HK1178050A - Implant devices for modulating bioactive agent release profiles - Google Patents

Abstract

Described herein are implant devices comprising at least one exposed biodegradable inner core surface, the inner core being surrounding partially by a membrane sheath which comprises a biocompatible polymer. A bioactive agent can be released from the inner core.

Description

Implant device for modulating bioactive agent release characteristics

Cross Reference to Related Applications

This application is based on and claims priority rights to prior U.S. provisional application No. 61/244,726 filed on 9/22, 2009 and prior U.S. provisional application No. 61/375,143 filed on 8/19, 2010, each of which is incorporated herein by reference in its entirety.

Background

In the field of pharmaceutical formulations, there is a class of drug delivery formulations designed to release a biologically active agent for a desired period of time after a single administration. Depot formulations are one name used to describe these depot formulations. Depot formulations can be manufactured in a number of ways. A typical formulation method for preparing a depot or implant is by making a solid matrix comprising the bioactive agent and a polymeric excipient. The purpose of the polymer excipient of the implant is to limit the influx of water, which in turn controls the dissolution of the bioactive agent, followed by the release of the bioactive agent from the implant matrix. In addition to the physical and chemical properties of the bioactive agent, the amount of bioactive agent in the implant affects the rate of release of the bioactive agent. That is, increasing the amount of bioactive agent will increase the rate of release. Unfortunately, some implant formulations require high amounts of bioactive agent therein so that sufficient bioactive agent can be utilized to obtain the required dosage and duration for a particular medical indication. However, the high amount of bioactive agent incorporated in the implant may result in the release of the bioactive agent too quickly or even at an uncontrolled rate.

As such, there is a need for new implant devices that can be loaded with high amounts of bioactive agents while still maintaining a satisfactory release, such as an extended release profile (releaseprofiler) or a release profile with a low initial burst, among others. The present invention fulfills these needs and others.

Disclosure of Invention

Described herein are implant devices that can be used to release bioactive agents. In one aspect, an implant device is disclosed that includes an inner core having a surface surrounded by a membrane sheath and having an exposed surface not surrounded by the membrane sheath; wherein the inner core comprises a biodegradable polymer having a bioactive agent dissolved or dispersed therein; wherein the membrane sheath comprises a biocompatible polymer and is substantially free of the bioactive agent; and wherein the exposed surface has a surface morphology formed by fluid treatment of the exposed surface.

In a further aspect, an implant device includes an inner core having a longitudinal surface surrounded by a membrane sheath and having exposed proximal and distal surfaces not surrounded by the membrane sheath; wherein the inner core comprises a biodegradable polymer having a bioactive agent dissolved or dispersed therein; wherein the membrane sheath comprises a biocompatible polymer and is substantially free of the bioactive agent; and wherein at least one of the exposed proximal or distal surfaces has a surface morphology formed by fluid treatment of the exposed proximal or distal surfaces.

In a further aspect, an implant device is prepared by a method comprising: a. forming a core having a desired shape from a mixture of a biodegradable polymer and a bioactive agent; b. forming a membrane sheath around the core; c. removing at least a portion of the membrane sheath to provide an exposed core surface not surrounded by the membrane sheath; contacting the exposed core surface with a sufficient amount of fluid for a sufficient time to alter the surface morphology of the exposed core surface.

In a further aspect, an implant device is prepared by a method comprising: a. forming a core having a desired shape from a mixture of a biodegradable polymer and a bioactive agent; b. forming a membrane sheath around only a portion of the core, such that the core comprises an exposed surface after forming the membrane sheath; c. contacting the exposed core surface with a sufficient amount of fluid for a sufficient time to change the surface morphology of the exposed core surface.

In a further aspect, an implant device is prepared by a method comprising: a. extruding a mixture of a biodegradable polymer and a bioactive agent through an internal coaxial nozzle to form a core; b. forming a composite strip by simultaneously co-extruding a biocompatible polymer through an outer coaxial nozzle to apply a membrane sheath substantially coextensive around the core; c. cutting the composite strip of step (b) into one or more slats (slat) comprising one longitudinal surface and two end surfaces; contacting at least one end surface of the one or more splines from step (c) with a sufficient amount of fluid for a sufficient time to alter the surface morphology of the at least one end surface, thereby providing the implant device.

The benefits of the present invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The benefits of the following description will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

The sheath may also contain a suspending or dissolving amount of a bioactive agent (which may be the same or different from the bioactive agent in the core). Likewise, the sheath can comprise other additives disclosed herein, such as pharmaceutical additives, excipients, viscosity modifiers, and the like.

Brief Description of Drawings

Fig. 1 is an isometric cross-sectional view of an exemplary implant device having a core surrounded by a membrane housing.

FIG. 2 is a top cross-sectional view of a co-extrusion apparatus that may be used to manufacture an implant device having a core surrounded by a membrane housing.

Detailed description of the invention

Before the present compounds, compositions, composites, articles, devices, and/or methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific compounds, compositions, composites, articles, devices, methods, or uses, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:

throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a biologically active agent" includes mixtures of two or more such agents, and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

Unless specifically indicated to the contrary, the weight percentages of a component are based on the total weight of the formulation or composition in which the component is included.

"releasable agent" refers to an agent that can be mixed with the disclosed polymer and subsequently released therefrom, for example, when the polymer erodes.

"bioactive agent" refers to an agent having biological activity. Biological agents can be used to treat, diagnose, cure, alleviate, prevent (i.e., prophylactically), ameliorate, modulate, or have other beneficial effects on diseases, conditions, infections, and the like. A "releasable bioactive agent" is a bioactive agent that can be released from the disclosed device. Bioactive agents also include those substances that affect the structure or function of a subject, or prodrugs that become bioactive or more bioactive after being placed in a predetermined physiological environment.

The term "implant device" refers to any item that is greater than 1mm in length in at least one dimension (one dimension) of the device. In a further aspect, the device has one dimension from 1mm to 50mm, 1.2mm to 45mm, 1.4mm to 42mm, 1.6mm to 40mm, 1.8mm to 38mm or 2.0mm to 36mm, 5.0mm to 33mm or 10mm to 30 mm. In a further aspect, the device has one dimension greater than 3cm, even up to or greater than 10cm, 20cm, or even 30 cm.

Disclosed are compounds, compositions, and components useful for, in conjunction with, useful in the preparation of, or as a product of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a number of different polymers and agents are disclosed and discussed, unless specifically indicated to the contrary, each and every combination and permutation of the polymers and agents are specifically contemplated. Thus, if a class of molecules A, B and C is disclosed as well as a class of molecules D, E and F and one example of a combination molecule a-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. As such, in this example, combinations of each of a-E, A-F, B-D, B-E, B-F, C-D, C-E and C-F are specifically contemplated and should be considered from A, B and C; D. e and F; and example combinations A-D. Similarly, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the subgroups of A-E, B-F and C-E are specifically contemplated and should be considered to be from A, B and C; D. e and F; and example combinations A-D. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. As such, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

In one aspect, the implant device of the present invention comprises an inner core having a surface surrounded by a membrane sheath and having an exposed surface not surrounded by the membrane sheath; wherein the inner core comprises a biodegradable polymer having a bioactive agent dissolved or dispersed therein; wherein the membrane sheath comprises a biocompatible polymer and is substantially free of the bioactive agent; and wherein the exposed surface has a surface morphology formed by fluid treatment of the exposed surface. Such implant devices may have a variety of shapes, such as a rod, fiber, disc, sheet, bead, ribbon, or cylinder.

Two or more exposed surfaces can be treated with the disclosed fluid treatment, wherein the fluid comprises a coating polymer, as discussed further herein. For example, one implant end may be treated with a rapidly degrading polymer while a second implant end may be treated with a slower degrading polymer to achieve biphasic degradation and exposure of the different ends.

In a further aspect, an implant device includes an inner core having a longitudinal surface surrounded by a membrane sheath and having exposed proximal and distal surfaces not surrounded by the membrane sheath; wherein the inner core comprises a biodegradable polymer having a bioactive agent dissolved or dispersed therein; wherein the membrane sheath comprises a biocompatible polymer and is substantially free of the bioactive agent; and wherein at least one of the exposed proximal or distal surfaces has a surface morphology formed by fluid treatment of the exposed proximal or distal surfaces. For example, referring to fig. 1, an implant device 10 includes an inner core 20, the inner core 20 comprising a biodegradable polymer having a bioactive agent dissolved or dispersed therein. The inner core 20 is surrounded by a membrane sheath 30 having an exposed longitudinal surface 40. Implant device 10 has two other exposed surfaces at the proximal and distal ends. At each end, the exposed surfaces include an inner exposed surface of a biodegradable polymer comprising a bioactive agent dissolved or dispersed therein and an outer exposed surface of a membrane sheath substantially free of the bioactive agent. The biodegradable inner core of implant device 10 can release the bioactive agent from the implant device, for example, into the surrounding tissue of a subject, such as a human, in which the implant device is implanted.

The implant devices of the present invention can be prepared by a variety of different methods. In one aspect, an implant device can be prepared by a method comprising: a. forming a core having a desired shape from a mixture of a biodegradable polymer and a bioactive agent; b. forming a membrane sheath around the core; c. removing at least a portion of the membrane sheath to provide an exposed core surface not surrounded by the membrane sheath; contacting the exposed core surface with a sufficient amount of fluid for a sufficient time to alter the surface morphology of the exposed core surface.

Forming the core of the implant device may be accomplished by first mixing at least one biodegradable polymer with at least one bioactive agent to create a mixture. Mixing of the biodegradable polymer with the bioactive agent can be performed using techniques known in the art. For example, the polymer and agent may be dry blended (i.e., mixed with granules of the polymer and agent) using, for example, a Patterson-Kelley V-blender, or pelletized prior to the processing step, prior to forming the desired shaped core. It is contemplated that other components such as, for example, excipients may be mixed with the polymer and the agent prior to processing the mixture into a core.

The mixing step may include the use of a solvent. However, in other aspects, the mixing of the biodegradable polymer and the bioactive agent does not include the use of a solvent. Numerous benefits are obtained when the use of solvents is avoided during mixing. First, the use of a solvent during mixing requires additional processing steps to remove the solvent. Second, if the delivery system is to be implanted in a subject, the selected solvent must be biocompatible if any residual solvent remains in the device. Solvents can adversely affect the overall morphology of the delivery system, which can result in undesirable release patterns. Solvents can adversely affect the stability of the bioactive agent during the manufacturing process. Finally, the solvent level needs to be controlled because it must be low enough to meet regulatory guidelines.

Processing of the mixture into an inner core can be performed under conditions such that the bioactive agent is intimately mixed, dispersed, or dissolved throughout the polymer or only in certain portions of the polymer. The mixture may be processed into a core of a desired shape by a variety of techniques, such as, for example, melt extrusion, injection molding, compression molding, or roller pressing the mixture into a desired shape or configuration. Compression manufacturing techniques may include, but are not limited to, tableting. Depending on the processing conditions, the biodegradable polymer used as starting material in the mixing step may or may not be the same as the polymer present in the final device. For example, the polymer may undergo polymerization or depolymerization reactions during processing, which ultimately may result in a different polymer than that used prior to processing. As such, the term "polymer" as used herein includes both biocompatible and biodegradable polymers, including the polymers used as starting materials as well as the final polymers present in the final device.

In one aspect, an inner core having a desired shape is first processed as discussed above, and then a membrane sheath is formed around the core. In other aspects discussed below, the inner core and the membrane sheath can be co-processed, such as via co-extrusion, to provide an implant device. When the inner core is first formed, the film sheath can then be formed using methods known in the art. In one aspect, the membrane sheath may be formed by spraying or dip coating a solution comprising a biocompatible polymer onto the inner core. In this aspect, the membrane sheath may be formed around the entire inner core such that the inner core has no exposed surfaces. After forming the membrane sheath, a portion of the membrane sheath can be removed, for example by dissolving or physically cutting away a portion of the membrane sheath to provide an exposed inner core surface. In other aspects, a film sheath can be formed that surrounds only a portion of the core such that the core includes an exposed surface after the film sheath is formed.

In another aspect, the implant device can be made by co-extrusion, for example by a process comprising: a. extruding a mixture of a biodegradable polymer and a bioactive agent through an internal coaxial nozzle to form a core; b. forming a composite strip by simultaneously co-extruding biocompatible polymers through external coaxial orifices to apply a membrane sheath substantially coextensive around the core; c. cutting the composite strip of step (b) into one or more strips comprising one longitudinal surface and two end surfaces; contacting at least one end surface of the one or more splines from step (c) with a sufficient amount of fluid for a sufficient time to alter the surface morphology of the at least one end surface, thereby providing the implant device. For example, the method can be used to prepare an implant device as shown in FIG. 1.

Referring to fig. 2, the co-extrusion process may be implemented in a variety of co-extrusion apparatuses known in the art. Fig. 2 shows a cross-section 60 of such a device. In the co-extrusion process, a mixture of a biocompatible polymer and a bioactive agent, which may be formed as discussed above, is flowed through the inner coaxial orifice 65 while a biocompatible polymer, which will form a membrane sheath, is flowed through the outer coaxial orifice 60. The inner coaxial nozzle 65 and the outer coaxial nozzle 60 may then be narrowed into molded sections 68 and 70 where the biocompatible polymer and biodegradable polymer/bioactive agent mixture are combined and shaped into the desired shape of the implant device, in this example a cylinder. The coextruded composite strip then emerges at the exit point 80 of the apparatus. After coextrusion, the coextruded composite strip may be cut into one or more strips comprising one longitudinal surface and two end surfaces, as discussed above and shown in fig. 1. As such, after cutting the coextruded strip, the implant device may be formed by cutting the strip into individual strips each including a longitudinal surface and proximal and distal surfaces, as discussed above. The strip may be cut into as many strips as desired to produce the desired number of implant devices or the desired longitudinal length of implant devices.

After forming the implant device with the desired shape, at least one exposed surface of the implant device is treated with a fluid to change the surface morphology, or coated with a polymer solution to change the exposed surface. Treating the implant device with a fluid means contacting the device with a solution of a polymer coating the implant device, or contacting the device with a solvent that alters the surface morphology of the exposed surface. By varying the surface morphology of the exposed surfaces, the release characteristics of the implant device can be varied or tailored for specific drug delivery applications.

In one aspect, treating the exposed surface of the implant device comprises contacting the exposed surface of the implant device, preferably the exposed surface of the inner core, with a solvent. Thus, in some aspects, fluid refers to a solvent that is substantially free of other components, such as polymers. That is, in one aspect, fluid refers to a solvent or liquid that is substantially free of polymer, such that the implant device is not coated but exposed to the solvent. Examples of suitable solvents that can alter the surface morphology of the exposed surface include, but are not limited to, methylene chloride, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof. In some aspects, the solvent may be a non-solvent for the bioactive agent, or may be a solvent in which the bioactive agent has limited solubility. Such solvents may be selected by one skilled in the art and will generally depend on the choice of bioactive agent.

In another aspect, the fluid comprises a gas. In this regard, the fluid may also be free of additional polymer. Examples of suitable gases that may be effective in altering the surface morphology of the exposed surface include, but are not limited to, nitrogen, ethylene oxide, polyfluorochloro compounds, water vapor, organic solvent vapor, or mixtures thereof. Depending on the composition of the device and the gas selected, the device may be contacted with the gas at operating conditions such as room temperature, elevated temperature, or low temperature.

In a further aspect, the fluid may comprise a polymer solution or a solvent comprising a polymer dissolved or dispersed therein. In another aspect, the fluid may be a polymer alone, such as a liquid polymer, and may be applied to the exposed inner core surface of the implant device containing the bioactive agent. The polymer may be a biocompatible and/or biodegradable coating polymer, including any of those biodegradable or biocompatible polymers discussed below.

The delivery system may be exposed to the fluid one or more times. In another aspect, after the contacting step, the fluid can optionally be removed from the device. The amount of fluid removed from the device may vary and will depend on the desired release characteristics to be achieved. The device or coated article may be contacted with the fluid using techniques known in the art. In a further aspect, when the fluid is a liquid, the device or article may be contacted with the liquid by immersing the device in the liquid or spraying the liquid on the device. In another aspect, the contacting step can be continuous, wherein a steady stream of fluid is contacted with the device. In other aspects, when the fluid is a liquid, the contacting step can be performed by annular ring (annular ring) with aerosol solvent, pan coating (pan coating), or by vapor phase equilibration. In a further aspect, when the fluid is a gas, the device or coated article may be contacted with a steady flow of gas. Alternatively, the device may be placed in a chamber to be inflated with gas. In further aspects, all or a portion of the exposed surface of the polymer of the device can be fluid treated. That is, in some aspects, it is not necessary to treat the entire surface of the device. In some aspects, it is preferred to treat only the exposed surface of the inner core of the implant device or only one end of the implant device. For example, referring again to fig. 1, the proximal and/or distal ends of the implant device may be fluid treated so as to alter the surface morphology of the exposed surface of the inner core and/or the exposed surface of the proximal or distal membrane sheath.

The time of fluid exposure may vary depending on the fluid and the polymer at the surface and the desired release pattern to be achieved. The contacting step may vary from greater than zero, such as only a second, to minutes, to hours, or to days. In various aspects, the contact time is from 0.1 second to one hour, 0.5 second to 30 minutes, one second to 10 minutes, two seconds to 5 minutes, three seconds to 60 seconds, or five seconds to 30 seconds. In another aspect, the contact time is from one second to 10 seconds or one second to five seconds. In a further aspect, different fluids or different mixtures of fluids may be used during a series of fluid exposures.

In a further aspect, when the fluid is a liquid, the temperature of the contacting step is below the boiling point of the liquid. In another aspect, the temperature of the contacting step is below the melting point of the polymer. In another aspect, when the fluid is a gas, the pressure of the contacting step can be at or above atmospheric pressure.

A variety of biocompatible or biodegradable polymers can be used to form a film sheath or as a coating polymer for fluids. The biocompatible polymer may also be a biodegradable polymer. As such, in some aspects, the biocompatible polymer forming the membrane sheath substantially free of bioactive agents can be the same as the polymer forming the biodegradable inner core. In one aspect, the biocompatible polymer may be one or more of: polyesters, polyhydroxyalkanoates, polyhydroxybutyrates, polydioxanones, polyhydroxyvalerates, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphoesters, polydioxanones, polyphosphoesters, polyhydroxyalkanoates, polycarbonates, polyalkyl carbonates, polyorthocarbonates, polyesteramides, polyamides, polyamines, polypeptides, polyurethanes, polyalkylene alkyls (polyalkylene alkyls), polyalkylene oxalates, polyalkylene succinates, polyhydroxyalkanoates, polyacetals, polycyanoacrylates, polyketals, polyetheresters, polyethers, polyalkylene glycols, polyalkylene oxides, polyethylene glycols, polyethylene oxides, polypeptides, polysaccharides, or polyvinylpyrrolidone. Other non-biodegradable but durable and biocompatible polymers include, but are not limited to, ethylene vinyl acetate, polytetrafluoroethylene, polypropylene, polyethylene, and the like. Similarly, other suitable non-biodegradable polymers include, but are not limited to, silicones and polyurethanes.

The biodegradable polymer forming the inner core or coating may include any of those listed above or any other biodegradable polymer known in the art. In a further aspect, the biocompatible and/or biodegradable polymer can be poly (lactide), poly (glycolide), poly (lactide-co-glycolide), poly (caprolactone), poly (orthoester), poly (phosphazene), poly (hydroxybutyrate) or copolymers containing poly (hydroxybutyrate), poly (lactide-co-caprolactone), polycarbonate, polyesteramide, polyanhydride, poly (dioxanone), poly (alkylene alkylate), copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethane, poly (amino acid), polyamide, polyesteramide, polyetherester, polyacetal, polycyanoacrylate, poly (oxyethylene)/poly (oxypropylene) copolymer, polyacetal, polyketal, polyphosphoester, polyhydroxyvalerate or copolymers containing polyhydroxyvalerate, poly (hydroxy valerate-containing) copolymer, poly (lactide-co-caprolactone), poly (carbonate), poly (polyesteramide), poly (anhydride), poly (dioxanone), poly (alkylene alkylate), poly (ethylene glycol-co-phthalate), poly (ethylene-co-acrylate), poly (oxyethylene)/poly (, Polyalkylene oxalates, polyalkylene succinates, poly (maleic acid) and copolymers, terpolymers, combinations or blends thereof.

In still further aspects, useful biodegradable and biocompatible polymers are those comprising one or more residues (residues) of lactic acid, glycolic acid, lactide, glycolide, caprolactone, hydroxybutyrate, polyhydroxyvalerate, dioxanone, polyethylene glycol (PEG), polyethylene oxide, or combinations thereof. In still further aspects, useful biodegradable polymers are those comprising one or more residues of lactide, glycolide, caprolactone, or a combination thereof.

In one aspect, useful biodegradable and biocompatible polymers are those that include one or more blocks of hydrophilic or water-soluble polymers including, but not limited to, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP), along with one or more blocks of another biocompatible or biodegradable polymer including lactide, glycolide, caprolactone, or a combination thereof.

In particular aspects, the biodegradable and/or biocompatible polymer can include one or more lactide residues. For this purpose, the polymer may comprise any lactide residue, including all racemic and stereospecific forms of lactide, including but not limited to L-lactide, D-lactide and D, L-lactide or mixtures thereof. Useful polymers including lactide include, but are not limited to, poly (L-lactide), poly (D-lactide), and poly (DL-lactide); and poly (lactide-co-glycolide) s including poly (L-lactide-co-glycolide), poly (D-lactide-co-glycolide), and poly (DL-lactide-co-glycolide); or a copolymer, terpolymer, combination or blend thereof. Lactide/glycolide polymers can be conveniently manufactured by melt polymerization via ring opening of lactide and glycolide monomers. In addition, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available. The L-polymer is more crystalline and absorbs more slowly than the DL-polymer. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Homopolymers of lactide or glycolide are also commercially available.

When the biodegradable and/or biocompatible polymer is poly (lactide-co-glycolide), poly (lactide), or poly (glycolide), the amount of lactide and glycolide in the polymer can vary. In a further aspect, the biodegradable polymer comprises from 0 to 100 mol%, 40 to 100 mol%, 50 to 100 mol%, 60 to 100 mol%, 70 to 100 mol% or 80 to 100 mol% lactide and from 0 to 100 mol%, 0 to 60 mol%, 10 to 40 mol%, 20 to 40 mol% or 30 to 40 mol% glycolide, wherein the amount of lactide and glycolide is 100 mol%. In a further aspect, the biodegradable polymer can be poly (lactide), 95: 5 poly (lactide-co-glycolide), 85: 15 poly (lactide-co-glycolide), 75: 25 poly (lactide-co-glycolide), 65: 35 poly (lactide-co-glycolide), or 50: 50 poly (lactide-co-glycolide), wherein the ratio is a molar ratio.

In a further aspect, the biodegradable and/or biocompatible polymer can be poly (caprolactone) or poly (lactide-co-caprolactone). In one aspect, the polymer can be poly (lactide-caprolactone), and in various aspects can be 95: 5 poly (lactide-co-caprolactone), 85: 15 poly (lactide-co-caprolactone), 75: 25 poly (lactide-co-caprolactone), 65: 35 poly (lactide-co-caprolactone), or 50: 50 poly (lactide-co-caprolactone), wherein the ratio is a molar ratio.

When the biodegradable or biocompatible polymer comprises a lactide-based polymer, the lactide-based polymer may comprise any lactide residue, including all racemic and stereospecific forms of lactide, including but not limited to L-lactide, D-lactide, and D, L-lactide, or mixtures thereof. Useful polymers including lactide include, but are not limited to, poly (L-lactide), poly (D-lactide), and poly (DL-lactide); and poly (lactide-co-glycolide) s including poly (L-lactide-co-glycolide), poly (D-lactide-co-glycolide), and poly (DL-lactide-co-glycolide); or a copolymer, terpolymer, combination or blend thereof. Lactide/glycolide polymers can be made by ring opening of lactide and glycolide monomers. In addition, racemic DL-lactide, L-lactide, and D-lactide polymers are commercially available. L-polymers are more crystalline and absorb more slowly than DL-polymers. Copolymers of L-lactide with DL-lactide are commercially available, except for copolymers comprising glycolide and DL-lactide or L-lactide. Homopolymers of lactide or glycolide are also commercially available.

In some aspects, it may be desirable to contact or mix the disclosed biodegradable and/or biocompatible polymers with one or more plasticizers to alter the physical properties of the resulting composition (e.g., to reduce the T_g). Useful plasticizers include all FDA approved plasticizers such as benzyl benzoate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl sebacate, dimethyl sebacate, acetyl phthalate, diethyl phthalate, dibutyl phthalate, dipropyl phthalate, dimethyl phthalate, dioctyl phthalate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gelatin, glycerin, glyceryl monostearate, monoglycerides, mono-and di-acetylated monoglycerides, glycerin, mannitol, mineral and lanolin alcohols, petrolatum and lanolin alcohols, castor oil, vegetable oil, coconut oil, polyethylene glycol, polymethacrylates and copolymers thereof, polyethylene-pyrrolidone, propylene carbonate, Propylene glycol, sorbitol, suppository base (suppositoriy base), diacetin, triacetin, triethanolamine, esters of citric acid, triethyl citrate, acetyl tributyl citrate, triethyl citrate, and esters of phosphoric acid.

The biodegradable polymer can erode, allowing release of the agent in the inner core of the implant device. A variety of releasable agents may be used in the composition. In general, any agent that is desired to be released over time can be used. As such, the releasable agent may be a bioactive agent, a cosmetic such as an emulsion (lotion), or other substance, such as an agricultural product (agricultural product). The releasable agent may be dissolved or dispersed in the polymer and may be present in any suitable amount, which generally depends on the intended use of the composition.

A variety of bioactive agents can be used with the implant device. As discussed above, the bioactive agent may be blended, mixed, or otherwise combined with the biodegradable polymer of the inner core. In one aspect, the bioactive agent can be pre-formulated into a defined particle, such as spray dried with sugar. In another aspect, at least a portion of the bioactive agent can be dissolved in the biodegradable polymer. In a further aspect, at least a portion of the bioactive agent can be dispersed in the biodegradable polymer of the inner core.

As discussed above, the mixing of the bioactive agent and the polymer may or may not be performed with an additional solvent (other than the polymer). The amount of bioactive agent incorporated into the composition varies depending on the particular drug, the desired therapeutic effect, and the desired time span. Since various compositions are expected to provide therapeutic dosage regimens for a variety of purposes, there is no strict lower or upper limit on the amount of drug incorporated into the composition. The lower limit will generally depend on the activity of the drug and the time span over which it is released from the device. One skilled in the pharmaceutical art can determine the level of toxicity and the minimum effective dose of a given drug.

Various forms of bioactive agents that can be released from the implant device into a subject can be used. Liquid or solid bioactive agents can be incorporated into the devices described herein. The bioactive agent may be water soluble or water insoluble. In some aspects, the bioactive agent is at least minimally water soluble, preferably moderately water soluble. The bioactive agent may comprise a salt of the active ingredient. As such, the bioactive agent can be an acidic, basic, or amphoteric salt. They may be nonionic molecules, polar molecules or molecular complexes capable of hydrogen bonding. Bioactive agents can be included in the device, for example, in the form of uncharged molecules, molecular complexes, salts, ethers, esters, amides, polymeric drug conjugates, or other forms to provide effective biological or physiological activity.

Examples of bioactive agents that can be incorporated into the device include, but are not limited to, small molecules, peptides, proteins such as hormones, enzymes, antibodies, antibody fragments, antibody conjugates, nucleic acids such as aptamers, iRNA, siRNA, DNA, RNA, antisense or similar nucleic acids (antisense nucleic acid or peptide), antisense or similar nucleic acid analogs (antisense nucleic acid analogs peptide), VEGF inhibitors, macrolides, dopamine agonists, dopamine antagonists, low molecular weight compounds, high molecular weight compounds, or conjugated bioactive agents. Bioactive agents contemplated for use in the disclosed compositions include anabolic agents, antacids, anti-asthmatics, anticholesterolemic (anti-cholesteleometic) and anti-lipidic agents, anticoagulants, anticonvulsants, anti-diarrheal agents, antiemetics, anti-infective agents including antibacterial and antimicrobial agents, anti-inflammatory agents, anti-maniac agents, antimetabolites, anti-cachexia agents, anti-neoplastic agents, anti-obesity agents, antipyretics and analgesics, antispasmodics, antithrombotic agents, antitussive agents, anti-uricemic agents, anti-anginal agents, antihistamines, appetite suppressants, biologicals, cerebral dilators, coronary dilators, bronchodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoietics, expectorants, gastro-intestinal tranquilizers, hyperglycemic agents, hypnotics, hypoglycemics, immunomodulators, ion exchange resins, laxatives, antidiarrheal agents, Mineral supplements, mucolytics, neuromuscular drugs, peripheral vasodilators, psychopharmaceuticals, sedatives, stimulants, thyroid and antithyroid drugs, tissue growth agents, uterine relaxants, vitamins or antigenic materials.

Other bioactive agents include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenic factors, dextromethorphan hydrobromide, noscapine, chlorhexidine citrate, clofedanol hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, benzpheanolamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine phosphate, codeine sulfate, morphine mineral supplements, cholestyramine, N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenylpropanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones, interferons, cytokines, and vaccines.

Representative drugs that may be used as bioactive agents in the compositions include, but are not limited to, peptide drugs, protein drugs, therapeutic antibodies, desensitizing materials, antigens, anti-infective agents such as antibiotics, antimicrobials, antivirals, antibacterials, antiparasitics, antifungal substances and combinations thereof, antiallergics, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anticholinergics, sympathomimetics, sedatives, miotics, psychostimulants, tranquilizers, vaccines, estrogens, progestational agents, humoral factors (humorals), prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardiac agents, non-steroidal anti-inflammatory agents, anti-parkinson's, antihypertensives, beta-adrenergic blockers, nutraceuticals, and benzophenanthridine alkaloids. The agent may further be a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like.

Other bioactive agents include, but are not limited to, analgesics such as acetaminophen, acetylsalicylic acid, and the like; anesthetics such as lidocaine, xylocaine, and the like; anorectic agents such as dexthyroxine, phendimetrazine tartrate and the like; antiarthritics such as methylprednisolone, ibuprofen and the like; antiasthmatic agents such as terbutaline sulfate, theophylline, ephedrine, and the like; antibiotics such as sulfisoxazoles, penicillin G, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, and the like; antifungal agents such as amphotericin B, nystatin, ketoconazole, and the like; antiviral agents such as acyclovir, amantadine, and the like; anticancer drugs such as cyclophosphamide, methotrexate and ethiproleTriptolide and the like; anticoagulants such as heparin, warfarin, and the like; anticonvulsants such as sodium phenytoin, diazepam and the like; antidepressants such as isocarboxazid, amoxapine, and the like; antihistamines such as diphenhydramine hydrochloride, chlorpheniramine maleate, and the like; hormones such as insulin, progestins, estrogens, corticosteroids, glucocorticoids, androgens, and the like; tranquilizers such as thorazine, diazepam, chlorpromazine hydrochloride, reserpine, chlordiazepoxide hydrochloride (HCl), and the like; antispasmodics such as belladonna alkaloids, dicyclomine hydrochloride and the like; vitamins and minerals such as essential amino acids, calcium, iron, potassium, zinc, vitamin B₁₂And the like; cardiovascular agents such as prazosin hydrochloride, nitroglycerin, propranolol hydrochloride, hydralazine hydrochloride, pancreatic lipase, succinate dehydrogenase, and the like; peptides and proteins such as LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptide, growth release factor, angiotensin, FSH, EGF, Bone Morphogenetic Protein (BMP), Erythropoietin (EPO), interferon, interleukin, collagen, fibrinogen, insulin, factor VIII, factor IX, insulin, beta-glucosidase, and the like,Alpha-glucosidase,Vasopressin, ACTH, human serum albumin, gamma globulin, structural proteins (structural proteins), blood product proteins, complex proteins, enzymes, antibodies, monoclonal antibodies, and the like; prostaglandins; a nucleic acid; a carbohydrate; fat; anesthetics such as morphine, codeine, and the like, psychotherapeutic drugs (psychotherapeutic drugs); antimalarial drugs, L-dopa, diuretics such as furosemide, spironolactone, and the like; antiulcer drugs such as ranitidine hydrochloride, cimetidine hydrochloride and the like.

The bioactive agent can also be an immunomodulator, including, for example, cytokines, interleukins, interferons, colony stimulating factors, tumor necrosis factors, and the like; allergens such as cat dander, birch pollen, house dust mites, grass pollen (grass pollen), and the like; antigens of bacterial organisms such as Streptococcus pneumoniae (Streptococcus pneumniae), Haemophilus influenzae (Haemophilus influenzae), Staphylococcus aureus (Staphylococcus aureus), Streptococcus pyogenes (Streptococcus pyrones), Corynebacterium diphtheriae (Corynebacterium diphteriae), Listeria monocytogenes (Listeria monocytogenes), Bacillus anthracis (Bacillus anthracis), Clostridium tetani (Clostridium tetani), Clostridium botulinum (Clostridium botulinum), Clostridium perfringens (Clostridium perfringens), Neisseria meningitidis (Neisseria meningitidis), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Streptococcus mutans (Streptococcus mutans), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Salmonella typhi (Salmonella typhi), Neisseria gonorrhoeae (Salmonella choleraesuis), Streptococcus mutans (Streptococcus pyogenes), Salmonella choleraesuis (Salmonella choleraesula), Salmonella choleraesula (Salmonella choleraesuis), Streptococcus pneumoniae (Salmonella cholerae), Escherichia coli (Salmonella choleraesuis), Escherichia coli (Salmonella cholera), and Escherichia coli (Salmonella cholera), Clostridium parainfluenza (Clostridium perfringens), Clostridium (Clostridium perfringens), Clostridium (Clostridium), Clostridium (Clostridium), Clostridium (Clostridium), Clostridium (Clostridium, Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium leprae (Mycobacterium leprae), Treponema pallidum (Treponema pallidum), Leptospira interrogans (Leptspirosis), Borrelia burgdorferi (Borrelia burgdorferi), Campylobacter jejuni (Campylobacter jejuni), and the like; antigens such as the following viruses: smallpox, influenza a and b, respiratory syncytial virus, parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex 1 and 2, cytomegalovirus, EB virus, rotavirus, rhinovirus, adenovirus, papilloma virus, poliovirus, mumps virus, rabies, rubella, coxsackie virus, equine encephalitis, japanese encephalitis, yellow fever, rift valley fever, lymphocytic choriomeningitis, hepatitis b and the like; fungi, protozoa and parasitic organisms such as the following antigens: cryptococcus neoformans (Cryptococcus neoformans), Histoplasma capsulatum (Histoplasma), Candida albicans (Candida albicans), Candida tropicalis (Candida tropicalis), Nocardia asteroides (Nocardia asteroids), Rickettsia rickettsii (Rickettsia ricktsii), Rickettsia typhimurium (Rickettsia typhi), Mycoplasma pneumoniae (Mycosoma pneoniae), Chlamydia psittaci (Chlamyda psittaci), Chlamydia trachomatis (Chlamydia trachomatis), Plasmodium falciparum (Plasmodium falciparum), Trypanosoma (Trypasa brucei), Schistosoma immitis (Entamoebahistolytica hispida), Protosoma vaginalis (Toxoplasma Trichomonas), and Trichostoma vaginalis analogs. These antigens may be in the form of complete killers of organisms, peptides, proteins, glycoproteins, carbohydrates, or combinations thereof.

In a further specific aspect, the bioactive agent comprises an antibiotic. The antibiotic may be, for example, one or more of the following: amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, ansamycin, geldanamycin, herbimycin, carbacephem, chlorocephem, carbapenem, ertapenem, doripenem, imipenem/cilastatin, meropenem, cephalosporins (first generation), cefadroxil, cefazolin, cephalothin (Cefalotin) or cephraxin (Cefalothin), cephalexin, cephalosporins (second generation), cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cephalosporins (third generation), cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefbuperazine, ceftizoxime, ceftriaxone, cephalosporins (fourth generation), cephalosporins (fifth generation), cephalosporins (fourth generation), cephalosporins, cefbipole, glycopeptides, teicoplanin, vancomycin, macrolides, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, spectinomycin, monobactams, aztreonam, penicillins, amoxicillins, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, polypeptides, bacitracin, colistin, polymyxin B, quinolones, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, sulfonamides, mafenin, baguon (old name), sulfacetamide, sulfamethoxazole (old name), sulfasalazine, doxycycline, erythromycin, doxycycline, and doxycycline, Sulfisoxazole, trimethoprim-sulfamethoxazole (trimethoprim) (TMP-SMX), tetracyclines, including demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline and others; arsinamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platemycin, pyrazinamide, quinupristin/dalfopristin, Rifampin (Rifampicin, referred to in the united states as Rifampin), tinidazole, ropinirole, ivermectin, moxidectin, Afamelanotide, cilengitide, or combinations thereof. In one aspect, the bioactive agent can be a combination of Rifampicin (Rifampicin, referred to as Rifampin in the united states) and minocycline.

In some aspects, the device itself may be a carrier and/or may be combined with other carriers or additives. Other pharmaceutical carriers may also be used. Examples of solid carriers other than polymers (if solid) include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers other than polymers (if liquid) are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. Other pharmaceutically acceptable carriers or components that may be mixed with the biologically active agent may include, for example, fatty acids, sugars or salts.

In one aspect, the composition may be in the form of a kit. The kit may comprise suitable packaging or containers for the composition. Examples include, but are not limited to, sterile packaging. Since the disclosed compositions are suitable for use as injectable compositions, the kits may include prepackaged injection devices, including injection devices that contain an implant device. Suitable injection devices include, but are not limited to, syringes, trocars, and others.

As discussed above, the implant device can be used to administer a bioactive agent to a subject in need thereof, e.g., to treat a disease for which the bioactive agent can be effective. The composition may be administered to any tissue or fluid of a subject. Likewise, the mode of administration may be any suitable mode, such as subcutaneous injection, oral administration, parenteral (partial) administration, enteral (enteral) administration, and the like. In some aspects, a liquid composition comprising one or more low viscosity polymers can be injected into a subject. The nature of the composition administered will generally be selected based on the desired dosage of the biologically active agent, which will vary greatly depending on the disease, but can be readily determined by one skilled in the pharmaceutical art.

An "effective amount" of a composition refers to the amount of the composition that will achieve the desired therapeutic result. Thus, the effective amount will vary greatly depending on the composition, the bioactive agent, and the disease or condition being treated. The actual effective amount of a dose of the composition administered to a subject may be determined by physical and physiological factors such as body weight, severity of the condition, type of disease being treated, previous or concurrent therapeutic intervention, patient-specific complications, and may depend on the route of administration. Depending on the dose and route of administration, the preferred dose and/or the number of administrations of the effective amount may vary according to the response of the subject. One skilled in the art can determine an effective amount of the disclosed pharmaceutical composition.

In some non-limiting examples, the dose can include from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 mg/kg/body weight, about 10 mg/kg/body weight, about 50 mg/kg/body weight, about 100 mg/kg/body weight, about 200 mg/kg/body weight, about 350 mg/kg/body weight, about 500 mg/kg/body weight, to about 1000 mg/kg/body weight or more, and any derivable range therein. In non-limiting examples of ranges derivable from the numbers set forth herein, based on the numbers set forth above, about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 micrograms/kg/body weight to about 500 milligrams/kg/body weight, and similar ranges may be administered.

The bioactive agent can be present in the implant device or biodegradable inner core at any suitable weight percent, including higher loading weight percentages, such as up to 40% loading by weight of the implant device or biodegradable inner core. In one aspect, the implant device can be used to alter the pharmacokinetics of the bioactive agent. For example, the polymers may be used to reduce degradation of the bioactive agent.

The composition may be administered to any desired subject. The subject may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. The subject of the methods disclosed herein can be, for example, a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow (cow), a cat, a guinea pig, or a rodent. The term does not indicate a specific age or gender. As such, subjects of adults and infants, as well as fetuses, whether male or female, are contemplated. The compositions may also be administered by any suitable route, including parenteral, oral, and others. In a preferred aspect, the composition is injectable into a subject.

Many modifications and variations may be made in the compounds, composites, kits, articles, devices, compositions, and methods described herein. Other aspects of the compounds, composites, kits, articles, devices, compositions, and methods described herein will be apparent from consideration of the specification and practice of the compounds, composites, kits, articles, devices, compositions, and methods disclosed herein. It is intended that the specification and examples be considered as exemplary.

Claims (36)

1. An implant device comprising an inner core having a surface surrounded by a membrane sheath and having an exposed surface not surrounded by the membrane sheath;

wherein the inner core comprises a biodegradable polymer having a bioactive agent dissolved or dispersed therein;

wherein the membrane sheath comprises a biocompatible polymer and is substantially free of the bioactive agent;

wherein the exposed surface is flattened against the surface of the surrounded core.

2. The implant device of claim 1, wherein the exposed surface has a surface morphology formed by fluid treatment of the exposed surface.

3. The implant device of claim 1 or 2, wherein the exposed surface has a surface morphology formed by fluid treatment of the exposed surface, the fluid treatment comprising treating the exposed surface with a fluid that is free of polymer.

4. An implant device according to any one of the preceding claims, wherein the exposed surface has a surface morphology formed by fluid treatment of the exposed surface, the fluid treatment comprising treating the exposed surface with a fluid comprising: dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

5. The implant device of claim 1 or 4, wherein the exposed surface has a surface morphology formed by fluid treatment of the exposed surface, the fluid treatment comprising treating the exposed surface with a fluid comprising a biodegradable or biocompatible coating polymer.

6. The implant device of claim 5, wherein the biodegradable or biocompatible coating polymer comprises poly (lactide), poly (glycolide), poly (caprolactone), or copolymers, mixtures, or blends thereof.

7. The implant device of claim 5 or 6, wherein the biodegradable or biocompatible coating polymer is dissolved or dispersed in dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

8. An implant device according to any one of the preceding claims, wherein the device is shaped as a rod, a fiber, a disk, a sheet, a bead, a ribbon or a cylinder.

9. The implant device of any one of the preceding claims, wherein the biocompatible and/or biodegradable polymer of the inner core and/or the membrane sheath comprises poly (lactide), poly (glycolide), poly (caprolactone), or copolymers, mixtures or blends thereof.

10. An implant device comprising an inner core having a longitudinal surface surrounded by a membrane sheath and having exposed proximal and distal surfaces not surrounded by the membrane sheath;

wherein the inner core comprises a biodegradable polymer having a bioactive agent dissolved or dispersed therein;

wherein the membrane sheath comprises a biocompatible polymer and is substantially free of the bioactive agent; and

wherein at least one of the exposed proximal or distal surfaces has a surface morphology formed by fluid treatment of the exposed proximal or distal surfaces.

11. The implant device of claim 10, wherein the exposed proximal or distal surface has a surface morphology formed by fluid treatment of the exposed surface, the fluid treatment comprising treating the exposed surface with a fluid that is free of polymer.

12. The implant device of claim 10 or 11, wherein the exposed proximal or distal surface has a surface morphology formed by fluid treatment of the exposed surface, the fluid treatment comprising treating the exposed surface with a fluid comprising: dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

13. The implant device of claim 10 or 12, wherein the exposed proximal or distal surface has a surface morphology formed by fluid treatment of the exposed surface, the fluid treatment comprising treating the exposed surface with a fluid comprising a biodegradable or biocompatible coating polymer.

14. The implant device of claim 13, wherein the biodegradable or biocompatible coating polymer comprises poly (lactide), poly (glycolide), poly (caprolactone), or copolymers, mixtures, or blends thereof.

15. The implant device of claim 13 or 14, wherein the biodegradable or biocompatible coating polymer is dissolved or dispersed in dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

16. The implant device of any one of claims 10-15, wherein the biocompatible and/or biodegradable polymer of the inner core and/or the membrane sheath comprises poly (lactide), poly (glycolide), poly (caprolactone), or a copolymer, mixture, or blend thereof.

17. An implant device prepared by a method comprising:

a. forming a core having a desired shape from a mixture of a biodegradable polymer and a bioactive agent;

b. forming a membrane sheath around the core;

c. removing at least a portion of the membrane sheath to provide an exposed core surface not surrounded by the membrane sheath; and

d. contacting the exposed core surface with a sufficient amount of fluid for a sufficient time to change the surface morphology of the exposed core surface.

18. The implant device of claim 17, wherein step (d) comprises treating the exposed surface with a fluid that is free of polymer.

19. An implant device according to claim 17 or 18, wherein step (d) comprises treating the exposed surface with a fluid comprising: dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

20. The implant device of claim 17 or 19, wherein step (d) comprises treating the exposed surface with a fluid comprising a biodegradable or biocompatible coating polymer.

21. The implant device of claim 20, wherein the biodegradable or biocompatible coating polymer comprises poly (lactide), poly (glycolide), poly (caprolactone), or copolymers, mixtures, or blends thereof.

22. The implant device of claim 20 or 21, wherein the biodegradable or biocompatible coating polymer is dissolved or dispersed in dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

23. The implant device of any one of claims 17-22, wherein the biocompatible and/or biodegradable polymer of the inner core and/or the membrane sheath comprises poly (lactide), poly (glycolide), poly (caprolactone), or a copolymer, mixture, or blend thereof.

24. An implant device prepared by a method comprising:

a. forming a core having a desired shape from a mixture of a biodegradable polymer and a bioactive agent;

b. forming a membrane sheath around only a portion of the core, such that after forming the membrane sheath, the core comprises an exposed surface;

c. contacting the exposed core surface with a sufficient amount of fluid for a sufficient time to change the surface morphology of the exposed core surface.

25. The implant device of claim 24, wherein step (d) comprises treating the exposed surface with a fluid that is free of polymer.

26. The implant device of claim 24 or 25, wherein step (d) comprises treating the exposed surface with a fluid comprising: dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

27. The implant device of claim 24 or 26, wherein step (d) comprises treating the exposed surface with a fluid comprising a biodegradable or biocompatible coating polymer.

28. The implant device of claim 27, wherein the biodegradable and/or biocompatible coating polymer comprises poly (lactide), poly (glycolide), poly (caprolactone), or copolymers, mixtures, or blends thereof.

29. The implant device of claim 27 or 28, wherein the biodegradable or biocompatible coating polymer is dissolved or dispersed in dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

30. The implant device of any one of claims 24-29, wherein the biocompatible and/or biodegradable polymer of the core and/or the membrane sheath comprises poly (lactide), poly (glycolide), poly (caprolactone), or a copolymer, mixture, or blend thereof.

31. An implant device prepared by a method comprising:

a. extruding a mixture of a biodegradable polymer and a bioactive agent through an internal coaxial nozzle to form a core;

b. forming a composite strip by simultaneously co-extruding biocompatible polymers through external coaxial orifices to apply a membrane sheath substantially coextensive around the core;

c. cutting the composite strip of step (b) into one or more strips comprising one longitudinal surface and two end surfaces; and

d. contacting at least one end surface of one or more splines from step (c) with a sufficient amount of fluid for a sufficient time to alter the surface morphology of the at least one end surface to provide the implant device.

32. The implant device of claim 31, wherein step (d) comprises treating the exposed surface with a fluid that is free of polymer.

33. An implant device according to claim 31 or 32, wherein step (d) comprises treating the exposed surface with a fluid comprising: dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethyl sulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

34. The implant device of claim 31 or 33, wherein step (d) comprises treating the exposed surface with a fluid comprising a biodegradable or biocompatible coating polymer.

35. The implant device of claim 34, wherein the biodegradable or biocompatible coating polymer is dissolved or dispersed in dichloromethane, chloroform, acetone, anisole, ethyl acetate, methyl acetate, N-methyl-2-pyrrolidone, hexafluoroisopropanol, tetrahydrofuran, dimethylsulfoxide, water, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, Miglyol 810, isopropanol, ethanol, supercritical carbon dioxide, acetonitrile, water, or mixtures thereof.

36. The implant device of any one of claims 31-35, wherein the biodegradable polymer and/or the biodegradable polymer of the implant device comprises poly (lactide), poly (glycolide), poly (caprolactone), or a copolymer, mixture, or blend thereof.