Implantable device for sustained release of polymer 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 membrane polymer matrix contains a hydrophobic polymer in combination with a hydrophilic compound, and the weight ratio of hydrophobic polymer to hydrophilic compound within the membrane polymer matrix ranges from about 0.25 to about 200. [Selected Figure] Figure 1

Description

[Technical Field]

[0001] Related applications

[0001] This application claims priority to U.S. Patent Application No. 62 / 675,994 (filed May 24, 2018), which is incorporated herein by reference in its entirety. [Background technology]

[0002]

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

[0003]

[0003] According to one embodiment of the present invention, an implantable device for delivering a polymer drug compound is disclosed. The device comprises a core having an outer surface and a membrane layer disposed adjacent to the outer surface of the core. The core comprises a core polymer matrix in which a drug compound having a molecular weight of about 0.5 kDa or more is dispersed, and this polymer matrix contains a hydrophobic polymer. Furthermore, the membrane layer comprises a membrane polymer matrix in which a polymer drug compound is optionally dispersed, and this membrane polymer matrix contains a hydrophobic polymer in combination with a hydrophilic compound. The weight ratio of the hydrophobic polymer to the hydrophilic compound in the membrane polymer matrix is ​​in the range of about 0.25 to about 200.

[0004]

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

[0005]

[0005] A complete and possible disclosure of the present invention, including an optimal form, intended for those skilled in the art, is described more specifically in the remainder of this specification with reference to the accompanying drawings.

[0006] [Figure 1]

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

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

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

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

[0010] This graph shows the cumulative release rate of bromelain against the release time (hours) for Examples 1 to 4. [Figure 6]

[0011] This graph shows the release rate of bromelain (μg / hour) against the release time (hours) for Examples 1 to 4. [Figure 7]

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

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

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

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

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

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

[0018] It is a graph showing the cumulative release rate of bromelain with respect to the release time (hours) of Examples 19 to 20. [Figure 14]

[0019] It is a graph showing the release rate (μg / hour) of bromelain with respect to the release time (hours) of Examples 19 to 20. [Figure 15]

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

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

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

[0023] It is a graph showing the release rate (μg / hour) of collagen with respect to the release time (hours) of Examples 24 to 27. [Figure 19]

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

[0025] It is a graph showing the release rate (μg / hour) of bromelain with respect to the release time (hours) of Examples 28 to 30.

Mode for Carrying Out the Invention

[0007]

[0026] Reference numerals repeatedly used in this specification and the drawings are intended to represent the same or similar features or elements of the present invention.

[0008]

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

[0009]

[0028] Generally speaking, the present invention is directed to an implantable device capable of delivering a macromolecular drug compound to suppress and / or treat the condition, disease and / or cosmetic condition of a patient (e.g., human, pet, livestock, racehorse, etc.). The implantable device can have various different geometric shapes, such as cylindrical (rod), disc-shaped, ring, donut-shaped, helical, elliptical, triangular, oval, etc. In one embodiment, for example, the device may generally have a circular cross-sectional shape such that the overall structure is in the form of a cylinder (rod) or a disc. In such an embodiment, 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 typically ranges from about 1 to about 25 millimeters. The cylindrical device may have a length of, for example, about 5 to about 50 millimeters, while the disc-shaped device may have a length of about 0.5 to about 5 millimeters.

[0010]

[0029] Regardless of their specific shape or size, the device is multilayer in that it contains at least one membrane layer positioned adjacent to the outer surface of the core. The core contains a core polymer matrix containing a hydrophobic polymer and a polymeric drug compound dispersed within this core polymer matrix. Typically, the polymeric drug compound constitutes about 5 wt% to about 60 wt% of the core, about 10 wt% to about 50 wt% in some embodiments, and about 15 wt% to about 45 wt% in some embodiments, while the core polymer matrix constitutes about 40 wt% to about 95 wt% of the core, about 50 wt% to about 90 wt% in some embodiments, and about 55 wt% to about 85 wt% in some embodiments. The membrane layer also contains a membrane polymer matrix in which the drug compound may optionally be dispersed. The membrane polymer matrix contains a combination of a hydrophobic polymer and a hydrophilic compound (e.g., a hydrophilic polymer) that is soluble in water and / or expandable. To help achieve the desired release of polymeric drug compounds, the weight ratio of hydrophobic polymers to hydrophilic compounds in the membrane polymer matrix is ​​selectively controlled, for example, within the range of about 0.25 to about 200, about 0.4 to about 80 in some embodiments, about 0.8 to about 20 in some embodiments, about 1 to about 16 in some embodiments, and about 1.2 to about 10 in some embodiments.

[0011]

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

[0012]

[0031] Naturally, the actual dose level of the drug compound delivered varies depending on the specific drug compound used and the duration for which its release is intended. The dose level is generally high enough to provide a therapeutically effective amount of the drug compound that yields the desired therapeutic outcome; that is, to provide a level or amount effective in reducing or alleviating the symptoms of the condition to which the drug compound is administered. The exact amount required varies depending on several factors, including the subject being treated, the age and general condition of the subject to which the polymeric drug compound is delivered, the capacity of the subject's immune system, the desired degree of effect, the severity of the condition being treated, the specific polymeric drug compound selected, and the mode of administration of the composition. A suitable effective dose can be readily determined by those skilled in the art. For example, the effective dose is typically in the range of about 5 μg to about 200 mg, about 5 μg to about 100 mg per day in some embodiments, and about 10 μg to about 1 mg of the polymeric drug compound delivered per day in some embodiments.

[0013]

[0032] Herein, various embodiments of the present invention will be described in more detail.

[0014] I. Core

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

[0015]

[0034] In certain embodiments, the core polymer matrix may contain a semicrystalline olefin copolymer. The melting temperature of such an olefin copolymer, as determined according to ASTM D3418-15, can be, for example, in the range of about 40°C to about 140°C, about 50°C to about 125°C in some embodiments, and about 60°C to about 120°C in some embodiments. Such copolymers generally consist of 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 component 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 acid (e.g., acrylic acid, methacrylic acid, etc.), (meth)acrylate (e.g., acrylate, methacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, etc.), etc. A wide variety of such copolymers can be used in polymer compositions, for example, 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.), and so on. Regardless of the specific monomer selected, the inventors have found that certain aspects of the copolymer can be selectively controlled to help achieve desired release properties. For example, the polar monomer content of the copolymer can be selectively controlled within the range of about 10 wt% to about 60 wt%, about 20 wt% to about 55 wt% in some embodiments, and about 25 wt% to about 50 wt% in some embodiments. Conversely, the olefin monomer content of the copolymer can also be in the range of approximately 40 wt% to 90 wt%, approximately 45 wt% to 80 wt% in some embodiments, and approximately 50 wt% to 75 wt% in some embodiments.

[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. The density of the ethylene vinyl acetate copolymer is determined according to ASTM D1505-10 to be about 0.900 to about 1.00 grams per cubic centimeter (g / cm³). 3 In some embodiments, this is approximately 0.910 to 0.980 g / cm³. 3 In some embodiments, the amount is approximately 0.940 to 0.970 g / cm³. 3This can be within the range. Examples of suitable ethylene vinyl acetate copolymers that may be used include those available from Celanese under the name ATEVA® (e.g., ATEVA® 4030AC), from DuPont under the name ELVAX® (e.g., ELVAX® 40W), and from Arkema under the name EVATANE® (e.g., EVATANE 40-55). Various techniques can be commonly used to form ethylene vinyl acetate copolymers with desirable properties, and these are known in the art. In one embodiment, the polymer is produced by copolymerizing an ethylene monomer and a vinyl acetate monomer under high pressure. Vinyl acetate can be produced by oxidizing butane to produce acetic anhydride and acetaldehyde, which can be reacted together to form ethylidene diacetate. Ethylidene diacetate can then be thermally decomposed in the presence of an acid catalyst to form a 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. Patent No. 2,425,389, Oxley et al., U.S. Patent No. 2,859,241, Schnizer, and U.S. Patent No. 4,843,170, Isshiki et al. Vinyl acetate monomers 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 produce ethylidene diacetate. In another embodiment, vinyl acetate monomers 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 zeolite.

[0017]

[0036] One or more drug compounds that can suppress and / or treat a patient's condition, disease, and / or cosmetic condition are also dispersed within a core polymer matrix. The drug compounds may be prophylactic, therapeutic, and / or cosmetically active systemically or topically. Independently, at least one drug compound in the core is a “macromolecule” compound in the sense that it has a large molecular weight, such as about 0.5 kilodaltons ("kDa") or more, about 1 kDa or more in some embodiments, about 5 kDa to about 250 kDa in some embodiments, and about 20 kDa to about 200 kDa in some embodiments. Typically, the bioactivity of such compounds is determined by the specific three-dimensional (e.g., folding) structure of the molecule. This three-dimensional molecular structure is substantially maintained by specific non-covalent interactions such as hydrogen bonds and hydrophobic interactions (hydrophobicity) between atoms. Drug compounds may occur naturally or be artificially produced by any method known to the art. Typically, it is also desirable that the drug compound be stable at high 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 maintains a stable state at temperatures of about 25°C to about 120°C, 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 in some embodiments, and about 50°C to about 70°C in some embodiments.

[0018]

[0037] Specific examples of suitable macromolecular drug compounds may include, for example, proteins, peptides, enzymes, antibodies, interferons, interleukins, blood factors, vaccines, nucleotides, lipids, and their analogs, derivatives, and combinations. Suitable proteins or peptides may include, for example, adrenocorticotropic hormone, angiotensin, beta-endorphin, bombesin, calcitonin, calcitonin gene-related polypeptide, cholecystokinin-8, colony-stimulating factor, 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 others. Appropriate antibodies (e.g., monoclonal antibodies) may include, but are not limited to, HIV monoclonal antibody 2F5, rituxumab, infliximab, trastuzumab, adalimumab, omalizumab, tositumomab, efalizumab, and cetuximab. Appropriate interferons may include interferon alpha-2b, pegylated interferon alpha-2b, interferon alpha-2b + ribavirin, interferon alpha-2a, pegylated interferon alpha-2a, interferon beta-1a, and interferon beta. Appropriate blood factors may include alteplase / tenecteplase and rhesus factor VIIa. Appropriate interleukins may include interleukin-2. Appropriate vaccines may include whole viral particles, recombinant proteins, subunit proteins such as gp41, gp120, and gp140, DNA vaccines, plasmids, bacterial vaccines, polysaccharides such as extracellular capsule polysaccharides, and other vaccine vectors.Similarly, suitable nucleic acids may include RNA-based or DNA-based molecules, such as oligonucleotides, aptamers, ribozymes, DNAzymes, and small interfering RNAs, such as messenger RNA (mRNA), transfer RNA (tRNA), ribosome (rRNA), interference RNA (iRNA), and small interfering RNA (siRNA).

[0019]

[0038] The core may also optionally contain one or more excipients, such as contrast agents, release modifiers, fillers, plasticizers, surfactants, crosslinkers, flow aids, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc., to improve its properties and processability. When used, the optional excipients typically constitute about 0.01 wt% to about 20 wt% of the core, about 0.05 wt% to about 15 wt% in some embodiments, and about 0.1 wt% to about 10 wt% in some embodiments. 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, and zirconium-based compounds (e.g., zirconium dioxide). One specific example of such an agent is barium sulfate. Other known antimicrobial and / or preservatives can also be used to help prevent bacterial surface growth and adhesion, such as, for example, metal compounds (e.g., silver, copper, or zinc), metal salts, and quaternary ammonium compounds.

[0020]

[0039] Regardless of the specific components used, the core can be formed via various known techniques, such as hot-melt extrusion, injection molding, solution casting, dip coating, spray coating, microextrusion, and coacervation. In one embodiment, hot-melt extrusion technology can be used. Hot-melt extrusion is generally a solvent-free method in which the components of the core (e.g., hydrophobic polymers, pharmaceutical compounds, and optional excipients) are melt-blended and optionally shaped in a continuous manufacturing process, enabling consistent output quality at high processing rates. This technique is particularly suitable for various types of hydrophobic polymers, such as olefin copolymers, which typically exhibit a relatively high degree of long-chain branching with a broad molecular weight distribution. This combination of characteristics can lead to shear reduction of the copolymer during the extrusion process, which helps facilitate hot-melt extrusion. Furthermore, polar comonomer units (e.g., vinyl acetate) can function as "internal" plasticizers by suppressing crystallization of polyethylene chain segments. This can result in a lower melting point for olefin copolymers, improving the overall flexibility of the resulting material and enhancing its ability to be formed into devices of a wide variety of shapes and sizes.

[0021]

[0040] In hot-melt extrusion, the molten blend can be formed at a temperature range of about 40°C to about 200°C, in some embodiments about 60°C to about 180°C, and in some embodiments about 80°C to about 150°C. Any of the various molten blending techniques can be used in general. For example, the components can be fed separately or together into an extruder which includes at least one screw rotatably loaded and housed in 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 may include a housing or barrel, as well as a screw whose one end is rotationally driven by a suitable drive mechanism (typically including a motor and gearbox). A twin-screw extruder which includes two separate screws may be used if desired. The configuration of the screw is not particularly important and may include any number and / or directions of threads and grooves, which is known in the art. For example, a screw typically includes threads that form generally helical grooves extending centrifugally around the core of the screw. The feed section and the melt section may be defined along the length of the screw. The feed section is the input portion of the barrel, to which the olefin copolymer and / or pharmaceutical compound is added. The melt section is the phase change section, where the copolymer changes from a solid to a liquid-like state. While there is no precisely defined line between these sections when an extruder is manufactured, it is within the ordinary skill of a person skilled in the art to ensure that the feed section and the melt section where the solid-to-liquid phase change occurs are identified. Although not strictly necessary, an 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 distributing and / or dispersing mixing elements may be used within the mixing and / or melt section of the extruder. Suitable distributing mixers for a single-screw extruder may include, for example, Saxon, Dulmage, Cavity Transfer mixers. Similarly, suitable dispersing mixers may include Blister rings, Leroy / Maddock, CRD mixers, etc.As is well known in the art, mixing can be further improved by using pins in 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 the length ("L") to the diameter ("D") of the screw can be selected to achieve an optimal balance of throughput of the components and blend. The L / D value can be, for example, in the range of about 10 to about 50, in some embodiments about 15 to about 45, and in some embodiments about 20 to about 40. The length of the screw can be, for example, in the range of about 0.1 to about 5 meters, in some embodiments about 0.4 to about 4 meters, and in some embodiments about 0.5 to about 2 meters. Similarly, the diameter of the screw can be about 5 to about 150 millimeters, in some embodiments about 10 to about 120 millimeters, and in some embodiments about 20 to about 80 millimeters. In addition to the length and diameter, other aspects of the extruder can be selected to help achieve the desired degree of blending. For example, the screw speed can be selected to achieve the desired residence time, shear rate, melt processing temperature, etc. For example, the screw speed can be in the range of about 10 to about 800 revolutions per minute ("rpm"), in some embodiments about 20 to about 500 rpm, and in some embodiments about 30 to about 400 rpm. Also, the apparent shear rate during melt blending can be about 100 seconds -1 ~ about 10,000 seconds -1 and, in some embodiments, about 500 seconds -1 ~ about 5000 seconds -1 and, in some embodiments, about 800 seconds -1 ~ about 1200 seconds -1 and can be in the range of. The apparent shear rate is equal to 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] When melt-blended together, the resulting polymer composition may be in the form of pellets, sheets, fibers, filaments, etc., which can be fabricated onto a core using various known fabrication techniques, such as injection molding, compression molding, nanomolding, overmolding, blow molding, and 3D printing. Injection molding may involve, for example, two main 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 completed and controls the holding pressure to fill the cavity with additional material and compensate for volume shrinkage that occurs during cooling. After the shot is made, it can then be cooled. Once cooling is complete, the mold is opened and the part is ejected, for example with the help of an ejection pin in the mold, to complete the molding cycle. Any suitable injection molding equipment can generally be used in this invention. In one embodiment, an injection molding apparatus can be used that includes a first mold base and a second mold base that together define a mold cavity having the shape of a core. The molding apparatus includes a resin channel extending from the outer surface of half of the first mold through a sprue to the mold cavity. A polymer composition can be supplied to the resin channel using various techniques. For example, the composition can be supplied (e.g., in the form of pellets) to a feed hopper attached to an extruder barrel containing a rotating screw (not shown). As the screw rotates, the pellets move forward and are subjected to pressure and friction, which generates heat and melts the pellets. A cooling mechanism may also be provided to solidify the resin in the mold cavity into a desired core shape (e.g., disc shape, cylindrical shape, etc.). For example, the mold base may 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 shown above, another technique suitable for forming cores of desired shape and size is three-dimensional printing. In this method, the polymer composition can be incorporated into a printer cartridge that is easily adapted for use by a printer system. The printer cartridge may contain, for example, a spool or other similar device that supports the polymer composition. For example, when supplied in the form of a filament, the spool may generally have a cylindrical rim around which the filament is wound. The spool may also have a defined bore or spindle so that it can be easily loaded into the printer when in use. Any of the various three-dimensional printer systems can be used in this invention. A particularly suitable printer system is an extrusion-based system, which is often called a "fused deposition modeling" system. 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 may be configured to move the printhead in the horizontal xy-plane within the build chamber based on signals provided by the controller. The printhead is supported by a gantry and configured to print the structure onto the platen in a layer-by-layer manner based on signals provided by a controller. For example, the printhead may be a dual-chip extruder head.

[0025] II. Membrane layer

[0044] As shown above, the implantable device includes at least one membrane layer positioned adjacent to the outer surface of the core. The number of membrane layers may vary depending on the device-specific configuration, the properties of the drug compound, and the desired release profile. For example, the device may contain only one membrane layer. Referring, for example, to Figures 1 and 2, one embodiment of the implantable device 10 is shown, which includes a core 40 having a generally circular cross-sectional shape and is elongated so that the resulting device is generally essentially cylindrical. The core 40 defines an outer peripheral surface 61 on which the membrane layer 20 is positioned. Similar to 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. Using the device 10, the drug compound can be released from the core 40 through the membrane layer 20, thereby exiting from the outer surface 21 of the device.

[0026]

[0045] Naturally, in other embodiments, the device may contain multiple film layers. For example, in the devices of Figures 1 and 2, one or more additional film layers (not shown) can be placed on top of film layer 20 to assist in further controlled release of the drug compound. In other embodiments, the device can be configured such that the core is located between or sandwiched between separate film layers. Referring, for example, to Figures 3 and 4, one embodiment of an implantable device 100 is shown, which contains a core 140 having a generally circular cross-sectional shape, and the resulting device is elongated so that it is generally essentially disc-shaped. The core 140 defines an upper outer surface 161 on which the first film layer 120 is located and a lower outer surface 163 on which the second film layer 122 is located. Similar to the core 140, the first film layer 120 and the second film layer 122 also have a generally circular cross-sectional shape and cover the core 140 overall. If desired, the edges of the film layers 120 and 122 may extend beyond the periphery of the core 140, thereby allowing them to be sealed together to cover any exposed area of ​​the outer peripheral surface 170 of the core 140. Using device 100, the drug compound can be released from the core 140 through the first film layer 120 and the second film layer 122, thereby exiting the outer surfaces 121 and 123 of the device. Naturally, if desired, one or more additional film layers (not shown) may be placed on top of the first film layer 120 and / or the second film layer 122 to aid in further controlled release of the drug compound.

[0027]

[0046] Regardless of the specific configuration used, the film layer generally contains a film polymer matrix comprising the hydrophobic polymers and hydrophilic compounds described above. The polymer matrix typically constitutes about 30 wt% to 100 wt% of the film layer, about 40 wt% to 99 wt% in some embodiments, and about 50 wt% to 90 wt% in some embodiments. As shown above, the weight ratio of hydrophobic polymers to hydrophilic compounds in the film polymer matrix can range from about 0.8 to about 20, about 1 to about 16 in some embodiments, and about 1.2 to about 10 in some embodiments. Such hydrophilic compounds may constitute, for example, about 1 wt% to about 50 wt% of the membrane polymer matrix, about 2 wt% to about 40 wt% in some embodiments, and about 5 wt% to about 30 wt% in some embodiments, while hydrophobic polymers typically constitute about 50 wt% to about 99 wt% of the membrane polymer matrix, about 60 wt% to about 98 wt% in some embodiments, and about 70 wt% to about 95 wt% in some embodiments. In such embodiments, the hydrophilic compounds may similarly constitute about 1 wt% to about 50 wt% of the membrane layer, about 2 wt% to about 40 wt% in some embodiments, and about 5 wt% to about 30 wt% in some embodiments. 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 alginate, potassium and calcium, carboxymethylcellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycol (e.g., polyethylene glycol), collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polysaccharides, hydrophilic polyurethanes, polyhydroxyacrylates, dextran, xanthan gum, hydroxypropylcellulose, methylcellulose, proteins, ethylene vinyl alcohol copolymers, water-soluble polysilanes and silicones, water-soluble polyurethanes, and combinations thereof.Particularly suitable hydrophilic polymers are polyalkylene glycols, for example, those having molecular weights of about 100 to 500,000 grams per mole, about 500 to 200,000 grams per mole in some embodiments, and about 1,000 to 100,000 grams per mole in some embodiments. Specific examples of such polyalkylene glycols include, for example, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and polyepichlorohydrin.

[0028]

[0047] When using multiple film layers, it is typically desirable that each film layer contains a polymer matrix comprising a hydrophobic polymer and a hydrophilic compound. For example, the first film layer may contain a first film polymer matrix, and the second film layer may contain a second film polymer matrix. In such embodiments, the first and second polymer matrices each contain a hydrophobic polymer and a hydrophilic compound. The hydrophilic compound and hydrophobic polymer in one film layer may be the same as or different from those used in another film layer. In one embodiment, for example, both the first and second polymer matrices use the same hydrophilic compound (e.g., hydrophilic polymer) and hydrophobic polymer (e.g., α-olefin copolymer). Similarly, the hydrophobic polymer used in the film layer may be the same as or different from the hydrophobic polymer used in the core. In one embodiment, for example, both the core and the film layer use the same hydrophobic polymer (e.g., α-olefin copolymer). In other embodiments, the film layer may use a hydrophobic polymer (e.g., α-olefin copolymer) having a lower melt flow index than the polymer used in the core. In particular, this can further help in controlling the release of drug compounds from the device. For example, the ratio of the melt flow index of the hydrophobic polymer used in the core to the melt flow index of the hydrophobic polymer used in the membrane layer may be about 1 to about 20, about 2 to about 15 in some embodiments, and about 4 to about 12 in some embodiments. The melt flow index of the hydrophobic polymer in the membrane layer may range from about 1 to about 80 g / 10 min, about 2 to about 70 g / 10 min in some embodiments, and about 5 to about 60 g / 10 min in some embodiments, when determined according to ASTM D1238-13 at a temperature of 190°C and a load of 2.16 kilograms. Examples of suitable ethylene vinyl acetate copolymers that may be used may include those available from Celanese under the name ATEVA® (e.g., ATEVA® 4030AC or 2861A).

[0029]

[0048] As shown above, the film layer used in the device may optionally contain the polymer drug compound described above dispersed within a polymer matrix. The drug compound in the film layer may be the same as or different from the drug compound used in the core. Independently, when such a polymer drug compound is used in the film layer, the film layer generally contains the drug compound in such an amount that the ratio of the concentration (wt%) of the drug compound in the core to the concentration (wt%) of the drug compound in the film layer is greater than 1, about 1.5 or more in some embodiments, and about 1.8 to about 4 in some embodiments. When used, the drug compound typically constitutes only about 1 wt% to about 40 wt%, about 5 wt% to about 35 wt%, and about 10 wt% to about 30 wt% of the film layer. Naturally, in other embodiments, the film layer generally does not contain such polymer drug compound before being released from the core. When multiple membrane layers are used, each membrane layer may generally contain the drug compound in such an amount that the ratio of the weight percentage of the drug compound in the core to the weight percentage of the drug compound in the membrane layer is greater than 1, about 1.5 or more in some embodiments, and about 1.8 to about 4 in some embodiments.

[0030]

[0049] The film layer and / or core may optionally contain one or more excipients described above, such as contrast agents, fillers, plasticizers, surfactants, crosslinkers, flow aids, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc., to improve properties and processability. When used, the optional excipients typically constitute about 0.01 wt% to about 60 wt% of the film layer, about 0.05 wt% to about 50 wt% in some embodiments, and about 0.1 wt% to about 40 wt% in some embodiments.

[0031]

[0050] One or more nonionic, anionic, and / or amphoteric surfactants can also be used to help create a uniform dispersion. When used, such surfactants typically constitute about 0.05 wt% to about 8 wt% of the core, about 0.1 wt% to about 6 wt% in some embodiments, and about 0.5 wt% to about 3 wt% in some embodiments. Nonionic surfactants that typically have a hydrophobic base (e.g., a long-chain alkyl group or alkylated aryl group) and a hydrophilic chain (e.g., a chain containing an ethoxy and / or propoxy moiety) 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, and fatty acids (C8-C8). 18Nonionic surfactants may include, but are not limited to, ethoxylated esters of acids, condensation products of ethylene oxide with long-chain amines or amides, condensation products of ethylene oxide with 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, 8 to 18 carbon atoms in some embodiments, and 12 to 14 carbon atoms in some embodiments. Polyoxyethylene-modified sorbitan fatty acid esters (e.g., monoesters, diesters, triesters, etc.) are a particularly useful group of nonionic surfactants. These substances are typically prepared by adding ethylene oxide to 1,4-sorbitan esters. The addition of polyoxyethylene converts lipophilic sorbitan ester surfactants into hydrophilic surfactants that are generally soluble or dispersible in water. Such substances are commercially available under the name TWEEN® (e.g., TWEEN® 80 or polyethylene(20) sorbitan monooleate).

[0032]

[0051] The film layer may be formed using the same or different techniques as those used for forming the core, such as hot melt extrusion, injection molding, solution casting, dip coating, spray coating, microextrusion, or coacervation. In one embodiment, hot melt extrusion technology can be used. The core and film layer may also be formed separately or simultaneously. In one embodiment, for example, the core and film layer may be formed separately and then joined together using known joining techniques, such as stamping, hot sealing, or adhesive bonding.

[0033] III. Using the device

[0052] The implantable device of the present invention can be used in a variety of different ways to suppress and / or treat a patient's condition, disease, or cosmetic condition. The device can be implanted subcutaneously, orally, mucous membranes, etc., using standard techniques. The delivery route may be intrapulmonary, intragastrointestinal, subcutaneous, intramuscular, or delivery to the central nervous system, intraperitoneal, or intraorgan delivery. Where desired, the device may be sealed in a package (e.g., a sterile blister package) before use. There are various materials and methods for sealing the package, which are known in the art. In one embodiment, for example, the package may contain a substrate having any number of layers desired to achieve the desired level of protective properties, e.g., one or more, one to four layers in some embodiments, and one to three layers in some embodiments. Typically, the substrate contains a polymer film and is formed from, for example, polyolefins (e.g., ethylene copolymer, propylene copolymer, propylene homopolymer, etc.), polyesters (e.g., polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, etc.), vinyl chloride polymer, vinyl chloride polymer, ionomer, etc., and combinations thereof. One or more panels of the film can be sealed together, for example, at the peripheral edges (e.g., heat-sealed), 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 the periphery to define a cavity in which the device will be placed. To use the device, the package can be opened, for example, by breaking the seal, and then the device can be removed and implanted in the patient.

[0034]

[0053] The present invention can be better understood by referring to the following embodiments.

[0035] Test method

[0054] Drug Release: The release of drug compounds (e.g., bromelain) can be determined using an in vitro method. More specifically, an embedded device sample can be placed in 150 ml of sodium azide aqueous 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 shaken continuously at 100 rpm. A temperature of 37°C is maintained throughout the release experiment to mimic in vivo conditions. The sample is periodically removed by completely replacing the sodium azide aqueous solution. The concentration of the drug compound in the solution is determined by UV / Vis absorption spectroscopy using a Cary 1 split-beam instrument. From this data, the amount of drug compound released at each sampling interval (micrograms per hour) is calculated and plotted over time (in hours). Furthermore, the cumulative release rate of the drug compound is also 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 value by 100. Next, we plot this percentage over time.

[0036] Examples 1-4

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

[0037]

[0056] Table 1 shows the bromelain and Ateva® 4030AC content in different core layers.

[0038] [Table 1]

[0039]

[0057] After forming the sample, the release rate was tested as described above. The results are shown in Figures 5 and 6.

[0040] Examples 5-7

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

[0041] [Table 2]

[0042]

[0059] After forming the sample, the release rate was tested as described above. The results are shown in Figures 7 and 8.

[0043] Examples 8-13

[0060] Six different types of core-membrane embedded devices are formed by using core layers containing 40 wt% hydrophobic polymer and 60 wt% biologics in combination with membrane layer components of varying concentrations. The core layer is formed by melt-mixing bromelain powder with Ateva® 4030AC using a Haake Rheomix 600p. First, Ateva® 4030AC pellets are packed into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p is performed using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder is added to the Ateva® 4030AC molten material and melt-mixing is continued at 50°C for 3 minutes. After melt-mixing, the blend is removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing is 50°C, the pressing time is 3 minutes, and the pressure is 100 bar. To avoid adhesion of the molten EVA film to the press surface, 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 disc with a diameter of 23 mm is punched out from the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain embedding. A film layer is 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 occurs at a temperature of 170°C and the resulting disc has a thickness of 0.5 mm and a diameter of 25 mm. Solvent bonding technique is used to form the core film embedding. That is, a small amount of toluene is applied to the side of the disc using a brush, and then the sandwiched layers are joined together and pressed. Maintain the pressure for 24 hours to evaporate the toluene. After this time, seal the edges of the core layer using a high-concentration toluene solution of Ateva® 4030AC applied with a plastic pipette.Allow the toluene on the edges to dry for at least 48 hours. Table 3 shows the content of the core and film layers used in each example.

[0044] [Table 3]

[0045]

[0061] After forming the sample, the release rate was tested as described above. The results are shown in Figures 9 and 10.

[0046] Examples 14-18

[0062] Five different types of core-membrane embedded devices are formed by using core layers containing 40 wt% hydrophobic polymer and 60 wt% biopharmaceutical in combination with membrane layer components of varying concentrations. The core layer is formed by melt-mixing bromelain powder with Ateva® 4030AC using a Haake Rheomix 600p. First, Ateva® 4030AC pellets are packed into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p is performed using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder is added to the Ateva® 4030AC molten material and melt-mixing is continued at 50°C for 3 minutes. After melt-mixing, the blend is removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing is 50°C, the pressing time is 3 minutes, and the pressure is 100 bar. To avoid adhesion of the molten EVA film to the press surface, 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 disc with a diameter of 23 mm is punched out from the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain embedding. A film layer is formed by melt-mixing Ateva® 2861A and Luviskol® VA64 using a Haake Rheomix 600p, similar to the method described above, except that the mixing occurred at a temperature of 170°C, the temperature used during pressurization was 100°C, and the resulting disc had a thickness of 0.5 mm and a diameter of 25 mm. Solvent bonding technique is used to form the core film embedding. That is, a small amount of toluene is applied to the side of the disc using a brush, and then the sandwiched layers are joined together and pressed. Maintain pressure for 24 hours to evaporate the toluene. After this time, seal the edges of the core layer using a high-concentration toluene solution of Ateva® 4030AC applied with a plastic pipette. Allow the toluene on the edges to dry for at least 48 hours.Table 4 shows the content of the core and film layers used in each example.

[0047] [Table 4]

[0048]

[0063] After forming the sample, the release rate was tested as described above. The results are shown in Figures 11 and 12.

[0049] Examples 19-20

[0064] Two different types of core-membrane embedded devices are formed by using core layers containing 40 wt% hydrophobic polymer and 60 wt% biopharmaceutical in combination with membrane layer components of varying concentrations. The core layer is formed by melt-mixing bromelain powder with Ateva® 4030AC using a Haake Rheomix 600p. First, Ateva® 4030AC pellets are packed into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p is performed using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder is added to the Ateva® 4030AC molten material and melt-mixing is continued at 50°C for 3 minutes. After melt-mixing, the blend is removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing is 50°C, the pressing time is 3 minutes, and the pressure is 100 bar. To avoid adhesion of the molten EVA film to the press surface, 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 disc with a diameter of 23 mm is punched out from the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain embedding. A film layer is 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, in the same manner as described above, except that the resulting disc had a diameter of 25 mm. Solvent bonding technique is used to form the core film embedding. That is, a small amount of toluene is applied to the side of the disc using a brush, and then the sandwiched layers are joined together and pressed. The pressure is maintained for 24 hours to evaporate the toluene. After this time, the edges of the core layer are sealed using a high-concentration toluene solution of Ateva® 4030AC applied with a plastic pipette. Allow the toluene on the edges to dry for at least 48 hours.Table 5 shows the content of the core and film layers used in each example.

[0050] [Table 5]

[0051]

[0065] After forming the sample, the release rate was tested as described above. The results are shown in Figures 13 and 14.

[0052] Examples 21-23

[0066] Three different types of core-membrane embedded devices are formed by using core layers containing 40 wt% hydrophobic polymer and 60 wt% biologics in combination with membrane layer components of varying concentrations. The core layer is formed by melt-mixing bromelain powder with Ateva® 4030AC using a Haake Rheomix 600p. First, Ateva® 4030AC pellets are packed into the Rheomix 600p chamber and mixed at 50°C for 8 minutes. Mixing in the Rheomix 600p is performed using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder is added to the Ateva® 4030AC molten material and melt-mixing is continued at 50°C for 3 minutes. After melt-mixing, the blend is removed from the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing is 50°C, the pressing time is 3 minutes, and the pressure is 100 bar. To avoid adhesion of the molten EVA film to the press surface, 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 disc with a diameter of 23 mm is punched out from the EVA-bromelain sheet using a punching press to create a bromelain-containing core layer / monolithic bromelain embedding. A film layer is 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 the mixing occurred at a temperature of 50°C, the temperature used during pressurization was 80°C, and the resulting disc had a thickness of 0.5 mm and a diameter of 25 mm. Solvent bonding technique is used to form the core film embedding. That is, a small amount of toluene is applied to the side of the disc using a brush, and then the sandwiched layers are joined together and pressed. Maintain the pressure for 24 hours to evaporate the toluene. After this time, seal the edges of the core layer using a high-concentration toluene solution of Ateva® 4030AC applied with a plastic pipette.Allow the toluene on the edges to dry for at least 48 hours.

[0053] [Table 6]

[0054]

[0067] After forming the sample, the release rate was tested as described above. The results are shown in Figures 15 and 16.

[0055] Examples 24-27

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

[0056] [Table 7]

[0057]

[0069] After forming the sample, the release rate was tested as described above. The results are shown in Figures 17 and 18.

[0058] Examples 28-30

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

[0059]

[0071] To avoid adhesion of the molten Ateva® 4030AC film to the press surface, a low-adhesion, temperature-tolerant polyester foil (Hostaphan® RNK 23) is placed between the Ateva® 4030AC blend and the press plate. After cooling, the polyester film is removed. A temperature bonding technique is used to form the core film embedding. That is, the film layer and core rod are heated to 55°C for 30 minutes. Then, a single film layer is manually bonded to a single core rod by gently pressing the specimen while rolling it over an extended period of time. After this, the ends of the cylinder and the seams between the film layers are sealed using a high-concentration toluene solution of Ateva® 4030AC applied with a plastic pipette. The toluene at the ends and seams is allowed to dry for at least 48 hours. Table 8 shows the content of the core and film layers used in each example.

[0060] [Table 8]

[0061]

[0072] After forming the sample, the release rate was tested as described above. The results are shown in Figures 19 and 20.

[0062]

[0073] These and other modifications and variations of the present invention can be practiced by those skilled in the art without departing from the spirit and scope of the invention. In addition, it should be understood that the aspects of the various embodiments can be interchanged, either whole or in part. Furthermore, those skilled in the art will understand that the foregoing description is merely an example and is not intended to limit the invention, and is further described in the appended claims. The following is a description of the claims as they were at the time of filing the application. [Claim 1] An implantable device for delivering polymer drug compounds, A core having an outer surface, comprising a core polymer matrix in which a drug compound having a molecular weight of about 0.5 kDa or more is dispersed, wherein the polymer matrix contains a hydrophobic polymer; and The film layer is disposed adjacent to the outer surface of the core and comprises a film polymer matrix in which the polymer drug compound is optionally dispersed, wherein the film polymer matrix contains a hydrophobic polymer in combination with a hydrophilic compound, and the weight ratio of the hydrophobic polymer to the hydrophilic compound in the film polymer matrix is ​​in the range of about 0.25 to about 200; The embedded device, including the above. [Claim 2] The implantable device according to claim 1, wherein the device generally has a circular cross-sectional shape. [Claim 3] The implantable device according to claim 2, wherein the device has a diameter of approximately 0.5 to approximately 50 millimeters. [Claim 4] The embedded device according to claim 1, wherein the device is in the form of a cylinder. [Claim 5] The embedded device according to claim 1, wherein the device is in the form of a disk. [Claim 6] The implantable device according to claim 1, wherein the polymer 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] The implantable device according to claim 1, wherein the device is capable of releasing the polymer drug compound for a period of about 5 days or more. [Claim 8] The implantable device according to claim 1, wherein after 15 days, the device exhibits a cumulative release rate of approximately 20% to approximately 70% of the polymer drug compound. [Claim 9] The implantable device according to claim 1, wherein after 30 days, the device exhibits a cumulative release rate of approximately 40% to approximately 85% of the polymer drug compound. [Claim 10] The embedded device according to claim 1, wherein the hydrophobic polymer in the core polymer matrix, the membrane polymer matrix, or both comprises a semicrystalline olefin copolymer. [Claim 11] The embedded device according to claim 10, wherein the semicrystalline copolymer is derived from at least one olefin monomer and at least one polar monomer. [Claim 12] The embedded device according to claim 11, wherein the olefin monomer comprises ethylene. [Claim 13] The embedded device according to 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] The embedded device according to claim 11, wherein the polar monomer constitutes about 10 wt% to about 45 wt% of the copolymer. [Claim 15] The embedded device according to claim 10, wherein the olefin copolymer has a melting temperature of about 40°C to about 140°C, as determined according to ASTM D3418-15. [Claim 16] The embedded device according to claim 10, wherein the olefin copolymer comprises an ethylene vinyl acetate copolymer. [Claim 17] The implantable device according to claim 1, wherein the hydrophobic polymer in the core polymer matrix, the membrane polymer matrix, or both 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 embedded device according to claim 1, wherein the core polymer matrix is ​​formed entirely from the hydrophobic polymer. [Claim 19] The implantable device according to claim 1, wherein the polymer drug compound is a protein, peptide, enzyme, antibody, interferon, interleukin, blood factor, vaccine, nucleotide, lipid, or a combination thereof. [Claim 20] The embedded device according to claim 1, wherein the film polymer matrix constitutes approximately 30 wt% to 100 wt% of the film layer. [Claim 21] The implantable device according to claim 1, wherein the film layer does not contain the polymer drug compound. [Claim 22] The embedded device according to claim 1, wherein the polymer drug compound constitutes about 1 wt% to about 40 wt% of the film layer. [Claim 23] The implantable device according to claim 22, wherein the ratio of the concentration of the polymer drug compound in the core to the concentration of the polymer drug compound in the film layer is approximately 1.5 or more. [Claim 24] The implantable device according to claim 1, 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 film layer is 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 25] The embedded device according to claim 20, wherein the hydrophilic compound is a hydrophilic polymer. [Claim 26] The embedded device according to claim 25, wherein the hydrophilic polymer 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 27] The hydrophilic polymer includes sodium alginate, potassium or calcium, carboxymethylcellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycol, collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), polysaccharide, hydrophilic polyurethane, polyhydroxyacrylate, dextran, xanthan gum, hydroxypropylcellulose, methylcellulose, protein, ethylene vinyl alcohol copolymer, water-soluble polysilane, water-soluble silicone, water-soluble polyurethane, or a combination thereof. The implantable device according to claim 25. [Claim 28] The implantable device according to claim 1, wherein the core, the membrane layer, or both contain a contrast agent. [Claim 29] The embedded device according to claim 1, wherein the core defines the outer peripheral surface on which the film layer is arranged. [Claim 30] The embedded device according to claim 1, wherein the core defines an upper outer surface and a lower outer surface, and the film layer is disposed adjacent to the upper outer surface. [Claim 31] The embedded device according to claim 30, further comprising a second film layer disposed adjacent to the lower outer surface. [Claim 32] The implantable device according to claim 31, wherein the second membrane layer comprises a second membrane polymer matrix in which the polymer drug compound is optionally dispersed, the second membrane polymer matrix contains a hydrophobic polymer in combination with a hydrophilic compound, and the weight ratio of the hydrophobic polymer to the hydrophilic compound in the second membrane polymer matrix is ​​in the range of about 0.25 to about 200. [Claim 33] The implantable device according to claim 31, wherein the second membrane layer does not contain the drug compound. [Claim 34] The embedded device according to claim 1, wherein the core, the film layer, or both are formed by a hot-melt extrusion method. [Claim 35] A method for suppressing and / or treating a patient's condition, disease and / or cosmetic condition, comprising the step of implanting the device according to claim 1 under the patient's skin.

Claims

1. An implantable device for delivering polymer drug compounds, The aforementioned polymer drug compound is a protein, peptide, enzyme, antibody, interferon, interleukin, or blood factor. The core having an outer surface comprises a core polymer matrix in which a drug compound having a molecular weight of about 5 kDa or more is dispersed, wherein the polymer matrix contains a hydrophobic polymer, and the hydrophobic polymer contains an ethylene vinyl acetate copolymer; and The film layer is disposed adjacent to the outer surface of the core and comprises a film polymer matrix in which the polymer drug compound is optionally dispersed, wherein the film polymer matrix contains a hydrophobic polymer comprising ethylene vinyl acetate copolymer in combination with a hydrophilic compound, wherein the hydrophilic compound comprises a hydrophilic polymer, the hydrophilic polymer comprises polyalkylene glycol, and the weight ratio of the hydrophobic polymer to the hydrophilic compound in the film polymer matrix is ​​at least in the range of about 2.33 to about 200; Includes, The aforementioned device generally has a circular cross-sectional shape, In the case of a cylindrical shape, the entire outer peripheral surface of the core is covered with the film layer. In the case of a disc shape, the entire upper outer surface and lower outer surface of the core are covered with the film layer. The other surfaces are sealed with ethylene vinyl acetate copolymer. The device has a diameter of approximately 0.5 to approximately 50 millimeters. The aforementioned implantable device.

2. The embedded device according to claim 1, wherein the device is in the form of a cylinder.

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

4. The implantable device according to any one of claims 1 to 3, wherein the polymer 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.

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

6. An implantable device according to any one of claims 1 to 5, wherein after 15 days, the device exhibits a cumulative release rate of approximately 20% to approximately 70% of the polymer drug compound.

7. An implantable device according to any one of claims 1 to 6, wherein after 30 days, the device exhibits a cumulative release rate of approximately 40% to approximately 85% of the polymer drug compound.

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

9. An implantable device according to any one of claims 1 to 8, wherein the hydrophobic polymer in the core polymer matrix, the membrane polymer matrix, or both 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 all polymers constituting the core polymer matrix are hydrophobic polymers.

11. The embedded device according to any one of claims 1 to 10, wherein the film polymer matrix constitutes about 30 wt% to 100 wt% of the film layer.

12. The implantable device according to any one of claims 1 to 11, wherein the film layer does not contain the polymer drug compound.

13. The implantable device according to any one of claims 1 to 11, wherein the polymer drug compound constitutes about 1 wt% to about 40 wt% of the film layer.

14. The implantable device according to claim 13, wherein the ratio of the concentration of the polymer drug compound in the core to the concentration of the polymer drug compound in the film layer is about 1.5 or more.

15. The implantable device according to any one of claims 1 to 14, 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 film layer is 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.

16. The embedded device according to any one of claims 1 to 15, wherein the hydrophilic polymer constitutes about 1 wt% to about 30 wt% of the film polymer matrix.

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

18. The embedded device according to any one of claims 1 to 17, wherein the core defines the outer peripheral surface on which the film layer is arranged.

19. The embedded device according to any one of claims 1 to 18, wherein the core defines an upper outer surface and a lower outer surface, and the film layer is disposed adjacent to the upper outer surface.

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