. The
c YMER
change can be made during the refilling
procedure. A different drug or a placebo can be put into the pump in the same way. With an inner-chamber capacity of
about 45 milliliters of usable volume
and a delivery rate of about one millili ter per day the pump needs to be refilled in most situations about every 45 days. reliminary studies with dogs demon
P strated that the pump could infuse
heparin (or sterile water serving as an experimental control) intravenously for more than four years without blockage of the cannula or serious side effects. We then began implanting pumps for the in fusion of heparin in a series of human patients with severe clotting problems who had failed to respond to treatment with conventional measures. ( My col leagues in these studies were Buchwald, Varco, Thomas D. Rohde and Philip D. Schneider.) Most of the patients had suf
(0) con
fered from the recurrent formation of
sists of compressed drug or hormone. Tbe material enters tbe subcutaneous tissue by erosion
clots in their leg veins, with subsequent
IMPLANTABLE PELLETS include tbe tbree forms depicted here. Tbe simplest type and goes from tbere into tbe bloodstream. In anotber type of pellet
(b)
tbe drug or hormone is
put in a silicone-rubber capsule, tbrougb wbich it diffuses into tbe tissue. In tbe tbird type
(c)
tbe drug is contained in a matrix of polymer that degrades witbin tbe body, so tbat it enters tbe tissue botb by diffusion tbrougb tbe outer layer of tbe polymer and by erosion of tbe polymer.
migration of clots to the lungs, notwith standing treatment with the oral antico agulant sodium warfarin. Many of the patients had had the largest vein in the abdomen (the inferior vena cava) tied off surgically to prevent the movement
space (which is filled with cerebrospinal
improvement on the membranes has re
of clots to the lungs, a procedure tha t
fluid) and are otherwise protected from
mained essentially the same in concept,
is generally a last resort and that intro
chemotherapeutic
do not
although its design has been changed
duces many complications of its own.
cross the barrier between the brain and
several times. It is now being manufac
About a third of the patients were giv
the general circulation of the blood. The
tured under the trade name Infusaid
ing themselves heparin from four to six times per day by subcutaneous or even
drugs that
reservoir is also useful in chronic forms
by the Metal Bellows Corporation of
of fungal meningitis, when high concen
Sharon, Mass. It consists of a cylindri
intravenous injection. Heparin, as the
trations of antibiotics in the cerebrospi
cal disk about the size and shape of an
most effective anticoagulant drug avail
nal fluid are needed. The usefulness of
ice-hockey puck. The disk is made of
able, had prevented the recurrent for
the device lies in its ability to provide
the relatively light metal titanium, so
mation of clots in these patients previ
easy entrance to the otherwise fairly in
that its empty weight is only 190 grams
ously, but only at the cost of frequent
(6.7 ounces). The titanium is compatible
injections or continuous infusion, a pro
with body tissues.
cedure that requires prolonged hospital
accessible subarachnoid space. The concept of a subcutaneous drug reservoir evolved further in 1970 when Henry Buchwald,
The inside of the disk is divided into
ization.
Richard L. Varco,
two chambers by a cylindrical titanium
When these patients entered the hos
Perry L. Blackshear, lr. (my father),
bellows, which forms a barrier between
pital at the University of Minnesota,
Frank D. Dorman and I at the Universi
the compartments that is collapsible but
we first established their intravenous re
ty of Minnesota School of Medicine de
impermeable. The outer compartment
quirement for heparin by means of in
signed an implantable infusion pump
contains a fluorocarbon in a liquid-va
fusions from a pump outside the body.
and began testing it. The purpose of the
por combination; it serves as the propel
The pump was then implanted (with lo
device was to provide a means of contin
lant. The inner chamber contains the in
cal anesthesia) under the skin of the
uously delivering heparin to ambula
fusate, the drug to be delivered.
chest wall, a procedure identical with
tory patients with severe clotting prob
The principle underlying the opera
the implantation of a cardiac pacemak
Heparin can be given only by
tion of the pump is the basic physical
er. The delivery cannula was threaded
injection or infusion, and so it is admin
concept that a liquid in equilibrium with
through a tributary vein into the superi
istered almost exclusively to hospital
its vapor phase exerts a constant vapor
or vena cava. After being discharged
ized patients. Injections are impractical because they are needed every four to
pressure at a given temperature, regard
from the hospital a patient was to return
less of its volume. Hence in the relative
every week or two for blood tests and
six hours, a function of heparin's short
ly constant temperature of the body the
every four to eight weeks for refilling of
half-life in the circulation; furthermore,
fluorocarbon exerts a constant pressure
the pump.
recent studies of patients with various
on the infusate and forces it through a
We have now implanted about 20
clotting problems have shown that the
series of filters and flow-regulating re
pumps for the delivery of heparin; some
lems.
continuous infusion of heparin carries
sistance elements into a vein or an ar
of them have been in place for more
less risk of bleeding complications than periodic injections do.
tery. The infusion rate of a particular
than two years. The results of these pre
infusate is therefore constant for any
liminary trials have been encouraging.
We first tried to administer heparin by
given combination of propellant chemi
Our main objective was to prevent the
diffusion through silicone-rubber mem
cal, flow restrictor and infusate temper
recurrence of obstructing clots in the
branes; the attempts failed mainly be
ature and viscosity.
lungs and deep in the venous system.
cause of the large size of the heparin
The amount of active drug delivered
In more than 2 50 patient-months of the
molecule. The pump we designed as an
can be altered by changing the concen-
infusion of heparin through the pump
70 © 1979 SCIENTIFIC AMERICAN, INC
u
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TIME (HOURS)
375 milligrams every three hours. The concentration of procainamide
PEAK-AND-V ALLEY PATTERN of the level of a drug in the blood appears when the concentration resulting from intermittent
in the blood serum remains in the therapeutic range unless a dose is
oral doses is plotted over time. Here the drug is procainamide, which
missed
regulates abnormal rhythms of the heart, and the normal dose
ly gives rise to a drug concentration that is toxic to some patients.
80
(color) is
(broke1l colored lille).
A dose of
B
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B
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(EX),
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CONTROL OF DIABETES is difficult with the conventional daily
cise
injection of insulin, as is shown in these curves reflecting the concen
unregulated insulin concentrations of diabetics do not prevent wide
tration of insulin and glucose in the hlood of three diabetics
swings in glucose. Implantable devices could provide steadier levels.
and three nondiabetics
(blac k).
day their regimen was injection
(color) 7:00 A.M. on the first (IN), breakfast (8), lunch (L), exer-
Beginning at
snack
dinner
supper
and sleep. Higher but
A different version of graph was published by others in
Mayo Clillic Proceedillgs;
G.
D. Molnar and
it appears with their permission.
71 © 1979 SCIENTIFIC AMERICAN, INC
only one clinically suggestive episode of thrombosis in a leg vein was encoun tered, and we saw no lung clots. The pump functioned accurately and reli ably, maintaining fairly constant levels of heparin in the blood. The versatility that distinguishes the pump from passive devices for diffusion
was demonstrated during the refilling procedure. At that time the rate of deliv ery of heparin could be adjusted easily by changing the concentration of the drug in the new solution of infusate. Side effects have been rare. Perhaps the best feature of the pumps is that they enable a patient to go about his daily activities with little more inconvenience than he would have with a cardiac pace maker. One patient even played a week ly game of volleyball with no ill effects, although this is not an activity we would recommend in the circumstances. second clinical application of the
A pump utilized a main advantage of
certain implantable systems, the ability to deliver a drug to a specific target area or organ. We installed the pump to pro vide an intra-arterial infusion of a che motherapeutic drug for the treatment of 100
cancers of the liver. These tumors, in cluding not only hepatoma, or primary liver cancer, but also metastatic cancers originating in the bowel or the pancreas, are in most cases rapidly fatal. Che motherapy has had little effect, notwith standing its success in the treatment of many other types of cancer. The liver is unusual in that blood flows to it not only through arteries but also through veins. Most of the organ's normal blood supply is venous, but the blood supply of a liver tumor is almost exclusively arterial. Here was an open ing for the delivery of a chemotherapeu tic agent by infusion directly into the hepatic artery, which supplies the liver with arterial blood. We knew the pump could be implanted successfully for long periods of time; what was uncertain was whether a cannula in the hepatic artery would remain open when the drug being infused was not an anticoagulant and whether the high pressure and different clotting environment of the arterial sys tem would cause problems. Studies with dogs indicated that the pump would work. Then our group (Buchwald, Varco, Rohde, Theodor B. Grage, Pericles P. Vassilopoulos and I)
implanted pumps in five patients with liver cancer. The pumps were placed un der the skin of the abdominal wall and the cannulas were threaded through a branch artery into the hepatic artery. When the incisions had healed, the pa tients received alternating infusions of 5-fluorodeoxyuridine (the chemothera peutic agent) and water (to keep the can nula open during a respite when the drug showed signs of reaching toxic lev els), each infusion continuing for sever al weeks. The pumps worked satisfactorily, and the patients were able to leave the hospi tal and resume their normal activities. The effects of the drug were less satis factory. In some patients the symptoms improved and the tumors temporarily stopped growing, but all the patients eventually died or developed more widespread tumors. This result empha sizes the need to test new drugs and dif ferent schedules of delivery for this type of cancer. We hope also to develop an implant able infusion device that would provide a total artificial replacement for the beta cells of the pancreas. These cells nor mally secrete insulin in a predictable
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