IMPLANTABLE THERAPEUTIC SYSTEMS

Introduction Of Implant In 1861 Lafarge first introduced the concept of implantable systems for sustained drug administration. The concept was later used to produce solid implants containing steroid hormonoes.initiating the use of implantable system for long- term delivery.these traditional pharmaceutical pellets consisted of pure drug with no added excipient and were defined as small. Rod shaped or ovoid shaped. sterile tablets consisting of the highly purified drug. usually compressed without excipient. Intended for subcutaneous implantation in body tissue. The devices thus prepared had a high degree of hardness and virtually zero porosity. since water did not penetrate the matrix, drug release occurred principally by surface dissolution. Due to the inherently poor solubility of steroid drugs. this method provided a good form of depot medication. There are still a few of the traditional implants in commercial use. including desoxycorticosterone acetate (percorten pellet. Ciba) . and estradiol and testosterone (Progynon and Oerton pellets. respectively . Schering). For incorporation of a variety of therapeutic agents with different physicochemical properties and for better control of drug release a limited number of excipient is now used. Thus more recent implants usually contain the drug in a rate controlling systems. These systems are available in a variety of sizes and shapes. Some of the recently approved implantation products include leuprolide acetate and nafarelin acetate in biodegradable dl-lactic and glycolic acidc copolymer for one-month release (Lupron depot micro spheres. TAP and Zoladex pellot ICI, respectively). Also new on the market is a silicone polymer capsule system containing levonorgestrone for five year contraception (Norplant. Wyeth-Ayerst). In addition, several implantable pumps for prolonged drug delivery are in commercial use. With rapid advances in implantation therapy and excipients to control the release pattern, the USP XXII identifies a much broader definition of implants, recognizing the presence of excipients and implantation in the body at sites other than subcutaneous. Advantages And Disadvantages Of Implantation Therapy Implants possess several advantages, but also disadvantages, as drug delivery systems depending on the nature of the drug being delivered. A brief overview of both the advantage and disadvantages of implantable drug delivery is given below. Advantages: The advantages of implantation therapy include.

Convenience:Effecting drug concentrations in the bloodstream can be maintained for long periods by methods such as continuous intravenous infusion or frequent injections. However, under these regimens patients are often required to stay in hospital during administration for continuous medical monitoring. A short-acting drug exacerbates the situation, as the number of injections or the infusion rate must be increased, in order to maintain a therapeutically effective level of the drug. In contrast, implantation therapy permits patients to receive medication outside the hospital setting with minimal medical surveillance. Implantation therapy is also characterized by a lower incidence of infection related complications in comparison to indwelling catheter-based infusion system Compliance: By allowing a reduction, or complete elimination, of patient-involved dosing compliance is increased immensely. A person can forget to take a tablet, but drug delivery from an implant is largely independent of patient input. Some implantable systems involve periodical refilling but despite this factor the patient has less involvement in delivering the required medication. Potential for controlled release:Implants are available which deliver drugs by zero-order controlled release kinetics. Zero order controlled release offers the advantages of (a) Avoiding the peaks (risk of toxicity) and troughs (risk of ineffectiveness) of conventional therapy; (b) Reducing the dosing frequency; (c) Increasing patient compliance. Potential for intermittent release: Externally programmable pumps can facilitate intermittent release. Intermittent release can facilitate drug release in response to such factors as : (a) Circadian rhythms; (b) Fluctuating metabolic needs; (c) The pulsatile release of many peptides and proteins. Potential for bio-responsive release: Bio-responsive release from implants

is

an

area

of

ongoing

research.

Improved drug delivery: Using an implant system the drug is delivered locally or to be systemic circulation with minimal interference buy biological or metabolic barriers. For example, the drug moiety by passed the gastrointestinal tract and the liver. The bypassing effect is particularly of benefit to drugs, which are either absorbed poorly or easily inactivated in the gastrointestinal tract and/or the liver before systemic distribution. Flexibility: Considerable flexibility is possible with these systems, in the choice of materials, methods of 2

manufacture, degree of drug loading, drug release rate etc. Commercial an implantable dosage form diversifies the product portfolio of a given drug. From a regulatory perspective, it is regarded as a new drug product and can extend the market protection of the drug for an additional 5 years (for a new drug entry) or 3 years (for existing drugs) Disadvantages: The disadvantages of implantation therapy include such factors as: Invasive: Either a minor or a major surgical procedure is required to initiate therapy. The requires the appropriate surgical personnel, and may be traumatic, time-consuming. Cause some scar formation at the site of implantation and in a very small portion of patient may result in surgery-related complications. The patient may also feel uncomfortable wearing the device. Termination: Non-biodegradable polymeric implants and osmotic pumps also be surgically retrieved at the end of treatment. Although a biodegradable polymeric implant does not require surgical retrieval. its continuing biodegradation makes it difficult to terminate drug delivery. or to maintain the correct does at the end of its lifetime. Danger of device failure: There is no concomitant danger with this therapy that the device may for some reason fail to operate. which again requires surgical intervention to correct. Limited to potent drugs : The size of an implant is usually small. in order to minimize patients discomfort. Therefore most systems have a limited loading capacity so that often only quite potent drugs such as hormones. May be suitable for delivery by implantable devices. Possibility of adverse reactions: The site of implantation receives a high concentration of the drug delivered by an implant. This local high drug concentration may trigger adverse reactions. Biocompatibility issues: Concerns over body responses to a foreign material often raise the issues of biocompatibility and safety of an implant. Commercial disadvantages: Developing an implantable drug delivery system requires an enormous amount of R&D investment in terms of cost, effort and time. If a new biomaterial is proposed to fabricate an implant its safety and incompatibility must be thoroughly evaluated to secure the approval of regulatory authorities. These issues can attribute to significant delay in the development marketing and cost of a new implant. 3

Mechanism Of Drug Release From Implantable Devices Drug release from most implantable devices is controlled by any one of six different mechanisms discussed below. Although an attempt is made here to cover the most importable types it is not possible to cover all the mechanisms under investigation. Diffusion controlled These devices are based on Flicks law of diffusion which states the rate of transfer of a diffusing substance through unit area of a section. In this case the rate of release is controlled by diffusion of drug through a polymeric membrane. In general nonerodible diffusion-controlled drug delivery system work best for drugs with molecular weight of 1000 Daltons or less. Domb et al have shown that the essential parameters affecting permeability of peptides through a hydrogel are the volume of solute and the water content of the membrane which are correlated to its pore size. Diffusioncontrolled devices can be further classified into membrane-permeation controlled matrix-controlled and micro reservoir-dissolution controlled. Membrane-permeation controlled In membrane-permeation controlled devices the drug reservoir is surrounded by a membrane (coating) and because of the presence of he two distinct drug-reservoir and membrane phases these are known as heterogeneous devices when the device containing a highly hydrophilic drug is placed in the aqueous dissolution medium water penetrates the coating and dissolves the drug and the concentrated drug solution diffuses out through the polymeric membrane. The release rate of the drug is controlled by the diffusion rate of drug solution through the polymeric membrane. The rate of drug release dM/dt through a spherical membrane-permeation controlled system with saturated reservoir is given by equation. DM/dt = 4DK(C1 C2) ab / b-a.(1) Where, D is the diffusivity of drug unit thickness of polymer k is the partition coefficient (ratio of solubility of drug in the polymer divided by the solubility of drug in the surrounding medium) of drug across the polymer membrane c2 is the concentration of drug inside the sphere c2 is the concentration of drug in the surroundings a is the inner radius of the coat and b is the outer radius of the coat. Mathematical models describing the effect of device geometry on the release pattern have been developed. An important advantage of the reservoir system as shown by eq. (1), is that at steady state zero-order drug release is possible. It the drug elimination rate is constant during therapy, a constant drug-plasma level may be achieved. On the other hand any disruption or crack in the membrane could lead to the release of a large amount of drug (dose dumping) with possible toxic effects in the patient. Furthermore reservoir systems are generally more expensive to manufacture. Diffusion-controlled reservoir systems can also be based on a biodegradable polymer. In this case, the drug is encapsulated in a biodegradable polymer and the release rate is determined by the principles governing membrane-permeation controlled systems. Only after the entire drug is exhausted from the device does the polymer undergo significant erosion and eventually dissolves. Currently marketed and approved membrane reservoir systems for implantation therapy include the 4

Ocusert an ocular insert for controlled pilocarpine release for the treatment of glaucoma; Progestasert. a T-shaped contraceptive intrauterine device the controlled progesterone release and Norplant which is comprised of six small injectable cylinders for controlled release of levonorgestrone for contraception.

Matrix controlled In matrix-controlled devices the drug is uniformly distributed (dissolved of dispersed) throughout the polymer and hence these are known as homogeneous devices. In the presence of dissolution medium drug at the surface dissolves first and is released in the dissolution medium. In many cases the dissolved drug creates a depletion boundary separating the empty or drug-depleted polymer from the drug-loaded polymer matrix. Water penetrates the channels and a pore created by drug depletion and dissolves the drug at the depletion boundary. The drug release rate is controlled by the diffusivity barrier provided by the empty matrix which increases in thickness with time. This increased thickness results in a decrease in drug release rate with time. For a matrix system that is exposed to the dissolution medium on all the sides the surface area of the inward-moving depletion boundary decrease resulting in a decrease I in drug release rate which depends on the devicegeometry. Mathematical equation describing release have been reported which predict that in general the drug release rate is expected to decrease with time. In case of damage to the device though the drug release rate may increase slightly significant dose dumping is not expected. Therefore these devices have a safety design superior to that of the membrane-controlled system. Furthermore matrix systems are less expensive to manufacture. It has been shown that manipulation of the shape or drug distribution may allow a constant delivery rate. Microreservoir dissolution-controlled In these devices the drug reservoir is made of a suspension of solid drug particles in an aqueous solution of a water miscible polymer forming millions of microscopic drug reservoirs in a polymer matrix. the device is coated with a rate-controlling membrane to further modify the drug release rate. Among the other factors the release rate is dependent on the solubility of drug in the liquid compartment and on the polymer matrix. Mathematical relationships for the control of drug release have been described. The Syncro-Mate-M implant provides an example of this type of device. It is a cylindrical implant fabricated by dispersing the drug reservoir (a suspension of norgestomer in an aqueous solution of PEG 400) in silicone elastomers. This emulsion is placed into medical-grade silicone tubing and polymerized in situ. The tubing is then cut to obtain a cylinder-shaped device with open ends. This device is implanted subcutaneously in he earflap of livestock for about 20 days delivery of norgestomet for control and synchronization of estrus and ovulation. Other examples include the Nitrodics system and a dual-release vaginal contraceptive ring system. Chemically controlled Chemically controlled drug delivery systems regulate the drug release rate by a chemical reaction with the polymer. Their principal advantage is that in contrast to a nonbioerodible system the 5

polymer is dissolved and absorbed by the body and there is no need for surgical removal of the device at the completion of drug delivery. However the fate of these polymeric products in the body must be carefully observed and rigorous testing is required to confirm the safety of the polymer. The two predominant mechanisms for chemically controlling drug release are bioerosion and pendent chain. Bioerosion The bioerosion or biodegradation systems (both terms are used interchangeably in this article) involve breakdown of the polymer into small water-soluble molecules. Bioerosion-controlled devices are matrix controlled with uniform drug distribution inside the polymer. As the polymer is broken down water comes in contact with the drug leading to its dissolution and release. Depending on the hydrophilicity of the polymer and device properties such as porosity and the presence of watersoluble components water may penetrate throughout the device or come in contact only with the surface. In the former case polymer erosion starts throughout the matrix; these devices are known as bulk eroding. Although the drug release initially occurs predominantly from the erosion of the polymer from the surface eventually the entire matrix may break down and most of the remaining drug could be released in a burst. On he other hand if the polymer is hydrophobic and water does not penetrate inside the device, erosion occurs only on the surface; these devices can be called surface eroding. The drug release rate from a surface eroding polymeric matrix with uniform drug distribution is given by eq. dM/dt = KS..(2) Where, K is a constant related to the drug concentration in the matrix and the rate of polymer erosion and S is the surface area of the system. In general, due to erosion of polymer, the surface area of devices of the most common shapes decreases over time, rate of this decrease is geometry dependent. For systems with a high initial surface are to-volume ratio such as a slab the surface area and hence the release rate, decreases only slightly. On the other hand with devices of spherical geometry where the surface area-to-volume ratio is the lowest the surface area and hence release rate decreases rapidly with time. Therefore, matrix drug-release devices with shapes of slab geometry may provide less deviation in drug release over time than those with spherical geometry. In practice because of imperfections such as pin holes, the presence of water-soluble drugs and polymer hydrophilicity, bioerodible delivery systems are most commonly bulk-erosion controlled. The drug release from these systems depends on a combination of diffusion bulk erosion and surface erosion, making a theoretical prediction of drug release rate much more difficult. An important advantage of this type of system is that the drug-release profile may be controlled by manipulation of the size and shape of the device amount of drug loading addition of other excipients and the intrinsic degradation rate and molecular weight of the polymer. Pendent chain The other mechanism for chemically controlled release of drug is known as the pendent-chain system where the drug is attached to the polymer backbone by a labile chemical linkage. In the presence of water or enzymes the labile linkage breads to release the drug. The pendent chain may be water soluble or insoluble; a water-soluble backbone may serve as a drug carrier to a specific cell 6

or organ where the drug is released by metabolism. Insoluble pendent chains on the other hand serve as a depot from which the drug is slowly released. In either case after completion of the drug release the polymer-drug linkage. Varying the hydrophilicity of the polymer backbone and the device geometry can control the rate of linkage degradation and therefore the drug release. An important disadvantage of this system compared to bioerosion-controlled systems is that since the drug is covalently linked to the polymer the drug-polymer conjugate may be viewed as a new chemical entity by the regulatory agencies and extensive safety testing may be needed. Solvent activated Solvent-activated systems release active agents because of controlled penetration of a solvent into the device; they may be controlled by swelling or osmotic pressure. Swelling controlled Swelling-controlled systems are similar to matrix-type devices except that the dispersed drug is immobilized inside a glassy polymer and therefore there is no diffusion of drug. When this device is placed in water the outer polymer region begins to swell, resulting in relaxation of the polymer chains. This allows the otherwise locked drug to diffuse outward. Therefore two fronts are observed: one moving inward, separating the polymer in the glassy stare from the rubbery state and the second moving outward separating the swollen rubbery polymer from the surrounding aqueous medium. The drug release is determined by the rate of relaxation of the chains that unlock the drug. Osmotically controlled In one example of an osmotically controlled system an osmotically active agent such as watersoluble salt is placed inside a rigid semi permeable polymer housing, which is separated from the drug compartment by a movable partition. The semi permeable housing draws water inside by osmosis, leading to an increase in volume and exertion of pressure on the movable partition. The partition, in turn pushes the drug out of the compartment through a delivery orifice or cannula. Thus, the drug delivery rate is controlled by the mass movement of water across the semi permeable membrane. Osmotic pump provide a predictable, zero-order release rate independent of the physicochemical properties of the drug and therefore afford an excellent means of evaluating effects of long-term, zero-order administration into animals. Alza corp. markets several implantable osmotic pump devices. Alzet osmotic pumps have been extensively evaluated for local as well as systemic drug delivery in may animal models. Delivery rates from these pumps range from 1 to 10 L/h, and a release duration from three days to four weeks. The smallest of these osmotic pump, model 10003d, weighs about 350 mg and is designed for small research animals, weighing about 20 g. although these pumps are very useful in providing constant drug release in animals, they have found minimal therapeutic application in humans because of the need for surgical implantation and removal lack of external regulation and in situ refillability. However a variation of the osmotic pumps where a drug or and osmotically active agent is surrounded by a semi permeable membrane containing a single laser-drilled hole (the OROS system is being used for oral delivery of drugs such as phenylpropanolamine (Acutrim, Ciba0 and nifedipine (pericardia-XL, Pfizer)

Externally regulated These systems have the important advantage that the drug-delivery rate cat be externally increased on demand even after the device has been implanted. Four predominant techniques have been evaluated with externally modulated implant: magnetically controlled ultrasonically activated thermally activated and electrically controlled. Magnetically controlled In magnetically controlled drug-delivery systems the drug and magnetic beads are uniformly dispersed inside semi elastic polymer matrix made of a nonbiodegradable polymer such as ethylenevinyl acetate copolymer (EV Ac). When the device is placed in a dissolution medium the drug release follows matrix diffusion control. However, when the device is placed in a magnetic field, the magnetic beads attempt to a align with the applied magnetic field including a torque on the magnet and a slight rearrangement of the polymer. In an oscillating magnetic field, the beads tend to oscillate compressing and expanding the polymer in the process. This is proposed to result in a pulsatile flow of the dissolution medium through the pores in the elastic polymer and along the concentration gradient of the drug resulting in an increase in the drug-release rate. This effect of the oscillating magnetic field is further enhanced by an increase in polymer elasticity (e.g., by increasing the vinyl acetate content) and the frequency and strength of the magnetic field. Ultrasonically activated In these systems the drug is uniformly distributed inside a polymer and an external ultrasonic field is applied to activate drug release. They have been evaluated for both nonbiodegradable polymers (EVAc) and biodegradable polymers [polyesters, polyanhydrides, polyglycolides, polylactides and sebacic acid]. In the case of biodegradable polymers application of ultrasound increased the drug release as well as the polymer degradation rate. It is believed that the cavitation induced by the ultrasonic waves may be partially responsible for this effect as reduced polymer degradation and drug release was observed in a degassed buffer. In both the biodegradable and nonbiodegradable polymer systems the drug release rate was controlled by the intensity frequency and duration of the ultrasound. For in vivo evaluation devices made of EVAc and insulin or polyanhydrides and p-amminohippurate were implanted in rats and an ultrasonic applicator head was placed over the treated area for the delivery of ultrasonic waves to the implant. The rate of drug delivery was increased with no histologically detectable damage to the rat skin. Thermally activated A series of thermosensitive hydrogels that show significant swelling changes in water in response to temperature have been prepared and evaluated. These polymers respond to temperature change based on the Flory-Huggins theory that a change in temperature affects hydrogen bonding which, in turn, affects swelling. A linear correlation is observed between the diffusion coefficient for entrapped drug and polymer swelling. Based on their origin by thermosinsitive interaction these polymers can be classified into those base on polymer-water interactions and those based on polymer-polymer interactions. In the first group, a series of poly (N-alkyl substituted acrylamides) have been evaluated for the effect of cross-linking density on the temperature dependence of swilling. At low temperatures the 8

polymer is in an unswollen state due to the increased hydrogen bonding interaction. This swilling leads to increased solute diffusion and hence drug release. Thus thermosensitivity of the polymer network has been shown to primarily due to polymer-water interactions and hydrophobic interactions of the side groups. In the second group two interacting polymers with repulsive or attractive polymer-polymer interaction are combined to form a hydrogel. With an increase in temperature, swilling increases as the polymer responds not only to the polymer-water interactions but also to increased polymerpolymer interactions. Hoffman demonstrated the applicability of hydrogels based on N-isopropylacrylamide (NIPAAm) or N-isopropylacrylamide-methacrylic copolymers with methylenebis (acrylamide) (MBAAm) in providing temperature-responsive release of vitamin B12. By manipulation of temperature, pulsatile release of Indomethacin and insulin has been reported. Electrically controlled Electrically controlled systems provide drug release by the action of an applied electric field on a rate-limiting barrier membrane or a solute thus modulating its transport across it. Grimshaw reported four different mechanisms for the transport of proteins and neutral solutes across hydrogel membranes: Electrically and chemically induced swelling of a membrane to alter the effective pore size and permeability Electrophoretic augmentation of solute flux within a membrane Electroosmotic augmentation of solute flux within the membrane and Electrostatic partitioning of charged solutes into charged membranes. Propanolol hydrochloride delivery devices containing a drug reservoir with a pair of electrodes placed across a poly (2-hydroxyethyl methacrylate) (PHEMA) membrane, cross-linked with ethylene glycol (1 % v/v) have been evaluated for modulated drug delivery. Controlled and predictable propranolol hydrochloride release in response to the electric field was observed with a linear relationship between current and propranolol hydrochloride permeability. Variables for this mechanism have been extensively evaluated for Transdermal delivery (iontophoresis) systems. Self-regulated These are biofeedback-controlled system, where the drug release rate is dependent on the bodys need for the drug at a given time. From a therapeutic viewpoint these systems may come closest to duplicating the release from a gland such as the pancreas. A variety of mechanisms have been employed to obtain self-regulated delivery. Ionic strength and pH responsive These devices take advantage of the fact that polymers containing weakly acidic or basic side groups develop a charge in alkaline or acidic pH respectively. In a cross-linked water-insoluble polymer, this results in water uptake and corresponding swelling of the polymeric membrane with opening of molecular pores and increased drug release rate. Siegel demonstrated the application of cross-linked 9

polymeric gels (methyl methacrylate-N, N-dimethylaminoethl methacrylate co polymer) in drug delivery. IN this case, the polymer is unionized and hydrophobic in neutral pH. A reduction in the pH of the gel leads to ionization of the gel-forming polymer with subsequent swelling which results in molecular pores for release of drug.Thus,this system has shown to effectively control caffeine release at different pH.In terms of practical usefulness.This concept has been extended to glucose sensitive release of insulin as describe below. Glucose responsive Immobilized Glucose Oxidase. Glucose Oxidase catalyses a reaction between glucose and oxygen in the body fluids to form gluconic acid, which reduces the pH of the microenvironment. This is related to the concentration of gluconic acid and hence glucose. The insulin-release systems based on glucose Oxidase utilize this drop in pH to trigger an increased release. Heller reported on application of Ph-sensitive biodegradable polyorthoesters in which insulin is immobilized. The biodegradable polymer matrix is coated with a hydrogen containing immobilized glucose Oxidase. Glucose diffusing into the hydrogel is oxidized to gluconic acid causing a drop in pH. This increases the erosion rate of the polymer releasing entrapped insulin. Thus, insulin release in modulated by the concentration of glucose in the surrounding fluids. Langer took advantage of the fact that like many other insulin has a pH of minimum solubility around its isoelectric point. They used modified insulin (with three additional lysine molecules) change the isoelectric point of insulin from around 5.0 to 7.4 thus at physiological pH insulin has the lowest solubility. In the presence of glucose and immobilized glucose Oxidase the resultant drop in pH leads to an increase in insulin solubility with an increase in release rate. Another such system employs drug encapsulated in special phospholipids vesicles that change structure and permeability with changes in ph temperature or glucose concentration. Competitive binding Brownlee and Cerami discovered the principle of competitive binding. It involves the preparation of glycosylated insulin which combines with Concavalin A (Con A), a Carbohydrate- binding protein. Con A is immobilized on sepharose beads and the glycosylated insulin is bound to it. The beads are encapsulated in a suitable membrane which is permeable to both glucose and insulin. Blood glucose diffuses into the device and replaces insulin from the con a-insulin complex by competitive binding. The free insulin diffuse out of the rate-controlling membrane and is thus released in an active and more stable against aggregation than commercial insulin. This device has been shown to produce glucose-dependent insulin release both in vitro and in vivo. However, the release of insulin has been found to be nonlinearly dependent on glucose. The device was implanted intraperitoneally in dogs whose pancreas had been removed and bloodglucose levels were compared with those of normal and diabetic dogs after administration of 500mg/kg dextrose bolus dose. The implanted dogs responded to blood-glucose levels in a manner similar to that of normal dogs. The levels were maintained in the dog for the two days of in vivo evaluation. Urea responsive Heller was first to demonstrate the feasibility of a self-regulated hydrocortisone delivery system 10

responding to the presence of urea. The device of disks containing hydrocortisone incorporated into a biodegradable polymer (n-hexyl half-easer of methyl vinyl ether and maleic anhydride) with pH dependent degradation. This disk is coated with a hydrogen containing immobilized urease. In physiological-buffer base line hydrocortisone release is obtained by the hydrolysis of the polymer and diffusion of drug. In the presence of urea the enzyme urease increases the ph of the microenvironment by converting urea into ammonium bicarbonate and ammonium hydroxide. This increase in pH results in increased hydrolysis of the biodegradable polymer and increased hydrocortisone release. The latter was shown to be proportional to the concentration of urea present. Preparation Of Implants Materials : Although many polymers can by used to prepare rate-limiting membranes for controlled release relatively few are employed for implantation purpose because in addition to being a good ratelimiting barrier the polymer should also be biocompatible and sterilizable. Implantable polymers can be classified into biodegradable and nonbiodegradable polymers. Several nonpolymeric materials such as fatty substances (e.g. cholesterol) and metals (e.g. titanium, stainless steel 316) may be used in implantation devices. Silicone polymers Silicone polymers are among the most widely used polymers in controlled drug delivery. They provide several advantages such biocompatibility ease of fabrication resistance to heat sterilization and high permeability for many lipophillic drugs. They are available in polymer form or as multicomponent system to be polymerized in situ. Depending on the components different degrees of elasticity can be conferred upon the polymer matrix. Therapeutic products prepared with silicone elastomers include Norplant a subdermal implant to deliver levonorgestrel for contraception a dual-release vaginal ring and certain Transdermal patches. Polyethylene-vinyl acetate Ethylene vinyl acetate (EVAc) copolymers gave been used for many investigational and commercial devices. The vinyl acetate of the copolymer can vary from very small amounts to 40%. Increasing the vinyl acetate content increase elasticity permeability and glass transition temperature and reduces crystalline. The polymer is being used in the Alza ocular insert (Ocusert) and in IUD reservoir-type systems (Progestasert). Cellulose acetate Cellulose is naturally occurring and one of the most abundant organic polymers. Although various cellulose derivatives are used in controlled drug delivery devices application to implants is usually restricted to cellulose acetate. Cellulose acetate is formed by the acetylation of the hydroxyl groups in he glucose backbone. This acetylation increases water sorption by the polymer and at about 13% acetylation the polymer is water-soluble. A further increase in acetylation increase hydrophobicity. The polymer becomes insoluble at around 19%acetylation: water sorption decreases with further acetylation. Commercial cellulose acetate is available with 36 to 43 % acetylation. Because of their high water permeability and low salt permeability cellulose acetate membranes have been used extensively in the Alzet osmotic pumps. 11

Processes: Processes used in manufacturing these devices depend on the type. In any case implants need to be sterile and therefore they are prepared aseptically or under reduced bioburden and then sterilized most commonly using gamma radiation. Traditional steroid implants are prepared by compressing large crystals of drug under high pressure or by the solidification of molten drug in cylindrical molds. Diffusion-controlled polymeric devices can be prepared by a variety; of techniques. Membrane type polymeric devices may be prepared by coextrusion of the drug core and the polymeric membrane as in the case of silicone capsules. Spherical membrane-coated devices are prepared with conventional pharmaceutical coating equipment such as a pan coater or a Wurster coating apparatus, Many specialized techniques gave been developed for coating microcapsules. Matrix-type devices are simpler to prepare: techniques include compression under high pressure with or without heat solvent casting of drug dispersion in polymer solution meltextrusion and in situ polymerization. Testing: Besides sterility drug content and content uniformity implants need to be evaluated for the rate of the drug release. Several in vitro release-testing procedures are used for this purpose. The shakingflask technique or its minor modifications are commonly used. The implant is placed inside a screwcapped flask-containing buffer at physiological pH and ionic strength. The flask is placed in water bath at 37 degree centigrade oscillating at a low speed to provide mild agitation. Periodically samples are removed from the flask and the buffer is replenished. The samples are analyzed for the cumulative amount of drug released. A major disadvantage of this technique is that for poorly soluble drugs frequent replenishing of the entire medium is necessary in order to maintain sink conditions. Another disadvantage is that with chemically unstable drugs significant drug activity can be lost before sampling. Modifications of this technique include the incorporation of ethanol in the dissolution medium to increase to solubility of poorly soluble drugs and shortening the in vitro duration of drug release. A flow-through cell system provides an alternative to the shaking-flask technique while minimizing the above-mentioned disadvantages. In this system the implant is placed in a flow cell maintained at 37 degree centigrade. The dissolution medium is gently perused through the flow cell and the perfused is collected by a fraction collector for subsequent analysis or passed through on line detectors for immediate analysis of drug content. Hollenbeck successfully utilized the above concept for determining the release rate from polyanhydrides implants containing 1.3-bis (2-chloroethyl-1nitrosourea (BCNU), a water-unstable drug. Both the rate of drug and monomer release was monitored using the above technique. An added advantage is the extensive characterization of release profiles and possibilities for complete automation of the release studies. For a methotrexate microsphere formulation in biodegradable polyanhydrides good correlation was observed between in vitro release profiles obtained using the flow-through cell system and in vivo drug levels. Regulatory assessment All novel drug delivery systems are considered new drugs requiring complete new drug applications as a basis of approval. Besides the safety and efficacy demonstration plasma-blood level variation and drug pharmacodynamics need to be established. Establishment of the reproducibility of release, 12

both in vivo and in vitro demonstration of the absence of dose dumping and a well-defined pharmacokinetic profile to support drug labeling is needed. Therapeutic Applications Of Implant Ocular disease Several different implantable systems have been evaluated to provide prolonged oclular delivery. These include membrane-controlled devices implantable silicone devices, and implantable infusion systems. An example of the membrane-controlled system is the ocusert containing pilocarpine base and alginic acid in a drug reservoir surrounded by a release-rate controlling ethylene-vinyl acetate membrane. The ocusert system provides an initial burst followed by a near zero order delivery of pilocarpine at 20 or 40 g/h for a period of seven days. The device is well tolerated in adults, with satisfactory control of intraocular pressure and minimal side effects. However it appears to be poorly tolerated in the geriatric population where most of the therapeutic need exists.

Implantable devices evaluated for ocular cancer treatment include silicone rubber balloon containing an antineoplastic agent. BCNU. The device consists of two sheets of silicon rubber glued at the edges with silicon adhesive to form a balloon like sac through which a silicone tube is inserted. By a diffusional process, the BCNU solution is slowly released through the silicone tube. Upon completion of delivery, the device is refilled with drug solution.

The implantable infusion pump system evaluated consists of a miniaturized and computerized pumping device with silastic tubing leading to the site for infusion so drug.

Contraception Norplant a subdermal implant for long-term delivery of the contraceptive agent levonorgestrel gas recently been approved for marketing by the FDA. The device consists of six silicone membrane capsules each containing about 36 mg of levonorgestrel. The capsules are piaced subdermally on the inside of the upper arm or the forearm in a fan-shaped pattern through a trocar from a single trocar entry point. Cumulatively the six capsules deliver about 70 g/day in vitro and 90 g/day in vivo for the first 100 days with a gradual decrease to about 30 g/day at about 800 days. This rate of delivery appears to continue for over five years. Clinically, Norplant users have a net pregnancy rate of below 1.5 in 100 women at four years. At the end of four years 42 % of the women continued with the method indicating acceptability comparable with that of other methods. Other polymer-based systems under study for contraception include vaginal rings generally composed of silicon rubber used for 3 to 76 months often with a removal period of one week monthly to allow for 13

menstruation; the progestasert an ethylenevinyl acetate copolymer intrauterine drug-releasing device which lasts for one year: and suspensions of injectable microspheres or rods composed of biodegradable polymers.

Dental application Polymeric implants have been evaluated for several dental applications involving local prolonged administration of fluoride antibacterials and antibiotics. For sustained-release fluoride delivery stannous fluoride was incorporated into different dental cements. Another dispersed in the hydroxyethyl methacrylate and methyl methacrylate copolymer hydrogel coated with an outer layer of the same copolymers in different proportion so as to be rate limiting in drug release. The device, about 8 mm long and containing 42 mg of fluoride in the core was attached to the buccal surface of the maxillary first molar and designed to release 0.5 mg of fluoride per day for 30 days. Although increased fluoride concentration were found in the saliva of the subjects erythema or small ulcers were also detected on the buccal mucosal opposite to the device. A modification of this system containing only 17.5 mg of fluoride in a nylon suture system providing 0.15 mg of fluoride per day resulted in 63% fewer carious enamel lesions than in rats without any treatment.

Ethycellulose slabs containing polyethylene glycol and chlorhexidine as an antibacterial agent gave also been evaluated. The slabs have the additional advantage that they can be cut to fit the periodontal pocket and can be inserted quickly with minimal discomfort to the patient. Acrylic polymers have also been evaluated for such a system. Sustained-release implants made of hollow cellulose fibers have also been extensively evaluated. Hollow gibers containing 20% solution of chlorhexidine gluconate and placed in periodontal pockets resulted in significant clinical improvement with relief of discomfort, reduced gingival flow, and less bleeding on probe. Finally matrix systems composed of ethylene-vinyl acetate copolymer and releasing tetracycline (on site therapeutic system) are being tested clinically to treat periodontal disease. Although all these systems led to a reduction of microbial count one of their major disadvantages is the need to remove the device at the end of the 3 to 5 days release period.

The localized nature of dental diseases and the ease of implantation make sustained-release systems of resorbable and biodegradable polymers highly suitable. Research is on going in the area but for commercialization any such delivery system would need to overcome obstacles such as ease of application and patient acceptability and have to complete with conventional delivery systems such as a mouthwash.

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Immunization Polymeric implants are being evaluated for enhanced immune response to antigens. The concept here is to provide pulsatile or continuous administration of the antigen over a prolonged time period. Wise et al. evaluated immunization efficacy of ethylene-vinyl acetate copolymer pellets containing bovine serum albumin as model antigen. The immune response was comparable to that achieved by two injections of bovine serum albumin in complete Freunds adjuvant (Freunds adjuvant is an oil-in-water suspension containing bacteria).

Cancer Silicone rod implants similar to those used for delivery of levonorgestrone have been evaluated for delivery of testosterone propionate or ethinyl estradiol in patients with prostate cancer. Lupron depot manufactured by Takeda chemical industries is an implantation system providing one month depot release of leuprolide acetate. a synthetic analogue of the gonadotropin-releasing hormone (GhRH). The implat consists of biodegradable microspheres prepared from polylactic glycolic copolymer at 50:50 composition. Containing 10% leuprolide acetate for the treatment of prostate cancer sanders et al. reported on a similar delivery system for nafarelin acetate. an agonistic analogue of lutenizing hormone releasing hormone (LHRH). Zoladex manufactured buy ICI Pharma provides one month depot release of goserelin acetate from a biodegradable implantable rod . For the treatment of prostate cancer. Biodegradable implants Containing polyanhydrides. P (CPP:SA) 20:80 ( copolymer of carboxyphenoxy propane and sebacic acid) and BCNU for the treatment of glioblastoma multiform. A form of brain cancer have also been evaluated. Microsphere formulations containing the same polyanhydrides have been evaluated for 24 to 36 delivery of methotrexate . Narcotic antagonists Naltrexone has been extensively evaluated in implant from long- term delivery of narcotic antagonists. Natrexone freebase. Its hydrochloride. Or the pamoate acid salt has been prepared in a variety of polymers and dosage forma for prolonged narcotic antaginist activity . Though in vitro delivery of up to 50 day has been achieved by some of the systems. in vivo duration of release has been shorter . Nuwayser et al. reported on biodegradable polymer-coated microspheres containing naltrexone base. The polymers evaluated were poly lactide. poly lactic glycolide 65:35 and polycaprolactone-colactide 90:10. Diffusion controlled, linear naltrexone release was observed from the coated microspheres lasting for about 50 days. The microspheres produced about 60 day s of morphine antagonist response in implanted rats.

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Other applications Numerous insulin - delivery systems have been prepared and evaluated for a biofeedback approach and have been described previously. Biodegradable implantable delivery systems have been developed to provide prolonged release of antibiotic to wou Self-regulated

These are biofeedback-controlled system, where the drug release rate is dependent on the bodys need for the drug at a given time. From a therapeutic viewpoint these systems may come closest to duplicating the release from a gland such as the pancreas. A variety of mechanisms have been employed to obtain self-regulated delivery.

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