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http://jba.sagepub.com/Journal of Biomaterials Applications

http://jba.sagepub.com/content/8/3/247The online version of this article can be found at:

DOI: 10.1177/088532829400800305

1994 8: 247J Biomater ApplMonica J. Nitsch and Umesh V. Banakar

Implantable Drug Delivery

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Implantable Drug Delivery

MONICA J. NITSCH

Medical Student 4th Year

University of Nevada at RenoSchool of MedicineReno, NV 89557

UMESH V. BANAKAR, PH.D.*Director of Research

Section Head: Pharmaceutical Sciences

Associate Professor of PharmaceuticsSt. Louis College of Pharmacy

4588 Parkview Place

St. Louis, MO 63110

*Author to whom correspondence should be addressed.

INTRODUCTION

onventional drug delivery utilizes routes of administration,C namely, oral, rectal, intravenously, and topical, that deliver drugsubstances that are immediately released in bolus fashion. For a time,the drug concentration will be adequate for therapeutic effectiveness,but eventually the drug concentration falls below the minimum effec-tive concentration and another dose of the drug is required. The in-creased frequency of dosing to sustain a therapeutic concentration maybe several times daily, which not only results in variable drug concen-trations, but also noncompliance by the patient unable to maintainthis regimen. The ideal drug concentration profile would be a sustained

therapeutic level without variation or the need for repeated dosing(Figure 1).

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Figure 1. Conventional drug dosing and drug concentrations (from Reference [3D.

Pharmaceutical companies continue to develop new drugs with thegoal of augmenting the duration of action and thus, reducing the fre-

quency of dosing. It was not until recently that the delivery systemsthemselves were modified in order to facilitate controlled-release drugdelivery that would also sustain the duration of action within the ther-

apeutic range. These advancements in drug delivery have affordedmany new and exciting areas of research and development aimed to op-timize pharmaceutically-related therapy for many diseases. Thesetechnical advances in drug delivery are rapidly progressing to realityand it is anticipated that they will be used more frequently in clinicalpractice over the next decade. Major advances have already been madein the area ofcontraception with the development of the Norplant im-plantable system (1]. In addition, the insulinpump for diabetes is beingperfected by several investigators and is widely reported in the litera-ture [2].Implantable pumps and infusion systems are two of the several in-

novative technologies developed in drug delivery over the past twodecades. These systems employ a mechanism involving a reservoir of

drug substance and an energy source to drive drug release. Eachmechanism offers unique opportunities for rate and duration for con-



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trolled delivery of drug substances directly into the bloodstream either

locally or systemically. Further, the control of drug delivery in thismanner reduces the adverse effects of drugs and improves overall

e$icacy and compliance by avoiding repeated insertions of needles intoperipheral vasculature.The implantable device is surgically introduced and completely sub-

cutaneous with nominal chance of infection. Fluids or drugs are in-

jected into the portal chamber and flow through the catheter directlyinto the bloodstream. The needle may be removed or an external pump,

many of which are ambulatory, may be attached for continuous infu-sion.

Overall, there are several advantages to these systems including the

psychological benefit to the patient who experiences less pain, less anx-iety and less disruption of daily routines while remaining ambulatoryduring treatment. In addition, implantable systems are valuablebecause they enable drug substances to overcome the absorption barri-ers encountered by oral and peripheral intravenous administration,specifically: plasma proteins, first pass hepatic effects, gastrointestinalabsorption, and the blood brain barrier. Each ofthese biological barri-ers prevents a percentage of drug substance from reaching its targetsite and active receptor. Implantables, whether for local or systemic ad-ministration, can also protect healthy tissue by eliminating peaks andtroughs resulting from periodic dosing, thus minimizing toxic sideeffects.

Unfortunately, there are potential problems with the use of implant-able systems. These include: biocompatibility, biodegradability, theneed for a minor surgical procedure for implantation/removal, possiblemalfunction or imprecise drug delivery, and financial expense. How-ever, research and development continue to progress toward alleviatingthese problems.The focus of this article is to provide an overview of the essentials of

drug delivery using implantable pumps and infusion systems. Theauthors intend to present not only the mechanics of this technology,but also its clinical applications and current investigational uses,while commenting on forthcoming applications as well.

I11fPLANTrIBLE DRUG DELIVERY SYSTEMS

Classification

In general, the release of the drug from the delivery system is acti-vated by some physical process(es) and/or is facilitated by an external



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Figure 2. Classification of rate-controlled systems (from Reference [3]).

energy source which ultimately controls the rate of drug delivery [3].Such rate-controlled drug delivery systems can be classified as follows:1) preprogrammed drug delivery systems; 2) energy modulated drugdelivery systems; or 3) feedback-regulated drug delivery systems, asillustrated in Figure 2.

Preprogrammed Drug Delivery Systems .

Pre-programmed drug delivery systems are designed to release the

drug substance at a specific rate that depends on Ficks Laws of Diffu-sion, which considers particle size and concentration gradients as thedriving force (Figure 3). The rate of the drug release can be expressedas:

Q _ D*A*(C, - C) (1)t h

&dquo;



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Figure 3. The process of diffnsion (from Reference [9]).

where Q is the cumulative amount diffused, D is the diffusivity,Aisthe surface area, C. is the solubility ofthe drug in the medium, C is theamount diffused at time t, and h is the thickness of the diffusionmembrane.

Polymeric SystemsPolymers have been used extensively in controlled drug delivery

systems and offer several variations on the theme of implantables.There are

nondegradable polymers,those which are not

hydrolyticallyor enzymatically cleaved in vivo [41, and synthetic biodegradablesystems available [5).Several characteristics are desired in the development of a drug

system using polymers (Table 1). In addition, the ideal implantabledevices should possess all the characteristics as listed in Table 2 [5-9].The permeability of the polymeric membrane contributes to the rate

Tabls 1. Characteristics of the ideal

polymer drug delivery system.

Extracted from Reference [51,



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Table 2. Characteristics of the ideal implantable drug delivery system.

Extracted from References [5-9].

of drug diffusion and release [9]. The rate of drug release frompolymeric systems is given by:

__ xm..~Ka~.~ ~Dd ~Dm~CR (2)t K-1,D-h, + KalmDdhm

(2)

where K-,, and K,,,- are the partition coefficients for the interfacial par-titioning of drug molecules from the reservoir to the rate-controllingmembrane and from the membrane to the aqueous diffusion layer; D-and Dd are the diffusian coefficients in the rate-controlling membranewith a thickness of h- and in the aqueous diffusion layer with a thick-ness of h,. C, is the drug concentration in the reservoir compartment[9]. .

Polymeric Systems DesignsMatrix Systems are prepared by homogenous dispersement of drug

particles throughout a solid nonerodible polymer [9]. Drug releaseoccurs by diffusion through the polymer matrix or by leaching or acombination of both (Figure 4).At higher drug loadings, pores andchannels are created by the dissolved drug particles and leaching con-tributes significantly to release [10]. The matrix may be composed ofeither a lipophilic or hydrophilic polymer depending on the propertiesof the drug and the rate of drug release desired.

The rate of drug release from such a matrix-type polymeric system istime-dependent and at steady state is given by:

QZ - (2DoCRDp)~~2 (3)tl/2= o R p (3)

where D. is the initial drug loading dose, CR is the drug solubility in



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the polymer, and Dp is the diffusivity of the drug molecules in thepolymer matrix.Bioerodible Systems are polymer based systems whereby the polymer

itself slowly erodes in the biological environment ata

controlled rate,which leads to drug release. The rate of drug release is dependent onthe rate of bioerosion of the polymer system alone. One problem withthis system, however, is the decrease in surface area as the polymersystem erodes, which makes the drug release rate variable (Figure 5).Swelling Control Systems involve dissolved or dispersed drug within

a polymer matrix that is unable to diffuse through that matrix [9]. Bio-logical fluid enters the matrix at a controlled rate, resulting in swellingof the matrix, physical and chemical changes in the matrix structureand release of drug [11]. The rate of drug release is dependent on therate of diffusion of biological fluid into the polymer matrix (Figure 6).

Magnetically Controlled Systems contain drug and small magneticbeads dispersed within a polymer. When the system is exposed to bio-

logical fluid, the drug is released by diffusion with concentration gradi-ents driving drug release. However, with the addition of an oscillatingexternal magnetic field, physical changes occur, leading to further drugrelease [9]. More simply, the physical structure of the polymer is altereddue to the movement of the magnetic beads within the magnetic fieldwhich creates new channels for drug release, thus increasing the over-all rate of release (Figure 7).

Figure 4. Matrix systems (from Reference [9]).



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Figure 5. Bioerodible systems (from Reference [91).

Figure 6. Swelling controlled systems (from Reference [9]).



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Figure 7. Magnetically controlled systems (from Reference [9]).

Energy Modulated Drug Delivery Systems

Energy modulated drug delivery systems release drug molecules bythe activation of some physical process(es) and/or by the energy sup-plied by an external source. The energy required for these systems caneither be passively-obtained energy or actively-obtained energy. Passively-obtained energy results from the interaction between the deliverysystem and the surroundings which generates the energy for drugrelease, i.e., osmotic pressure.Actively-obtained energy, on the otherhand, comes from external energy sources that are added to the

delivery system either internally, such as with magnetic beads, orexternally, such as from mechanical infusion pumps. The rate of drugdelivery is therefore controlled by the regulation of the energy or the

physical process(es) applied to the system (Figure 2) [3).

Osmotic PumpsOsmotic pumps are usually capsular in shape and are manufactured

in several sizes. Figure 8 depicts the cross section of this system. The

innermost compartment is the drug reservoir composed of syntheticelastomer; it is chemically inert and impermeable to most formula-tions. The drug reservoir is surrounded by a sleeve of osmotically activeagents and a semipermeable membrane which also serves as the hous-ing for the pump. The system works with exposure to an aqueousenvironment such as that after subcutaneous implantation.As wateris drawn to the osmotically active agent through the semipermeable



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membrane, pressure is supplied to the collapsible drug reservoir anddrug is expelled through the delivery portal, which is an orifice withprecise dimensions. The entire process is completely dependent on the

osmotic pressure createdand

is independent of drug properties. There-fore, the energy required for drug release is passively supplied to thedrug delivery system from the environment which characterizes this

energy modulated system as one containing a passively-obtainedenergy source. The rate ofdrug release (~,Ut) from the system in vitro isgiven by:

Q P&dquo;~ml~a - .~ (4)t

-

h-~J~d (4)

where Pw,A~, and h- are, respectively, the water permeability, the effec-

tive surface area, and the thickness of the semipermeable housing;

Figure 8. Osmotic pumps (from Reference [12D.



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(~r, - x) is the differential osmotic pressure between the drug deliverysystem with an osmotic pressure of 7r, and the environment with anosmotic pressure of 1r4; and Sd is the aqueous solubility ofthe drug com-

ponentin the solid formulation

[12].One of the most widely used osmotic devices for investigational pur-poses is theALZEV osmotic pump, first developed in the mid-1970s. Ithas the basic design described earlier and is manufactured in varioussizes; delivery rates vary between 0.5 and 10 JlI per hour and deliverydurations vary between 3 days and 4 weeks (Figure 9).ALZEV osmotic

pumps have been utilized for delivery in several investigational studies

using a variety of agents (Table 3) and animal species (Table 4).Although most osmotic pumps provide a constant rate of drugdelivery, they have the capability of delivering drugs at variable rates.This possibility is important for clinical situations where the level of

drug needed for therapeutic effectiveness is influenced by additionalendogenous factors, i.e., circadian rhythm. Endocrine studies of hor-monal patterns have demonstrated that their physiologic effect is onlyobserved with on/off or pulsatile administration [13]. For example,

Figure 9. Various sizes and delivery rates of ALZET pumps (from Reference [13]).



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Table 3. Classification of agents delivered byALZEP Osmotic Pump.(alphabetical listing)

Extracted from Reference (131.

Table 4. Major animal species in whichALZEPpumps have been used. (alphabetical listing)

Extracted from Reference ~13].



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Lynch and colleagues used a coil wrapped around the pump core whichcontained melatonin solutions alternated with drug-free solutions

[14-15]. The two solutions were not miscible and remained separate

(Figure 10). The systems were implanted subcutaneously in rats andallowed to run for 6 days while urine samples were collected. Theresults demonstrate the possibility ofpulsatile administration and theability to accomplish it with implantable systems (Figure 11).

InfusorsEarly infusion systems relied on gravity to generate the force for

drug administration and required bulky equipment attached to the

patient which hindered ambulation. With the development ofportableinfusors by Baxter, outpatient therapy and inpatient ambulation hasbecome possible for patients prescribed for continuous infusiontherapy.The basic infuser system compromises a reservoir composed of a

balloon within a housing unit and three feet of tubing (Figure 12). The

system functions by Poiseuilles law of capillary flow and the rate ofinfusion of drug is given by:

Q = r4*- (5)~ _ .~ 8-qllwhere Q is the infusion rate, r is the inner radius of the glass flowrestrictor, P is the reservoir pressure minus venous pressure, 77 is the

viscosity of the drug, and is the length of glass flow restrictor [13].The system is based on the cross-link density ofcarbon-carbon double

bonds of polyisoprene. The bonds provide a low level ofhysteresis andwhen used in the reservoir, serve to create a constant pressure on thefluid regardless of the volume remaining in the reservoir [13]. Sincethe energy for drug release is generated by the interaction between thesystem and the surroundings and not by any batteries or externalmechanical source, this system is classified as a passively-obtainedenergy source system.Infuser systems have been used for chemotherapy, analgesia, chronic

nausea, at-home heparin therapy and for thalassemia as outlined inthe clinical applications section of this article. The utility of infusorswill continue to expand along with the technology and soon it may bepossible and practical to treat other disorders that require continuousinfusion of drugs or fluids at home.



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.5!*BEbo

-E- EC3r.gu

2mG7

~-0c011o

.R0

SScl

b2P4

o

EaE



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Figure 11. Rhythmic infusion of melatonin (from References [14-15]).

Infusion PumpsInfusion pumps are devices with intrinsic power sources and themeans for replenishment of the reservoir while implanted. Theirenergy is actively-obtained as it is generated solely by the system anddoes not come from any interaction with the surrounding biologicalsystem. There are three basic types of infusion pumps that will becharacterized.

Vapor pressure powered pump is a dual-chamber device with a reser-voir and a chamber for an inexhaustive volatile liquid (Figure 13). Thecharging fluid is chosen for its ability to produce the appropriate vaporpressure at physiologic temperatures. The fluid chosen is commonly afluorocarbon [3]. Since physiologic temperature is fairly constant, thepressure generated by the charging fluid will also be constant. The twochambers are separated by a metal sheet that is freely movable.Drug release is powered by the vapor pressure of a charging fluid con-

tained in the pump. When filled, the vapor pressure produced by thecharging fluid forces the metal bellows to collapse on the drug reser-

voir, expressing drug through a filter into an accumulation chamber



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Figure 12. Basic Infusor (from Reference [13]).

Figure 13. Vapor-pressure powered infusion system (from Reference [13]).



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and into the valving system. Based on the specified infusion program,a second valve opens at the appropriate time, allowing a precise volumeof drug to flow from the accumulation chamber to the catheter. The

drug delivery rate can be modified by altering the concentration of theactive drug in the infusate as well as by changing the size of thecannula used.The rate of delivery is defined by:

_ (P, _ Pe) (6)t 40.74r~(L)

~

where d and (l) are, respectively, the inner diameter and the length ofthe delivery cannula; (Ps - P~) is the difference between the vaporpressure in the pumping compartment (PJ and the pressure at the

implantation site (Ps); and 11 is the viscosity of the drug formulationused [3].Refilling the reservoir is accomplished by percutaneous injection into

the pump, which has a self-sealing septum. The power source is&dquo;refueled&dquo; by the compression of the original propellant with the sy-ringe during refilling of the infusate chamber.An example system isthe Infusaid1,) Infusion System. Clinical experiences with such systemsare described later in the article.

Peristaltic Pumps consist of a U-shaped chamber that is in contactwith a flexible tube which is pressed with rollers to create sufficient

force to occlude its lumen (Figure 14). The rollers are attached to amotor-driven rotor. The drug reservoir is composed of silicone rubberpouches 0.5mm thick, which are percutaneously refilled through a sili-cone rubber septum in the reservoir. Pump rate and hence drug releaserate is controlled by an external remote control [9].

Implantable Microcomputer SystemsThe miniaturization ofcomputer chips has also contributed to techni-

cal advances in implantable drug delivery systems.AProgrammableImplantable Medication System (PIMS) has been developed byAPL(Figure 15). The physician and the patient have devices that must beoperated separately, therefore selection of patients to utilize this devicemust be carefully considered. The portion that contains the microcom-

puter is called the Implantable Program Infusion Pump (IPIP). The

physician is able to program the IPIP with the main terminal, whichhas telephonic capability. The patient can also self-administer medica-tion within the limits set forth by the physician. The IPIP can also



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Figure 14. Peristaltic powered infusion system (from Reference [13]).

store data about its operation which can be retrieved by the physicianfor future therapeutic decision-making [13].The advantages of a PIMS include those listed earlier for implant-

able drug delivery systems. What is exciting about this technology is

the possibility of including a physiological sensor that could regulatemedication delivery to the exact biological needs of the patient. Thisleads to the last category of rate-controlled drug delivery systems,namely, the feedback-regulated systems.

Feedback-Regulated Drug Delivery Systems

Drug release in the feedback-regulated system involves the ability ofthe system to monitor the chemical environment, i.e., measure a partic-

ular triggering agent (analyte) viaa

biosensor, processthis

informa-tion and modify the drug release accordingly.

Biosensors

The development of biosensors is also a progressive area of currentresearch. Biosensors transduce or convert biological changes into elec-trical signals that can be registered and appropriately evaluated. In so



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doing, they can detect and note subtle changes, even at the molecularlevel [16]. They synergistically combine biochemistry and microelec-tronics to simplify biochemical and chemical analysis on the micro- and

macroscale [17].A biosensor incorporatesa

biological sensing elementthat is either intimately connected to or integrated with a transducer.Most biosensors produce digital electronic signals that are proportionalto the concentrations of specific chemicals or sets of chemicals.Generally speaking, when biological molecules interact specifically

and reversibly, they induce a change in one or more physicochemicalparameters associated with the interaction. Changes in concentrationsof ions and gases as well as in heat, absorbance, mass, conductance, andelectron transfer can be converted to electrical signals. The transducerresponds to the changes induced by the biocatalytic process and relaysthis information to an interfacing detector that records or displays the

data [18, 19].The major challenge in biosensor development lies in converting a

biological change into an event that can be transduced to an electricalsignal [20, 21]. Fiber optics, semiconductor technologies and immobili-zation techniques can provide this link between a specific biologicalchange and a simple physical measurement [22-251. Most of todaysmodel biosensors incorporate biologically selective materials: enzymes,multienzyme systems, cells, antibodies, organelles, bacterial cells, ortissue sections of mammals or plants. The transducer elements usedinclude electrochemical sensors, enzyme thermistors [26], optical sen-

sors, optoelectronic devices [27], electrochemical-sensitive transistors[28], and piezoelectric sensors. There are two broad categories of biosen-sors : potentiometric or amperometric.Potentiometric biosensors are designed to measure and quantitate

electrical changes, i.e., potential difference between electrodes. This

category is further subdivided by electrode makeup. Enzyme electrodescombine an ion-selective sensor with an immobilized enzyme, which

provides a highly selective and sensitive device for determiningsubstrate concentrations. Modified electrodes utilize redox reactions,which often require cofactors. Cofactor-modified electrodes are yet more

complex and consist of enzyme protein, a cofactor and other enzymes.

Amperometric biosensors are designed to measure and quantitateusing principles other than electrical.An example is the optical biosen-sors, which can be reversible or irreversible depending on whether the

analyte is consumed by the system. Briefly, this type utilizes laseroptics to detect spectral changes in molecular structure to directlymeasure analyte concentration.Another type of amperometric biosensor is the enzyme-based type. In



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this example, the Ion-Selective Field-Effect Transistors (ISFEI!5) re-

place the traditional metallic substance that acts as the &dquo;gate&dquo; throughwhich the current flows. If a thin layer of gel containing an enzyme is

then appliedover

the ISFETs ion-selective membrane (Figure 16),a

biosensing device, the Enzyme-Sensitive Field-Effect TransistorENFET, is created. The analyte, which is contained in the overlyingsolution, becomes trapped within the gels pores.As it then percolatesthrough the gel, the enzyme catalyzes its modification. The underlyingISFET monitors either the consumed analyte or the generated product.The intricacy of the relationship between the response of the ISFET

and the concentration of the substrate does not lend itself to a simpli-fied mathematical expression. It depends upon the rate constant for theanalyte-enzyme reaction, the diffusion constant of the detected species,the concentration of the immobilized enzyme, product-inhibition ofthe

enzymatic reaction, and other factors [16].The ENFET has some advantages over the ISFET system, mainly its

size and its ability to control the thickness of the enzyme-loaded mem-branes [29]. ENFETs have already been developed for the detection ofurea [30], penicillin [31], glucose [32], and acetylcholine [33]. It is thedevelopment of the ENFET that measures glucose that is germane tothis article as it relates to the future development of implantableinsulin pumps. This is further explained in the following section onclinical applications.

Figure 16. ENFET sensor (from Reference I16]).



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CLINICALAPPLICATIONSAND RESEARCH

VITH IMPLANTABLESAND INFUSION PUMPS

While several systems have been described, it is equally important toexplore clinical applications, both current and future, of this technol-ogy. Table 5 lists many therapeutic applications of implantables andinfusion systems under investigation for a variety of diseases. In addi-

tion, selected clinical situations will be addressed in more detail in thefollowing sections.

Implantable Insulin Pumps

Diabetes mellitus is the most common cause of blindness in peopleunder the age of 65 in the western world [79]. In addition, when uncon-

trolled, this metabolic disorder leads to microvascular diseases such asretinopathy, peripheral neuropathy, cardiomyopathy and renal failure.The progress of these complications has also been related to the dura-tion and severity ofthe disease [80]. If the metabolic parameters couldbe controlled or normalized, there may be hope of preventing, if notarresting, the progression of these serious complications.The second reason for considering the development of a rate-con-

trolling delivery system for insulin is related to the pharmacologicalproblems associated with the insulin molecule. Conventional therapyfor insulin dependent diabetics has involved subcutaneous injections of

insulin throughout the day. Multiple injections are partly due to theshort half life of the molecule (20 minutes); even though delayedrelease preparations exist, the problem is compounded by the manyactions of insulin in the body. Figure 17 illustrates the exponentialchanges observed even with small changes in the amount of insulinadministered. Ib create an optimal balance between catabolism andanabolism, finer control of insulin administration for diabetics iswarranted.

The development of rate-controlled insulin delivery systems has oc-curred over the last 15 years and implantable insulin pumps havebecome reality for a select number of patients. These devices have notonly provided better blood glucose control, but have greatly improvedthe quality of life of their users.There are two basic system types: the closed-loop and the open-loop

systems. The closed-loop system, developed byAlbisser et al. in 1974and Pfeiffer et al. [81-83], is commercially available as Biostator8.There are three components: a glucose sensor, an insulin or drugdelivery pump and a computer controller that regulates the intra-



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Figure 17. Dose-response curve for insulin in normal physiology and in untreatedinsulin-dependent diabetes (from: Rate ControlledDrugAdministration andAction, CRC

Press, H.A. J. Struyker-Boudier, ed., Boca Raton, FL, 1986, p. 145).

venous administration of insulin based on a measured amount of

glucose. Peripheral venous blood glucose levels are continuously moni-tored at the bedside and a computer calculates how much insulin orglucose should be returned to the circulation to maintain normal glu-cose levels. The constant monitoring tightly controls glucose levelswith meals, hypoglycemic episodes, and hyperglycemic ketoacidosis.Hence, it has important applications in the hospital setting for acutelyill patients, such as those requiring surgery, those that are pregnant, orthose that suffer from ketoacidosis. Unfortunately, the size and cost ofthis system limit its use to the hospital setting. In addition, because ofthe mandatory intravenous administration, there is an increased riskfor thrombosis and infection.

The open-loop systems are more like the PIMS system; they arecompact, implantable, and programmable. First introduced by Pickupet al.

[84],the Continuous

SubcutaneousInsulin Infusion

(CSII) systemuses infusors to administer basal and prandial rates of insulin into thesubcutaneous tissue of the anterior abdominal wall. The patient alsomonitors blood glucose for additional control. The system consists of a

pump, power supply, insulin reservoir, delivery pathway, and a suitableequipped and instructed operator, i.e., the patient.As the insulin is

infused, it precipitates and forms a depot [85]. The absorption of



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Figure 18. Mean glycosylated hemoglobin (HbA,,) concentrations in insulin-dependentdiabetics managed by conventional insulin treatment (CIT) or continuous subcutaneousinsulin infusion (CSII). Dotted lines are normal range (from: Rate Controlled Drug

Administration andAction, CRC Press, H.A. J. Struyker-Boudier, ed., Boca Raton, FL,1986, p. 152).

infused insulin is similar to that of traditionally injected insulin [85,

86];however, the average time for

absorptionis shortened for infused

insulin from 6-8 minutes for the injections to 3-5 minutes for infusedinsulin. Pharmacokinetically, the infused insulin follows two-compartment modelling [87].Also, there is a reported 20% decrease inthe amount of insulin infused reaching the systemic circulation overtime for reasons that have remained unknown; it may be due to local

enzymatic breakdown of the insulin molecule prior to absorption.In general, the results have been encouraging. Many patients have

been receiving CSII at home and work for up to 3 years or more [88-91].Clinical trials have demonstrated the effectiveness of CSII compared toConventional Injection Treatment (CIT). Patients were randomly

allocated to their usual unchanged injection or to CSII. In both studies,the glycemic control was separated as assessed by HbA1c concentrations

(Figure 18) [92-94].Some ofthe current applications of implantables for insulin delivery

have been reported in the literature and are listed in Table 6. It mustbe noted, however, that by using these devices, one is not curing di-abetes. The goal is to gain control and to minimize complications of



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Table 6. Samples of insulininfusionlimplantable systems in use.

long term uncontrolled diabetes. In addition, the risks of the technol-

ogy itself must be weighed carefully when selecting patients to receiveit. Sepsis and thrombosis are very fatal complications that must beavoided if possible.

Contraception

Contraceptive methods have evolved over the past several decades.The most common means of contraception is by oral contraceptives,namely the formulations employing progestins and estrogens. How-ever, usage of oral contraceptives is not without problems (Table 7). Thecircumvent these problems and others, including the first pass effect,

Table 7. Relative advantages and disadvantages ofthe oral contraceptive method.



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which leaves the drug up to 80% metabolized prior to approaching the

target site, new approaches have been developed which include thesubdermal implants that have recently been approved by the FDA.

Several mechanismsof

drug release from these implantable systemshave been investigated (Table 8). Currently, implantable contraceptivesare primarily of the diffusion and chemical type.

Norplant and Norplant-2~ are examples of implantable devices thatprovide low-dose, long term contraception via sustained delivery of theactive agent, levonorgestrel. Both implantable systems utilize a non-biodegradable polymeric silastic capsule as a matrix for drug deliverywhen placed in the subcutaneous region. NorplantO consists of a hollowcapsule, 20 mm in length and 2.4 mm in diameter, and is filled with36-40 mg ofthe progestin, levonorgestrel. Six ofthese silastic capsulesare placed in the subcutaneous layers of the upper arm. The drug is

released via diffusion ofapproximately 6 mcg per capsule per day, suffi-cient to achieve an antifertility effect [99]. On the other hand,Norplant-2@ consists of a homogenized matrix comprised of 50% sili-cone rubber and 50% levonorgestrel compressed to a shape of a rod offinite dimensions. These rods are then covered with ultra thin siliconerubber tubing which aids in holding the rod in place during dissolution[100]. Two of these rods are implanted in the upper arm, and togetherdeliver approximately 30 mcg of levonorgestrel per day, sufficient forcontraception [98]. Both Norplant@ systems can remain implanted for

up to 5 years. Pregnancy rates during their use have ranged from 0-1%

worldwide [101-103]; side effectsare

depicted in Table9.Upon discon-tinuation, pregnancy rates are restored to 75-86% according to litera-

Table 8. Mechanisms of contraceptive steroid release from subdermal implants.

Extracted from Reference [99].



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Table 9.Adverse effects related to theuse of Norplant&dquo; systems.

Extracted from Reference (104].

ture reports [101]. It must be noted that although most women are can-

didates for NorplantO, a woman with any of the contraindications listedin Table 10 should seek alterative methods for contraception. Overall,the Norplant@ system has provided women with an effective, long termchoice for contraception.And, because of its one-time dose lasting five

years, patient compliance improves to 100%.

FUTURE PROSPECTS IN CLINICAL RESEARCH

Cardiovascular Disease

Cardiovascular disease remains one of the major sources for mortal-

ity and morbidity in the western world. Even with the progress maderegarding life styles, dietary habits and the identification of cardiac

Table 10. Contraindications for theuse of Norplani~ systems.

Extracted from Reference [99].



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risk factors (smoking, obesity, diabetes, hypercholesterolemia, and

hypertension), further developments are warranted.The treatment of hypertension has greatly improved over the past 20

years. Now, most patients can be effectively treated with a variety ofantihypertensive drugs. The downside to this treatment is the fact thatit is a daily, mostly lifetime commitment for the patient. This burdenis also carried by patients who have angina pectoris, certain cardiacarrhythmias, and peripheral vascular diseases. Patients on theseschedules are at risk for the same problems mentioned in the introduc-tion of this article, namely, variable drug levels, potential side effects,toxicities, and in the case of centrally acting antihypertensives or betaadrenoceptor blockers, &dquo;the rebound phenomenon.&dquo;The benefits of rate-controlled drug delivery in cardiovascular dis-

ease cannot be overemphasized. This is a lifelong disease where suc-cessful treatment requires the patient to carry an enormous amount of

responsibility toward compliance with drug regimens.For a long time, emergent hypertensive patients have received in-

travenous infusions of vasodilators such as sodium nitroprusside ofdiazoxide. The cyanide in sodium nitroprusside is toxic and most ofthe time, administration is controlled by shutting off the infusion.

Recently, attempts have been made to develop a computerized vaso-dilator infusion system [105-107]. One of these systems is the IMED

digitally controlled infusion pump interfaced with a Proportional-Integrative-Derivative (PID) controller algorithm [105]. In this system,

the infusion rates are revised at one minute intervals by computing theincremental increase or decrease in blood pressure proportional to thecorrective action derived by the PID controller algorithm. In one studyemploying over 1000 patients, the variation in the computer controlled

system was halfthat for the manual control [108). The following is oneexample of the feedback regulated systems discussed earlier.Cardiac failure involves the inability of the heart to pump blood. This

functional insufficiency may be due to various factors includingvalvular disease, cardiomyopathies, hypertension, or ischemic heartdisease. During the treatment of cardiac failure, three principles areemployed. First, digitalis-like agents or other positive inotropic agentsare administered to increase contractility of the myocardium. Second,diuretics are given to reduce the extracellular fluid content of the body.Third, vasodilators are administered to decrease preload and afterloadof the heart.

Rate-controlled administration for treatment ofcongestive heart fail-ure has included the continuous -infusion of dobutamine [341 andamrinone [35]. In addition, combined infusions of nitroglycerin and



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dobutamine have been given with very effective results [109]. Future

developments may involve implantable infusion systems with the com-

ponents of the systems previously described.

Cardiac arrhythmias, like cardiac failure, can progress to deathquickly without intervention. Most of the anti-arrhythmic drugs havenarrow therapeutic indices and variable pharmacokinetics. Most stud-ies of rate-controlled delivery have involved intravenous lidocaine usedfor ventricular arrhythmias following acute myocardial infarction.Anautomated control system described by Collins andArzbaecher [110]for cardiac arrhythmias in experimental animals is based upon the de-tection of the ventricular premature beats which then trigger a

computer-controlled release of lidocaine. This open-loop system hasalso been tested in humans [111].Any closed-loop system would have todetect the arrhythmias separately and could possibly have a host of

agents ready to be infused in the emergent situation.

Anticoagulation Therapy

Anticoagulation treatment is necessary following thrombophlebitis,pulmonary embolism, post myocardial infarction and post operatively.Heparin is the classic agent given subcutaneously or intravenously,while warfarin is an oral agent. Unfortunately, warfarin is complicatedby the wide variations in responses by patients leading to underdosingand thrombosis, or overdosing and hemorrhage. It has been estimated

that patients often treated with warfarin are within the therapeuticrange only 55-65% of the time [112].Additionally, the coagulation fac-tors themselves have complex kinetics of synthesis and degradation.While heparin has been administered by the Travenol Infuser [36]with good results, the ultimate system would involve a closed-loop com-puter controlled biosensor able to detect changes in the activity of thedifferent clotting factors in plasma.

Antibiotic Therapy

The utilities of rate controlled systems in the treatment of a varietyof infectious diseases are numerous. Long term administration ofamikacin and netilmicin for osteomyelitis has been studied using theInfusaid3 pump [37] and other infusion pump models [38]. By using theportable infusion systems, the patient is able to return home andresume regular activities.Another example is the intrauterine device

containing antibiotics for the treatment of pelvic inflammatory dis-ease, providing long term treatment that will also produce higher drug



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concentrations at the desired site [39]. Other examples include theintravenous administration of zidovudine using a pump for HIVinfection [40], and ceftazidime for cystic fibrosis patients with severe

Pseudomonas sp. infections [41].

Chemotherapy ,

There are numerous studies involving continuous infusions of che-

motherapeutic agents. It has long been speculated that the intra-arterial infusion into the tumor itself would maximize the efficacy ofthese toxic chemicals. By avoiding more systemic distribution, sideeffects could be minimized. In addition, and perhaps of great impor-tance, is the possibility that terminally ill patients may be more am-bulatory, hence able to return home should they wish to. Current ex-

amples of implantables and infusion systems used for chemotherapyare listed in Table 5. Clearly, as the ability to target drugs to specificreceptors improves, which is an area of site specific drug delivery, moreinfusion systems will be developed and modified for selective delivery ofdrugs, not only to certain regions of the body, but to certain cell lines.

Cancer Pain .

One of the dreadful sequelae of cancer is the pain associated with it.Efforts to manage and alleviate cancer pain have included the adminis-

tration of opiate-derivatives, such as morphine sulfate. Unfortunately,the potential for addiction and overdose are real and valid concerns forthe patient and clinician. To overcome these problems, the patient con-trolled administration device (PCA) was developed. This device is porta-ble, programmable and administers a continuous infusion of morphinesulfate with the patient able to administer additional intermittentboluses. Only a predetermined amount of drug is allowable per unittime (e.g., one hour), and the patient can only receive a predeterminednumber of boluses of a predetermined amount of drug in an allowableamount of time as well. The PCA pump is in wide usage. Table 5 lists

some of the studies conducted using infusion systems.

Endocrinology

Treatment of several diseases involving hormonal imbalances are

currently being investigated for possible rate-controlled drug delivery.Table 5 outlines the clinical research using implantables and infusion

systems for acromegaly [42], growth retardation [43], anovulatory



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infertility [44-471, and idiopathic hypogonadotropism [48J. Since mosthormonal systems are based on negative feedback mechanisms, therewill be several applications for this technology once the closed-loop

(biosensor) system is perfected.Finally, additional animal studies are being performed to investigate

the utility of this technology for intrauterine fetal infusions duringpregnancy. Prostaglandin E, has been delivered via positioned pumpsin attempts to regulate the life span of the corpus luteum [113]. In addi-tion, insulin has been delivered through implanted osmotic pumpsdirectly into the fetus of the rhesus monkey to achieve chronic hyperin-sulinemia in utero during the 19 days prior to delivery [114, 115]. Fetal

plasma insulin concentrations were nearly 100 times normal, whilematernal plasma insulin and glucose concentrations were unaffected.

At birth, the neonate was

symptomatically hypoglycemic.A similar approach has been attempted on fetal pigs to achievechronic hyperinsulinemia and to determine the influence of insulinand somatomedin on fetal growth [116]. Pumps were implanted intothe forearm of the 90 day fetus, which received 3 units per day ofinsulin for 14 days. Despite higher levels of somatomedin activity inthe insulin-treated fetuses, there was no significant difference in fetalgrowth from controlled saline-infused fetuses.

CONCLUDING REMARKS

Clearly, the utility of this technology will cross all biomedical disci-plines resulting in more effective therapeutic treatments and a higherquality of medicine. One can only assume that as each of the aspects of

implantable drug delivery systems are further investigated, advance-ments will_ quickly transcend the laboratory and become commonlyused devices in clinical practice.Future research efforts should continue to concentrate on increased

flexibility of the systems, improved biocompatibility, and expandingthe list of compounds compatible with components of the implantedsystems. Miniaturization ofnot only the drug delivery systems but alsoof the

drugs placedin them is

currently being explored.Just as there

is pressure to develop the smallest possible implantable pump, there isincreasing pressure to develop drugs of uniquely high molar potencies.Daily doses of such drugs will be in the range of a few milligrams orless, hence more doses per fill.As the above problems are overcome, additional applications and util-ities of implantables and infusion systems will be discovered. In thenext decade, the combination of the computer technology with drug



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delivery will certainly revolutionize the entire industry and possiblymodern medicine.

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