Implantable devices for the sustained release of macromolecular drug compounds

Abstract

An implantable device for delivering a polymeric drug compound is provided. The device includes a core having an outer surface and a membrane layer disposed adjacent to the outer surface of the core. The core includes a core polymer matrix having a drug compound dispersed therein, the polymer matrix containing a hydrophobic polymer. The membrane layer further includes a membrane polymer matrix having the polymeric drug compound optionally dispersed therein. The concentration of the polymeric drug compound in the core is greater than the concentration of the polymeric drug compound in the membrane layer. [Selected Figure] Figure 1

Description

[Technical Field]

[0001] Related Applications

[0001] This application claims priority to U.S. Patent Application No. 62 / 675,982 (filed May 24, 2018), the entire contents of which are incorporated herein by reference. [Background technology]

[0002]

[0002] Biological macromolecular drug compounds are typically composed of one or more oligomeric or polymeric chains that form a three-dimensional structure held together by noncovalent forces. While these drug compounds have the potential for numerous therapeutic benefits, controlling the delivery of these compounds over sustained periods has traditionally been challenging. For example, many implantable delivery devices are formed by solubilizing the drug compound within a matrix polymer. These solubilized drug molecules can diffuse through the implant and be released into the patient. Unfortunately, drug elution is highly dependent on the diffusion coefficient of the drug molecule, which in turn is inversely proportional to the molecular weight of the drug molecule. Thus, macromolecular drug compounds tend to have low diffusion coefficients due to their large molecular weight. Furthermore, such compounds often have chain entanglements, which can further reduce the effective diffusion coefficient. Given these difficulties, there is a continuing need for implantable delivery devices that can deliver effective amounts of macromolecular compounds over sustained periods. Summary of the Invention

[0003]

[0003] According to one embodiment of the present invention, an implantable device for delivering a polymeric drug compound is disclosed. The device includes a core having an outer surface and a membrane layer disposed adjacent to the outer surface of the core. The core includes a core polymer matrix having a drug compound dispersed therein, the drug compound having a molecular weight of about 0.5 kDa or greater, the polymer matrix containing a hydrophobic polymer. The membrane layer further includes a membrane polymer matrix having the polymeric drug compound optionally dispersed therein. The concentration of the polymeric drug compound in the core is greater than the concentration of the polymeric drug compound in the membrane layer.

[0004]

[0004] Other features and aspects of the present invention are described in more detail below. [Brief explanation of the drawings]

[0005] A full and enabling disclosure of the present invention, including the best mode thereof, directed to one skilled in the art, is set forth more particularly in the remainder of the specification, which makes reference to the accompanying drawings in which:

[0006] [Figure 1]

[0006] FIG. 1 is a perspective view of one embodiment of an implantable device of the present invention. [Figure 2]

[0007] FIG. 2 is a cross-sectional view of the implantable device of FIG. 1. [Figure 3]

[0008] FIG. 1 is a perspective view of another embodiment of an implantable device of the present invention. [Figure 4]

[0009] FIG. 4 is a cross-sectional view of the implantable device of FIG. 3. [Figure 5]

[0010] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 1 to 4. [Figure 6]

[0011] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) in Examples 1 to 4. [Figure 7]

[0012] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 5 to 7. [Figure 8]

[0013] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) in Examples 5 to 7. [Figure 9]

[0014] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 8 to 13. [Figure 10]

[0015] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) for Examples 8 to 13. [Figure 11]

[0016] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 14 to 18. [Figure 12]

[0017] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) for Examples 14 to 18. [Figure 13]

[0018] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 19 and 20. [Figure 14]

[0019] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) in Examples 19 and 20. [Figure 15]

[0020] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 21 to 23. [Figure 16]

[0021] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) in Examples 21 to 23. [Figure 17]

[0022] 1 is a graph showing the cumulative release rate of collagen versus release time (hours) for Examples 24 to 27. [Figure 18]

[0023] 1 is a graph showing the collagen release rate (μg / hour) versus the release time (hours) for Examples 24 to 27. [Figure 19]

[0024] 1 is a graph showing the cumulative release rate of bromelain versus the release time (hours) in Examples 28 to 30. [Figure 20]

[0025] 1 is a graph showing the release rate (μg / hour) of bromelain versus the release time (hours) in Examples 28 to 30. DETAILED DESCRIPTION OF THE INVENTION

[0007]

[0026] Repeat use of reference characters in the present specification and figures is intended to represent the same or analogous features or elements of the present invention.

[0008]

[0027] It should be understood by those skilled in the art that this discussion describes exemplary embodiments only and is not intended to limit the broader aspects of the invention.

[0009]

[0028] Generally speaking, the present invention is directed to implantable devices capable of delivering polymeric pharmaceutical compounds to inhibit and / or treat conditions, diseases, and / or cosmetic conditions in patients (e.g., humans, pets, livestock, racehorses, etc.). The implantable devices can have a variety of different geometric shapes, such as cylindrical (rod), disc, ring, donut, spiral, elliptical, triangular, oval, etc. In one embodiment, for example, the device may have a generally circular cross-sectional shape such that the overall structure is in the form of a cylinder (rod) or disc. In such embodiments, the device typically has a diameter of about 0.5 to about 50 millimeters, in some embodiments about 1 to about 40 millimeters, and in some embodiments about 5 to about 30 millimeters. The length of the device can vary but is typically in the range of about 1 to about 25 millimeters. Cylindrical devices may have lengths of, for example, about 5 to about 50 millimeters, while disc-shaped devices may have lengths of about 0.5 to about 5 millimeters.

[0010]

[0029] Regardless of the particular shape or size, the device is multilayered in that it contains at least one membrane layer disposed adjacent to the outer surface of the core. The core contains a core polymer matrix comprising a hydrophobic polymer and a polymeric drug compound dispersed within the core polymer matrix. Typically, the polymeric drug compound constitutes about 5 wt% to about 60 wt%, in some embodiments about 10 wt% to about 50 wt%, and in some embodiments about 15 wt% to about 45 wt% of the core, while the core polymer matrix constitutes about 40 wt% to about 95 wt%, in some embodiments about 50 wt% to about 90 wt%, and in some embodiments about 55 wt% to about 85 wt% of the core. The membrane layer also contains a polymer matrix within which the drug compound may optionally be dispersed. Notably, the concentration (wt%) of the drug compound in the core polymer matrix is ​​greater than the concentration (wt%) of the drug compound in the membrane layer. For example, in certain embodiments, the membrane layer is generally free of such drug compound. Of course, in other embodiments, the membrane layer may contain the drug compound such that the ratio of the concentration of the drug compound in the core to the concentration of the drug compound in the membrane layer is greater than 1, in some embodiments greater than about 1.5, and in some embodiments, from about 1.8 to about 4.

[0011]

[0030] By selectively controlling the specific properties of the core and membrane layers as described above, as well as the manner in which they are formed, the inventors have discovered that the resulting device can be effective for the sustained release of polymeric drug compounds over extended periods of time. For example, the implantable device can release the drug compound over a period of about 5 days or more, in some embodiments, about 10 days or more, in some embodiments, about 20 to about 60 days, and in some embodiments, about 25 to about 50 days (e.g., about 30 days). Furthermore, the inventors have discovered that the drug compound can be released in a controlled manner (e.g., zero-order or near-zero-order) over the release period. For example, after 15 days, the cumulative release rate of the implantable device can be about 20% to about 70%, in some embodiments, about 30% to about 65%, and in some embodiments, about 40% to about 60%. Similarly, after 30 days, the cumulative release rate of the implantable device can still be about 40% to about 85%, in some embodiments, about 50% to about 80%, and in some embodiments, about 60% to about 80%. The "cumulative release rate" can be determined by dividing the amount of drug compound released over a specific time interval by the total amount of drug compound initially present, and then multiplying this number by 100.

[0012]

[0031] Of course, the actual dosage level of the drug compound delivered will vary depending on the particular drug compound used and the intended duration of release. Dosage levels are generally high enough to provide a therapeutically effective amount of the drug compound that produces the desired therapeutic result, i.e., a level or amount effective to reduce or alleviate the symptoms of the condition for which the drug compound is administered. The exact amount required will vary depending on, among other factors, the subject being treated, the age and general condition of the subject to whom the polymeric drug compound is delivered, the competence of the subject's immune system, the degree of desired effect, the severity of the condition being treated, the particular polymeric drug compound selected, and the mode of administration of the composition. An appropriate effective amount can be readily determined by one of skill in the art. For example, effective amounts typically range from about 5 μg to about 200 mg, in some embodiments from about 5 μg to about 100 mg per day, and in some embodiments, from about 10 μg to about 1 mg of polymeric drug compound delivered per day.

[0013]

[0032] Various embodiments of the invention will now be described in more detail.

[0014] I. Core

[0033] As mentioned above, the core polymer matrix generally contains at least one polymer that is hydrophobic in nature, so that it can maintain structural integrity for a certain period of time when placed in an aqueous environment such as a mammalian body, and can be sufficiently stable for long-term storage before use.Examples of hydrophobic polymers suitable for this purpose may include, for example, silicone polymers, polyolefins, polyvinyl chloride, polycarbonate, polysulfone, styrene-acrylonitrile copolymers, polyurethanes, silicone polyether-urethanes, polycarbonate-urethanes, silicone polycarbonate-urethanes, etc., and combinations thereof.Of course, hydrophilic polymers that are coated or otherwise encapsulated with hydrophobic polymers are also suitable for use in the core polymer matrix. Typically, the melt flow index of the hydrophobic polymer ranges from about 0.2 to about 100 g / 10 min, in some embodiments from about 5 to about 90 g / 10 min, in some embodiments from about 10 to about 80 g / 10 min, and in some embodiments from about 30 to about 70 g / 10 min, as determined according to ASTM D1238-13 at a temperature of 190° C. and a load of 2.16 kilograms.

[0015]

[0034] In certain embodiments, the core polymer matrix may contain a semi-crystalline olefin copolymer. The melting temperature of such olefin copolymers, as determined according to ASTM D3418-15, may range, for example, from about 40°C to about 140°C, in some embodiments from about 50°C to about 125°C, and in some embodiments, from about 60°C to about 120°C. Such copolymers are generally derived from at least one olefin monomer (e.g., ethylene, propylene, etc.) and at least one polar polymer grafted onto the polymer backbone and / or incorporated as a constituent of the polymer (e.g., block or random copolymer). Suitable polar monomers include, for example, vinyl acetate, vinyl alcohol, maleic anhydride, maleic acid, (meth)acrylic acids (e.g., acrylic acid, methacrylic acid, etc.), (meth)acrylates (e.g., acrylates, methacrylates, ethyl acrylate, methyl methacrylate, ethyl methacrylate, etc.), and the like. A wide variety of such copolymers can generally be used in the polymer compositions, such as ethylene vinyl acetate copolymers, ethylene (meth)acrylic acid polymers (e.g., ethylene acrylic acid copolymers and partially neutralized ionomers of these copolymers, ethylene methacrylic acid copolymers and partially neutralized ionomers of these copolymers, etc.), ethylene (meth)acrylate polymers (e.g., ethylene methacrylate copolymers, ethylene ethyl acrylate copolymers, ethylene butyl acrylate copolymers, etc.), etc. Regardless of the particular monomers selected, the inventors have discovered that certain aspects of the copolymer can be selectively controlled to help achieve desired release characteristics. For example, the polar monomer content of the copolymer can be selectively controlled within a range of about 10 wt% to about 60 wt%, in some embodiments, about 20 wt% to about 55 wt%, and in some embodiments, about 25 wt% to about 50 wt%. Conversely, the olefin monomer content of the copolymers may similarly range from about 40 wt% to about 90 wt%, in some embodiments from about 45 wt% to about 80 wt%, and in some embodiments, from about 50 wt% to about 75 wt%.

[0016]

[0035] In one particular embodiment, for example, the core polymer matrix may contain an ethylene vinyl acetate polymer, which is a copolymer derived from at least one ethylene monomer and at least one vinyl acetate monomer, and the density of the ethylene vinyl acetate copolymer is about 0.900 to about 1.00 grams cubic centimeter (g / cm), as determined according to ASTM D1505-10. 3 ), in some embodiments from about 0.910 to about 0.980 g / cm 3 and in some embodiments, from about 0.940 to about 0.970 g / cm 3The viscosity may range from 0.01 to 0.01 MPa. Examples of suitable ethylene vinyl acetate copolymers that may be used include those available from Celanese under the designation ATEVA® (e.g., ATEVA® 4030AC), from DuPont under the designation ELVAX® (e.g., ELVAX® 40W), and from Arkema under the designation EVATANE® (e.g., EVATANE 40-55). Any of a variety of techniques can generally be used to form ethylene vinyl acetate copolymers having the desired properties and are known in the art. In one embodiment, the polymer is produced by copolymerizing ethylene and vinyl acetate monomers in a high-pressure reaction. Vinyl acetate can be produced by oxidizing butane to produce acetic anhydride and acetaldehyde, which can be reacted together to form ethylidene diacetate. The ethylidene diacetate can then be pyrolyzed in the presence of an acid catalyst to form vinyl acetate monomer. Examples of suitable acid catalysts include aromatic sulfonic acids (e.g., benzenesulfonic acid, toluenesulfonic acid, ethylbenzenesulfonic acid, xylenesulfonic acid, and naphthalenesulfonic acid), sulfuric acid, and alkanesulfonic acids such as those described in U.S. Pat. Nos. 2,425,389 (Oxley et al.), 2,859,241 (Schnizer), and 4,843,170 (Isshiki et al.). Vinyl acetate monomer can also be produced by reacting acetic anhydride with hydrogen in the presence of a catalyst instead of acetaldehyde. This method directly converts vinyl acetate from acetic anhydride and hydrogen without the need to generate ethylidene diacetate. In yet another embodiment, vinyl acetate monomer can be produced by the reaction of acetaldehyde with a ketone in the presence of a suitable solid catalyst, such as a perfluorosulfonic acid resin or a zeolite.

[0017]

[0036] Also dispersed within the core polymer matrix are one or more drug compounds capable of inhibiting and / or treating a patient's condition, disease, and / or cosmetic condition. The drug compounds may be systemically or locally active, prophylactically, therapeutically, and / or cosmetically. Regardless, at least one drug compound within the core is a "polymeric" compound, in the sense of having a large molecular weight, such as about 0.5 kilodaltons ("kDa") or greater, in some embodiments about 1 kDa or greater, in some embodiments about 5 kDa to about 250 kDa, and in some embodiments about 20 kDa to about 200 kDa. Typically, the biological activity of such compounds is determined by the unique three-dimensional (e.g., folded) structure of the molecule. This three-dimensional molecular structure is substantially maintained by specific non-covalent interactions, such as hydrogen bonding and hydrophobic interactions (hydrophobicity) between atoms. The drug compounds may be naturally occurring or artificially produced by any method known in the art. Typically, it is also desirable for the drug compound to be stable at elevated temperatures so that it can be incorporated into the polymer matrix at or near the melting temperature of the hydrophobic polymer used in the core polymer matrix. For example, the drug compound typically remains stable at temperatures of about 25°C to about 120°C, in some embodiments about 40°C to about 110°C, in some embodiments about 40°C to about 100°C, in some embodiments about 40°C to about 80°C, and in some embodiments about 50°C to about 70°C.

[0018]

[0037] Specific examples of suitable macromolecular drug compounds may include, for example, proteins, peptides, enzymes, antibodies, interferons, interleukins, blood factors, vaccines, nucleotides, lipids, etc., as well as analogs, derivatives, and combinations thereof. Suitable proteins or peptides may include, for example, adrenocorticotropic hormone, angiotensin, beta-endorphin, bombesin, calcitonin, calcitonin gene-related polypeptide, cholecystokinin-8, colony-stimulating factors, desmopressin, endothelin, enkephalin, erythropoietin, gastrin, glucagon, human atrial natriuretic polypeptide, interferon, insulin, growth factors, growth hormone, luteinizing hormone-releasing hormone, melanocyte-stimulating hormone, muramyl dipeptide, neurotensin, oxytocin, parathyroid hormone, peptide T, secretin, somatomedin, somatostatin, thyroid-stimulating hormone, thyrotropin-releasing hormone, thyrotropin-stimulating hormone, vasoactive intestinal polypeptide, vasopressin, and the like. Suitable antibodies (e.g., monoclonal antibodies) may include, but are not limited to, HIV monoclonal antibody 2F5, rituximab, infliximab, trastuzumab, adalimumab, omalizumab, tositumomab, efalizumab, and cetuximab. Suitable interferons may include interferon alpha-2b, pegylated interferon alpha-2b, interferon alpha-2b plus ribavirin, interferon alpha-2a, pegylated interferon alpha-2a, interferon beta-1a, and interferon beta. Suitable blood factors may include alteplase / tenecteplase and rhesus factor VIIa. Suitable interleukins may include interleukin-2. Suitable vaccines may include whole virus particles, recombinant proteins, subunit proteins such as gp41, gp120 and gp140, DNA vaccines, plasmids, bacterial vaccines, polysaccharides such as extracellular capsular polysaccharides, and other vaccine vectors.Similarly, suitable nucleic acids can include RNA- or DNA-based molecules, such as oligonucleotides, aptamers, ribozymes, DNAzymes, and small interfering RNAs, such as messenger (mRNA), transfer (tRNA), ribosomal (rRNA), interfering (iRNA), small interfering (siRNA), and the like.

[0019]

[0038] The core can also optionally contain one or more excipients, if desired, to improve properties and processability, such as contrast agents, release modifiers, bulking agents, plasticizers, surfactants, crosslinking agents, flow aids, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc. If used, optional excipients typically comprise from about 0.01 wt% to about 20 wt%, in some embodiments from about 0.05 wt% to about 15 wt%, and in some embodiments, from about 0.1 wt% to about 10 wt% of the core. In one embodiment, for example, a contrast agent can be used to help ensure that the device can be detected in x-ray-based imaging techniques (e.g., computed tomography, projection radiography, fluoroscopy, etc.). Examples of such agents include, for example, barium-based compounds, iodine-based compounds, zirconium-based compounds (e.g., zirconium dioxide), and the like. One particular example of such an agent is barium sulfate. Other known antimicrobial and / or antiseptic agents can also be used to help prevent bacterial surface growth and adhesion, such as metal compounds (e.g., silver, copper, or zinc), metal salts, quaternary ammonium compounds, and the like.

[0020]

[0039] Regardless of the specific components used, the core can be formed via a variety of known techniques, such as hot-melt extrusion, injection molding, solution casting, dip coating, spray coating, microextrusion, coacervation, and the like. In one embodiment, hot-melt extrusion technology can be used. Hot-melt extrusion is a generally solvent-free process in which the components of the core (e.g., hydrophobic polymer, drug compound, optional excipients, etc.) are melt-blended and optionally shaped in a continuous manufacturing process, allowing for consistent output quality at high throughput rates. This technology is particularly well-suited for various types of hydrophobic polymers, such as olefin copolymers. That is, such copolymers typically exhibit a relatively high degree of long-chain branching accompanied by a broad molecular weight distribution. This combination of attributes can result in shear thinning of the copolymer during the extrusion process, helping to facilitate hot-melt extrusion. Additionally, polar comonomer units (e.g., vinyl acetate) can function as "internal" plasticizers by inhibiting crystallization of polyethylene chain segments. This can result in a lower melting point for the olefin copolymer, improving the overall flexibility of the resulting material and its ability to be formed into devices of a wide variety of shapes and sizes.

[0021]

[0040] During hot-melt extrusion, melt blending can occur at temperatures ranging from about 40°C to about 200°C, in some embodiments from about 60°C to about 180°C, and in some embodiments, from about 80°C to about 150°C, to form the polymer composition. Any of a variety of melt-blending techniques can generally be used. For example, the components can be fed, separately or in combination, into an extruder including at least one screw rotatably loaded and housed within a barrel (e.g., a cylindrical barrel). The extruder can be a single-screw or twin-screw extruder. For example, one embodiment of a single-screw extruder can include a housing or barrel and a screw rotatably driven at one end by a suitable driver (typically including a motor and gearbox). If desired, a twin-screw extruder including two separate screws can also be used. The screw configuration is not particularly critical and can include any number and / or orientation of flights and grooves, as is known in the art. For example, the screw typically includes flights forming a generally helical groove extending centrifugal around the core of the screw. A feed section and a melt section may be defined along the length of the screw. The feed section is the input portion of the barrel where the olefin copolymer and / or drug compound are added. The melt section is a phase change section where the copolymer changes from a solid to a liquid-like state. While these sections are not precisely delineated when an extruder is manufactured, it is well within the ordinary skill of one skilled in the art to reliably identify the feed section and the melt section where the solid-to-liquid phase change occurs. Although not required, the extruder may also have a mixing section located adjacent to the extrusion end of the barrel and downstream of the melt section. If desired, one or more distributive and / or dispersive mixing elements may be used in the mixing and / or melt section of the extruder. Suitable distributive mixers for single-screw extruders may include, for example, Saxon, Dulmage, and Cavity Transfer mixers. Similarly, suitable dispersive mixers may include Blister ring, Leroy / Maddock, and CRD mixers.As is well known in the art, mixing can be further improved by using pins within the barrel that create folding and reorientation of the polymer melt, such as those used in Buss Kneader extruders, Cavity Transfer mixers, and Vortex Intermeshing Pin mixers.

[0022]

[0041] If desired, the ratio of screw length ("L") to diameter ("D") can be selected to achieve an optimal balance of component throughput and blending. L / D values ​​can range, for example, from about 10 to about 50, in some embodiments from about 15 to about 45, and in some embodiments, from about 20 to about 40. Screw lengths can range, for example, from about 0.1 to about 5 meters, in some embodiments from about 0.4 to about 4 meters, and in some embodiments, from about 0.5 to about 2 meters. Similarly, screw diameters can range from about 5 to about 150 millimeters, in some embodiments from about 10 to about 120 millimeters, and in some embodiments, from about 20 to about 80 millimeters. In addition to length and diameter, other aspects of the extruder can also be selected to aid in achieving the desired degree of blending. For example, screw speed can be selected to achieve the desired residence time, shear rate, melt processing temperature, and the like. For example, screw speeds can range from about 10 to about 800 revolutions per minute ("rpm"), in some embodiments from about 20 to about 500 rpm, and in some embodiments, from about 30 to about 400 rpm. The apparent shear rate during melt blending was approximately 100 s -1 ~about 10,000 seconds -1 , in some embodiments, about 500 seconds -1 ~about 5000 seconds -1 , in some embodiments, about 800 seconds -1 ~about 1200 seconds -1 The apparent shear rate can be in the range of 4Q / Π R 3 where Q is the volumetric flow rate of the polymer melt (m 3 / s), and R is the radius ("m") of the capillary (e.g., extruder die) through which the molten polymer flows.

[0023]

[0042] Once melt-blended together, the resulting polymer composition may be in the form of pellets, sheets, fibers, filaments, etc., which can be shaped into a core using various known shaping techniques, such as injection molding, compression molding, nanomolding, overmolding, blow molding, three-dimensional printing, etc. Injection molding, for example, can involve two major stages: an injection stage and a holding stage. In the injection stage, the mold cavity is filled with the molten polymer composition. The holding stage begins after the injection stage is complete, and the holding pressure is controlled to pack additional material into the cavity and compensate for the volumetric shrinkage that occurs during cooling. After the shot is produced, it can then be cooled. Once cooling is complete, the mold is opened, and the part is ejected, for example, with the aid of ejection pins in the mold, to complete the molding cycle. Any suitable injection molding equipment can generally be used in the present invention. In one embodiment, an injection molding apparatus can be used, including a first mold base and a second mold base that together define a mold cavity having the shape of the core. The molding apparatus includes a resin flow path extending from the outer surface of the first mold half through a sprue to the mold cavity. The polymer composition can be fed into the resin flow path using a variety of techniques. For example, the composition can be fed (e.g., in pellet form) into a feed hopper attached to an extruder barrel containing a rotating screw (not shown). As the screw rotates, the pellets are advanced and subjected to pressure and friction, which generates heat and melts the pellets. A cooling mechanism can also be included to solidify the resin into the desired core shape (e.g., a disk, cylinder, etc.) within the mold cavity. For example, the mold base can include one or more cooling lines through which a cooling medium flows to impart a desired mold temperature to the surface of the mold base for solidification of the molten material. The mold temperature (e.g., the temperature of the mold surface) can range from about 50°C to about 120°C, in some embodiments from about 60°C to about 110°C, and in some embodiments, from about 70°C to about 90°C.

[0024]

[0043] As indicated above, another suitable technique for forming cores of desired shapes and sizes is three-dimensional printing. In this method, the polymer composition can be incorporated into a printer cartridge that is easily adapted for use with a printer system. The printer cartridge can contain, for example, a spool or other similar device that carries the polymer composition. For example, when supplied in the form of a filament, the spool can have a generally cylindrical rim around which the filament is wound. The spool can also define a bore or spindle for easy loading into the printer during use. Any of a variety of three-dimensional printer systems can be used with the present invention. Particularly suitable printer systems are extrusion-based systems, often referred to as "fused deposition modeling" systems. For example, the polymer composition can be supplied to a build chamber of a printhead containing a platen and a gantry. The platen can move along the vertical z-axis based on signals provided by a computer-operated controller. The gantry is a guide rail system that can be configured to move the printhead in the horizontal x-y plane within the build chamber based on signals provided by the controller. The print head is supported by the gantry and configured to print the feature structure onto the platen in a layer-by-layer manner based on signals provided by the controller. For example, the print head may be a dual-tip extrusion head.

[0025] II. Membrane layer

[0044] As noted above, the implantable device contains at least one membrane layer disposed adjacent to the outer surface of the core. The number of membrane layers can vary depending on the specific configuration of the device, the nature of the drug compound, and the desired release profile. For example, the device may contain only one membrane layer. For example, referring to FIGS. 1 and 2, one embodiment of an implantable device 10 is shown, which contains a core 40 having a generally circular cross-sectional shape and is elongated so that the resulting device is generally cylindrical in nature. The core 40 defines an outer peripheral surface 61 around which the membrane layer 20 is disposed. Like the core 40, the membrane layer 20 also has a generally circular cross-sectional shape and is elongated to cover the entire length of the core 40. When the device 10 is used, the drug compound can be released from the core 40 through the membrane layer 20 and thereby exit the outer surface 21 of the device.

[0026]

[0045] Of course, in other embodiments, the device may contain multiple membrane layers. For example, in the device of FIGS. 1 and 2, one or more additional membrane layers (not shown) can be disposed over membrane layer 20 to further aid in controlled release of the drug compound. In other embodiments, the device can be configured so that the core is disposed or sandwiched between separate membrane layers. For example, with reference to FIGS. 3 and 4, one embodiment of an implantable device 100 is shown that contains a core 140 having a generally circular cross-sectional shape and that has been elongated so that the resulting device is generally essentially disc-shaped. Core 140 defines an upper outer surface 161 on which first membrane layer 120 is located and a lower outer surface 163 on which second membrane layer 122 is located. Like core 140, first membrane layer 120 and second membrane layer 122 also have a generally circular cross-sectional shape that entirely covers core 140. If desired, the edges of membrane layers 120 and 122 may extend beyond the periphery of core 140, thereby sealing them together to cover any exposed areas of outer peripheral surface 170 of core 140. When device 100 is used, the drug compound may be released from core 140 through first membrane layer 120 and second membrane layer 122, thereby exiting the device's outer surfaces 121 and 123. Of course, if desired, one or more additional membrane layers (not shown) may be disposed over first membrane layer 120 and / or second membrane layer 122 to aid in further controlled release of the drug compound.

[0027]

[0046] Regardless of the particular configuration used, the membrane layer generally contains a membrane polymer matrix containing a hydrophobic polymer as described above. The polymer matrix typically comprises about 30 wt% to 100 wt%, in some embodiments about 40 wt% to about 99 wt%, and in some embodiments about 50 wt% to about 90 wt% of the membrane layer. When multiple membrane layers are used, it is typically desirable for each membrane layer to contain a polymer matrix including such a hydrophobic polymer. For example, a first membrane layer can contain a first polymer matrix, and a second membrane layer can contain a second polymer matrix. In such embodiments, the first and second polymer matrices each contain a hydrophobic polymer, which can be the same or different. Similarly, the hydrophobic polymer used in the membrane layer can be the same or different from the hydrophobic polymer used in the core. In one embodiment, for example, the core and membrane layer both use the same hydrophobic polymer (e.g., an α-olefin copolymer). In still other embodiments, the membrane layer may employ a hydrophobic polymer (e.g., an α-olefin copolymer) having a lower melt flow index than the polymer employed in the core. This, among other things, can further aid in controlling the release of the drug compound from the device. For example, the ratio of the melt flow index of the hydrophobic polymer employed in the core to the melt flow index of the hydrophobic polymer employed in the membrane layer may be from about 1 to about 20, in some embodiments from about 2 to about 15, and in some embodiments from about 4 to about 12. The melt flow index of the hydrophobic polymer of the membrane layer may range, for example, from about 1 to about 80 g / 10 min, in some embodiments from about 2 to about 70 g / 10 min, and in some embodiments from about 5 to about 60 g / 10 min, as determined, for example, according to ASTM D1238-13 at a temperature of 190°C and a 2.16 kilogram load. Examples of suitable ethylene vinyl acetate copolymers that may be employed include those available from Celanese under the designation ATEVA® (e.g., ATEVA® 4030AC or 2861A).

[0028]

[0047] As indicated above, the membrane layer used in the device can optionally contain a polymeric drug compound, as described above, dispersed within a polymer matrix. The drug compound in the membrane layer can be the same as or different from the drug compound used in the core. Regardless, when such a polymeric drug compound is used in the membrane layer, the membrane layer generally contains the drug compound in an amount such that the ratio of the concentration (wt%) of the drug compound in the core to the concentration (wt%) of the drug compound in the membrane layer is greater than 1, in some embodiments about 1.5 or greater, and in some embodiments about 1.8 to about 4. When used, the drug compound typically constitutes only about 1 wt% to about 40 wt%, in some embodiments about 5 wt% to about 35 wt%, and in some embodiments about 10 wt% to about 30 wt% of the membrane layer. Of course, in other embodiments, the membrane layer generally does not contain such a polymeric drug compound prior to release from the core. When multiple membrane layers are used, each membrane layer will generally contain the drug compound in an amount such that the ratio of the weight percentage of drug compound in the core to the weight percentage of drug compound in the membrane layer is greater than 1, in some embodiments is about 1.5 or greater, and in some embodiments is about 1.8 to about 4.

[0029]

[0048] The membrane layer and / or core may optionally contain one or more excipients described above to improve properties and processability, such as contrast agents, hydrophilic compounds, bulking agents, plasticizers, surfactants, crosslinking agents, flow aids, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc. If used, optional excipients typically comprise from about 0.01 wt% to about 60 wt%, in some embodiments from about 0.05 wt% to about 50 wt%, and in some embodiments, from about 0.1 wt% to about 40 wt% of the membrane layer.

[0030]

[0049] To help further control the release rate from the implantable device, for example, hydrophilic compounds can also be incorporated into the water-soluble and / or water-swellable polymer matrix of the membrane layer. If used, the weight ratio of hydrophobic polymer to hydrophilic compound within the membrane polymer matrix can range from about 0.25 to about 200, in some embodiments from about 0.4 to about 80, in some embodiments from about 0.8 to about 20, in some embodiments from about 1 to about 16, and in some embodiments from about 1.2 to about 10. Such hydrophilic compounds may comprise, for example, from about 1 wt% to about 50 wt%, in some embodiments from about 2 wt% to about 40 wt%, and in some embodiments from about 5 wt% to about 30 wt% of the membrane polymer matrix, while the hydrophobic polymer typically comprises from about 50 wt% to about 99 wt%, in some embodiments from about 60 wt% to about 98 wt%, and in some embodiments from about 70 wt% to about 95 wt% of the membrane polymer matrix. In such embodiments, the hydrophilic compound may similarly comprise about 1 wt% to about 50 wt%, in some embodiments, about 2 wt% to about 40 wt%, and in some embodiments, about 5 wt% to about 30 wt% of the membrane layer. Suitable hydrophilic compounds may include, for example, polymers, non-polymeric substances (e.g., glycerin, sugars, salts, peptides, etc.). Examples of suitable hydrophilic polymers include, for example, sodium, potassium, and calcium alginate, carboxymethylcellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycols (e.g., polyethylene glycol), collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polysaccharides, hydrophilic polyurethanes, polyhydroxyacrylates, dextran, xanthan, hydroxypropyl cellulose, methylcellulose, proteins, ethylene-vinyl alcohol copolymers, water-soluble polysilanes and silicones, water-soluble polyurethanes, and the like, as well as combinations thereof.Particularly suitable hydrophilic polymers are polyalkylene glycols, such as those having a molecular weight of about 100 to 500,000 grams per mole, in some embodiments about 500 to 200,000 grams per mole, and in some embodiments about 1,000 to about 100,000 grams per mole. Specific examples of such polyalkylene glycols include, for example, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyepichlorohydrin, and the like.

[0031]

[0050] One or more nonionic, anionic, and / or amphoteric surfactants may also be used to help create a uniform dispersion. When used, such surfactants typically comprise from about 0.05 wt% to about 8 wt%, in some embodiments from about 0.1 wt% to about 6 wt%, and in some embodiments from about 0.5 wt% to about 3 wt% of the core. Nonionic surfactants, which typically have a hydrophobic base (e.g., a long-chain alkyl group or an alkylated aryl group) and a hydrophilic chain (e.g., a chain containing ethoxy and / or propoxy moieties), are particularly suitable. Some suitable nonionic surfactants that can be used include ethoxylated alkylphenols, ethoxylated and propoxylated fatty alcohols, polyethylene glycol ethers of methyl glucose, polyethylene glycol ethers of sorbitol, ethylene oxide-propylene oxide block copolymers, fatty acids (C8-C9), and the like. 18Nonionic surfactants may include, but are not limited to, ethoxylated esters of ethylene oxide and long-chain amines or amides, condensation products of ethylene oxide and alcohols, fatty acid esters, monoglycerides or diglycerides of long-chain alcohols, and mixtures thereof. Particularly suitable nonionic surfactants may include ethylene oxide condensates of fatty alcohols, polyoxyethylene ethers of fatty acids, polyoxyethylene sorbitan fatty acid esters, and sorbitan fatty acid esters. The fatty components used to form such emulsifiers may be saturated or unsaturated, substituted or unsubstituted, and may contain 6 to 22 carbon atoms, in some embodiments 8 to 18 carbon atoms, and in some embodiments 12 to 14 carbon atoms. Polyoxyethylene-modified sorbitan fatty acid esters (e.g., monoesters, diesters, triesters, etc.) are a particularly useful group of nonionic surfactants. These materials are typically prepared by the addition of ethylene oxide to 1,4-sorbitan esters. The addition of polyoxyethylene converts the lipophilic sorbitan ester surfactants into hydrophilic surfactants that are generally soluble or dispersible in water. Such materials are commercially available under the name TWEEN® (e.g., TWEEN® 80 or polyethylene (20) sorbitan monooleate).

[0032]

[0051] The membrane layer can be formed using the same or a different technique than that used to form the core, such as hot melt extrusion, injection molding, solution casting, dip coating, spray coating, microextrusion, coacervation, etc. In one embodiment, a hot melt extrusion technique can be used. The core and membrane layer can also be formed separately or simultaneously. In one embodiment, for example, the core and membrane layer are formed separately and then joined together using known joining techniques, such as by stamping, hot sealing, adhesive bonding, etc.

[0033] III. Use of the Device

[0052] The implantable devices of the present invention can be used in a variety of different ways to inhibit and / or treat a patient's condition, disease, or cosmetic condition. The devices can be implanted subcutaneously, orally, mucosally, etc., using standard techniques. Delivery routes can be pulmonary, gastrointestinal, subcutaneous, intramuscular, or via introduction into the central nervous system, intraperitoneal, or intraorgan delivery. If desired, the device can be sealed in a package (e.g., a sterile blister package) prior to use. Materials and methods for sealing packages vary and are known in the art. In one embodiment, for example, the package can contain a substrate comprising any number of layers desired to achieve a desired level of protective properties, e.g., one or more, in some embodiments, one to four layers, and in some embodiments, one to three layers. Typically, the substrate comprises a polymer film, such as those formed from polyolefins (e.g., ethylene copolymers, propylene copolymers, propylene homopolymers, etc.), polyesters (e.g., polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), vinyl chloride polymers, vinyl chloridine polymers, ionomers, etc., as well as combinations thereof. One or multiple panels of the film can be sealed (e.g., heat sealed) together, for example, around peripheral edges, to form a cavity in which the device can be stored. For example, a single film can be folded at one or more points and sealed along its periphery to define a cavity in which the device is placed. To use the device, the package can be opened, for example, by breaking the seal, and the device can then be removed and implanted in a patient.

[0034]

[0053] The present invention may be better understood by reference to the following examples.

[0035] Test Method

[0054] Drug release: The release of a drug compound (e.g., bromelain) can be determined using an in vitro method. More specifically, an implantable device sample can be placed in 150 milliliters of aqueous sodium azide solution. The solution is sealed in a UV-protected 250 ml Duran® flask. The flask is then placed in a temperature-controlled water bath and continuously shaken at 100 rpm. A temperature of 37°C is maintained throughout the release experiment to mimic in vivo conditions. Samples are periodically removed by completely replacing the aqueous sodium azide solution. The concentration of the drug compound in solution is determined via UV / Vis absorption spectroscopy using a Cary 1 split-beam instrument. From this data, the amount of drug compound released (micrograms per hour) at each sampling interval is calculated and plotted over time (in hours). Additionally, the cumulative release rate of the drug compound is calculated as a percentage by dividing the amount of drug compound released at each sampling interval by the total amount of drug compound initially present and then multiplying this number by 100. This percentage is then plotted over time (in hours).

[0036] Examples 1 to 4

[0055] Four different types of core layers were formed with various concentrations of a hydrophobic polymer (Ateva® 4030AC) and a polymeric biological agent (bromelain). To form the samples, bromelain powder was first melt-mixed into Ateva® 4030AC using a Haake Rheomix 600p. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed for 8 minutes at 50°C. Mixing in the Rheomix 600p was performed using a roller-type rotor at 50 rpm. After 8 minutes, bromelain powder was added to the Ateva® 4030AC melt, and melt-mixing continued for 3 minutes at 50°C. After melt-mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) is placed between the EVA blend and the press plate. After cooling, the polyester film is removed. A disk with a diameter of 25 millimeters is punched out of the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain-embedded piece.

[0037]

[0056] The contents of bromelain and Ateva® 4030AC in the different core layers are presented in Table 1.

[0038] [Table 1]

[0039]

[0057] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 5 and 6.

[0040] Examples 5 to 7

[0058] Three different types of core membrane-implanted devices were formed using a core layer containing 20 wt% hydrophobic polymer and 80 wt% biologic in combination with various concentrations of membrane layer components. Bromelain powder was melt-mixed into Ateva® 4030AC using a Haake Rheomix 600p to form the core layer. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p was performed using a roller rotor at 50 rpm. After 8 minutes, bromelain powder was added to the Ateva® 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A disk with a diameter of 23 millimeters was punched out of the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain-embedded piece. The membrane layer was formed by melt-mixing Ateva® 4030AC and Luviskol® VA64 using a Haake Rheomix 600p in the same manner as described above, except that the resulting disk had a diameter of 25 millimeters. To form the core membrane embedment, a solvent bonding technique was used: a small amount of toluene was applied to the side of the disk using a brush, and then the sandwiched layers were immediately joined and pressed together. Pressure was maintained for 24 hours, and the toluene was allowed to evaporate. After this time, the edges of the core layer are sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette. The toluene is allowed to dry on the edges for at least 48 hours.Table 2 shows the core and membrane layer contents used in each example.

[0041] [Table 2]

[0042]

[0059] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 7 and 8.

[0043] Examples 8 to 13

[0060] Six different types of core membrane-implanted devices were formed using a core layer containing 40 wt% hydrophobic polymer and 60 wt% biologic in combination with various concentrations of membrane layer components. Bromelain powder was melt-mixed into Ateva® 4030AC using a Haake Rheomix 600p to form the core layer. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p was performed using a roller rotor at 50 rpm. After 8 minutes, bromelain powder was added to the Ateva® 4030AC melt, and melt mixing was continued for 3 minutes at 50°C. After melt mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A disk with a diameter of 23 millimeters was punched out of the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain-embedded piece. The membrane layer was formed by melt-mixing Ateva® 2861A and polyethylene glycol ("PEG") with a molecular weight of 100,000 grams per mole using a Haake Rheomix 600p, similar to the method described above, except that the mixing occurred at a temperature of 170°C and the resulting disk had a thickness of 0.5 millimeters and a diameter of 25 millimeters. To form the core membrane embedment, a solvent-bonding technique was used. That is, a small amount of toluene was applied to the side of the disk using a brush, and then the sandwiched layers were immediately joined and pressed together. The pressure is maintained for 24 hours to allow the toluene to evaporate, after which time the edges of the core layer are sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette.Allow the toluene to dry on the edges for at least 48 hours. Table 3 shows the contents of the core and membrane layers used for each example.

[0044] [Table 3]

[0045]

[0061] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 9 and 10.

[0046] Examples 14 to 18

[0062] Five different types of core membrane-implanted devices were formed using a core layer containing 40 wt% hydrophobic polymer and 60 wt% biologic in combination with various concentrations of membrane layer components. Bromelain powder was melt-mixed into Ateva® 4030AC using a Haake Rheomix 600p to form the core layer. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p was performed using a roller rotor at 50 rpm. After 8 minutes, bromelain powder was added to the Ateva® 4030AC melt, and melt mixing was continued for 3 minutes at 50°C. After melt mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A disk with a diameter of 23 millimeters was punched out of the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain-embedded piece. The membrane layer was formed by melt-mixing Ateva® 2861A and Luviskol® VA64 using a Haake Rheomix 600p in a manner similar to that described above, except that mixing occurred at a temperature of 170°C, the temperature used during pressing was 100°C, and the resulting disk had a thickness of 0.5 millimeters and a diameter of 25 millimeters. To form the core membrane embedment, a solvent-bonding technique was used: a small amount of toluene was applied to the side of the disk using a brush, and then the sandwiched layers were immediately joined and pressed together. The pressure is maintained for 24 hours to allow the toluene to evaporate. After this time, the edges of the core layer are sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette. The toluene is allowed to dry on the edges for at least 48 hours.Table 4 shows the core and membrane layer contents used in each example.

[0047] [Table 4]

[0048]

[0063] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 11 and 12.

[0049] Examples 19-20

[0064] Two different types of core membrane-implanted devices were formed using a core layer containing 40 wt% hydrophobic polymer and 60 wt% biologic in combination with various concentrations of membrane layer components. Bromelain powder was melt-mixed into Ateva® 4030AC using a Haake Rheomix 600p to form the core layer. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p was performed using a roller rotor at 50 rpm. After 8 minutes, bromelain powder was added to the Ateva® 4030AC melt, and melt mixing was continued for 3 minutes at 50°C. After melt mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A disk with a diameter of 23 millimeters was punched out of the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain-embedded piece. The membrane layer was formed by melt-mixing Ateva® 4030AC, polyethylene glycol ("PEG") with a molecular weight of 100,000 grams per mole, and bromelain powder using a Haake Rheomix 600p, similar to the method described above, except that the resulting disk had a diameter of 25 millimeters. To form the core membrane embedment, a solvent-bonding technique was used: a small amount of toluene was applied to the side of the disk using a brush, and then the sandwiched layers were immediately joined and pressed together. Pressure was maintained for 24 hours, and the toluene was allowed to evaporate. After this time, the edges of the core layer are sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette. The toluene is allowed to dry on the edges for at least 48 hours.Table 5 shows the core and membrane layer contents used in each example.

[0050] [Table 5]

[0051]

[0065] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 13 and 14.

[0052] Examples 21 to 23

[0066] Three different types of core membrane-implanted devices were formed using a core layer containing 40 wt% hydrophobic polymer and 60 wt% biologic in combination with various concentrations of membrane layer components. Bromelain powder was melt-mixed into Ateva® 4030AC using a Haake Rheomix 600p to form the core layer. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p was performed using a roller rotor at 50 rpm. After 8 minutes, bromelain powder was added to the Ateva® 4030AC melt, and melt mixing was continued for 3 minutes at 50°C. After melt mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A disk with a diameter of 23 millimeters was punched out of the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain-embedded piece. The membrane layer was formed by melt-mixing Ateva® 4030AC and polyethylene glycol ("PEG") with a molecular weight of 100,000 grams per mole using a Haake Rheomix 600p, similar to the method described above, except that mixing occurred at a temperature of 50°C, the temperature used during pressing was 80°C, and the resulting disk had a thickness of 0.5 millimeters and a diameter of 25 millimeters. To form the core membrane embedment, a solvent-bonding technique was used. That is, a small amount of toluene was applied to the side of the disk using a brush, and then the sandwiched layers were immediately joined and pressed together. The pressure is maintained for 24 hours to allow the toluene to evaporate, after which time the edges of the core layer are sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette.Allow the toluene to dry on the rim for at least 48 hours.

[0053] [Table 6]

[0054]

[0067] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 15 and 16.

[0055] Examples 24 to 27

[0068] Four different types of core membrane implantable devices were formed using a core layer containing 40 wt% hydrophobic polymer and 60 wt% biologic in combination with various concentrations of membrane layer components. The core layer was formed by melt-mixing collagen powder into Ateva® 4030AC using a Haake Rheomix 600p. First, Ateva® 4030AC pellets were loaded into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p was performed using a roller rotor at 50 rpm. After 8 minutes, the collagen powder was added to the Ateva® 4030AC melt, and melt-mixing continued for 3 minutes at 50°C. After melt-mixing, the blend was removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. To prevent the molten EVA film from adhering to the press surface, a low-adhesion, low-temperature-resistant polyester foil (Hostaphan® RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A disk with a diameter of 23 millimeters was punched out of the EVA-collagen sheet using a punching press to create a collagen-containing core layer / monolithic collagen embedment. The membrane layer was formed by melt-mixing Ateva® 4030AC and Luviskol® VA64 using a Haake Rheomix 600p in a manner similar to that described above, except that mixing occurred at a temperature of 50°C, the temperature used during pressing was 50°C, and the resulting disk had a thickness of 1.0 millimeter and a diameter of 25 millimeters. To form the core membrane embedment, a solvent-bonding technique was used: a small amount of toluene was applied to the side of the disk using a brush, and then the sandwiched layers were immediately joined and pressed together. Pressure was maintained for 24 hours, and the toluene was allowed to evaporate. After this time, the edges of the core layer are sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette. The toluene is allowed to dry on the edges for at least 48 hours.Table 7 shows the core and membrane layer contents used in each example.

[0056] [Table 7]

[0057]

[0069] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 17 and 18.

[0058] Examples 28 to 30

[0070] Three different types of core membrane implantable devices were formed using a core layer containing 40 wt% hydrophobic polymer and 60 wt% biologic in combination with various concentrations of membrane layer components. Core rods were formed by melt-blending bromelain powder into Ateva® 4030AC using a DSM benchtop twin-screw extruder with intermeshing conical screws. First, Ateva® 4030AC (1 mm fine powder) was dry-blended with bromelain. The blended mixture was then fed into the DSM extruder. The extrusion temperature was 60°C, and the screw speed was 50 rpm. The extruded filaments were cooled to room temperature and then cut into 30 mm long rods. The diameter of the extruded filaments was 3.4 mm. The membrane layer was formed by melt-blending Luviskol® VA64 powder into Ateva® 4030AC using a Haake Rheomix 600p. First, the Rheomix 600p chamber is filled with Ateva® 4030AC pellets and mixed for 8 minutes at 50°C. Mixing in the Rheomix 600p is performed using a roller-type rotor at 50 rpm. After 8 minutes, Luviskol® VA64 powder is added to the Ateva® 4030AC melt and melt mixing continues for 3 minutes at 50°C. After melt mixing, the blend is removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a heat press. The temperature during pressing is 50°C, the pressing time is 3 minutes, and the pressure is 100 bar.

[0059]

[0071] To prevent adhesion of the molten Ateva® 4030AC film to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) was placed between the Ateva® 4030AC blend and the press plate. After cooling, the polyester film was removed. To form the core membrane implant, a temperature bonding technique was used: the membrane layers and core rod were heated to 55°C for 30 minutes. A single membrane layer was then manually bonded to a single core rod by rolling the specimen over an extended period and applying gentle pressure. The ends of the cylinder and the seams between the membrane layer ends were then sealed using a concentrated solution of Ateva® 4030AC in toluene applied with a plastic pipette. The toluene was allowed to dry on the ends and seams for at least 48 hours. Table 8 shows the core and membrane layer contents used for each example.

[0060] [Table 8]

[0061]

[0072] Once the samples were formed, they were tested for release rate as described above, and the results are shown in Figures 19 and 20.

[0062]

[0073] These and other modifications and variations of the present invention may be practiced by those skilled in the art without departing from the spirit and scope of the present invention. In addition, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. Furthermore, those skilled in the art will appreciate that the foregoing description is merely exemplary and is not intended to limit the present invention, as further set forth in the appended claims. The claims as filed are as follows: [Claim 1] 1. An implantable device for the delivery of a macromolecular drug compound, comprising: a core having an outer surface, the core comprising a core polymer matrix having dispersed therein a drug compound having a molecular weight of about 0.5 kDa or greater, the polymer matrix comprising a hydrophobic polymer; and a membrane layer disposed adjacent to the outer surface of the core, the membrane layer comprising a membrane polymer matrix having the polymeric drug compound optionally dispersed therein, the concentration of the polymeric drug compound in the core being greater than the concentration of the polymeric drug compound in the membrane layer; The implantable device comprising: [Claim 2] 10. The implantable device of claim 1, wherein the device has a generally circular cross-sectional shape. [Claim 3] 3. The implantable device of claim 2, wherein the device has a diameter of about 0.5 to about 50 millimeters. [Claim 4] The implantable device of claim 1 , wherein the device is in the form of a cylinder. [Claim 5] 10. The implantable device of claim 1, wherein the device is in the form of a disk. [Claim 6] The implantable device of claim 1, wherein the polymeric drug compound constitutes about 5 wt% to about 60 wt% of the core and the core polymer matrix constitutes about 40 wt% to about 95 wt% of the core. [Claim 7] 10. The implantable device of claim 1, wherein the device is capable of releasing the polymeric drug compound for about 5 days or more. [Claim 8] 10. The implantable device of claim 1, wherein after 15 days, the device exhibits a cumulative release rate of about 20% to about 70% of the polymeric drug compound. [Claim 9] 10. The implantable device of claim 1, wherein after 30 days, the device exhibits a cumulative release rate of about 40% to about 85% of the polymeric drug compound. [Claim 10] 10. The implantable device of claim 1, wherein the hydrophobic polymer in the core polymer matrix comprises a semi-crystalline olefin copolymer. [Claim 11] 11. The implantable device of claim 10, wherein the semi-crystalline copolymer is derived from at least one olefinic monomer and at least one polar monomer. [Claim 12] 12. The implantable device of claim 11, wherein the olefin monomer comprises ethylene. [Claim 13] 12. The implantable device of claim 11, wherein the polar monomer comprises vinyl acetate, vinyl alcohol, maleic anhydride, maleic acid, acrylic acid, methacrylic acid, acrylate, methacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, or a combination thereof. [Claim 14] 12. The implantable device of claim 11, wherein the polar monomer comprises about 10 wt% to about 45 wt% of the copolymer. [Claim 15] 11. The implantable device of claim 10, wherein the olefin copolymer has a melting temperature of from about 40°C to about 140°C as determined according to ASTM D3418-15. [Claim 16] 11. The implantable device of claim 10, wherein the olefin copolymer comprises an ethylene vinyl acetate copolymer. [Claim 17] 10. The implantable device of claim 1, wherein the hydrophobic polymer has a melt flow index of about 0.2 to about 100 grams per 10 minutes as determined according to ASTM D1238-13 at a temperature of 190° C. and a load of 2.16 kilograms. [Claim 18] The implantable device of claim 1 , wherein the polymer matrix is ​​formed entirely from the hydrophobic polymer. [Claim 19] 10. The implantable device of claim 1, wherein the macromolecular drug compound is a protein, peptide, enzyme, antibody, interferon, interleukin, blood factor, vaccine, nucleotide, lipid, or combination thereof. [Claim 20] 10. The implantable device of claim 1, wherein the membrane layer comprises a membrane polymer matrix comprising a hydrophobic polymer. [Claim 21] 21. The implantable device of claim 20, wherein the membrane polymer matrix comprises about 30 wt% to 100 wt% of the membrane layer. [Claim 22] 21. The implantable device of claim 20, wherein the membrane layer does not contain the polymeric drug compound. [Claim 23] 21. The implantable device of claim 20, wherein the polymeric drug compound comprises about 1 wt% to about 40 wt% of the membrane layer. [Claim 24] 21. The implantable device of claim 20, wherein the ratio of the concentration of the polymeric drug compound in the core to the concentration of the polymeric drug compound in the membrane layer is about 1.5 or greater. [Claim 25] 21. The implantable device of claim 20, wherein the ratio of the melt flow index of the hydrophobic polymer in the core to the melt flow index of the hydrophobic polymer in the membrane layer is from about 1 to about 20, as determined according to ASTM D1238-13 at a temperature of 190°C and a load of 2.16 kilograms. [Claim 26] 21. The implantable device of claim 20, wherein the membrane polymer matrix also contains a hydrophilic compound. [Claim 27] 27. The implantable device of claim 26, wherein the hydrophilic compound constitutes about 1 wt% to about 50 wt% of the membrane polymer matrix and the hydrophobic polymer constitutes about 50 wt% to about 99 wt% of the membrane polymer matrix. [Claim 28] 21. The implantable device of claim 20, wherein the hydrophilic compound comprises a hydrophilic polymer. [Claim 29] 29. The implantable device of claim 28, wherein the hydrophilic polymer comprises sodium, potassium, or calcium alginate, carboxymethylcellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycol, collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polysaccharides, hydrophilic polyurethanes, polyhydroxyacrylates, dextran, xanthan, hydroxypropyl cellulose, methylcellulose, proteins, ethylene vinyl alcohol copolymers, water soluble polysilanes, water soluble silicones, water soluble polyurethanes, or combinations thereof. [Claim 30] 10. The implantable device of claim 1, wherein the core, the membrane layer, or both, contain a contrast agent. [Claim 31] 10. The implantable device of claim 1, wherein the core defines an outer peripheral surface around which the membrane layer is disposed. [Claim 32] 10. The implantable device of claim 1, wherein the core defines an upper outer surface and a lower outer surface, and the membrane layer is disposed adjacent the upper outer surface. [Claim 33] 33. The implantable device of claim 32, further comprising a second membrane layer disposed adjacent the lower outer surface. [Claim 34] 34. The implantable device of claim 33, wherein the second membrane layer comprises a second polymer matrix optionally having a polymeric drug compound dispersed therein, and wherein the concentration of the polymeric drug compound in the core polymer matrix is ​​greater than the concentration of the polymeric drug compound in the second membrane layer. [Claim 35] 33. The implantable device of claim 32, wherein the second membrane layer does not contain the drug compound. [Claim 36] 10. The implantable device of claim 1, wherein the core, the membrane layer, or both are formed by a hot melt extrusion process. [Claim 37] 37. A method of inhibiting and / or treating a condition, disease and / or cosmetic condition in a patient, the method comprising the step of subcutaneously implanting a device according to any one of claims 1 to 36 in the patient.

Claims

1. 1. An implantable device for the delivery of a macromolecular drug compound, comprising: The polymeric drug compound may be a protein, peptide, enzyme, antibody, interferon an interleukin, an interleukin, or a blood factor; a core having an outer surface, the core comprising a core polymer matrix having dispersed therein a drug compound having a molecular weight of about 5 kDa or greater, the polymer matrix comprising a hydrophobic polymer, the hydrophobic polymer comprising an ethylene vinyl acetate copolymer; and a membrane layer disposed adjacent to the outer surface of the core, the membrane layer comprising a membrane polymer matrix having the polymeric drug compound optionally dispersed therein, the concentration of the polymeric drug compound in the core being greater than the concentration of the polymeric drug compound in the membrane layer; Including, the membrane layer comprises a membrane polymer matrix comprising a hydrophobic polymer comprising an ethylene vinyl acetate copolymer and a hydrophilic compound, the hydrophilic compound comprising a hydrophilic polymer, the hydrophilic polymer comprising a polyalkylene glycol, the membrane polymer matrix comprising at least 70 wt % to about 99 wt % ethylene vinyl acetate copolymer; the membrane polymer matrix comprises 80 wt % to 100 wt % of the membrane layer; the device has a generally circular cross-sectional shape; When the core is in the form of a cylinder, the entire outer peripheral surface of the core is covered with the membrane layer; When the core is in the form of a disk, the entire upper and lower outer surfaces of the core are covered with the film layer, Other surfaces are sealed with ethylene vinyl acetate copolymer. the device has a diameter of about 0.5 to about 50 millimeters; The implantable device.

2. The implantable device of claim 1 , wherein the device is in the form of a cylinder.

3. 3. The implantable device of claim 1 or 2, wherein the device is in the form of a disk.

4. 4. The implantable device of claim 1, wherein the polymeric drug compound comprises from about 5 wt % to about 60 wt % of the core, and the core polymer matrix comprises from about 40 wt % to about 95 wt % of the core.

5. The implantable device of any one of claims 1 to 4, wherein the device is capable of releasing the polymeric drug compound for about 5 days or more.

6. The implantable device of any one of claims 1 to 5, wherein after 15 days, the device exhibits a cumulative release rate of about 20% to about 70% of the polymeric drug compound.

7. The implantable device of any one of claims 1 to 6, wherein after 30 days, the device exhibits a cumulative release rate of about 40% to about 85% of the polymeric drug compound.

8. 8. The implantable device of any one of claims 1 to 7, wherein the ethylene vinyl acetate copolymer has a melting temperature of from about 40°C to about 140°C as determined according to ASTM D3418-15.

9. 9. The implantable device of any one of claims 1-8, wherein the ethylene vinyl acetate copolymer has a melt flow index of about 0.2 to about 100 grams per 10 minutes as determined according to ASTM D1238-13 at a temperature of 190°C and a load of 2.16 kilograms.

10. The implantable device according to any one of claims 1 to 9, wherein the polymers constituting the core polymer matrix are all formed from hydrophobic polymers.

11. The implantable device of any one of claims 1 to 10, wherein the membrane layer does not contain the polymeric drug compound.

12. The implantable device of any one of claims 1 to 10, wherein the polymeric drug compound comprises from about 1 wt% to about 40 wt% of the membrane layer.

13. 13. The implantable device of any one of claims 1 to 10 and 12, wherein the ratio of the concentration of the polymeric drug compound in the core to the concentration of the polymeric drug compound in the membrane layer is about 1.5 or greater.

14. 14. The implantable device of any one of claims 1 to 13, wherein the ratio of the melt flow index of the hydrophobic polymer in the core to the melt flow index of the hydrophobic polymer in the membrane layer is from about 1 to about 20, as determined according to ASTM D1238-13 at a temperature of 190°C and a load of 2.16 kilograms.

15. The implantable device of any one of claims 1 to 14, wherein the hydrophilic compound comprises from about 1 wt% to about 30 wt% of the membrane polymer matrix.

16. The implantable device of any one of claims 1 to 15, wherein the core, the membrane layer, or both, contain a contrast agent.

17. An implantable device according to any preceding claim, wherein the core defines an outer peripheral surface around which the membrane layer is disposed.

18. 18. The implantable device of any one of claims 1 to 17, wherein the core defines upper and lower outer surfaces, and the membrane layer is disposed adjacent the upper outer surface.

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