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


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


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


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



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.



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



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






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,


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


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.


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



N subcutaneous capsules,

IMPLANTABLE PUMP, which has the trade name Infusaid, is shown in operation during refilling

(bottom). The pump



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




tration of the drug in the infusate. The


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


tbe drug or hormone is

put in a silicone-rubber capsule, tbrougb wbich it diffuses into tbe tissue. In tbe tbird type


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


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


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


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




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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


regulates abnormal rhythms of the heart, and the normal dose

ly gives rise to a drug concentration that is toxic to some patients.


(color) is

(broke1l colored lille).

A dose of















































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(S U)

CONTROL OF DIABETES is difficult with the conventional daily


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




and sleep. Higher but

A different version of graph was published by others in

Mayo Clillic Proceedillgs;


D. Molnar and

it appears with their permission.


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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Implantable drug-delivery systems.

Implantable drug-delivery systems are being developed to release drugs to the bloodstream continuously as well as free patients from being hospitalize...
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