HK1068544A - Sustained release drug delivery system containing codrugs - Google Patents

Description

Sustained release drug delivery system comprising codrugs

Technical Field

The present invention relates generally to an improved system for delivering a drug. In particular, the present invention relates to a polymer-based sustained release drug delivery system and a method of delivering a drug using the delivery system.

Background

The desirability of sustained release has long been recognized in the pharmaceutical field. Many polymer-based systems have been proposed to accomplish the goal of sustained release. These systems generally rely on degradation of the polymer or diffusion through the polymer as a means of controlled release.

Implantable drug delivery systems provide an attractive alternative to oral, parenteral, suppository, and topical administration. For example, implantable drug delivery provides greater localization than other modes of administration, as compared to oral, parenteral, and suppository modes of administration. Implantable drug delivery devices are therefore particularly desirable in situations where a clinician desires a more localized therapeutic drug effect. In addition, the ability of implantable drug delivery devices to deliver drugs directly to the desired site of action allows clinicians to use drugs that are relatively poorly absorbed or unstable in biological fluids, which often has great advantages. Implantable drug delivery devices allow therapeutic doses to be obtained at a desired site of action while maintaining low or negligible systemic levels. Thus, implantable drug delivery devices are particularly attractive in situations where the drug in question is toxic or poorly scavenging or both toxic and poorly scavenging.

Implantable drug delivery systems have the advantage of being applied subcutaneously, as compared to topical administration. Which can be implanted surgically and thus can deliver drugs locally and in high concentrations over a long period of time. In contrast, topical application of drugs is generally limited to the epidermis, and repeated applications must be made periodically to maintain the concentration of the drug within its therapeutically effective range. Delivery by transdermal routes, such as by transdermal patches, has the disadvantage of systemic delivery of the drug.

Despite the obvious advantages of implantable drug delivery devices, there are still some areas where further improvements are needed for implantable devices. For example, there is a need for a simple drug delivery device that can release a drug at a constant rate. Prior art efforts to address these problems have met with limited success because of the difficulty of assembly and inconvenience of application.

Accordingly, there is a need for improved drug delivery devices that can provide sustained drug delivery over a long period of time in vivo without requiring complex manufacturing processes.

Modern surgical methods use a variety and quantity of devices that are typically placed and left in the body for extended periods of time. Such devices include, without limitation, sutures, stents, surgical screws, joint prostheses, prosthetic valves, plates, pacemakers, and the like. Over time, such devices have proven useful, but there are still some problems associated with implanted surgical devices. For example, stents, prosthetic valves, and to some extent even sutures, can cause restenosis problems after vascular surgery. Thus, systemic administration often must be combined with implanted surgical devices, which increases the risk of postoperative bleeding. Surgical implants are sometimes subject to immune reactions or rejection. Therefore, it is sometimes necessary to forgo surgical implant treatment or use immunosuppressive drugs in combination with certain surgical implants. There are often reports of drugs used in rate-controlled biodegradable polymers in an effort to avoid systemic therapy. Such systems are designed to release the drug as the polymer erodes. This severely limited the choice of drugs and polymers.

Accordingly, there is a need for an improved drug delivery device that can deliver drugs having anti-restenosis or immunosuppressive activity over an extended period of time to the vicinity of a surgical graft at a sustained concentration within a therapeutically effective concentration range of the drug.

Many efforts have been made to reduce patient contact with pathogenic microorganisms during surgery, and nevertheless, implantation of surgical devices involves introducing into the body a foreign body that may transmit to the patient various viruses and/or bacteria. Thus, surgical procedures often result in infections that patients are not normally predisposed to, and which can compromise or negate the effectiveness of the implant treatment. Therefore, administration of antibiotics, corticosteroids and/or antiviral drugs is often additionally performed at the time of implant therapy to prevent or treat infection. However, systemic administration of such antimicrobial compositions often results in undesirable side effects.

Accordingly, there is a need for an improved drug delivery device that can deliver a drug having antibacterial activity to the vicinity of a surgical implant over an extended period of time at a sustained release concentration within a range of therapeutically effective concentrations of the drug.

Surgical implants often cause other deleterious side effects such as pain and swelling. Patients with surgical implants are routinely treated with anti-inflammatory and analgesic agents such as steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents (NSAIDs) such as aspirin, cefacoxib, rofecoxib, or indomethacin, other analgesic agents such as paracetamol, and opiates. Because some patients after surgery have a fever, such patients are usually treated with antipyretics such as aspirin, ibuprofen, naproxen, or paracetamol. Patients often exhibit poor tolerance to certain NSAIDs, steroids and opiates. In addition, some NSAIDs may act as blood thinners and anticoagulants, which may increase the risk of postoperative bleeding.

Accordingly, there is a need for an improved drug delivery device that is capable of delivering a drug having anti-inflammatory, analgesic and/or antipyretic activity over an extended period of time to the vicinity of a surgical implant at a sustained release concentration within the therapeutically effective concentration range of the drug.

Summary of the invention

Certain embodiments of the present invention provide a sustained release system comprising a polymer matrix and a prodrug dispersed within the polymer, wherein the prodrug has the general formula a-L-B, wherein: a represents a drug moiety having a therapeutically active form that produces a clinical response in a patient; l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and B represents a moiety which, when attached to A, results in a prodrug having a lower solubility than the therapeutically active form of A. In certain embodiments, the linker L is hydrolyzed in body fluids. In other embodiments, the linker L is enzymatically cleaved. Examples of linkages that may be used include one or more hydrolyzable groups selected from the group consisting of esters, amides, carbamates, carbonates, cyclic ketals, thioesters, thioamides, thiocarbamates, thiocarbonates, xanthates, and phosphates.

Other embodiments of the present invention provide a sustained release formulation comprising a polymer matrix and a prodrug dispersed within the polymer, wherein the prodrug has the general formula A: B, wherein A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient; the: represents the ionic bond between a and B which dissociates under physiological conditions to produce said therapeutically active form of a; and B represents a moiety which when ionically bonded to A results in a prodrug having a solubility less than that of A in the therapeutically active form.

In certain preferred embodiments, the therapeutically active form of A has a solubility in water of more than 1mg/ml, whereas the prodrug has a solubility in water of less than 1mg/ml, and more preferably less than 0.1mg/ml, 0.01mg/ml or even less than 0.001 mg/ml.

In certain preferred embodiments, the therapeutically active form of a has a solubility in water which is 10 times higher than that of said prodrug and a solubility in water which is at least 100, 1000 or even 10000 times higher than that of said prodrug.

In certain preferred embodiments, the sustained release formulation, when disposed in a biological fluid (e.g., serum, synovial fluid, cerebrospinal fluid, lymph, urine, etc.), can provide sustained release of the therapeutically active form of a for at least 24 hours, and during the release the concentration of the prodrug in the fluid outside the polymer is less than 10% of the concentration of the therapeutically active form of a, and even more preferably less than 5%, 1% or even 0.1% of the concentration of the therapeutically active form of a.

In certain preferred embodiments, the logP value of the therapeutically active form of a is at least 1 logP unit lower than the logP value of the prodrug, and more preferably at least 2, 3 or even 4 logP units lower than the logP value of the prodrug.

In certain preferred embodiments, prodrugs of their linked forms produce clinically responsive ED₅₀ED than therapeutically active form of A₅₀At least 10 times higher, and more preferably than the therapeutically active form of ED of A₅₀At least 100, 1000 or even 10000 times higher. That is, in many embodiments, the prodrug itself is not inert in terms of producing a clinical response.

In certain embodiments, B is a hydrophobic aliphatic moiety.

In some cases, B is a drug moiety that upon cleavage of said linker L or dissociation of said ionic bond results in a therapeutically active form, and may be the same or different drug as a.

In other embodiments, B is a biologically inert moiety upon cleavage from the prodrug.

In many preferred embodiments, the therapeutically effective amount of a of the therapeutically active form is released from the polymer matrix for a duration of at least 24 hours, and more preferably at least 72 hours, 100, 250, 500 or even 750 hours. In certain embodiments, the therapeutically active form of a is released from the polymer matrix for a duration of at least one week, more preferably two weeks or more preferably at least three weeks. In certain embodiments, the therapeutically active form of a is released from the polymer matrix for a duration of at least one month, more preferably two months or even more preferably six months.

In certain embodiments, the ED of the prodrug₅₀ED than therapeutically active form of A₅₀At least 10 times higher. In a preferred embodiment, the ED of the prodrug₅₀ED than therapeutically active form of A₅₀At least 100 times higher, or more preferably at least 1000 times higher.

In some embodiments, the therapeutically active form of a is at least 10 times more soluble in water than the prodrug. In a preferred embodiment, the therapeutically active form of a is at least 100-fold more soluble in water than the prodrug, or more preferably at least 1000-fold more soluble in water.

The a (and optionally B) moiety may be selected from drugs such as immune response modifiers, antiproliferative agents, corticosteroids, angiostatic (angiostatic) steroids, antiparasitic agents, drugs for the treatment of glaucoma, antibiotics, antisense compounds, differentiation modulators, antiviral agents, anticancer agents, and non-steroidal anti-inflammatory drugs.

In certain embodiments, the polymer matrix is non-bioerodible, while in other embodiments it is bioerodible. Examples of non-bioerodible polymeric matrices can be polyurethanes, polysiloxanes, poly (ethylene-co-vinyl acetate), polyvinyl alcohol, and derivatives and copolymers thereof.

Examples of bioerodible polymeric matrices can be polyanhydrides, polylactic acids, polyglycolic acids, polyorthoesters, polyalkylcyanoacrylates, and derivatives and copolymers thereof.

In certain embodiments, the polymer matrix is selected under conditions that reduce the interaction between the prodrug located in the matrix and the protein components in the surrounding bath liquid, e.g., by forming a matrix with physical (pore size, etc.) and/or chemical (ionized groups, hydrophobicity, etc.) properties that can exclude proteins from the inner matrix, e.g., proteins greater than 100kD can be excluded from the inner matrix, and more preferably proteins with dimensions greater than 50kD, 25kD, 10kD, or even 5kD can be excluded from the inner matrix.

In certain embodiments, the polymeric matrix is not substantially a limiting factor in the rate of release of the therapeutically active form of a from the matrix.

In other embodiments, the polymer matrix affects the release rate. For example, the matrix may be derivatized to have charge or hydrophobic properties that allow chelation of the prodrug over release of the monomers (a and B). Likewise, the polymer matrix may also affect the pH dependence of the hydrolysis reaction, or may create a microenvironment that is different from the pH of the body fluid bath, such that the hydrolysis and/or solubility of the prodrug in the matrix is different from the hydrolysis and/or solubility in the surrounding fluid. Such polymers may influence the release rate, as well as the hydrolysis rate of the prodrug, in such a way by different electrons, hydrophobicity, or chemical interaction with the prodrug.

In certain embodiments, at least one of a or B is an antineoplastic agent. Examples of antineoplastic agents include anthracyclines (anthracyclines), vinca alkaloids, purine analogs, pyrimidine analogs, inhibitors of pyrimidine biosynthesis, and/or alkylating agents. Examples of the antitumor agent include 5-fluorouracil (5FU), 5 ' -deoxy-5-fluorouridine, 2 ' -deoxy-5-fluorouridine, fluorocytosine, 5-trifluoromethyl-2 ' -deoxyuridine, arabinoxy (arabinonoxyl) cytosine, cyclocytidine, 5-aza-2 ' -deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid, pyrazolofuranidin, 6-azauridine, azalipine, 3-deazauridine, arabinosyl cytosine, cyclocytidine, 5-aza-2 ' -deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, and the like, Cladribine, 6-mercaptopurine, pentostatin, 6-thioguanine, and fludarabine phosphate.

In certain preferred embodiments, the antineoplastic agent is a fluorinated pyrimidine, and more preferably 5-fluorouracil, e.g., in certain embodiments A is preferably 5-fluorouracil.

In certain embodiments, at least one of a or B is an anti-inflammatory agent illustratively such as a non-steroidal anti-inflammatory drug (diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nahumstone, naproxen, piroxicam, and the like) or a glucocorticoid (e.g., aclometasone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, cortisone, dinaphthadine, desoximetasone, diflorasone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone, fluprednide, flurandrenolide, fluticasone, hydrocortisone, methasone aceponate, mometasone furoate, prednisolone, prednisone, and rofleponide).

In certain preferred embodiments, A is an antineoplastic fluorinated pyrimidine, such as 5-fluorouracil, and B is an anti-inflammatory agent, such as fluocinolone, triamcinolone acetonide, diclofenac, or naproxen.

In some embodiments, the prodrug is selected from the group consisting of 5fu (iii) covalently bound to fluocinolone, 5fu (iv) covalently bound to naproxen, and 5fu (v) covalently bound to diclofenac. Examples of prodrugs include:

5 FU-fluocinolone (III),

5 FU-naproxen (IV), and

5 FU-diclofenac (V).

Another aspect of the invention relates to a coated drug device. For example, in certain embodiments, the present invention provides a pharmaceutical device having a coating adhered to at least one surface, wherein the coating comprises the subject polymer matrix and a low solubility prodrug. Such coatings may be applied to surgical instruments such as screws, plates, liners, sutures, prosthetic anchors, tacks, staples, electrical leads, valves, membranes. The device may be a catheter, an implantable vascular access port, a blood reservoir, a blood tract, a central venous catheter, an arterial catheter, a vascular graft, an intra-aortic balloon pump, a heart valve, a cardiovascular suture, an artificial heart, a pacemaker, a ventricular assist pump, an extracorporeal device, a blood filter, a hemodialysis device, a blood perfusion (hemoperfusion) device, a plasmapheresis device, a filter suitable for use in a blood vessel.

In a preferred embodiment, the coating may be applied to a vascular stent. In some cases, particularly where the stent is an expandable stent, the coating is flexible to accommodate the compressed and expanded state of the stent.

In certain embodiments, the weight of the coating attributable to the prodrug is per cm²About 0.05mg to about 50mg of prodrug, and more preferably 5 to 25mg/cm of surface coated with said polymer matrix²。

In certain embodiments, the coating has a thickness of 5 microns to 100 microns.

In certain embodiments, the prodrug is present in the coating in an amount of 5% to 70% by weight, and more preferably 25% to 50% by weight, of the weight of the coating.

In another aspect of the invention, a method of treating intraluminal tissue of a patient is provided. In general, the method comprises the steps of:

(a) providing a stent having an inner surface and an outer surface, said stent having a coating on at least a portion of the inner surface, the outer surface, or both the inner surface and the inner surface; said coating comprising a low solubility pharmaceutical prodrug dissolved or dispersed in a biologically tolerable polymer;

(b) placing the stent on the appropriate intraluminal tissue site; and

(c) the stent is expanded.

Another aspect of the invention relates to a coating composition for localized delivery of a drug from a surface of a drug device in vivo.

The composition comprises a polymer matrix and a prodrug of low solubility as described above. The coating composition may be provided in the form of a liquid or suspension for application to the surface of a medical device by spraying and/or dipping the device in the composition. In other embodiments, the coating composition is provided in powder form, which upon addition of a solvent can be reconstituted into a liquid or suspension that can be applied to the surface of the medical device by spraying and/or dipping the device in the composition.

Another aspect of the invention relates to an injectable composition for delivering a drug to a patient. The composition comprises a polymer matrix and a prodrug of low solubility as described above, and may be provided in the form of a liquid or suspension suitable for delivery by needle injection.

Additional advantages of the present invention will become readily apparent to those skilled in this art from the following detailed description, wherein only the preferred embodiment of the invention is shown and described, simply by way of illustration of the best mode contemplated of carrying out the invention. It will be appreciated that the invention is capable of other and different embodiments and its several details are capable of modification in various respects, all without departing from the scope of the present invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive.

Brief description of the drawings

Figure 1 is a time-dependent graph of prodrug release from a polymer-prodrug dispersion of the present invention.

Figure 2 is a time-dependent graph of prodrug release from a polymer-prodrug dispersion of the present invention.

Fig. 3 is a side plan view of an unexpanded stent of the present invention.

Fig. 4 is a side plan view of a deployed stent of the present invention.

FIG. 5 is a release profile of TC-112 from PVA coated glass slides into buffer at pH 7.4.

FIG. 6 is a release profile of TC-112 from a silicone-coated glass slide into a buffer at pH 7.4.

FIG. 7 is a release profile of 5-fluorouracil (5FU) and Triamcinolone Acetonide (TA) from coated inserts.

FIG. 8 is a release profile of 5-fluorouracil (5FU) and Triamcinolone Acetonide (TA) from coated inserts.

FIG. 9 illustrates the in vitro release pattern of a high dose coated stent.

FIG. 10 shows the drug release profile between a grafted stent and an unimplanted stent for comparison.

Fig. 11A and 11B show the effect of gamma irradiation and plasma treatment on drug release. Group B: treatment with plasma and treatment with gamma radiation. Group C: treatment was performed without plasma and with gamma radiation. Group D: treatment with plasma was performed without gamma irradiation. Group F: no plasma, no gamma irradiation.

To carry outBest mode for carrying out the invention

Detailed description of the invention

I. Definition of

The term "active" as used herein refers to therapeutic or pharmacological activity.

The term "ED₅₀"refers to the dosage of drug that produces 50% of the maximal response or effect.

The term "IC₅₀"refers to a dosage of drug that inhibits biological activity by 50%.

The term "LD₅₀"refers to the dose of drug that is 50% dead of the test subject.

The term "therapeutic index" refers to the index of expression of LD₅₀/ED₅₀To define a pharmacotherapeutic index.

A "patient" or "individual" to be treated by a method of the invention may refer to a human or non-human animal.

"physiological conditions" describe conditions in vivo in an organism, i.e., in vivo conditions. Physiological conditions include the acidic and basic environment of body cavities and organs, enzymatic cleavage, metabolism, and other biological processes, and preferably refer to physiological conditions of vertebrates such as mammals.

"LogP" refers to the logarithm of P (partition coefficient). P is a measure of how the substance is distributed between the fat (oil) and the water. P itself is a constant. It is defined as the ratio of the concentration of the compound in the form of neutral molecules in the aqueous phase to the concentration of the compound in the immiscible solvent.

Partition coefficient, P ═ organic ]/[ water ], where [ ] ═ concentration

LogP＝log₁₀(partition coefficient) log₁₀P

In practice, the LogP value will vary with its measurement conditions and the dispensing solvent selected. A LogP value equal to 1 means that the concentration of the compound in the organic phase is 10 times higher than in the aqueous phase. An increase of1 in logP value indicates a 10-fold increase in the concentration of the compound in the organic phase compared to the compound in the aqueous phase. Thus, a compound with a logP value of 3 has a solubility in water 10 times higher than a compound with a logP value of 4 and a solubility in water of a compound with a logP value of 3 100 times higher than a compound with a logP value of 5. Compounds with logP values of 7-10 are generally considered to be low solubility compounds.

II. Examples of the embodiments

The present invention provides a drug delivery system that can provide various release profiles, e.g., which can provide various dosages and/or various lengths of time. Thus, the present invention satisfies the need for an insertable, injectable, inhalable, or implantable drug delivery system that provides controlled drug release kinetics over time, and in particular, locates a desired drug activity in the vicinity of a desired site while avoiding the complications associated with prior art devices.

The system of the present invention comprises a polymer and a prodrug having low solubility dispersed in the polymer. The polymer is permeable to the prodrug and does not substantially limit the release rate of the prodrug from the polymer and provides sustained release of the drug.

Once administered, the system continues to deliver the prodrug to the desired active site, but does not necessarily require additional invasive penetration into these areas. Instead, the system remains in the body and serves as a source of sustained prodrug supply to the affected area. The system of the invention allows for long-term release of the drug over a specified period of days, weeks, months (e.g., from about 3 months to about 6 months) or years (e.g., from about 1 year to about 20 years, such as from about 5 years to about 10 years) until the prodrug is exhausted.

The intraluminal medical device comprises the sustained release drug delivery coating. The stent coating of the present invention may be applied to the stent by conventional coating methods such as dip coating, spray coating and dip coating.

In one embodiment, the intraluminal medical device comprises a radially extending expandable tubular stent having an inner luminal surface and an opposing outer surface extending along a longitudinal stent axis. The stent may comprise a permanent implantable stent, an implantable graft stent, or a temporary stent, wherein a temporary stent is defined as a stent that is expandable within a vessel and thereafter extractable from the vessel. The stent structure may include helical stents, memory helical stents, nickel-titanium alloy stents, mesh stents, skeletal stents, cannulated stents, permeable stents, stents with temperature sensors, porous stents, and the like. The stent may be deployed by conventional means, such as by an expandable balloon catheter, by an automatic deployment mechanism (after release from the catheter), or by other suitable means. The radially extending expandable tubular stent may be a graft stent, wherein said graft stent is a composite device having a stent inside or outside a graft. The graft may be a vascular graft, such as an ePTFE graft, a biological graft, or a woven graft.

The drug combination may be incorporated into or attached to the stent by a number of methods. In one exemplary embodiment, the pharmaceutical combination is incorporated directly into the polymer matrix and sprayed onto the outer surface of the stent. Over time, the drug combination elutes from the polymer matrix and into the surrounding tissue. The drug combination is preferably retained on the stent for at least three days up to about six months, and more preferably for seven to thirty days.

The prodrug dissolves slowly in physiological fluids but dissociates relatively rapidly into at least one pharmaceutically active compound once dissolved in physiological fluids. In some embodiments, the prodrug has a dissolution rate of about 0.001 μ g/day to about 10 μ g/day. In certain embodiments, the prodrug has a dissolution rate of about 0.01 to about 1 μ g/day. In a particular embodiment, the prodrug has a dissolution rate of about 0.1 μ g/day.

The low solubility pharmaceutical prodrug is incorporated into a physiologically compatible (i.e., physiologically tolerable) polymeric carrier. In some embodiments of the invention, the low solubility prodrug is present in the form of a plurality of particles dispersed in the polymeric carrier. In such cases, it is preferred that the low solubility pharmaceutical prodrug be relatively insoluble in the polymeric carrier, despite the limited solubility coefficient of the low solubility pharmaceutical prodrug relative to the polymeric carrier, and still be within the scope of the present invention. In either case, the polymeric carrier solubility of the low solubility pharmaceutical prodrug should be such that the prodrug will be dispersed throughout the polymeric carrier while still being substantially in particulate form.

In some embodiments of the invention, the low solubility pharmaceutical prodrug is dissolved within the polymeric carrier. In such cases, it is preferred that the polymeric carrier be a relatively non-polar or hydrophobic polymer that can act as a good solvent for the relatively hydrophobic low solubility pharmaceutical prodrug. In such cases, the solubility of the low solubility pharmaceutical prodrug in the polymeric carrier should be such that the prodrug will be completely dissolved in the polymeric carrier and the drug will be uniformly distributed within the polymeric carrier.

The polymers of the invention include any biologically tolerable polymer that is permeable to the prodrug and at the same time has a permeability that is not a major rate-determining factor for the release rate of the prodrug from the polymer.

In some embodiments of the invention, the polymer is non-bioerodible. Examples of non-bioerodible polymers for use in the present invention include poly (ethylene-co-vinyl acetate) (EVA), polyvinyl alcohol, and polyurethanes, such as polycarbonate-based polyurethanes. In other embodiments of the invention, the polymer is bioerodible. Examples of bioerodible polymers for use in the present invention include polyanhydrides, polylactic acids, polyglycolic acids, polyorthoesters, polyalkylcyanoacrylates or their derivatives and copolymers. As described in detail below, the skilled artisan will appreciate that the choice of a bioerodible polymer or a non-bioerodible polymer will depend on the final physical form of the system. Other examples of polymers include polysiloxanes and polymers derived from hyaluronic acid. The skilled artisan will appreciate that the polymers of the invention are prepared under conditions suitable to impart thereto a permeability which is not the primary rate-determining factor for the release of the low-solubility prodrug from the polymer.

In addition, suitable polymers include naturally occurring (collagen, hyaluronic acid, and the like) or synthetic materials that are biologically compatible with body fluids and mammalian tissues and that are substantially insoluble in the body fluids with which the polymer will come into contact. In addition, suitable polymers may substantially prevent interaction between the low solubility prodrug dispersed/suspended in the polymer and protein components in body fluids. Because dissolution of the polymer or interaction with the protein component will affect the persistence of drug release, the use of rapidly dissolving polymers or polymers with high solubility in body fluids or polymers that allow the low solubility prodrug to interact with the protein component is avoided in some cases.

Other suitable polymers include polypropylene, polyesters, polyethylene vinyl acetate (PVA or EVA), polyethylene oxide (PEO), polypropylene oxide, polycarboxylic acids, polyalkylacrylates, cellulose ethers, silicones, poly (dl-lactide-co-glycolide), various Eudragrits (e.g., NE30D, RS PO and RL PO), polyalkyl-alkylacrylate copolymers, polyester-polyurethane block copolymers, polyether-polyurethane block copolymers, polydioxanone, poly- (β -hydroxybutyrate), polylactic acid (PLA), polycaprolactone, polyglycolic acid, and PEO-PLA copolymers.

The coatings of the present invention may be formed by mixing one or more suitable monomers with a suitable low solubility pharmaceutical prodrug and then polymerizing the monomers to form the polymer system. Thus, the prodrug is dissolved or dispersed in the polymer. In other embodiments, the prodrug is mixed into a liquid polymer or polymer dispersion, and the polymer is then further processed into the coating of the invention. Suitable further processing includes crosslinking with a suitable crosslinking prodrug, further polymerization of the liquid polymer or polymer dispersion, copolymerization with a suitable monomer, block copolymerization with a suitable polymer block, and the like. The further processing may entrap the drug in the polymer such that the drug is suspended or dispersed in the polymer carrier.

Any number of non-erodible polymers may be used in combination with the drug. Film-forming polymers useful for coating in such applications are absorbable or non-absorbable and must be biocompatible to minimize irritation of the vessel wall. Depending on the desired release rate or degree of stabilization of the desired polymer, the polymer is biologically stable or biologically absorbable, but bioabsorbable polymers are preferred because, unlike biologically stable polymers, they do not survive long term after implantation and thus do not cause any adverse chronic local reactions. Furthermore, bioabsorbable polymers do not run the risk that over a prolonged period of time they will cause a decrease in the adhesion between the stent and the coating due to the pressure of the biological environment which can move the coating and cause further problems even after the stent is embedded in tissue.

Suitable bioabsorbable film forming polymers useful in the present invention include polymers selected from the group consisting of aliphatic polyesters, poly (amino acids), (ether-ester) copolymers, polyalkylene oxalates, polyamides, poly (imino carbonates), polyorthoesters, polyoxaesters, polyamidoamides, polyoxaesters containing amido groups, poly (anhydrides), polymers containing phosphorus and nitrogen chains, biomolecules and mixtures thereof. For purposes of the present invention, aliphatic polyesters include homopolymers and copolymers of lactide (which includes d-, 1-and meso-lactide of lactic acid), epsilon-caprolactone, glycolide (which includes glycolic acid), hydroxybutyrate, hydroxyvalerate, p-dioxanone, trimethylene carbonate (and its alkyl derivatives), 1, 4-dioxepan-2-one, 1, 5-dioxepan-2-one, 6-dimethyl-1, 4-dioxane-2-one, and polymer mixtures thereof. Poly (iminocarbonates) useful for the purposes of the present invention include materials such as those described by Kemnitzer and Kohn, in the handbook of biodegradable polymers, edited by Domb, Kost and Wisemen, Hardwood A disclosure Press, 1997, page 251-272. (Ether-ester) copolymers for the purposes of the present invention include those copolymerized ester-ethers (e.g., PEO/PLA) described by Cohn in Journal of biomaterials research, Vol.22, pp.993-1009, 1988 and Younnes and Cohn, Polymer preprints (ACS Division of Polymer chemistry) Vol.30 (1), pp.498, 1989. Polyalkylene oxalates for the purposes of the present invention include US 4,208,511; 4,141,087, respectively; 4,130,639, respectively; 4,140,678, respectively; 4,105,034, respectively; and 4,205,399 (which are incorporated herein by reference). Polymers containing phosphorus-nitrogen chains, polymers based on mixed monomers of di-, tri-and higher order made from L-lactide, D, L-lactide, lactic acid, glycolide, glycolic acid, p-dioxanone, trimethylene carbonate and epsilon-caprolactone, e.g. by Allcock in the encyclopedia of Polymer Science, Vol.13, p.31-41, Wiley Interscience, John Wiley&Sons, 1988 and edited by Vandorpe, Schacht, Dejardin and Lemmouchi in the handbook of biodegradable polymers, Domb, Kost and Wisemen, Hardwood Academic Press, 1997, 161-The substances described in the pages (which are incorporated herein by reference). The polyanhydride is obtained in the form of HOOC-C₆H₄-O-(CH₂)_m-O-C₆H₄-a diacid of COOH, wherein m is an integer from 2 to 8, and copolymers thereof with aliphatic alpha-omega diacids having up to 12 carbon atoms. Polyoxalate polyoxamides and polyoxalate types comprising amine and/or amido groups are described in US5,464,929; 5,595,751, respectively; 5,597,579, respectively; 5,607,687, respectively; 5,618,552, respectively; 5,620,698, respectively; 5,645,850, respectively; 5,648,088, respectively; 5,698,213 and 5,700,583 (which are incorporated herein by reference). Polyorthoesters such as those described by Heller in the handbook of biodegradable polymers, Domb, Kost and Wisemen, Hardwoodacadimic Press, 1997, pages 99-118 (which is incorporated herein by reference). Film-forming polymeric biomolecules for the purposes of the present invention include naturally occurring materials that are enzymatically degradable or hydrolytically unstable in the human body, such as fibrin, fibrinogen, collagen, elastin, and absorbable biocompatible polysaccharides such as chitosan, starch, fatty acids (and esters thereof), glucose-based (gluco) -polysaccharides, and hyaluronic acid.

Suitable biologically stable film-forming polymers having a relatively low, slow tissue response such as polyurethanes, silicones, poly (meth) acrylates, polyesters, polyalkyleneoxides (polyethyleneoxides), polyvinylalcohols, polyethyleneglycols and polyvinylpyrrolidones, and hydrogels, such as those formed from crosslinked polyvinylpyrrolidones and polyesters, may also be used. Other polymers may also be used if they can be dissolved, solidified or polymerized on the stent. These include polyolefins, polyisobutylene and ethylene-alpha olefin copolymers; acrylic polymers (including methacrylates) and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketone; polyvinyl aromatic compounds such as polystyrene; polyvinyl esters such as polyvinyl acetateAn ester; copolymers of vinyl monomers with each other or with olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile styrene copolymers, ABS resins and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; an alkyd resin; a polycarbonate; a polyoxymethylene; polyimides; polyethers; epoxy resins, polyurethanes; artificial silk; rayon-triacetate, cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers (i.e., carboxymethyl cellulose and hydroxyalkyl cellulose); and combinations thereof. Polyamides for the purposes of the present application also include the form-NH- (CH)₂)_n-CO-and NH- (CH)₂)_x-NH-CO-(CH₂)_y-polyamides of CO, wherein n is preferably an integer from 6 to 13; x is an integer from 6 to 12; and y is an integer from 4 to 16. The materials listed above are intended to be illustrative and not limiting.

The polymer used for coating can be a film-forming polymer of sufficiently high molecular weight so that it is not a waxy or tacky substance. The polymer should also be capable of adhering to the stent and not being deformed easily by hemodynamic stress displacement after deposition onto the stent. The molecular weight of the polymer should be high enough to provide sufficient toughness so that the polymer is not wiped off during handling or deployment of the stent and must not crack during expansion of the stent. In certain embodiments, the polymer has a melting temperature above 40 ℃, preferably above about 45 ℃, more preferably above 50 ℃ and most preferably above 55 ℃.

Coatings can be prepared by mixing one or more therapeutic prodrugs with the coating polymer in a coating mixture. The therapeutic prodrug may be present as a liquid, finely divided solid, or any other suitable physical form. The mixture may or may not include one or more additives, for example, non-toxic auxiliary substances such as diluents, carriers, excipients, stabilizers, and the like. Other suitable additives may be prepared with the polymer and the pharmaceutically active prodrug or compound. For example, a hydrophilic polymer selected from the biocompatible film-forming polymers listed above may be added to the biocompatible hydrophobic coating to modify the release profile (or a hydrophobic polymer may be added to the hydrophilic coating to modify the release profile). One example is the addition of a hydrophilic polymer selected from the group consisting of polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, carboxymethyl cellulose, hydroxymethyl cellulose, and combinations thereof to an aliphatic polyester coating to modify the release profile. Suitable relative amounts can be determined by monitoring the in vitro and/or in vivo release profile of the therapeutic prodrug.

The thickness of the coating may determine the rate at which the active drug (active drug species) or prodrug elutes from the matrix. In effect, the active drug (active drug species) or prodrug is eluted from the matrix by diffusion through the polymer matrix. The polymer is permeable so that solids, liquids and gases can escape therefrom. The total thickness of the polymer matrix is in the range of one micron to about twenty microns or more. It is important to note that the primer and metal surface treatments are performed prior to attaching the polymer matrix to the medical device. For example, acid cleaning, strong base (alkaline) cleaning, salination, and parylene deposition may be used as part of the overall process.

In certain embodiments, a composite coating may be used. For example, the various coatings may differ in prodrug concentration, prodrug characteristics (active ingredient, linker, etc.), characteristics of the polymer matrix (composition, porosity, etc.), and/or the presence of other drugs or release modifiers.

To illustrate further, the poly (ethylene-co-vinyl acetate), polybutylmethacrylate, and the drug combination solution may be incorporated into or onto the stent in a number of ways. For example, the solution may be sprayed onto the stent or the stent may be immersed in the solution. Other methods include spin coating and RF plasma polymerization. In an exemplary embodiment, the solution is sprayed onto the stent and then dried. In another exemplary embodiment, the solution is charged to one polarity and the stent is charged to the opposite polarity. In this way, the solution and the stent will be attracted to each other. When using this type of spraying method, waste can be reduced and the thickness of the coating can be controlled more accurately.

In another exemplary embodiment, the drug combination or other therapeutic prodrug can be incorporated into a film-forming polyfluoro copolymer comprising a number of first moieties and a number of second moieties copolymerized with the first moieties to produce polyfluoro copolymers; wherein said one moiety is selected from the group consisting of polymerized vinylidene fluoride and polymerized tetrafluoroethylene, and said second moiety is different from the first moiety and is capable of providing toughness or elasticity to the polyfluoro copolymer, wherein the relative amounts of the one moiety and the second moiety are effective to provide coatings and films therefrom having properties useful for treating the implantable medical device.

In one embodiment of the invention, the outer surface of the expandable tubular stent of the intraluminal medical device of the invention comprises a coating of the invention. The outer surface of the coated stent is the surface that comes into contact with tissue and is biocompatible. "coated surface of a sustained release drug delivery system" is synonymous with "coated surface" which is coated, covered or impregnated with the sustained release drug delivery system of the present invention.

In an alternative embodiment, the luminal surface or the entire surface (i.e., the inner and outer surfaces) of the radially extending expandable tubular stent of the intraluminal medical device of the invention has a surface that is coated. The surface of the lumen having the coating of the sustained release drug delivery system of the present invention is also the surface that is in contact with the liquid and is biocompatible and hemocompatible.

U.S. Pat. Nos. 5,773,019, 6,001,386 and 6,051,576, all of which are incorporated herein by reference in their entirety, disclose implantable controlled release devices and drugs. The method of the invention for preparing a stent having a coated surface comprises depositing a coating on the stent, for example by dip coating or spray coating. In the case of coating one side of the stent, only the surface to be coated is dipped or sprayed. The surface treated may be all or a portion of the luminal surface, the outer surface, or both the inner and outer surfaces of the intraluminal medical device. The stent may be made of a porous material to allow more deposits or coatings to enter into the micropores or onto the applicable stent surface, wherein the micropores are preferably about 100 microns or less in size.

Problems associated with the treatment of restenosis and neointimal hyperplasia can be addressed by the selection of pharmaceutical prodrugs for coating the medical device. In certain preferred embodiments of the invention, the selected pharmaceutical prodrug is one low solubility moiety and comprises at least two pharmaceutically active compounds. The pharmaceutically active compounds may be of the same or different types of chemicals and may be formed in equimolar or unequal molar concentrations as required to provide optimal treatment based on the relative activity and other pharmacokinetic properties of the compounds. Pharmaceutical combinations, in particular in the case of the use of codrugs, may themselves advantageously be relatively insoluble in physiological liquids, such as blood and plasma, and have the property that any or all of the pharmaceutically active compounds can be regenerated when dissolved in the physiological liquid. In other words, to the extent that the low solubility prodrug is dissolved in physiological fluids, it is rapidly and efficiently converted to the pharmaceutically active compound of which it is composed once dissolved. Thus, the low solubility of the pharmaceutical prodrug ensures that the prodrug is able to persist in the vicinity of the lesion within the lumen. The rapid conversion of the low solubility pharmaceutical prodrug into its constituent pharmaceutically active compound ensures stable controlled administration of the pharmaceutically active compound in the vicinity of the lesion to be treated.

Examples of suitable first pharmaceutically active compounds include immune response modifiers such as cyclosporin a and FK 506, corticosteroids such as dexamethasone, fluocinolone acetonide and triamcinolone acetonide, angiostatic steroids such as trihydroxysteroids, antibiotics including ciprofloxacin, differentiation regulators such as retinoids (e.g., trans-retinoic acid, cis-retinoic acid, and the like), anticancer/antiproliferative prodrugs such as 5-fluorouracil (5FU) and BCNU, and nonsteroidal anti-inflammatory prodrugs such as naproxen, diclofenac, indomethacin, and flurbiprofen.

In some embodiments of the invention, the preferred first pharmaceutically active compound is 5 FU.

5-Fluorouracil (5FU).

Examples of suitable second pharmaceutically active compounds include immune response modifiers such as cyclosporin a and FK 506, corticosteroids such as dexamethasone, fluocinolone acetonide and triamcinolone acetonide, angiostatic steroids such as trihydroxysteroids, antibiotics including ciprofloxacin, differentiation regulators such as retinoids (e.g., trans-retinoic acid, cis-retinoic acid, and the like), anticancer/antiproliferative prodrugs such as 5-fluorouracil (5FU) and BCNU, and nonsteroidal anti-inflammatory prodrugs such as naproxen, diclofenac, indomethacin, and flurbiprofen.

In some embodiments of the invention, the second pharmaceutically active compound is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, diclofenac, and naproxen.

Triamcinolone acetonide diclofenac

Naproxen

The low solubility pharmaceutically active prodrugs of the invention may comprise residues of additional pharmaceutically active compounds. Such additional pharmaceutically active compounds include immune response modifiers such as cyclosporin a and FK 506, corticosteroids such as dexamethasone, fluocinolone acetonide and triamcinolone acetonide, angiostatic steroids such as trihydroxysteroids, antibiotics including ciprofloxacin, differentiation regulators such as retinoids (e.g., trans-retinoic acid, cis-retinoic acid, and the like), anticancer/antiproliferative prodrugs such as 5-fluorouracil (5FU) and BCNU, and nonsteroidal anti-inflammatory prodrugs such as naproxen, diclofenac, indomethacin, and flurbiprofen.

In certain embodiments, the low solubility pharmaceutical prodrug comprises at least two pharmaceutically active compound moieties covalently bonded, linked by a linker, ionically bonded, or mixed bond.

In some embodiments of the invention, the first and second pharmaceutically active compounds are covalently bound to each other directly. In the case of the first and second pharmaceutically active compounds and being bound directly to each other by a covalent bond, this bond may be formed by forming a suitable covalent link between the active groups on the respective active compounds. For example, an acidic group on a first pharmaceutically active compound can condense with an amine, acid, or alcohol on a second pharmaceutically active compound to form the corresponding amide, anhydride, or ester, respectively.

In addition to carboxylic acid, amine and hydroxyl groups, other suitable reactive groups that can form a linkage between pharmaceutically active moieties include sulfonyl, mercapto, and hydrohalic acids and anhydride derivatives of carboxylic acids.

In other embodiments, the pharmaceutically active compounds may be covalently linked to each other through an intermediate linker. The linker advantageously has two reactive groups, one of which may be complementary to the reactive group on the first pharmaceutically active compound and the other of which may be complementary to the reactive group on the second pharmaceutically active compound. For example, where both the first and second pharmaceutically active compounds have free hydroxyl groups, the linker may suitably be a diacid which will react with both compounds to form a di-ether bond between the two residues. In addition to carboxylic acid, amine and hydroxyl groups, other suitable reactive groups that can form a linkage between pharmaceutically active moieties include sulfonyl, mercapto, and hydrohalic acids and anhydride derivatives of carboxylic acids.

Suitable linkers are listed in table 1 below.

TABLE 1

Active group of first pharmaceutically active compound	Active group of second pharmaceutically active compound	Adapted to be connected
			Amines as pesticides	Amines as pesticides	Diacid(s)
Amines as pesticides	Hydroxy radical	IIAcid(s)
			Hydroxy radical	Amines as pesticides	Diacid(s)
Hydroxy radical	Hydroxy radical	Diacid(s)
			Acid(s)	Acid(s)	Diamines
Acid(s)	Hydroxy radical	Amino acids, hydroxyalkyl acids, mercaptoalkyl acids
			Acid(s)	Amines as pesticides	Amino acids, hydroxyalkyl acids, mercaptoalkyl acids

Suitable diacid linkers include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, tartaric acid, phthalic acid, isophthalic acid, and terephthalic acid. Although referred to as diacids, those skilled in the art will appreciate that in some cases the corresponding acid halide or anhydride (single or double sided) is preferred in the attachment of the reprodrug. One preferred anhydride is succinic anhydride. Another preferred anhydride is maleic anhydride. Other anhydrides and/or acid halides can be used by those skilled in the art to achieve good performance.

Suitable amino acids include gamma-butyric acid, 2-glycine, 3-aminopropionic acid, 4-aminobutyric acid, 5-aminopentanoic acid, 6-aminocaproic acid, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. The acid group of the suitable amino acid can in turn be converted to the anhydride or acid halide form before it is used as a linking group.

Suitable diamines include 1, 2-diaminoethane, 1, 3-diaminopropane, 1, 4-diaminobutane, 1, 5-diaminopentane, 1, 6-diaminohexane.

Suitable aminoalcohols include 2-hydroxy-1-aminoethane, 3-hydroxy-1-aminoethane, 4-hydroxy-1-aminobutane, 5-hydroxy-1-aminopentane, 6-hydroxy-1-aminohexane.

Suitable hydroxyalkyl acids include 2-hydroxyacetic acid, 3-hydroxypropionic acid, 4-hydroxybutyric acid, 5-hydroxyvaleric acid, 5-hydroxyhexanoic acid.

One skilled in the art will recognize that first and second pharmaceutical moieties (and third, etc. pharmaceutical moieties, present or absent) having suitable reactive groups can be screened and, by matching them to suitable linkers, a wide range of compounds of the invention can be prepared within the scope of the invention.

Examples of preferred pharmaceutically active prodrugs of low solubility include 5FU covalently bound to fluocinolone, 5FU covalently bound to diclofenac, and 5FU covalently bound to naproxen. Illustrative examples include the following:

5 FU-fluocinolone (via an oxalate linker).

5 FU-naproxen

5 FU-diclofenac

Examples of other codrugs include the following:

5-TC-70.1 (composite medicine of fluocinolone acetonide and 5-FU connected by formaldehyde)

5-TC-63.1 (composite medicine of naproxen and floxuridine connected through oxyacid)

3-TC-112 (Compound drug with naproxen and 5-FU connected by formaldehyde)

G-427.1 (Compound drug of triamcinolone acetonide and 5-FU directly connected)

TC-32 (composite drug with triamcinolone acetonide and 5-FU connected by formaldehyde)

Examples of some codrugs that link first and second pharmaceutically active compounds through different links include:

compound medicine of floxuridine and diclofenac (1: 1)

Compound medicine of floxuridine and diclofenac (1: 2)

Compound medicine of floxuridine and fluocinolone acetonide (1: 1)

Compound medicine of floxuridine and fluocinolone acetonide (1: 1)

Compound medicine of floxuridine and fluocinolone acetonide (1: 1)

Compound medicine of floxuridine and naproxen (1: 1)

Compound medicine of floxuridine and naproxen (1: 2)

In other embodiments, the first and second pharmaceutically active compounds may be combined to form a salt. For example, the first pharmaceutically active compound may be an acid and the second pharmaceutically active compound may be a base, such as an amine. As a particular example, the first pharmaceutically active compound may be diclofenac or naproxen (an acid), and the second pharmaceutically active compound may be ciprofloxacin (a base). A combination of diclofenac and ciprofloxacin will for example form the following salts:

ciprofloxacin-Dichlorophenolic acid

For systems of the invention to deliver a prodrug in a desired manner, e.g., in some embodiments in a constant or substantially linear manner, the solubility of the drug and the permeability of the polymer must be balanced such that the permeability of the polymer is not a rate-determining factor in the delivery of the drug. Thus, the rate of release of the prodrug is essentially the rate at which the prodrug dissolves in the surrounding aqueous medium. This release rate is almost essentially linear with time (so-called zero order kinetics).

The system of the present invention may be formed by mixing one or more suitable monomers with a suitable low solubility pharmaceutical prodrug and then polymerizing the monomers to form the polymeric system. Thus, the prodrug is dissolved or dispersed in the polymer. In other embodiments, the prodrug is mixed into a liquid polymer or polymer dispersion, and the polymer is further processed to form the system of the present invention. Suitable further processing includes crosslinking with a suitable crosslinking prodrug, further polymerization of the liquid polymer or polymer dispersion, copolymerization with a suitable monomer, block copolymerization with a suitable polymer block, and the like. The further processing may entrap the drug in the polymer such that the drug is suspended or dispersed in the polymer matrix.

In some embodiments of the invention, monomers used to form the polymer may be combined with the low solubility compound of the invention and mixed to produce a homogeneous dispersion of the compound of the invention in the monomer solution. The dispersion is then applied to the stent according to conventional coating methods, after which the crosslinking process is started with conventional initiators, such as UV rays. In other embodiments of the invention, the polymer composition is combined with the low solubility compound of the invention to form a dispersion. The dispersion is then applied to a stent and the polymer is crosslinked to form a solid coating. In other embodiments of the invention, the polymer and the low solubility compound of the invention are combined with a suitable solvent to form a dispersion, which is then applied to the stent in a conventional manner. The solvent is then removed by conventional means, such as thermal evaporation, so that the polymer (together forming the sustained release drug delivery system) and the low solubility drug of the present invention remain on the stent as a coating. A similar process may be used in the case of dissolving the low solubility pharmaceutical compound of the present invention in the polymer composition.

In some embodiments of the invention, the system comprises a relatively rigid polymer. In other embodiments, the system comprises a soft and malleable polymer. In still other embodiments, the system includes a polymer having adhesive properties. As discussed in detail below, the stiffness, elasticity, tackiness, and other properties of the polymer may vary widely depending on the particular final physical form of the system.

Embodiments of the system of the present invention can take many different forms. In some embodiments, the system includes a prodrug of low solubility, i.e., a prodrug suspended or dispersed in the polymer. In certain other embodiments, the system comprises a prodrug and a polymer in a semi-solid or gel form, which is suitable for injection into the body by a syringe. In other embodiments of the invention, the system comprises a prodrug and a soft-deformable polymer, which is suitable for insertion or implantation into the body by a suitable surgical method. In still other embodiments of the invention, the system comprises a hard, solid polymer that is suitable for insertion or implantation into the body by a suitable surgical method. In a further embodiment of the invention, the system comprises a polymer suitable for inhalation having a low solubility prodrug suspended or dissolved therein. In another embodiment, the system comprises a polymer having a prodrug suspended or dispersed therein, wherein the prodrug and polymer mixture forms a coating on a surgical device, such as a screw, stent, pacemaker, or the like. In certain embodiments of the invention, the device is comprised of a hard solid polymer that is shaped into the form of a surgical instrument such as a surgical screw, plate, stent, or the like, or a portion thereof. In other embodiments of the invention, the system comprises a polymer in the form of a suture having a drug dispersed or suspended therein.

In some embodiments of the present invention, a medical device is provided comprising a substrate having a surface, such as an outer surface, and a coating on the outer surface. The coating comprises a polymer and a prodrug having low solubility dispersed in the polymer, wherein the polymer is permeable to the prodrug and is not substantially a rate-limiting factor with respect to the rate of release of the prodrug from the polymer. In certain embodiments of the invention, the device comprises the prodrug suspended or dispersed in a suitable polymer, wherein the prodrug and polymer are coated over the entire substrate, e.g., surgical instrument. Such coating can be accomplished by spray coating or dip coating.

In other embodiments of the invention, the device comprises a prodrug and a polymer suspension or dispersion, wherein the polymer is rigid and forms part of a device that is inserted or implanted into the body. For example, in particular embodiments of the invention, the device is a surgical screw, stent, pacemaker, or the like coated with a prodrug suspended or dispersed in the polymer. In another particular embodiment of the invention, the polymer in which the prodrug is suspended forms the tip, cap or a part thereof of a surgical screw. In other embodiments of the invention, the polymer in which the prodrug is suspended or dispersed is coated onto a surgical instrument such as a surgical tube (e.g., colostomy, peritoneal lavage, catheter and intravenous tubing). In yet another embodiment of the invention, the device is an intravenous needle having a polymer and a prodrug (e.g., a prodrug of an anticoagulant such as heparin or codrugs thereof) coated thereon.

As discussed above, the devices of the present invention comprise bioerodible or non-bioerodible polymers. The choice of bioerodible or non-bioerodible polymer is made based on the desired end use of the system or device. In some embodiments of the invention, the polymer is advantageously bioerodible. For example, where the system is a coating on a surgically implantable device such as a screw, stent, pacemaker, or the like, the polymer is advantageously bioerodible. Other embodiments of the invention in which the polymer is advantageously a bioerodible polymer include devices that are implantable, inhalable, or injectable suspensions or dispersions of the prodrug in the polymer, wherein no additional components (such as screws or anchors) are used.

In some embodiments of the invention where the polymer is poorly permeable and bioerodible, the rate of bioerosion of the polymer is advantageously much slower than the release rate of the drug, such that the polymer remains in place for a substantial period of time after the drug is released, but is eventually bioeroded and absorbed into the surrounding tissue. For example, where the device is a bioerodible suture comprising a drug suspended or dispersed in a bioerodible polymer, the bioerodible rate of the polymer is advantageously slow enough that the drug can be released in a linear fashion over a period of about 3 to 14 days, while the suture will last for a period of about three weeks to about six months. Similar devices of the invention include surgical staples comprising a prodrug suspended or dispersed in a bioerodible polymer.

In other embodiments of the invention, the rate of bioerosion of the polymer is advantageously in the same order as the drug release rate. For example, where the system comprises the prodrug suspended or dispersed in a polymer that is coated onto a surgical device, such as an orthopedic screw, stent, pacemaker, or non-bioerodible suture, the polymer is advantageously bioerodible at a rate that can maintain a substantially constant surface area of the prodrug in direct contact with surrounding body tissue over time.

In some embodiments of the invention, the polymer is non-bioerodible, or bioerodible only at a rate that is slower than the dissolution rate of the low solubility pharmaceutical prodrug, and the diameter of the particle is such that when the coating is applied to the stent, the surface of the particle is exposed to the diameter of the surrounding tissue. In such embodiments, the dissolution of the low solubility prodrug is proportional to the surface area exposed by the particle.

In other embodiments of the invention, the polymeric carrier is permeable to water in the surrounding tissue, such as plasma. In such cases, an aqueous solution may penetrate into the polymer, thereby contacting the low solubility pharmaceutical prodrug. The rate of dissolution can be controlled by a variety of variables such as the permeability of the polymer, the solubility of the low solubility pharmaceutical prodrug, the pH of the physiological fluid, the ionic concentration, and the protein composition, among others. However, in certain embodiments, the permeability may be adjusted such that the rate of dissolution is controlled primarily by the solubility of the low solubility pharmaceutical prodrug in the surrounding liquid phase, or in some cases almost entirely by this approach.

In some embodiments of the invention, the polymer is not bioerodible. Non-bioerodible polymers are particularly useful where the system includes a polymer to be coated onto or form a component of a surgical instrument adapted to be permanently or semi-permanently inserted or implanted into the body. Examples of devices in which the polymer advantageously forms a permanent coating on a surgical device include orthopedic screws, stents, joint prostheses, prosthetic valves, permanent sutures, pacemakers, and the like.

The surgical system of the present invention is used in a manner suitable to deliver the desired therapeutic effect. For example, in some embodiments of the invention, the mode of administration is advantageously administration by injection. In this type of case, the system is a liquid that is introduced to the desired site by drawing the system into the barrel of a syringe and injecting it through a needle to the desired site. Such administration is suitable for intramuscular injection, for example, of sustained release formulations of microbicides including antibiotics, antivirals, and steroids. This mode of administration may also be used in situations where sustained release of a hormonal agent is desired, such as thyroid drugs, pro-drugs to control fertility, estrogens for estrogen therapy, and the like. The skilled clinician will recognize that this mode of administration is suitable for a variety of therapeutic settings and will be able to tailor the drug to a particular polymer and system to achieve a desired therapeutic effect.

In embodiments of the invention where the mode of administration is by injection, the system is advantageously a relatively non-polar drug suspended or dispersed in an adhesive polymeric carrier. In such cases, the system is a stable suspension or dispersion of the non-polar drug in a liquid polymer carrier. The polymeric carrier is advantageously non-bioerodible or will be bioerodible at a rate lower than the diffusion of the drug into the surrounding tissue. In such cases, the system is left in place relative to the surrounding tissue, preventing premature release of the drug into the surrounding tissue.

In other embodiments of the invention, the system is a relatively non-polar liquid suspended or dispersed in a liquid polymer. In such cases, the system further comprises an emulsifier that can maintain the relatively non-polar drug in a stable dispersion within the polymer. The polymeric carrier is advantageously non-bioerodible or bioerodible at a rate less than the rate of drug diffusion, such that the system maintains drug localization relative to surrounding tissue throughout the period of drug release.

The exact nature of the system of the present invention will depend on the desired therapeutic application, the physical state of the drug under physiological conditions incorporated into the system, and the like.

In some embodiments of the invention, the systems of the invention are advantageously solid devices of a shape and form suitable for implantation, e.g., subcutaneous implantation, and the like. In some embodiments of the invention, the system is in the shape of an elongated ovoid, the prodrug is a non-polar drug, such as a hormone, and the polymer is a solid polymer whose permeability is such that it is not the primary rate-determining factor limiting the rate of release of the drug. In a particular embodiment of the invention, the polymer is bioerodible. In other embodiments of the invention, the polymer is non-bioerodible.

In embodiments of the invention in which the device comprises a substrate and a coating on the substrate, as in the case of screws, stents, pacemakers, joint prostheses, etc., the device is applied essentially in the manner of a surgical instrument according to the related art. For example, a device of the invention comprising a screw coated with a composition comprising a low solubility prodrug, such as antibiotic or FU-naproxen, suspended or dispersed in a polymer, is screwed into bone in the same manner as screws are used in the prior art. The screw of the present invention then provides a sustained release of the drug in a sustained manner into the tissue surrounding the device, such as muscle, bone, blood, etc., thereby providing therapeutic benefits such as antibacterial, anti-inflammatory and antiviral effects.

As used in this specification and the appended claims, "sustained release" refers to release by rate kinetics, the permeability of the polymer is not the rate limiting factor for the rate of release of the drug.

In embodiments of the invention in which the device is a surgical instrument into which a prodrug and polymer have been incorporated as part of the device, the polymer is advantageously a solid having physical properties suitable for the particular application of the device. For example, where the device is a suture, the polymer will have strength and bioerodibility suitable for the particular surgical situation. In the case where the device is a screw, stent or the like, the polymer is advantageously a rigid solid which may form at least part of the surgical instrument. In certain embodiments of the invention, as in the case where the system is part of an articular prosthesis, the polymer is advantageously non-bioerodible and remains in place after the drug has been released into the surrounding tissue. In other embodiments of the invention, such as in the case of bioerodible sutures, the polymer is bioerodible after release of substantially all of the prodrug.

While exemplary embodiments of the present invention will be described in relation to the treatment of restenosis and related complications following percutaneous transluminal (transluminal) coronary angioplasty, it is important to note that local delivery of a drug/drug combination may be used to treat a variety of conditions in which any number of medical devices are used or to enhance the function and/or longevity of the device. For example, intraocular lenses that are placed to restore vision after cataract surgery are often damaged by the formation of secondary cataracts. Secondary cataracts are often the result of excessive cell growth on the lens surface and may be minimized by using a drug or drugs in conjunction with the device. Other medical devices that are often unusable due to tissue ingrowth or accumulation of proteinaceous matter in, on and around the device, such as shunts for hydrocephalus, dialysis grafts, bag attachment devices for colostomy, ear catheters, leads for atrial pulsers and implantable defibrillators, may also benefit from the device-drug combination approach.

Devices for improving the structure and function of a tissue or organ also show beneficial conditions when used in combination with appropriate pro-or complex drugs. For example, it may be possible to improve the osseointegration of orthopedic devices for increasing the stability of implanted devices by combining them with prodrugs such as bone morphogenic proteins. Likewise, other surgical devices, sutures, staples, anastomosis devices, vertebral discs, bone screws, suture anchors, hemostatic barriers, clips, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings, bone substitutes, intraluminal devices, and vascular supports may also provide enhanced patient benefits using this drug-device combination. Indeed, any type of medical device may be coated in some manner with a prodrug or codrug that has a therapeutic effect superior to that achieved using the device or prodrug alone.

Among the drugs that may be delivered using the subject devices are, for example: antiproliferative/antimitotic prodrugs, including natural products such as vinca alkaloids (i.e., vinblastine, vincristine, and vinorelbine), paclitaxel, epidophyllotoxins (i.e., etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin, enzymes (L-asparaginase that systemically metabolizes L-asparagine and deprives the cell's ability to synthesize its own asparagine); antiplatelet prodrugs; antiproliferative/antimitotic alkylating prodrugs such as nitrogen mustards (enbisin, cyclophosphamide and the like, melphalan, chlorambucil), aziridines and methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates-busulfan, nitrosoureas (carmustine (BCNU) and the like, streptozotocin), trazenes-Dacarbazine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs, and related inhibitors (mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine cladribine); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormonal substances (i.e., estrogens); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic prodrugs (such as tissue plasminogen activators, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; an anti-transfer agent; antisecretory agents (breveldin); anti-inflammatory agents: such as adrenocorticosteroids (cortisol, cortisone, fludrocortisone, prednisone, 6U-methasone, triamcinolone, betamethasone, and dexamethasone), non-carrier prodrugs (salicylic acid derivatives, aspirin; p-aminophenol derivatives, acetominophen; indoleacetic acid and indeneacetic acid (indomethacin, sulindac, and etodolac)), heteroaryl acetic acids (tolmetin, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, aurothiomalate), immunosuppressive agents (cyclosporin, tacrolimus (FK-506), and combinations thereof, Sirolimus (rapamycin), azathioprine, mycophenolic acid mofetil); pro-drugs of angiogenic blood vessels: vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF); an angiotensin receptor blocker; a nitric oxide donor; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor signal transduction kinase inhibitors.

In certain embodiments, the prodrug is formed with an opioid. Examples of opioids include morphine derivatives such as apomorphine, buprenorphine, codeine, dihydrocodeine, dihydroetorphine, diproporphine, etorphine, hydrocodone, hydromorphone, levorphanol, meperidine, metoprolone, o-methylnaltrexone, morphine, naloxone, naltrexone, normorphine, oxycodone, and oxymorphone. In other embodiments, the opioid is a fentanyl derivative, which can be derivatized to a prodrug, such as β -hydroxy-3-methylfentanyl.

The term "low solubility" as used in reference to the low solubility pharmaceutical prodrug refers to the solubility of the pharmaceutical prodrug in biological fluids such as plasma, lymph, peritoneal fluid and the like. Low solubility generally means that the pharmaceutical prodrug is only very sparingly soluble in aqueous solutions, particularly physiological solutions such as blood, plasma, and the like, at a pH of about 5 to about 8. Some low solubility prodrugs of the invention have a solubility of less than about 1mg/ml, with a solubility of less than about 100 μ g/ml, preferably less than about 20 μ g/ml, more preferably less than about 15 μ g/ml, and more preferably less than about 10 μ g/ml. Unless otherwise specified, solubility refers to solubility in water at 25 ℃, for example as measured by the method described in 1995 USP. This includes compounds that are slightly soluble (about 10mg/ml to about 1mg/ml), very slightly soluble (about 1mg/ml to about 0.1mg/ml) and particularly insoluble or insoluble compounds (less than about 0.01 mg/ml).

Suitable prodrugs for use in the present invention include prodrugs of: immune response modifiers such as cyclosporin A and FK 506, corticosteroids such as dexamethasone and triamcinolone acetonide, angiostatic steroids such as trihydroxysteroids, antiparasitic prodrugs such as atovaquone, prodrugs for the treatment of glaucoma such as diuretic acid, antibiotics including ciprofloxacin, differentiation regulators such as retinoids (e.g., trans-retinoic acid, cis-retinoic acid, and the like), antiviral prodrugs including high molecular weight low (10-mer) antisense compounds, anticancer prodrugs such as BCNU, nonsteroidal anti-inflammatory prodrugs such as indomethacin and flurbiprofen, and prodrugs comprising conjugates of at least two compounds linked by reversible covalent or ionic bonds, wherein said bond is capable of cleavage at a desired site in the body to yield the active form of each compound. In embodiments of the invention, the prodrug is relatively insoluble in aqueous media, including physiological fluids such as serum, mucus, peritoneal fluid, limbal fluid, and the like. Also in an embodiment of the invention, suitable prodrugs include lipophilic derivatives of hydrophilic drugs which readily convert to their hydrophilic drug form under accessible physiological conditions. Reference may be made to any standard pharmaceutical textbook for obtaining a low solubility form of a drug. In this respect, the invention is particularly applicable to prodrugs which have not been widely used to date due to their inherently low solubility or which have only been of limited use in oil-based or other lipid-based delivery vehicles. In certain embodiments, the present invention provides an intraluminal medical device for implantation within a vascular lumen, particularly adjacent to a intraluminal lesion, such as an atherosclerotic lesion, to maintain patency of the lumen. The invention provides, inter alia, a radially extending expandable tubular stent having an inner luminal surface and an opposite outer surface extending along a longitudinal stent axis, the stent having a coating on at least a portion of its inner or outer surface. The local delivery of a drug combination by a stent has the following advantages; that is, recoil of the vessel is prevented and it is remodeled by the supporting action of the stent, and various factors of neointimal hyperplasia or restenosis are prevented, as well as inflammation and thrombosis are reduced. Topical administration of such drugs to a stent-fixed coronary artery also has additional therapeutic benefits. For example, higher tissue concentrations than systemic administration can be achieved using local delivery. In addition, lower systemic toxicity than systemic administration can be achieved while maintaining higher tissue concentrations using local delivery. The use of local delivery by a stent also allows for a simpler method of patient compliance than systemic administration. Another benefit of combination drug therapy is that the dosage of each therapeutic drug, prodrug or compound can be reduced, thereby limiting their toxicity, and while still reducing restenosis, inflammation and thrombosis. Thus, stent-based topical treatment is a method of improving the therapeutic ratio (efficacy/toxicity) of an anti-restenosis, anti-inflammatory, anti-thrombotic drug, prodrug or compound.

Various stents may be used after percutaneous transluminal coronary angioplasty. Although any number of stents may be used in accordance with the present invention, for simplicity, a limited number of stents will be described in the exemplary embodiments of the present invention. The skilled person will appreciate that any number of stents may be used in connection with the present invention. In addition, as described above, other medical devices may also be used.

A commonly used stent is a tubular structure that is left within the lumen to alleviate occlusion. Stents are typically inserted into a lumen in an unexpanded form and then expanded either automatically or in situ with the aid of a second device. A typical method of inflation is through the use of a catheter-loaded angioplasty balloon which is inflated within a stenotic vessel or body lumen to sever or rupture an occlusion associated with a wall component of the vessel, thereby obtaining an enlarged lumen.

The stent of the present invention can be manufactured in a number of ways. For example, the stent may be fabricated from a hollow or formed stainless steel tube that may be machined by laser, electrical stamping, chemical etching, or other means. The stent is inserted into the body and placed in an unexpanded form at the desired site. In an exemplary embodiment, the expansion within the vessel can be accomplished by a balloon catheter, wherein the final diameter of the stent is a function of the diameter of the balloon catheter used.

It will be appreciated that the stent of the present invention may be incorporated into a shape memory material comprising, for example, a suitable nickel titanium alloy or stainless steel.

The structure formed from the stainless steel tube may be a self-expanding structure formed by shaping the stainless steel tube in a predetermined manner, for example it may be twisted into a braided configuration. In such embodiments, after the stent has been formed, it may be compressed so that it occupies a space small enough to be inserted into a blood vessel or other tissue by an insertion tool, including a suitable catheter, or a flexible shaft.

Once expelled from the catheter, the stent may be expanded to a desired configuration, where the expansion may be accomplished automatically or may be initiated by pressure, temperature changes, or electrical stimulation.

Regardless of the design of the stent, it is preferred to have a combined dose of the drugs applied with sufficient properties and at sufficient concentrations to provide an effective dose at the lesion area. In this regard, the "reservoir size" in the coating is preferably a size sufficient to administer the combined dosage of the drug at the desired site and in the desired amount.

In alternative exemplary embodiments, the entire inner and outer surfaces of the stent may be coated with the drug/drug combination at therapeutic doses. However, it is important to note that the coating technique can vary depending on the drug combination. The coating technique may also vary depending on the material comprising the stent or other intraluminal medical device.

Fig. 3 and 4 depict an embodiment of an intraluminal device (stent) of the present invention.

Fig. 3 shows a side plan view of a preferred unexpanded, radially extending expandable tubular stent 13 having a surface coated with a sustained release drug delivery system. In the undeployed state, the stent 13 has its outer boundaries 14A, 14B in the radial direction, as shown in fig. 3. The luminal surface 15, the outer surface 16, or the entire surface of the stent 13 may be coated with or comprise a sustained release drug delivery system. During the vessel expansion procedure, the luminal surface 15 is in contact with body fluids, such as blood, while the outer surface 16 is in contact with tissue when the stent 13 is expanded to support and enlarge the biological vessel or duct.

In an alternative embodiment, a reinforcing wire 17, which may or may not be present, connecting two or more adjacent components or loops of the stent structure 13 may be used to lock and/or maintain the stent in its expanded state when the stent is deployed. Such reinforcing wires 17 may be made of nitinol or other high strength material. A nitinol device is known to have a pre-formed shape and a transition temperature at which the nitinol device can return to its pre-determined shape. One method of treating the intraluminal tissue of a patient with a surface coated stent 13 of the present invention includes folding a radially expandable tubular stent and withdrawing the folded stent from the patient. Folding of the radially expandable tubular stent may be accomplished by raising the temperature to cause the reinforcement wire 17 to invert to its straightened state or other suitable state to cause folding of the stent 13 to remove the stent from the patient.

Fig. 4 shows an overall view of a radially extending expandable tubular stent in a deployed state with a sustained release drug delivery system coating the stent surface. As shown in fig. 4, the stent 13 in the expanded state has outer boundaries 24A, 24B in the radial direction. The luminal surface 14, the outer surface 16 or the entire surface of the stent 13 may be coated with or may contain the sustained release drug delivery system. During the vessel expansion procedure, its luminal surface 15 is in contact with body fluids such as blood, and its outer surface 16 is in contact with tissue when the stent 13 is expanded to support and expand the physiological vessel. The reinforcing wire 17 may be used to maintain the expanded stent in its expanded state, either as a permanent stent or a temporary stent. In the case of a stent 13 coated as a surface of a temporary stent, the reinforcing wire 17 may have the ability to fold the expanded stent.

Expansion of the stent may be accomplished by a balloon on the delivery catheter or by automatic expansion as the pre-stressed stent is released from the delivery vessel. Delivery catheters and methods for expansion of stents are well known to those skilled in the art. The expandable stent 13 may be an automatically expandable stent, a balloon-expandable stent, or an expandable-retractable stent.

The expandable stent may be comprised of a memory coil, mesh material, or the like.

III. Examples

The present invention may be more fully understood by reference to the following examples.

Prodrug TC-112 comprising a conjugate of 5-fluorouracil and naproxen linked by a reversible covalent bond and prodrug g.531.1 comprising a conjugate of 5-fluorouracil and fluocinolone were prepared according to the method described in US 6,051,576. The structures of these compounds were replicated as follows:

5-Fluorouracil (5-FU)

Naproxen

The following examples are illustrative of the invention disclosed. This example is not intended to be limiting and the skilled artisan will recognize that other embodiments are within the scope of the disclosed invention.

Example 1

80.5mg of prodrug TC-112 was dispersed into 20gm of a 10% (w/v) aqueous poly (vinyl alcohol) (PVA) solution. 5 glass sheets were then dip coated with this TC-112/PVA suspension and then air dried. The coating and air drying was then repeated four more times. At the end, about 100mg of TC-112/PVA was coated onto each glass slide. The coated glass sheet was then heat treated at 135 ℃ for 5 hours. After cooling to room temperature, the glass slides were placed in 20ml of 0.1M mol phosphate buffer (pH7.4, 37 ℃) for the release test. Samples were taken daily and the entire sustained release medium was replaced with fresh medium at each sampling. Drug release into the medium and TC-112 were determined by reverse phase HPLC. The half-life of TC-112 was 456 minutes in pH7.4 buffer and 14 minutes in serum.

The results are shown in FIG. 1, which shows the total cumulative release of TC-112 from PVA-coated glass sheets. The slope of the curve indicates a release of TC-112 of 10 μ g/day. The data indicates both the complete form and the composition of compound TC-112.

Example 2

12.0gm of siloxane fraction A (Med-6810A) was mixed with 1.2gm of siloxane fraction B (Med-6810B), degassed in a sonicator for 10 minutes, and then treated with a water pump. 41.2mg (TC-112) were dispersed in this degassed siloxane and degassed. 0.2gm of this mixture was coated on one surface of the glass sheet. The glass sheets (5 total sheets) were then placed in an oven and heated at 105 ℃ for 20 minutes to cure. After removing it from the oven and cooling to room temperature, 0.2gm of this mixture was coated on the other uncoated surface of each glass sheet. The coated glass sheet was then heat treated again at 105 ℃ for 20 minutes. After cooling to room temperature, the individual glass slides were placed in 20ml of 0.1M phosphate buffer (pH7.4, 37 ℃) for the release test. Samples were taken daily and the entire sustained release medium was replaced with fresh medium at each sampling time. Drug release into the medium (5FU and TA) and TC-112 was determined by HPLC.

The total TC-112 release of the silicone coating was calculated as follows. Naproxen has a molecular weight of 230.3, 5-fluorouracil has a molecular weight of 130.1, while the compound of the invention (TC-112) derived from both drugs has a molecular weight of 372.4. For naproxen xmg to be detected, this means that x 372.4/230.3mg of TC-112 was hydrolysed. The total TC-112 released is equal to the sum of the TC-112 detected in the release medium and the hydrolyzed TC-112. For example, up to day 6, 43.9mg naproxen was detected, which means 71.0(43.9 × 372.4/230.3) mg TC-112 was hydrolyzed, while 51.4mg TC-112 was detected in the buffer, so a total of 112.4mg (51.4 plus 71.0) TC-112 was released up to day 6.

The results are shown in FIG. 2, which shows the total cumulative release of TC-112 from the silicone-coated glass sheet. The slope of the curve indicates that the release of TC-112 was 13.3 μ g/day. This data, in turn, represents the complete compounds of the invention and components of the compounds of the invention. The similarity of the slopes demonstrates that the polymer has little effect on the release of the drug.

Example 3

A mixture of 3.3gm Chronoflex C (65D) (Lot # CTB-G25B-1234) dispersion containing 0.3gm Chronoflex C (65D) and 2.2gm Chronoflex C (55D) (Lot # CTB-121B-1265) dispersion containing 0.2gm Chronoflex C (55D), both in Dimethylacetamide (DMAC) (1: 10, w/w) was prepared by mixing the two dispersions together. To this mixture was added 6.0gm tetrahydrofuran (HPLC grade) and mixed. The final mixture was not a clear solution. Then, 101.5mg of a composite drug of 5-fluorouracil (5FU) and Triamcinolone Acetonide (TA) (the composite drug is defined as "TC-32") was added thereto and dissolved in the polymer solution.

Ten (10) HPLC inserts were then coated with the polymer/TC-32 solution by dipping and then air dried at ambient temperature. The coating and air drying process was repeated four (4) times (a total of 5) until a total of about 10mg of polymer/TC-32 was applied to each insert. The insert was then placed in an oven at 80 ℃ for 2 hours to remove residual solvent.

The inserts were placed in 20ml of 0.1m phosphate buffer, pH7.4, respectively, in glass tubes and the release of compound from the inserts was monitored initially at 37 ℃. Samples were taken daily and the entire media was replaced with fresh media at each sampling time. HPLC was used to determine the drug released into the medium. Since TC-32 has a short half-life in buffer, no TC-32 is detected in the release medium; only a certain number of parent drugs, 5-FU and TA could be detected. The release profile is shown in figure 7.

Example 4

To 5.0gm of stirred Dimethylacetamide (DMAC) were added 300mg of Chronof1ex C (65D) (Lot # CTB-G25B-1234) and 200mg of Chronoflex C (55D) (Lot # CTB-121B-1265). The polymer was slowly dissolved in DMAC (about 4 hours). Then 5.0gm THF was added to the polymer dispersion. The mixture was not a clear solution. 100.9mg of TC-32 was then added thereto and dissolved in the mixture.

Three (3) stents supplied by Guidant Corp were then coated with the polymer/TC-32 solution by dipping and then allowed to air dry at ambient temperature. The coating and air drying process was repeated several times until a total of about 2.0mg of polymer/TC-32 was applied to the stent. The coated stent was air dried overnight at ambient temperature in a biologically safe chamber. The stent was then dried under vacuum at 80 ℃ for 2 hours to remove residual solvent. They were then placed in 5.0ml of 0.1m phosphate buffer, pH7.4, respectively, in a glass tube and the release of the compound from the stent was monitored initially at 37 ℃. Samples were taken daily and the entire media was replaced with fresh media at each sampling. Drug release in the medium was measured by HPLC. The release profile is shown in figure 8. No TC-32 was detected in the release medium.

Example 5

The Polyurethane (PU) was first dissolved in tetrahydrofuran. The biologically reversible conjugate of 5-FU and TA is dissolved in this solution and the resulting solution is sprayed onto a coronal Tetra stent made by Guidant. After air drying, the stent was dried under vacuum at 50 ℃ for 2 hours to remove solvent residues, and then subjected to plasma treatment and gamma-irradiation. Two different levels of drug loading were applied to the stent: 80ug low dose (13%) and 600ug high dose (60%). The release rate was determined in vitro by placing the coated stent (expanded) in 0.1M phosphate buffer (pH 7.4) at 37 ℃. Samples were taken from the buffer periodically for HPLC analysis and the buffer was replaced to avoid any saturation effects.

The results shown in fig. 9 illustrate the in vitro release pattern of a high dose coated stent. This pattern followed a pseudo-logarithmic pattern, releasing about 70% in 10 weeks. Similar patterns were observed in stents loaded with both high and low doses. TA and 5-FU were released in an equimolar manner at all times during the experiment. No 5-FU/TA complex drug was detected in the release medium.

Example 6

Polyurethane (1.008gm) was added to 50.0gm Tetrahydrofuran (THF). The mixture was stirred overnight to dissolve the polymer. 5.0gm of the polymer solution was diluted with 10.0g of mTHF. To the polymer solution, 150.2mg of a complex drug of 5-fluorouracil (5FU) and Triamcinolone Acetonide (TA) (the complex drug is defined as "TC-32") was added and dissolved. The coating solution was prepared with a 60% loading of the complex drug. Coating solutions loaded with 13% codrug were also prepared. The bare stent (Tetra, Guidant, Lot # 1092154, 13mm Tetra) was washed with isopropanol, air-dried, and then sprayed with the coating solution by using a precision spray gun. The coating was repeated until a total of about 1.0mg of coating was applied to each stent. The coated stent was dried under vacuum at 50 ℃ for 2 hours to remove solvent residues, and then subjected to plasma treatment and gamma-irradiation.

The composite drug-coated stent was tested in two groups. The stents of group one were each placed in a glass tube containing 5.0ml of 0.1M phosphate buffer (pH 7.4). Samples were taken periodically and the concentration of the complexed drug in the buffer was checked by HPLC. The entire release medium was replaced after each sampling.

The stents of group two were placed in the body. On study day 1, TC-32 coated stents were implanted into the Left Anterior Descending (LAD) coronary artery of three pigs. The stents were collected on study day 5 and placed in 0.1M phosphate buffer as described for set one stent. The amount of each drug released into the matrix was measured by HPLC. The intact codrug is not detectable in the release medium.

The results are shown in FIG. 10, which shows a comparison of drug release profiles between expanded and unimplanted stents. The release pattern of the expanded and pre-implanted stent both indicate that in vivo release can be predicted by in vitro release patterns.

Example 7

Fourteen (14) pigs received three (3) stents expanded to the maximum in any of the three epicardial coronary arteries (LAD, LCX and RCA). Control stents were used alone in some animals, including uncoated Bare Metal coronary stents on Cross Sail Rx capsule delivery system (control) or PU coated coronary stents on Cross Sail Rx capsule delivery system (control). Stents coated with drug at low doses ((80. mu.g TA +5FU (13%))) or high doses (600. mu.g TA +5FU (60%)) were used in other animals. The stent is implanted into an artery of an animal. Each stent is delivered to a desired site in the artery and expanded with an expansion device. The pressure of the expansion device is selected to obtain a balloon having an arterial ratio of 1.1-1.2: 1.

After 28 days, the portion of the artery immediately adjacent to the stent was surgically removed and embedded in a methacrylate resin. Histologically 5- μm sections were excised and stained with vilkhovi elastin and hematoxylin and eosin stains, and the thickness of each excised section was measured. The results for the high and low dose drug coated stents are listed in the table below. The responses at day 28 of the low and high dose experimental groups showed a significant reduction in intimal thickness due to co-release of TA and 5FU from the polymer coated Tetra stent.

ζ p ═ 0.0008, uncoated metal vs low dose, p ═ 0.03 polymer vs low dose

P-0.002 Low dose of uncoated Metal pairs, p-0.04 Polymer pairs

Zeta p 0.02 high dose of unpainted metal pairs and p 0.07 high dose of polymer pairs

High dose of unpainted metal pair, high dose of p-0.07 polymer pair

Example 8

Fig. 11A and 11B show the effect of gamma irradiation and plasma treatment on drug release. After plasma treatment and gamma irradiation, the stent was expanded with an expansion catheter (3.0mm balloon size, 20mm length) and placed individually into glass tubes containing 5.0ml of 0.1M phosphate buffer (pH 7.4). Samples were taken periodically and the entire release medium was replaced after each sample. The amount of each drug released into the medium was measured by HPLC. No intact codrug was detected in the release medium.

Example 9:coating example A

1.0gm of EMM (poly (ethyl acrylate and methyl methacrylate) copolymer) obtained by evaporation and air drying of an aqueous dispersion of Eudragit NE30D was added to 9.0gm of acetone. To this dispersion, 51.5mg of a drug complex of 5-fluorouracil and fluocinolone (G.531.1) was added and dissolved after stirring. 10 HPLC inserts were coated with the codrug/copolymer by dipping it in the codrug/polymer solution followed by air drying. This coating process was repeated several times until approximately 30mg of the codrug/polymer was coated on each glass tube. The coated inserts were then each placed in 10.0ml of 0.1M phosphate buffer (pH7.4, 37 ℃) for release testing. Samples were taken daily and the entire release medium was replaced with fresh medium at each sampling. Drug release into the medium and drug complex were measured by HPLC.

Example 10:coating example B

441.8mg of poly (ethylene-co-vinyl acetate) (EVA) were weighed out and transferred into 15.0m1 THF. EVA swelled slowly and was then partially dissolved in THF by ultrasonic and magnetic stirring. 88.2mg of the codrug (TC32) was added thereto and dissolved in the polymer solution. The 9 HPLC inserts were then coated with the polymer/codrug solution by dipping and then air dried at ambient temperature. This coating and air drying was repeated several times until a total of about 10mg of polymer/codrug was applied to each insert. The insert was then placed in an oven at 50 ℃ for 1 hour to remove the residue of the solvent. The weight and diameter of the insert were checked and recorded before and after coating was completed. Then, the coated inserts were placed in 10.0ml of 0.1M phosphate buffer (pH7.4, 37 ℃) for release test. Samples were taken daily and the entire release medium was replaced with fresh medium at each sampling. Drug release into the medium and drug complex were measured by HPLC.

The above description and examples are intended to be illustrative of some embodiments of the invention and are not intended to be limiting in any way. It will be apparent to those skilled in the art that various modifications and variations can be made in the system, apparatus and method of the present invention without departing from the spirit or scope of the invention. All patents and publications cited herein are incorporated by reference in their entirety.

Claims (66)

1. A sustained release formulation comprising a polymer matrix and a prodrug of the formula A-L-B dispersed in the polymer, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and

b represents a moiety which when attached to A results in a prodrug having a lower solubility than the therapeutically active form of A;

wherein the therapeutically active form of A has a solubility in water higher than 1mg/ml and the prodrug has a solubility in water lower than 1 mg/ml.

2. A sustained release formulation comprising a polymer matrix and a prodrug having the general formula A: B dispersed in the polymer, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

the: represents the ionic bond between a and B which dissociates under physiological conditions to produce said therapeutically active form of a;

b represents a moiety which when ionically bonded to A results in a prodrug having a lower solubility than the therapeutically active form of A; and

wherein the therapeutically active form of A has a solubility in water higher than 1mg/ml and the prodrug has a solubility in water lower than 1 mg/ml.

3. A sustained release formulation comprising a polymer matrix and a prodrug of the formula A-L-B dispersed in the polymer, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and

b represents a moiety which when attached to A results in a prodrug having a lower solubility than the therapeutically active form of A;

wherein, when disposed in a biological fluid, the sustained release formulation provides sustained release of the therapeutically active form of A for a period of at least 24 hours, and during the release the prodrug is present in the fluid outside the polymer at a concentration of less than 10% of the concentration of the therapeutically active form of A.

4. A sustained release formulation comprising a polymer matrix and a prodrug having the general formula A: B dispersed in the polymer, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

the: represents the ionic bond between a and B which dissociates under physiological conditions to produce said therapeutically active form of a;

b represents a moiety which when bonded to the A ion results in a prodrug having a lower solubility than the therapeutically active form of A; and

wherein, when disposed in a biological fluid, the sustained release formulation provides sustained release of the therapeutically active form of a for a period of at least 24 hours, and the prodrug, during the release, is present in the fluid outside the polymer at a concentration of less than 10% of the concentration of the therapeutically active form of a.

5. A sustained release formulation comprising a polymer matrix and a prodrug of the formula A-L-B dispersed in the polymer, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and

b represents a moiety which when linked to A results in a prodrug having a lower solubility than the therapeutically active form of A;

wherein the therapeutically active form of a has a logP value which is at least 1 logP unit lower than the logP value of the prodrug.

6. A sustained release formulation comprising a polymer matrix and a prodrug of the general formula A: B dispersed in the polymer, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

the: represents the ionic bond between a and B which dissociates under physiological conditions to produce said therapeutically active form of a;

b represents a moiety which when bonded to the A ion results in a prodrug having a lower solubility than the therapeutically active form of A; and

wherein the therapeutically active form of a has a logP value which is at least 1 logP unit lower than the logP value of the prodrug.

7. A sustained release formulation as claimed in claim 1 or claim 2 wherein the prodrug has a solubility in water of less than 100 μ g/ml.

8. The sustained release formulation of any one of claims 1-6 wherein B is a hydrophobic aliphatic moiety.

9. The sustained-release formulation according to any one of claims 1 to 6, wherein B is a drug moiety having a therapeutically active form produced upon cleavage of the linker L or dissociation of the ionic bond.

10. The extended release formulation of claim 9, wherein a and B are the same drug moiety.

11. The extended release formulation of claim 9, wherein a and B are different drug moieties.

12. The sustained release formulation of any one of claims 1-6 wherein B is a biologically inert moiety after cleavage from the prodrug.

13. The sustained-release preparation according to any one of claims 1 to 6, wherein A is selected from the group consisting of an immune response modifier, an antiproliferative agent, a corticosteroid, a vasopressor steroid, an antiparasitic agent, a drug for the treatment of glaucoma, an antibiotic, an antisense compound, a differentiation regulator, an antiviral agent, an anticancer agent, and a non-steroidal anti-inflammatory agent.

14. The sustained release formulation of claim 9 wherein B is selected from the group consisting of immune response modifiers, antiproliferative agents, corticosteroids, angiostatic steroids, antiparasitic agents, drugs for the treatment of glaucoma, antibiotics, antisense compounds, differentiation modulators, antiviral agents, anticancer agents, and non-steroidal anti-inflammatory agents.

15. The extended release formulation of any one of claims 1-6, wherein the therapeutically active form of A is released from the polymer matrix for a duration of at least 24 hours.

16. The sustained release formulation of claim 9 wherein a is 5-fluorouracil (5FU) and B is naproxen.

17. An extended release formulation as claimed in any one of claims 1 to 6 or claim 9 wherein at least one of a or B is an anti-tumour agent.

18. The sustained-release formulation of claim 17, wherein the anti-neoplastic agent is selected from the group consisting of anthracyclines, vinca alkaloids, purine analogs, pyrimidine analogs, inhibitors of pyrimidine biosynthesis, and alkylating agents.

19. The sustained release formulation of claim 17, wherein the anti-neoplastic agent is a fluorinated pyrimidine.

20. The sustained-release formulation according to claim 17, wherein the antitumor agent is selected from the group consisting of 5-fluorouracil (5FU), 5 '-deoxy-5-fluorouridine, 2' -deoxy-5-fluorouridine, fluorocytosine, 5-trifluoromethyl-2 '-deoxyuridine, arabinoxycytosine, cyclocytidine, 5-aza-2' -deoxycytidine, arabinosyl 5-azacytosine, 6-azacytidine, N-phosphonoacetyl-L-aspartic acid, pyrazolofuranidin, 6-azauridine, azalipine, and 3-deazauridine.

21. The sustained-release formulation of claim 17, wherein the antitumor agent is a pyrimidine nucleoside analog selected from the group consisting of arabinosyl cytosine, cyclocytidine, 5-aza-2' -deoxycytidine, arabinosyl 5-azacytosine, and 6-azacytidine.

22. The sustained-release formulation according to claim 17, wherein the antitumor agent is selected from the group consisting of cladribine, 6-mercaptopurine, pentostatin, 6-thioguanine, and fludarabine phosphate.

23. A sustained release formulation as claimed in any one of claims 1 to 6 wherein the therapeutically active form of A is 5-fluorouracil.

24. The extended release formulation of any one of claims 1-6 or claim 9, wherein at least one of a or B is an anti-inflammatory agent.

25. The extended release formulation of claim 24, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent.

26. The sustained release formulation of claim 25 wherein the anti-inflammatory agent is selected from diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, nahumstone, naproxen, and piroxicam.

27. The extended release formulation of claim 24, wherein the anti-inflammatory agent is a glucocorticoid.

28. The sustained release formulation of claim 27 wherein the glucocorticoid is selected from the group consisting of aclometasone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, cortisone, dinaphthide, desoximetasone, diflorasone, flumethasone, flunisolide, fluocinolone, fluprednide, fluocinolone, fluticasone, hydrocortisone, methylprednisolone acetate, mometasone furoate, prednisolone, prednisone, and rofleponide.

29. The sustained release formulation of claim 9 wherein the therapeutically active form of B is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, diclofenac, and naproxen.

30. The sustained release formulation of claim 1, wherein the linker L is hydrolyzed in body fluids.

31. The sustained release formulation of claim 1 wherein the linkage L comprises one or more hydrolyzable groups selected from the group consisting of ester, amide, carbamate, carbonate, cyclic ketal, thioester, thioamide, thiocarbamate, thiocarbonate, xanthate, and phosphate.

32. The sustained release formulation of claim 1, wherein the linkage L is enzymatically cleaved.

33. The sustained release formulation of claim 1 wherein the prodrug, in its linked form, produces the ED of the clinical response₅₀ED than therapeutically active form of A₅₀At least 10 times higher.

34. The extended release formulation of claim 1, wherein the prodrug, in its linked form, has an ED that is greater than the therapeutically active form of a₅₀At least 1000 times higher ED producing said clinical response₅₀。

35. The extended release formulation of claim 1, wherein the therapeutically active form of a has a solubility in water that is at least 10 times greater than the prodrug.

36. The extended release formulation of claim 29, wherein the prodrug is selected from the group consisting of 5FU covalently bound to fluocinolone, 5FU covalently bound to naproxen, and 5FU covalently bound to sodium diclofenac.

37. The sustained-release formulation according to claim 9, wherein the prodrug is selected from the group consisting of ciprofloxacin-diclofenac (VI) and ciprofloxacin-naproxen,

ciprofloxacin-Dichlorophenolic acid

(VI)

38. The sustained release formulation of any one of claims 1-6 wherein the polymer is non-bioerodible.

39. The extended release formulation of claim 38, wherein the non-bioerodible polymer is selected from the group consisting of polyurethanes, polysiloxanes, poly (ethylene-co-vinyl acetate), polyvinyl alcohol, and derivatives and copolymers thereof.

40. The sustained release formulation of any one of claims 1-6 wherein the polymer is bioerodible.

41. The sustained release formulation of claim 40 wherein the bioerodible polymer is selected from the group consisting of polyanhydrides, polylactic acids, polyglycolic acids, polyorthoesters, polyalkylcyanoacrylates, and derivatives and copolymers thereof.

42. The sustained release formulation of any one of claims 1-6 wherein the polymer retains the prodrug at a specific physiological site and prevents decomposition of the prodrug.

43. The sustained release formulation of any one of claims 1-6 wherein the polymer reduces the interaction between the prodrug in the polymer and the protein component in the surrounding bath fluid.

44. The sustained release formulation of any one of claims 1-6 wherein the system is adapted to be injected or implanted into the body.

45. A medical device, comprising:

(i) a substrate having a surface; and the combination of (a) and (b),

(ii) a coating adhered to the surface, said coating comprising a polymer matrix having dispersed therein a low solubility prodrug, wherein said low solubility prodrug is represented by the formula a-L-B, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and

b represents a moiety which, when attached to a, results in a prodrug having a lower solubility than the therapeutically active form of a.

46. The device of claim 45, wherein the polymer matrix is not substantially a release rate limiting factor with respect to the release rate of the therapeutically active form of A from the coating.

47. The device of claim 45, wherein the substrate is a surgical instrument selected from the group consisting of a screw, a plate, a pad, a suture, a prosthetic anchor, a tack, a staple, an electrical lead, a valve, and a membrane.

48. The device of claim 45, selected from the group consisting of a catheter, an implantable vascular access port, a blood reservoir bag, a blood conduit, a central venous catheter, an arterial catheter, a vascular graft, an intra-aortic balloon pump, a heart valve, a cardiovascular suture, an artificial heart, a pacemaker, a ventricular assist pump, an extracorporeal device, a blood filter, a hemodialysis device, a blood perfusion device, a plasmapheresis device, and a filter adapted to be deployed within a blood vessel.

49. The device of claim 45 which is a vascular stent.

50. The apparatus of claim 49, wherein an expandable stent is provided thereon, and wherein the coating is flexible to accommodate compressed and expanded states of the expandable stent.

51. The device of claim 45, wherein the weight of the coating attributable to the prodrug is per cm²From about 0.05mg to about 50mg of prodrug on a surface coated with said polymer matrix.

52. The device of claim 45, wherein said coating has a thickness of 5 microns to 100 microns.

53. The device of claim 45, wherein the prodrug is present in an amount of 5% to 70% by weight of the coating.

54. A coated device assembly comprising a medical device for implantation in a patient, said medical device having one or more surfaces coated with a polymer formulation according to any one of claims 1 to 6 in a manner such that the coated surfaces release the therapeutically active form of A over a period of time when implanted in the patient.

55. The coated device of claim 54, wherein the device is a radially extending expandable tubular stent having an inner luminal surface and an opposite outer surface extending along a longitudinal stent axis.

56. A stent having at least one portion insertable or implantable into a patient, wherein the portion has a surface adapted to contact body tissue and wherein at least a portion of the surface is coated with a coating for the release of at least one biologically active substance, the coating comprising a polymer matrix having dispersed therein a low solubility prodrug, wherein the low solubility prodrug is represented by the formula A-L-B, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and

b represents a moiety which, when attached to a, results in a prodrug having a lower solubility than the therapeutically active form of a.

57. An intraluminal medical device coated with a sustained release system comprising a biologically tolerable polymer and a low solubility prodrug dispersed in the polymer, said device having an inner surface and an outer surface; the device has the system applied to at least a portion of the inner surface, the outer surface, or both.

58. A method for treating intraluminal tissue of a patient, the method comprising the steps of:

(a) providing a stent having an inner surface and an outer surface, said stent having a coating on at least a portion of the inner surface, the outer surface, or both the inner surface and the outer surface; said coating comprising a prodrug of a low solubility drug dissolved or dispersed in a biologically tolerable polymer;

(b) positioning the stent at a tissue site within the appropriate lumen; and

(c) the stent is expanded.

59. A coating composition for localized delivery of a drug from a surface of a medical device to the body, the composition comprising a polymer matrix having dispersed therein a low solubility prodrug, wherein the low solubility prodrug is represented by the formula A-L-B, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A; and

b represents a moiety which when attached to A results in a prodrug having a lower solubility than the therapeutically active form of A;

the coating composition is provided in the form of a liquid or suspension suitable for application to the surface of the medical device by spraying and/or dipping the device in the composition.

60. A coating composition for localized delivery of a drug from a surface of a medical device to the body, the composition comprising a polymer matrix having dispersed therein a low solubility prodrug, wherein the low solubility prodrug is represented by the formula A-L-B, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A;

b represents a moiety which when attached to A results in a prodrug having a lower solubility than the therapeutically active form of A;

the coating composition is provided in powder form and, upon addition of a solvent, may be reconstituted into a liquid or suspension form for application to the surface of the medical device by spraying and/or dipping the device into the composition.

61. An injectable composition for delivering a drug to a patient, the composition comprising a polymer matrix having dispersed therein a low solubility prodrug, wherein the low solubility prodrug is represented by the formula a-L-B, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A;

b represents a moiety which when attached to A results in a prodrug having a lower solubility than the therapeutically active form of A;

the composition is provided in the form of a liquid or suspension suitable for delivery by needle injection.

62. A method of making a sustained release system comprising mixing a polymer matrix with a therapeutically effective amount of a low solubility prodrug, wherein

(i) Said low solubility prodrug is represented by the general formula A-L-B, wherein

A represents a drug moiety having a therapeutically active form that produces a clinical response in a patient;

l represents a covalent linker linking A and B to form a prodrug, said linker being cleaved under physiological conditions to yield said therapeutically active form of A;

b represents a moiety which when attached to A results in a prodrug having a lower solubility than the therapeutically active form of A; and

(ii) the polymer matrix is permeable to the therapeutically active form of a and is not substantially a limiting factor for the release rate of the therapeutically active form of a from the polymer matrix.

63. The method of claim 62, further comprising the step of applying the mixture of polymer matrix and prodrug to a surgical device surface.

64. A method of treating a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect, comprising: administering to a mammal a therapeutically effective amount of a sustained release formulation according to any one of claims 1-6.

65. Use of a sustained release system according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a patient with a sustained dosage regimen of a therapeutically active form of a.

66. A sustained release formulation as claimed in claim 5 or 6 wherein the therapeutically active form of A has a logP value which is at least 2 logP units lower than the logP value of the prodrug.