WO1992002211A1

WO1992002211A1 - Multiple drug delivery system

Info

Publication number: WO1992002211A1
Application number: PCT/US1991/005574
Authority: WO
Inventors: Robert J. Leonard
Original assignee: Endocon, Inc.
Priority date: 1990-08-09
Filing date: 1991-08-06
Publication date: 1992-02-20
Also published as: EP0542915A1; JPH11508224A; AU8610391A; HUT69680A; CA2088982A1; HU9300313D0; AU660290B2

Abstract

A bioerodable implant providing for the parenteral release of at least two bioactive drugs is described. The implant comprises a non-polymeric core containing a core drug. The core is sheathed on selected surfaces with a polymeric coating, the sheathing having a drug incorporated within its matrix. The sheathing serves to limit the core surface area available for core erosion in order to yield time-invariant, zero-order release kinetics. Methods and apparatus used to form the bioerodable implant are also described.

Description

MULTIPLE DRUG DELIVERY SYSTEM

This invention relates generally to drug delivery systems and particularly to a bioerodible article capable of delivering a plurality of drugs when implanted subcutaneously.

Background of the Invention Since the elucidation of the clinical significance of certain bioactive substances and the development of various techniques for their synthesis, it has become clear that many of these substances will be useful only if a convenient method for delivering them in controlled doses can be provided.

For example, because materials like peptides are destroyed in the digestive tract when taken orally, they must be administered parenterally. Moreover, in some clinical situations, therapies involving bioactive substances often demand injections of a multiplicity of drugs at regular intervals for extended periods of time. It has also been observed that many drug compounds are more clinically effective when delivered in low, continuous doses as opposed to high, intermittent doses. This effect has been observed in a wide variety of compounds. Furthermore, there are numerous compounds which have a narrow optimum range of efficacy, above which the compound becomes toxic.

In view of such factors influencing the use of new drugs and affecting new applications of known and approved compounds, certain controlled-release drug delivery systems for providing continuous dosing have been sought. For example, attempts have been made to deliver several drugs in sequence, simultaneously utilizing cumbersome and complex systems requiring capillaries (See e.g. U.S. Patent Nos. 3,946,734 (Dedrick et al. ) ; 4,449,981 (Drake and Brocklehurst, and 4,720,384 (Di Lucio et al.. ) or osmotic pumps (See, e.g. U.S. Patent Nos. 4,203,441 (Theeuwees); 4,203,442 (Michaels); and 4,180,073 (Michaels)) .

Efforts have been made to employ delivery systems based on biodegradable polymers as subcutaneous implants for the controlled release of bioactive substances. Current erodible polymer-based systems are typically combined with a drug in one of the following ways: (1) matrix erosional systems (monolithic systems) in which a drug is evenly distributed in a polymer matrix and is released as the polymer breaks down in biological fluid; -and (2) diffusion/erosion systems in which drug release occurs as a result of diffusion of the drug through the polymer matrix and release of the drug as the surface of the device continually erodes.

Nonpolymer-based devices have also been used as subcutaneous implants for delivering a drug. Initially, pellets formed by compressing mixtures of a drug and an excipient were attempted. Such pellets, however, tended to rapidly absorb biological fluids and disintegrate after a short time, and thus exhibited undesirable and unpredictable kinetics.

Efforts have been directed toward drug-delivery systems that exhibit zero-order kinetics, i.e. release rates that are essentially time-invariant. These efforts have included various shapes that can be coated on one or more surfaces to limit the area available for drug release. Little success has been achieved in actually accomplishing sustained zero-order kinetics from an implant device jLn vivo.

Other problems remain to be solved with rec to implant devices. Some bioactive substances such as highly water soluble macromolecules exhibit volatile dissolution kinetics when used as subdermal implants in humans and animals. This can be unacceptable when the release rate of the drug is precipitous and displays first order kinetics, i.e. in which the flux of drug is proportional to the amount present in the delivery system. Additionally, certain macromolecules are known to swell and become trapped in either erosional or diffusional systems. It has also been observed that some peptides will aggregate when in sufficient concentration in biological fluids, thus preventing release from a delivery system.

A factor which affects the efficacy of a drug implant is the patient's normal inflammatory immune response which tends to encapsulate an implant in an envelope of fibrous tissue derived from monocytes, macrophages as well as ^*-ther components of the cellular immune system such as foam cells (lipophages) , collagen and vascular cells. Encapsulation is a significant rate limiting factor for drug release; in -some cases it may be the ultimate one in determining release kinetics.

It would be useful to develop an implant in which zero-order kinetics predominate for a time and, when sufficient fibrous tissue has formed, allow the fibrous capsule to then control the release and absorption of drug.

Summary of the Invention The invention provides a bioerodible implant capable of administering a drug at a rate that is time-invari nt. This time-invariant release rate (zero-order kinetic release) is achieved by limiting the area available for bioerosion of a core containing the drug, so that the surface-area available for bioerosion remains essentially constant as bioerosion proceeds. Maintenance of a constant surface-area available for bioerosion is accomplished by bonding or otherwise chemically and/or physically linking the core containing the drug to a bioerodible polymeric sheath, which sheath surrounds only selected areas of the core. Bonding is accomplished preferably by fusing the core to the immediately adjacent polymeric sheath layer. Fusion can occur through heating of the core and adjacent sheath.

The sheath may be selected to be less resistant to bioerosion than the core, so that the surface area of core available for erosion remains constant. This permits a zero-order release rate until the core has eroded completely. The sheath also can be selected to be more resistant to -~-

bioerosion than the core, so that the surface-area of the core available for erosion increases after some preselected interval. This permits a zero-order release for a first interval of time, followed by a burst and time variant release. In either instance, the sheath and the core are bioerodible so that the implant need not be removed when depleted of drug.

The invention also provides a bioerodible implant capable of administering a plurality of drugs when implanted into an animal. In one aspect of the invention, the implant provides for the release of two drugs; a first drug released from a core and a second drug released from a polymeric sheath surrounding selected surfaces of the core. Preferably, the sheath is bonded to the core. The sheath material serves both as a source of drug and as a means of limiting the surface-area of the core available for erosion to a constant surface-area. Thus, the invention can provide zero-order release kinetics of at least one core drug, while providing for simultaneous release of a second drug from the sheath.

The implant of the invention can be fabricated with a variety of core materials and a range of thicknesses and types of sheath. This allows for great flexibility in the rate and amount of core drug and sheath drug release. For example, the thickness of a sheath covering a cylindrical core may vary so that first portions of the sheath erode completely while other portions remain covering the core. When the first portions erode, the surface area of the core available for erosion temporarily increases, thereby effecting temporarily a higher rate of drug release.

In certain preferred embodiments of the invention, the core containing the drug is a "partially fused" core or a "totally fused" core. Such cores are characterized by nondiffusional, erosion-based, drug release and are particularly suited for achieving zero-order release kinetics when coated on selected surfaces.

In a partially-fused core, the core includes a core drug and a nonpolymeric carrier. The mixture of the core drug and nonpolymeric carrier are treated such that only the carrier, but not the drug, melts. The carrier then is allowed to recrystallize to form a matrix capturing the unmelted drug. This partially-fused core may be bonded to the sheath, preferably during the process of forming the partially-fused core. Partially-fused cores are particularly suited for delivering peptides, and according to one preferred embodiment, the core drug is an HIV proteinase inhibitor.

In a totally-fused core, the core contains a drug and only optionally a carrier. To form this core, substantially all of the drug (as well as the carrier, if present) is melted and recrystallized to form a matrix of drug (and carrier). This totally-fused core also may be bonded to the sheath, preferably during the process of forming the totally-fused core.

A preferred method for producing a preferred implant according to the invention involves forming a polymer film as a hollow sheath of relatively constant thickness. A core material then may be applied to the hollow of the sheath under conditions to permit the core to bond to the sheath at the core/sheath interface. In one preferred method, a sheath is formed by introducing polymer material into an annular space between a cylindrical chamber and a cylindrical pin disposed concentrically within that chamber. Conditions then are applied to the polymer to permit the polymer to be formed into a sheath. The pin may be removed leaving the hollow sheath seated within the chamber, and core material may be added to the hollow of the sheath within the cylindrical chamber.

In the case of a fused core, the core material may be melted after its introduction into the sheath. The chamber including the formed sheath and core material is treated under conditions to cause the core material to partially or totally melt, while leaving the sheath intact (although preferably the sheath becomes tacky). Then, the sheath and core are treated under conditions sufficient to cause the core materials to recrystallize, -.hereby forming a fused-core bonded to the inside surface of the sheath (either due to chemical interaction or physical intermixing of the ore material and sheath polymer at the core-sheath interface) .

The core also can be melted (partially or totally) before its introduction into the hollow of the formed sheath. Conditions may be applied to the core material to produce a partial or total melt. The melted material then is dispensed into the hollow of the forme sheath and is allowed to cool. The core material thus will recrystallize and bond to the polymer sheathing at the core-sheath interface.

Other methods also are provided, including coextrusion of the sheath and core.

Detailed Description of the Drawings FIG. 1 illustrates the release kinetics of core drug from an implant of this invention when the sheathing is selected to erode prior to complete erosion of the core;

FIG. 2 illustrates an exploded view of an apparatus for forming an implant of this invention; and

FIG. 3 illustrates a cross-sectional view of the apparatus of FIG. 2 in an operational mode for forming the sheath of the invention.

Detailed Description of the Invention This invention pertains in one aspect to a drug implant for sustained zero-order release of at least one drug. The term "zero order release" is defined as that rate of drug release which is independent of the concentration of remaining drug. This is manifested as a sustained release that is constant over time. Zero order release is accomplished by sheathing the drug only on selected surfaces, so as to provide a constant surface area for bioerosion.

The importance of having a relatively constant surface area available for erosion is underscored by the fact that, in most erosional implants, the surface area of the implant will constantly change with time. This results in non zero-order release kinetics that vary in unpredictable ways.

In a cylinder, (L > D) the total surface area derives from its outer cylindrical surface and its ends [total surface area = 2 (irr ) + -rrDL] . Given a fixed diameter, duration and total release rate can be regulated by adjusting the total length of the device and the number of surfaces exposed to erosion. Bonding of the outer cylindrical surface of a core shaped as a cylinder to a sheath limits the surface area available for erosion to the cylinder's ends (less than 50% of the total surface area of the cylinder). Significantly, drug release kinetics from such a sheathed cylinder are no longer controlled by a continually diminishing surface area, but are related to a constant area,

2 2(τrr ). Not only is the drug release rate significantly reduced, but the drug release kinetics are converted to zero order. Furthermore, the initial burst, which is characteristic of noncoated cores, also is significantly reduced.

This invention thus pertains in one aspect to an implant having a core containing a first drug, which core is bound to a polymeric sheath on at least one surface. The shaped core preferably is a pellet or cylinder. The core contains at least one drug evenly distributed within the core body and on the core surface, referred to as a "core drug". The sheath may contain a second drug evenly distributed within the matrix of the polymer. The term "bond" or "bonded" refers to the fact that the components of core and sheath at the core/sheath interface are secured to one another by, for example, chemical bonds, ionic bonds or physical bonds such as by intermixing at the core/sheath interface or by elastic forces of the sheath against the core.

Chemical and/or physical linkage of the core and sheath at the core/sheath interface inhibits erosion at this interface. Without bonding between the core and sheath, liquid such as biological fluid tends to cause the sheath to pull away from the core and to cause erosion at the core/sheath interface. This may be due in part to the liquid being taken up by the sheath itself. In any event, enhanced erosion at the core/sheath interface creates a space between the sheath and core and increases the surface-area available for erosion. The invention overcomes this problem by bonding the core to the sheath at the core/sheath interface.

The delivery system of the invention can be modified to suit a wide variety of drug and clinical applications by adjusting a variety of factors, including the following:

1. polymer sheath thickness;

2. type of polymer;

3. core drug concentration;

4. selection of core drug carrier;

5. length of core;

6. diameter of core; and

7. type of core

For example, the sheath may be more resistant to bioerosion than the core. Thus, substantially all the core erodes before the sheath erodes. This can ensure that a constant core surface area encounters the erosion medium and that zero-order kinetics is achieved throughout erosion of the core. Alternatively, the sheath may be less resistant to erosion than the core. In this instance, the sheath will erode before the core erodes, resulting in an increase in the surface area of core available for erosion and consequently an increase in the release rate of the drug. This release pattern is shown n Fig. 1.

Referring to Fig. 1, the initial release of core drug is time invariant (i.e. zero-order), identified in FIG. l from time 0 to 1. Once the sheathing has eroded, the surface area available for erosion is significantly increased. The effect is an increased dosage, as identified in FIG. 1 from time 1 to 2. Not shown here is the temporal release of sheathing drug. Typically this would show an initial burst and a steady decline.

A. The Core

The core drug is bound or otherwise distributed within the core matrix in a variety of ways. The core can be formed using standard tabletting procedures. Preferably, however, the core is l sed, either partially or totally. Such fused cores have release kinetics that are determined by surface erosion, not diffusion. Cores having release kinetics determined by erosion, rather than diffusion, are preferred, since diffusion based cores are characterized by release kinetics that vary with time.

Methods for making partially-fused and totally-fused cores have been described in co-pending applications Serial No. 07/163,328, "Partially Fused Peptide Pellet" (filed March 2, 1988) and Serial No. 07/475,200, "Flash-Flow Fused Medicinal Implants" (filed February 5, 1990) respectively, the disclo^sures of which are incorporated herein by . ierence. Briefly, for a core thet is partially-fused, a nonpolymer carrier having a lower melting point than the core drug is selected so that when a homogeneous mixture of the carrier and drug is heated, a partial melt may be formed with substantially all of the carrier melting and substantially all of the drug not melting. The partial melt then is allowed to cool, with the carrier recrystallizing to form a hardened core matrix capturing the core drug. For a totally-fused core, the drug (and optionally a nonpolymer carrier) is melted and recrystallized to form a totally fused matrix of drug (and carrier, if present).

The nonpolymer carriers useful for making totally-fused and partially-fused cores are lipophilic. They also are bioerodible and, therefore, do not have to be removed surgically when the drug has been depleted as is the case with many of the prior art devices. Preferably, the nonpolymer carriers are metabolized or excreted as the core erodes. Most preferably, the nonpolymer carriers are those that occur naturally in the human body.

The nonpolymer carriers according to the invention are of relatively small molecular weight as compared to the macromolecular polymer carriers of the sheath or sleeve. For example, the molecular weight of a preferred nonpolymer carrier, cholesterol acetate, is approximately 428 daltons, whereas the molecular weight of the typical, preferred polymer carrier of the sheath is on the order of 10 3 - 106 daltons, depending on the degree of polymerization. The nonpolymer carriers according to the invention also are typically smaller than the core drug that is captured in the matrix of the recrystallized carrier. Preferably, the nonpolymer carriers also are highly crystalline. The foregoing properties contribute to the favorable erosion characteristics of the formed core.

The nonpolymer carrier may be cholesterol or a cholesterol derivative including, but not limited to, cholesterol acetate and cholesterol chloride and cholesterol palmitate. Other preferred nonpolymer carriers include sterols other than cholesterol, steroids, steroid derivatives and analogues and other bioerodible compounds having lipophilic and crystalline properties, size and a melting temperature similar to cholesterol and cholesterol derivatives. Other carriers that may be substituted include certain fatty acids or neutral fats such as mono-, di- or triglycerideε (or a combination of two or more of such lipid molecules) that have erosion properties and release kinetics similar to the foregoing sterols when combined with a core drug melted, recrystallized and implanted in the body. The carrier must have a melting temperature such that it is a solid at body temperature (above about 40°C) and such that the core drug of choice will not degrade or otherwise lose its bioactivity when in a suspension of the melted carrier at about the melting temperature of the carrier for a short duration.

The core drug may be any bioactive small molecular weight material, naturally occurring or synthetic. Included are steroids such as aldosterone, androstane, androstene, androstenedione, androsterone, cholecalciferol, cholεtane, cholic acid, corticosterone, cortisol, cortisol acetate, cortisone, cortisone acetate, deoxycorticosterone, digitoxigenin, ergocalciferol, ergosterol, estradiol, 17-α, estradiol-17β, estriol, estrane, estrone, hydrocortisone, lanosterol, lithocholic acid, mestranol, β-methasone, predniεone, pregnane, pregnenolone, progesterone, spironolactone, testosterone, triamcinolone and their derivatives. Also included are the classes of peptides known as neuropeptides and regulatory peptides. Specific examples include, but by no means are limited to, growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, so atostatin and its analogues, gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, alpha and beta melanocyte-stimulating hormones, peptide molecules which stimulate erythrocyte, leucocyte and immunocyte growth and function such as colony stimulating factors (CFS 1 and 2), erythropoietin and lymphokines (including interleukin I and II), angiotensin I and II, bradykinin, kallidin, adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing peptides. It should be understood that the term peptide is intended to include small proteins, and particularly those molecules having on the order of about 100 amino acids or less.

Nearly all core drugs that are peptides have between about 8 and 60 amino acids and range from approximately 1,000 to 7,500 daltons in molecular weight (although one unusually small peptide core drug, peptide-T, has only three amino acids and, therefore, has approximately the same molecular weight as a preferred carrier, cholesterol acetate.) Other drugs include drugs such as scopolamine and nitroglycerin, neurotransmitters, antiviral and antibacterial agents, ribonucleic acids and nucleotides. Virtually any bioactive, small molecular weight material may be used according to the invention.

Because part of the core's surface is bonded to the polymer sheath, limited surface is available for core drug erosion. Thus, very low release rates can be achieved, and ideal candidates for core drugs are those that are efficacious in small dosages, i.e. compounds that are unusually potent. In one embodiment, the core drug is the 19-nor-testosterone derivative Norgesto et® (Roussel Pharmaceutical Inc., Somerville, N.J.). This progestin can be given in microgram quantities to eliminate estrous in a 500 kilogram cow. An unusually potent compound useful in the invention is erythropoietin. This hormone is manufactured with a very high specific activity and has been used to treat anemias associated with renal failure and multiple myeloma. See, Ludwig et al. , "Erythropoietin Treatment of Anemia Associated with Multiple Myeloma", New England J. Med. , 322:1693, June 14, 1990).

One particularly preferred embodiment of the invention is a partially-fused core containing a non-polymer carrier and an HIV-l proteinase inhibitor as the bioactive core drug. HIV proteinase-inhibitors are di- and tri-peptide derivatives of the pol gene product of human immunodeficiency virus (HIV-l) the infectious agent responsible for acquired immune deficiency syndrome (AIDS) in humans. See, Roberts et _al. "Rational Design of Peptide-Based HIV Proteinase Inhibitors", Science 248: 358 (1990), incorporated herein by reference. Powdered HIV proteinase inhibitor can be mixed with powdered nonpolymer carrier having a lower melting temperature than the HIV proteinase inhibitor such as, for example, cholesterol acetate. The mixture can be heated until the cholesterol acetate, but not the proteinase inhibitor, melts. The partial melt is then allowed to cool, with the cholesterol acetate recrystallizing to form the core. The HIV proteinase inhibitor is thus bound in a complex skeletal network of the recrystallized carrier.

The HIV proteinase inhibitor/cholesterol acetate core erodes slowly in vitro due to the lipophilicity and high cryεtallinity of the carrier. The relatively larger molecular size of the HIV proteinase inhibitor, as compared to the cholesterol acetate, makes its escape through the crystal matrix of the cholesterol acetate unlikely, if not impossible. Therefore release of HIV proteinase inhibitor iε eroεional, not diffuεional.

In another preferred embodiment of a partially-fused core, the core drug can be the nucleotide derivative azidothy idine (zidovudine, formerly AZT, Burroughs-Welcome, Inc.), as well as inhibitorε of viral reverεe tranεcriptive εuch aε dideoxycytidine (ddC-Hoffmann, LaRoche, Inc.) and dideoxyadenosine (ddA-Bristol-Meyers Co.).

A further embodiment of the core material of the invention is a totally-fused core containing an active steroid drug and cholesterol. In a totally-fused core, the core drug (a drug and optionally a carrier) is melted and recrystallized to form a crystal matrix of drug. According to a preferred embodiment for making such a core, a thin layer or "skin" of a mixture of the starting materials is applied to a thin layer of conductive metal . Preferably the surface upon which the skin is applied is coated with a nonstick material such as polytetrafluoroethylene (Teflon®). When a heat source well above the melting temperature of the starting materials is applied to the conductive metal, the starting materials mixture reaches a clear melt state in less than 10 seconds, beading like mercury and exhibiting excellent flow characteristicε when inclined at an angle of about 45° to horizontal. When εo inclined, the melted material iε motivated to leave the area of the heat εource the moment it reaches the melt stage. This eliminates the risk of degradation posed by overexposure to heat, which is a persistent problem of other methods for preparing fused pellets. Moreover, since the procedure is atmospheric, there is no capturing of air. (See U.S. Patent No. 4,748,024 the discloεure of which is incorporated herein by reference.)

B. The Sheathing

The sheathing or coating around the core is designed to function as a receptacle for a second drug and as a means for limiting the surface area of the core available for erosion. The sheathing is a biopolymer that is nontoxic, erodible and compatible with the fabrication methods disclosed herein.

Particularly preferred are thoεe polymeric materialε that can be combined with a drug as a monolithic, matrix erosional system in which a drug is evenly distributed in the polymer matrix and is releaεed as the polymer sheath itself erodes. Polymers also suitable for sheathing are those combined with a drug as a diffusion/erosion εyεtem in which drug releaεe occurε as a result of diffusion of the drug through the polymer matrix, as well as release of the drug due to erosion of the sheath.

Materials suitable for use aε εheathing are well-known and include polylactic acid, polyglycolic acid, co-polymers of polylactic and polyglycolic acids, polyanhydrides and polycaprolactone. Some representative examples of poly (lactide/glycolide) biodegradable polymers suitable for use in this invention are described by Kitchell and Wise, Methods In Enzymoloqy, Volume 112 (1985).

If poly (lactide/glycolide) is chosen aε the polymer εheathing material, it iε important to match the εolubility/deformability parameters of the sheath to the drug activity and drug mode of action.

Polycaprolactone is particularly preferred as the sheath material when it is desired that erosion of the sheath take place only after all of the core has been eroded.

Drugs suitable for incorporation into the polymer sheathing can be any of the core drugs described previously. Particularly preferred drugε used in the polymeric sheathing are those that are capable of acting in concert with the core drug in order to augment the core drug's efficacy. For example, a preferred combination of core drug and sheath drug is trenbelone acetate and estradiol benzoate, respectively. Both drugs, when adminiεtered together, are known to increaεe feeding efficiency in cowε. Another example involveε an implant having the ability to deliver agents from the sheath that a -^~ capable of protecting against tissue response to .he macromolecules (e.g., peptides and proteins) being released from the core face-ends. For example, the sheath may include anti-inflammatory factors, antipeptidases and/or potent proteolytic enzyme inhibitors such as polysulfated glycosoaminoglycans which inhibit or diminiεh the processes which cause the loεε of cartilagenous mucopolysaccharides (e.g. Adequan® - Luitpold Pharmaceuticals, Inc., Shirley, NY 11987) .

In another embodiment, a biocompatible dye can be incorporated into the sheathing to protect light labile core drug compounds, such as trenbelone acetate, from photo-decomposition. The dye protects the bioactive substance from light during handling and storage, thus requiring no special conditions for packaging.

Another preferred embodiment is the combination of peptide-based HIV-l proteinase inhibitor as the core drug, and an immuno-modulator such as interferon, colony stimulating factor, or interleukin as the sheath drug. Such a combination can be used as a therapeutic against human immunodeficiency virus (HIV) . The core drug proteinase-inhibitors inhibit proteolytic cleavage of important HIV-l polyproteins such as the gag and gag-pol gene products; and sheath drug immunomodulators such as interleukin, would mobilize the immune system by, for example, activating T-cells. See, e.g. E.R. Unanue and P.M. Allen, "The Basis for the Immunoregulatory Role of Macrophages and other Accessory Cells", Science:236 551-557 (1987) .

In yet another embodiment for AIDS therapy, nucleotide analogues such as azidothymidine (AZT) can be used in the core to combat the virus and erythropoietin can be used in the sheath to combat anemia and bone marrow suppression associated with administration of azidothymidine. See, M. Fischl et al. , "Recombinant Human Erythropoietin for patients with AIDS Treated with Zidovudine, New England J. Med. , 322:1488-1493 (1990). Moreover, implants of the invention can provide long-term, combined therapy where primary and secondary (opportunistic) infection iε present. Thus, in addition to anti-viral medications, antibiotics such as doxycycline may be administered simultaneously to combat mycoplasma infections. Multiple drug release at low, but continuous dosageε may help defer the eventual reεistance of HIV-l to AZT. Lower levels of drugs which avoid hepatic effects will further reduce toxicity. Furthermore, simultaneous dosing methods will permit eaεier screens of optimum drug combinations and possible synergistic effects.

The sheathed implant of the invention thus offers potential for use in AIDS therapy by producing a drug that meets the general goal of employing combination therapieε to help prevent the development of drug reεiεtance by HIV-l. Furthermore, aε previouεly diεcuεsed, most drug implants are ultimately controlled by an immunereεponεe which encapεulates the implant in fibrous tisεue. The degree of εuch an immune response in the AIDS patient is questionable, at best. One therefore might expect to see a slower and more incomplete tissue immune response in the AIDS patient and, as a result, more eratic release kinetics than other types of delivery systemε. Therefore, the polymer εheath of the invention will control core drug release until such time as a tissue collects in the HIV-infected patient. The polymer sheath can be engineered to burst at this time, thus turning the syεtem over to the fibrous tissue. The implant of this invention which permits elements of both self-controlled release and then tissue-controlled release offers great utility in this particular clinical setting.

The sheathed implant of this invention can also be effective in providing multiple drug delivery for use in drug addiction therapy. For example, a partially-melted core comprising buprenorphine, other thebaine or oripavine derivatives, or any narcotic agonist or antagonist can be formulated with a sheath containing a second bioactive compound useful in the management of clinical addiction.

The sheathed implant of the invention also can be effective in providing varying dosage levels of a single drug. For example, the sheath implant can be a pellet having the ability to deliver an initially high dose of a particular compound (e.g. an "induction" dose), such as an interferon, from both the sheath and core face-ends until the sheath dose is depleted; at which time a lower maintenance dose of the same compound continues at zero order from the core face-ends, while the drug-depleted sheath remains in place.

The drawings illustrate a preferred method and apparatus for forming the polymeric sheathing of the invention.

An assembly for forming an implant of the invention is shown in Figs. 2 and 3. The asεembly includes a central holding block 10, a bottom block 12 and a top block 1.4. The blockε 10, 12, 14 have εubstantially flat facing εurfaces such that they may be positioned in face-to-face relationεhip with reεpect to one another. The blockε 10, 12, 14 alεo include a εtructure which permitε the blockε to be preciεely aligned with reεpect to one another and locked together in face-to-face relationεhip. In particular, the central holding block 10 includeε a plurality of guide pins 16 extending from the upwardly facing surface 17 and the downwardly facing surface 18 of the holding block 10. These guide pins preferably are fitted within and permanently affixed to channels extending through the holding block 10. The upwardly facing surface of the bottom block 12 and the downwardly facing surface of the top block 14 are provided with εlotε 20 which are poεitioned and sized to matingly receive the guide pins of the holding block 10 εo aε to precisely position and align the various blocks 10, 12, 14 when they are held in face-to-face relationship with one another. The various blocks also are provided with threaded bores 22 which are axially aligned with respect to one another when the blocks are positioned in face-to-face relationship. A threaded screw 24 may be threaded into the aligned bores 22 to lock the various blocks to one another. The holding block 10 has at least one cylindrical bore 26 extending through the holding block 10 from the upwardly facing surface 17 to thedownwardly facing εurface 18. The bore 26 preferably has a smooth surface and is lined with a nonstick material such as polytetrafluoroethylene (PTFE). The bottom block 12 has one or more cup-shaped depressions 28 cut into the upwardly facing surface of the bottom block extend: g only partly through the bottom block. The depression 28 is sized and positioned to mate with the cylindrical bore 26 when the holding block 10 and bottom block 12 are aligned and positioned in face-to-face relationship. Preferably the depresεion 28 also is PTFE-lined. Together, the bore 26 and depression 28 form a test-tube shaped cavity.

The top block 14 has a pin 30 extending normal to the downwardly facing surface of the top block 14. Preferably the pin is PTFE-lined and is sized and shaped to fit within the test-tube shaped cavity so that an annular space 32 is formed between the similarly shaped pin 30 and cavity when the various blocks 10, 12, 14 are positioned in face-to-face relationship (Fig. 3) . This annular space 32 is intended for receiving sheath material and eεsentially forms a mold for forming the sheath of the invention.

In a preferred embodiment the er.cire asεembly iε made of stainless steal, except for the teflon linings of the cylindrical bore 26, depression 28 and pin 30. The various blocks are disk shaped and have a diameter of approximately 25 millimeters. The central holding block is about 9 millimeters in thickness and defines a cylindrical bore having an inside diameter of about 3.2 millimeters. The cup-shaped depression 28 in the bottom block 12 has an inside diameter also of about 3.2 millimeters at the upwardly facing surface of the bottom block 12and has a depth of about 1.5 millimeters. The pin is approximately 10 millimeters long and defines an elongated rod with an outside diameter of about 2.2 millimeters. Thus, the annular space 32 formed when the various blocks are positioned in face-to-face relationship has a thickness of about .5 millimeters and defines a central lumen of about 2.2 millimeters.

To form a sheathed implant according to the invention, the bottom block 12 and holding block 10 first are positioned in face-to-face relationship with one another to form the test-tube shaped cavity. Then, powdered sheath polymer (which may be mixed with a drug) is dispenεed into the teεt-tube εhaped cavity. The entire assembly then is heated until the powdered sheath polymer is capable of flowing (i.e. the glasε-tranεition phaεe) . Then, the top block 14 iε assembled in face-to-face relation with the holding block 10. To do this, the pin 30 is guided into the open end of the test-tube shaped cavity by aligning the guide pins 16 extending upwardly from the holding block 10 with the corresponding slots 20 on the downwardly facing surface of the top block 12. The top block 12 is gently presεed downwardε, and the sheath material iε caused to flow into the annular space 32 created between the pin 30 and the test-tube shaped cavity.

Preferably, the foregoing process is carried out in an oven. The oven may be an aluminum block containing individual heating chambers sized to receive the block aεsembly. Heat thus is applied to raise the temperature near the glass-tranεition temperature of the polymer. This temperature is easily determined by those of ordinary skill in the art and, in many circumstances thiε temperature will be on the order of about 100°. At thiε temperature, the polymer begins to get tacky and begins to exhibit flow properties. Because of the close fit between the pin 30 and the test-tube shaped cavity, the flowable polymer then is compressed into a thin-walled tube as the top block 14 is brought into face-to-face relation with the central holding block 10. Once the central holding block and top block have been brought into face-to-face relationship, the top block assembly may be removed from the oven and allowed to cool. The pin 30 then may be removed, leaving a thin sleeve or coating of polymer (including, optionally, drug) within the test-tube shaped cavity formed by the holding block 10 and bottom block 12.

The foregoing method avoidε the use of εolventε and liquid polymers. It will be understood by one of ordinary skill in the art, however, that solvents and liquid polymers also may be used according to the invention. In particular, a liquid suspension of sheathing polymer (and optionally drug) may be introduced into the test-tube shaped cavity formed by the holding block and bottom block. The top block then may be brought into face-to-face relationship with the holding block, thereby causing the pin 30 to be introduced into the test-tube shaped cavity. Again, because of the close fit between the pin and the test-tube shaped cavity, the liquid polymer is squeezed into the annular space 32. The polymer material then may be allowed to cure within the annular space, thereby forming the sheath.

Once the sheathing is formed, the core material then is introduced into the polymer-coated cavity. Core material can be introduced into the polymer- coated cavity in a variety of ways. The introduced core material can be in the form of a powder, which powder comprises powdered core drug or powdered core drug in combination with a carrier, as described previously. If the core material is introduced as a powder, then the melting of the core material will occur within the polymer coated cavity. Alternatively, core material can also be introduced in an already melted condition.

To accomplish melting of core material inside the polymer-coated cavity, core material is introduced into the polymer coated cavity and heated. The amount of heat applied will be a function of the number and type of components of the core material. For example, if a partially fused core is desired, enough heat is supplied to completely melt the non-polymeric carrier while leaving the core drug unmelted. Heating the core material may be accomplished by placing the entire asεembly in an oven. Heating the assembly serves two purposes: providing enough heat to melt core components and providing enough heat to bond the outer periphery of the core to the adjacent polymer sheath material. The partial melt then is allowed to cool within the sheath. Preferably, presεure iε applied to the surface of the melted material as the melted material recrystallizeε. Thiε will result in a more uniform surface as crystallization proceeds, and also will promote better bonding between the core material and sheath at the core-sheath interface.

The sheath core then is removed from the stainlesε steel holding block. This may be facilitated by cooling the asεembly, preferably in dry ice. This cooling facilitates release of the sheath from the surface of the cavity formed by the holding block and bottom block. The sheathed core that is released from the assembly defines a test-tube shaped cylinder, one of whose ends iε exposed and the other of whose ends is curved and protected by the sheath. Both ends of the sheathed core may be cut to form a sheathed cylinder having uniform ends unprotected by the polymeric sheathing.

The core material also may be melted prior to its introduction into the formed sheath. Although the heat supplied by the melted core material may be sufficient to cause bonding at the core-sheath interface when the melted material is introduced into the formed sheath, it still may be preferable to introduce the melted material into a heated sheath to promote better bonding at the core-sheath interface.

It will be recognized by those of ordinary skill in the art that other methods of forming a core bonded to a sheath may be employed according to the invention. For example, partially melted core material may be coextruded with sheath material to form the sheathed implant of the invention. In this instance, the partially melted core material may be extruded as a solid cylinder and the sheath material may be extruded as a hollow cylinder surround:-g the core material.

In the embodiments described, the core material is formed into a core within the sheath. It should be understood, however, that an erodable core may be formed first, and then the formed core may be bonded to the sheath by for example, a biocompatible adhesive or even by applying molten sheath material onto the surface of the formed core such that the heat from the sheath material causeε localized melting and recryεtallization of the core only at the core-εheath interface.

It also should be understood that both the core material and the sheathing may include either the same subεtance or complimentary εubεtances to promote bonding at the core-sheath interface. For example, the sheath polymer may include some of the core material nonpolymer carrier to promote a crystalline nonpolymer structure interlocking with and extending into the sheath.

Thoεe skilled in the art will recognize or will be able to ascertain with no more than routine experimentation numerous equivalents to the specific products and procesεeε deεcribed herein. Such equivalents are considered to be within the scope of the invention and are intended to be covered by the following claims in which I claim:

Claims

1. An implant capable of sustained release of a drug comprising, a bioerodable core containing at least one drug and having an outer surface covered only partly by a polymer sheath, wherein the core is bonded to the sheath.

2. An implant as claimed in claim 1 wherein the core is fused to the sheath.

3. An implant as claimed in claim 2 wherein the core is fused.

4. An implant as claimed in claim 3 wherein the core is in the shape of a cylinder.

5. An implant as claimed in claim 1 wherein the core is fused.

6. An implant as claimed in claim 5 wherein the core contains a nonpolymer carrier, and wherein said at least one drug is bound in a crystalline matrix of said carrier.

7. An implant as claimed in claim 6 wherein said at least one drug is a peptide.

8. An implant as claimed in claim 1 wherein the core is in the shape of a cylinder having a cylindrical surface and two ends, and wherein the cylindrical surface is covered by the polymer sheath and at least one of the ends is free of polymer sheath.

9. An implant as claimed in claims 1 - 8 wherein the sheath comprises a material selected from the group consiεting of polylactic acid, polyglycolic acid, co-polymerε of polylactic acid, co-polymers of polyglycolic acid, polycaprolactone and polyanhydride.

10. An implant as claimed in claims 1 - 8 wherein the sheath containε a sheath drug.

11. An implant as claimed in claim 10 wherein the sheath comprises a material selected from the group consisting of polylactic acid, polyglycolic acid, co-polymers of polylactic acid, co-polymers of polyglycolic acid, polycaprolactone and polyanhydride.

12. An implant as claimed in claim 1 wherein the εheath a biocompatible dye.

13. An implant aε claimed in claim 1 wherein the εheath and core are constructed and arranged so that erosion of the sheath will outlast the erosion of the core.

14. An implant aε claimed in claim 1 wherein the sheath and the core contain an excipient capable of promoting bonding between the εheath and the core.

15. A method for forming a sustained-releaεe implant comprising forming a core containing a drug, forming a sheath, and bonding the sheath to the core only on εelected εurfaces thereby leaving other surfaces of the core exposed.

16. A method as claimed in laim 15 wherein the sheath is bonded to the core by heating at least one of the sheath and core to fuse the sheath to the core.

17. A method as claimed in claim 16 wherein the core is formed by melting and recrystallizing core material.

18. A method as claimed in claim 17 wherein the sheath is formed prior o forming the core and wherein the core material is melted and recrystallized within the sheath.

19. A method as claimed in claim 15 further characterized by forming a cylindrical core having two ends and a cylindrical surface, bonding the sheath to the cylindrical surface and leaving at least one end of the cylindrical core free from sheath material thereby leaving at least one end of the core exposed for erosion.

20. A method for preparing a sustained-release implant comprising disposing a polymeric thin-walled sheath along the inner surface of the charter, dispensing nonpolymeric cc materials into the sheath, heating the nonpolymeric material to a temperature sufficient to melt it, and cooling the melted material to form a recrystallized, nonpolymeric core bonded to the sheath.

21. A suεtained release device for treatment of HIV infection in a patient, the device having a non-polymeric cylindrical core comprising a first drug capable of inhibiting replication of HIV-l virus, the core bonded only on its curved surface to a polymeric sheathing, the sheathing having incorporated thereinto a second drug, the second drug capable of modulating the patient's immune response.

22. The device of claim 21, wherein the first drug is HIV-proteinase inhibitor or therapeutically effective analogues thereof, and the second drug is selected from the group consisting of interferon and interleukin.

23. The device of claim 21, wherein the first drug is selected from the group consisting of azidothymidine, dideoxycytidine and dideoxyadenosine, and the second drug is human erythropoietin or therapeutically effective analogues thereof.