Implantable device for sustained release of macromolecular drug compounds

Abstract

An implantable device for delivering a macromolecular drug compound is provided. The device includes a core having an outer surface and a film layer adjacent the outer surface of the core. The core comprises a core polymer matrix within which a drug compound having a molecular weight of about 0.5 kDa or greater is dispersed, the polymer matrix containing a hydrophobic polymer. Further, the membrane layer comprises a membrane polymer matrix within which the macromolecular drug compound is optionally dispersed. The membrane polymer matrix contains a hydrophobic polymer in combination with a hydrophilic compound, and a weight ratio of the hydrophobic polymer to the hydrophilic compound within the membrane polymer matrix is from about 0.25 to about 200.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Application Serial No. 62 / 675,994 (filed May 24, 2018), which is incorporated herein by reference in its entirety.

[0003] This application is a divisional application of a patent application filed on May 20, 2019, with application number 2019800103704, and named "Implantable device for sustained release of macromolecular drug compounds". Background Art

[0004] Biomacromolecule drug compounds are usually composed of one or more oligomeric chains or polymeric chains, thereby forming a three-dimensional structure held together by non-covalent forces. Although these drug compounds have the potential to achieve multiple therapeutic effects, it is traditionally difficult to controllably deliver these compounds within a sustained period. For example, a variety of implantable delivery devices are formed by dissolving drug compounds in a matrix polymer. These dissolved drug molecules can diffuse through implants and release into patients. But unfortunately, drug elution is highly dependent on the diffusion coefficient of drug molecules, which is inversely proportional to the molecular weight of drug molecules. Therefore, macromolecular drug compounds tend to have lower diffusion coefficients due to their larger molecular weight. In addition, such compounds usually have chain length entanglements, which may further reduce the effective diffusion coefficient. Considering these difficulties, there continues to be a need for implantable delivery devices that can deliver macromolecular compounds in an effective amount within a sustained period. Summary of the invention

[0005] According to one embodiment of the present invention, an implantable device for delivering macromolecular drug compounds is disclosed. The device includes a core having an outer surface and a film layer 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 greater is dispersed, and the polymer matrix contains a hydrophobic polymer. In addition, the film layer comprises a membrane polymer matrix, in which macromolecular drug compounds are optionally dispersed, wherein the membrane polymer matrix contains a hydrophobic polymer combined with a hydrophilic compound. The weight ratio of the hydrophobic polymer to the hydrophilic compound in the membrane polymer matrix is ​​from about 0.25 to about 200.

[0006] Other features and aspects of the invention are described in greater detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] A full and enabling disclosure of the invention, including the best mode to one of ordinary skill in the art, is more particularly set forth in the remainder of the specification with reference to the accompanying drawings, in which:

[0008] Figure 1 is a perspective view of one embodiment of an implantable device of the present invention;

[0009] Figure 2 yes Figure 1 A cross-sectional view of an implantable device;

[0010] Figure 3 is a perspective view of another embodiment of an implantable device of the present invention;

[0011] Figure 4 yes Figure 3 A cross-sectional view of an implantable device;

[0012] Figure 5 is a graph showing the cumulative release ratio of bromelain of Examples 1-4 versus release time (hours);

[0013] Figure 6 is a graph showing the release rate (μg / h) versus release time (hours) of the bromelain of Examples 1-4;

[0014] Figure 7 is a graph showing the cumulative release ratio of bromelain of Examples 5-7 versus release time (hours);

[0015] Figure 8 is a graph showing the release rate (μg / h) versus release time (hours) of the bromelain of Examples 5-7;

[0016] Fig. 9 is a graph showing the cumulative release ratio of bromelain of Examples 8-13 versus release time (hours);

[0017] Fig.10 is a graph showing the release rate (μg / h) versus release time (hours) of the bromelain of Examples 8-13;

[0018] Fig.11 is a graph showing the cumulative release ratio of bromelain of Examples 14-18 versus release time (hours);

[0019] Fig.12 is a graph showing the release rate (μg / h) versus release time (hours) of the bromelain of Examples 14-18;

[0020] Fig.13 is a graph showing the cumulative release ratio of bromelain of Examples 19-20 versus release time (hours);

[0021] Fig.14 is a graph showing the release rate (μg / h) versus release time (hours) of the bromelain of Examples 19-20;

[0022] Fig.15 is a graph showing the cumulative release ratio of bromelain of Examples 21-23 versus release time (hours);

[0023] Fig.16 is a graph showing the release rate (μg / h) versus release time (hours) of the bromelain of Examples 21-23;

[0024] Fig.17 is a graph showing the cumulative release ratio of collagen of Examples 24-27 versus release time (hours);

[0025] Fig.18 is a graph showing the release rate (μg / h) versus release time (hours) of collagen of Examples 24-27;

[0026] Fig.19 is a graph showing the cumulative release ratio of bromelain of Examples 28-30 versus release time (hours); and

[0027] Fig. 20 is a graph showing the release rate (μg / h) versus release time (hours) for Bromelain of Examples 28-30.

[0028] Repeat use of reference characters in the present specification and drawings is intended to represent the same or analogous features or elements of the present invention. DETAILED DESCRIPTION

[0029] Those of ordinary skill in the art will appreciate that the discussion presented is merely a description of exemplary embodiments and is not intended to limit the broader aspects of the invention.

[0030] In general, the present invention relates to an implantable device capable of delivering macromolecular drug compounds to prevent and / or treat illnesses, diseases and / or cosmetic conditions in patients (e.g., people, pets, farm animals, racehorses, etc.). Implantable devices can have various geometric shapes, such as cylinders (rods), discs, rings, doughnuts, spirals, ellipses, triangles, ovals, etc. For example, in one embodiment, the device can have a generally circular cross-sectional shape so that the overall structure is in the form of a cylinder (rod) or a disc. In such embodiments, the device will generally have a diameter of about 0.5 to about 50 millimeters, about 1 to about 40 millimeters in some embodiments, and about 5 to about 30 millimeters in some embodiments. The length of the device may vary, but is generally in the range of about 1 to about 25 millimeters. A cylindrical device may, for example, have a length of about 5 to about 50 millimeters, while a disc-shaped device may have a length of about 0.5 to about 5 millimeters.

[0031] Regardless of specific shape or size, the device is multilayered because it includes at least one film layer positioned adjacent to the outer surface of the core. The core includes a core polymer matrix, which includes a hydrophobic polymer and a macromolecular drug compound dispersed in the core polymer matrix. Typically, the macromolecular drug compound will constitute about 5% by weight to about 60% by weight of the core, about 10% by weight to about 50% by weight in some embodiments, and about 15% by weight to about 45% by weight in some embodiments, and the core polymer matrix constitutes about 40% by weight to about 95% by weight of the core, about 50% by weight to about 90% by weight in some embodiments, and about 55% by weight to about 85% by weight in some embodiments. One or more film layers also include a film polymer matrix, and the drug compound can be optionally dispersed in the film polymer matrix. The film polymer matrix contains a combination of a hydrophobic polymer and a hydrophilic compound (e.g., a hydrophilic polymer) that is soluble and / or swellable in water. To help achieve the desired release of macromolecular drug compounds, the weight ratio of hydrophobic polymer to hydrophilic compound within the film polymer matrix is ​​selectively controlled, such as in the range of about 0.25 to about 200, in some embodiments about 0.4 to about 80, in some embodiments about 0.8 to about 20, in some embodiments about 1 to about 16, and in some embodiments about 1.2 to about 10.

[0032] By selectively controlling the specific properties of the core and one or more membrane layers as indicated above and the way they are formed, the inventors have found that the resulting device can effectively release macromolecular drug compounds over a long period of time. For example, implantable devices can release drug compounds in a time period of about 5 days or longer, about 10 days or longer in some embodiments, about 20 days to about 60 days in some embodiments, and about 25 days to about 50 days (e.g., about 30 days) in some embodiments. In addition, the inventors have also found that drug compounds can be released in a controlled manner (e.g., zero-order or near-zero-order) in the release time period. For example, after 15 days, the cumulative release ratio of the implantable device can 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 ratio of the implantable device can 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 ratio" can be determined by dividing the amount of drug compound released during a specific time interval by the total amount of drug compound initially present, and then multiplying this value by 100.

[0033] Undoubtedly, the actual dosage level of the delivered drug compound will vary depending on the specific drug compound used and the time period of its intended release. The dosage level is generally high enough to provide a therapeutically effective amount of the drug compound to give the desired treatment result, that is, effectively reduce or alleviate the level or amount of the symptoms of the disease to which the drug is applied. The required precise amount will vary, especially depending on the subject being treated, the age and general condition of the subject delivering the macromolecular drug compound, the ability of the subject's immune system, the degree of the desired effect, the severity of the disease being treated, the selected specific macromolecular drug compound and the mode of administration of the composition. An appropriate effective amount can be easily determined by those skilled in the art. For example, the effective amount will generally be 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 macromolecular drug compounds are delivered per day in some embodiments.

[0034] Various embodiments of the invention will now be described in more detail.

[0035] I. Core

[0036] As indicated above, the core polymer matrix contains at least a polymer that is substantially hydrophobic in nature so that it can maintain its structural integrity for a period of time when placed in an aqueous environment, such as in a mammal, and is sufficiently stable to be stored for an extended period of time before use. For this purpose, examples of suitable hydrophobic polymers may include, for example, silicone polymers, polyolefins, polyvinyl chloride, polycarbonates, polysulfones, styrene acrylonitrile copolymers, polyurethanes, silicone polyether-polyurethanes, polycarbonate-polyurethanes, silicone polycarbonate-polyurethanes, and the like, and combinations thereof. Of course, hydrophilic polymers 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 is 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 kg.

[0037] In certain embodiments, the core polymer matrix may contain a semi-crystalline olefin copolymer. The melting temperature of such an olefin copolymer may be, 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, as determined according to ASTM D3418-15. Such copolymers are generally derived from at least one olefin monomer (e.g., ethylene, propylene, etc.) and at least one polar monomer grafted onto the polymer backbone and / or incorporated as a component of the polymer (e.g., block or random copolymers). 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) acrylic acid esters (e.g., acrylates, methacrylates, ethyl acrylates, methyl methacrylates, ethyl methacrylates, etc.), and the like. A variety of such copolymers can generally be employed in the polymer composition, 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.), and the like. Regardless of the specific monomers selected, the inventors have discovered that certain aspects of the copolymers can be selectively controlled to help achieve the 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 %, 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 copolymer can similarly be within the range of about 40 wt % to about 90 wt %, in some embodiments, about 45 wt % to about 80 wt %, and in some embodiments, about 50 wt % to about 75 wt %.

[0038] For example, in one embodiment, 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 ethylene-vinyl acetate copolymer may also have a density of about 0.900 to about 1.00 grams per cubic centimeter (g / cm 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 3 Examples of suitable ethylene-vinyl acetate copolymers that may be employed include those which may be named (For example 4030AC) purchased from Celanese under the name (For example 40W) from DuPont and under the name (e.g., EVATANE 40-55) purchased from Arkema. As known in the art, any of various techniques can generally be used to form ethylene-vinyl acetate copolymers with desired properties. In one embodiment, polymers are produced by copolymerizing ethylene monomers and vinyl acetate monomers in a high pressure reaction. Vinyl acetate can be produced by butane oxidation to produce acetic anhydride and acetaldehyde, which can react together to form ethylene diethyl ester. Then, ethylene diethyl ester can be thermally decomposed to form vinyl acetate monomers in the presence of an acid catalyst. 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 described in U.S. Patent Nos. 2,425,389, 2,859,241 of Schnizer and 4,843,170 of Isshiki et al. to Oxley et al. Vinyl acetate monomers can also be produced by reacting acetic anhydride with hydrogen instead of acetaldehyde in the presence of a catalyst. This process converts vinyl acetate directly from acetic anhydride and hydrogen without the need to produce ethylene diethyl ester. In yet another embodiment, vinyl acetate monomer can be produced by reacting acetaldehyde and ketene in the presence of a suitable solid catalyst such as a perfluorosulfonic acid resin or a zeolite.

[0039] One or more pharmaceutical compounds capable of preventing and / or treating the patient's condition, disease and / or cosmetic state are also dispersed in the core polymer matrix. The pharmaceutical compound may be systemically or locally preventive, therapeutic and / or cosmetically active. In any case, at least one pharmaceutical compound in the core is a "macromolecule" compound in terms of its large molecular weight such as about 0.5 kilodaltons ("kDa") or greater, about 1kDa or greater in some embodiments, about 5kDa to about 250kDa in some embodiments, and about 20kDa to about 200kDa in some embodiments. In general, the biological activity of such compounds depends on the unique three-dimensional (e.g., folding) structure of the molecule. This three-dimensional molecular structure is generally maintained by specific non-covalent bonding interactions, such as hydrogen bonding and hydrophobic bonding interactions (hydrophobicity) between atoms. The pharmaceutical compound may be naturally occurring or artificially produced by any method known in the art. In general, the pharmaceutical compound is also required to 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 pharmaceutical compounds are typically stable at temperatures from about 25°C to about 120°C, in some embodiments from about 40°C to about 110°C, in some embodiments from about 40°C to about 100°C, in some embodiments from about 40°C to about 80°C, and in some embodiments from about 50°C to about 70°C.

[0040] Specific examples of suitable macromolecular drug compounds may include, for example, proteins, peptides, enzymes, antibodies, interferons, interleukins, blood factors, vaccines, nucleotides, lipids, and the like, as well as analogs, derivatives, and combinations thereof. Suitable proteins or peptides may include, for example, adrenocorticotropic hormone, vasoconstrictin, 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 factor, 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 α-2b, PEG interferon α-2b, interferon α-2b + ribavirin, interferon α-2a, pegylated interferon α-2a, interferon β-1a and interferon β. Suitable blood factors may include alteplase / tenecteplase and Rh 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 capsule polysaccharides, and other vaccine vectors. Likewise, suitable nucleic acids may include RNA- or DNA-based molecules, such as oligonucleotides, aptamers, RNases, DNases, and small interfering RNAs, such as messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), interfering RNA (iRNA), small interfering RNA (siRNA), and the like.

[0041] If desired, the core may also optionally contain one or more excipients, such as radiocontrast agents, release modifiers, fillers (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. to enhance properties and processability. When adopted, the optional one or more excipients generally constitute about 0.01% by weight to about 20% by weight of the core, and about 0.05% by weight to about 15% by weight in some embodiments, and about 0.1% by weight to about 10% by weight in some embodiments. For example, in one embodiment, radiocontrast agents can be used to help ensure that the device can be detected in imaging techniques based on X-rays (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), etc. A specific example of such an agent is barium sulfate. Other known antimicrobial and / or preservative agents may also be employed to help prevent surface growth and adsorption of bacteria, such as metal compounds (eg, silver, copper, or zinc), metal salts, quaternary ammonium compounds, and the like.

[0042] Regardless of the specific components used, the core can be formed by various known techniques, such as by hot melt extrusion, injection molding, solvent casting, dipping, spraying, micro extrusion, coagulation, etc. In one embodiment, hot melt extrusion technology can be used. Hot melt extrusion is generally a solvent-free process, wherein the components of the core (such as hydrophobic polymers, one or more pharmaceutical compounds, optional excipients, etc.) can be melt blended and optionally shaped in a continuous manufacturing process, thereby achieving consistent output quality with a high throughput rate. This technology is particularly well suited for various types of hydrophobic polymers, such as olefin copolymers. That is, this type of copolymer usually exhibits a relatively high degree of long chain branching, with a wide molecular weight distribution. The combination of this property can cause the copolymer to shear thinning during extrusion, which helps to promote hot melt extrusion. In addition, polar comonomer units (such as vinyl acetate) can act as "internal" plasticizers by preventing polyethylene segments from crystallizing. This can cause the melting point of olefin copolymers to be lower, which improves the overall flexibility of the resulting material and enhances its ability to be formed into devices with various shapes and sizes.

[0043] In the hot melt extrusion process, melt blending can occur 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 to form a polymer composition. Generally, any of a variety of melt blending techniques can be used. For example, the components can be supplied to an extruder separately or in combination, and the extruder includes at least one screw that can be rotatably mounted and housed in a barrel (e.g., a cylindrical barrel). The extruder can be a single screw or a twin screw extruder. For example, one embodiment of a single screw extruder may include a housing or barrel and a screw, and the screw can be driven to rotate at one end by a suitable drive device (usually including a motor and a gearbox). If necessary, a twin screw extruder comprising two separate screws can be used. The configuration of the screw is not particularly critical, and may include threads and channels of any number and / or orientation as known in the art. For example, the screw generally includes threads that form a substantially spiral channel extending radially around the screw core. The feed section and the melting section can be defined along the length of the screw. The feed section is the input portion of the barrel to which one or more olefin copolymers and / or one or more pharmaceutical compounds are added. The melting section is the phase change section where the copolymer changes from a solid to a liquid-like state. Although there is no accurate delineation of these sections when manufacturing the extruder, the feeding section and the melting section where the phase change from solid to liquid occurs can be reliably identified within the capabilities of those of ordinary skill in the art. Although not necessarily required, the extruder may also have a mixing section adjacent to the output end of the barrel and located downstream of the melting section. If necessary, one or more distribution and / or dispersive mixing elements may be used in the mixing and / or melting section of the extruder. Suitable distributive mixers for single-screw extruders may include, for example, Saxon, Dulmage, cavity transfer mixers, etc. Similarly, suitable dispersive mixers may include bubble 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 form folding and redirection of the polymer melt, such as those used in Buss kneading extruders, cavity transfer mixers, and vortex bite pin mixers.

[0044] If necessary, the ratio of the length ("L") to the diameter ("D") of the screw can be selected to achieve the optimal balance between the throughput and blending of the components. The L / D value can be, for example, from about 10 to about 50, from about 15 to about 45 in some embodiments, and from about 20 to about 40 in some embodiments. The length of the screw can be, for example, from about 0.1 to about 5 meters, from about 0.4 to about 4 meters in some embodiments, and from about 0.5 to about 2 meters in some embodiments. Similarly, the diameter of the screw can be from about 5 to about 150 millimeters, from about 10 to about 120 millimeters in some embodiments, and from about 20 to about 80 millimeters in some embodiments. In addition to the length and diameter, other aspects of the extruder can also be selected to help achieve the desired degree of blending. For example, the speed of the screw can be selected to achieve the desired residence time, shear rate, melt processing temperature, etc. For example, the screw speed can be from about 10 to about 800 revolutions per minute ("rpm"), from about 20 to about 500rpm in some embodiments, and from about 30 to about 400rpm in some embodiments. The apparent shear rate during melt blending may also be about 100 seconds -1 to about 10,000 seconds -1 , in some embodiments about 500 seconds -1 to about 5000 seconds -1 , and in some embodiments about 800 seconds -1 to about 1200 seconds -1 The apparent shear rate is equal to 4Q / πR 3 , where Q is the volume 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.

[0045] Once melt blended together, the resulting polymer composition can be in the form of pellets, sheets, fibers, filaments, etc., and can be formed into a core using various known forming techniques, such as injection molding, compression molding, nano molding, overmolding, blow molding, three-dimensional printing, etc. Injection molding can occur, for example, in two main stages, namely the injection stage and the holding stage. In the injection stage, the mold cavity is filled with a molten polymer composition. After the injection stage is completed, the holding stage begins, wherein the holding pressure is controlled to fill additional materials into the cavity and compensate for the volume shrinkage that occurs during cooling. After the shot has been formed, it can be subsequently cooled. Once cooling is completed, the molding cycle is completed when the mold is opened and the parts are discharged, such as by means of a ejector pin in the mold. Generally, any suitable injection molding equipment can be used in the present invention. In one embodiment, the injection molding equipment that can be used includes a first mold base and a second mold base, which together define a mold cavity with a core shape. The molding equipment includes a resin flow path extending from the outer surface of the first mold half through a gate to the mold cavity. Various techniques can be used to supply the polymer composition to the resin flow path. For example, the composition can be supplied (e.g., in the form of pellets) to a feed hopper attached to an extruder barrel comprising a rotating screw (not shown). As the screw rotates, the pellets are moved forward and subjected to pressure and friction, which generates heat to melt the pellets. A cooling mechanism can also be provided to solidify the resin into the desired shape of the core (e.g., a disc, a rod, etc.) in the mold cavity. For example, the mold base may include one or more cooling lines through which a cooling medium flows to impart the desired mold temperature to the surface of the mold base, thereby solidifying the molten material. The mold temperature (e.g., the temperature of the mold surface) may be from about 50°C to about 120°C, from about 60°C to about 110°C in some embodiments, and from about 70°C to about 90°C in some embodiments.

[0046] As indicated above, another suitable technique for forming a core having a desired shape and size is three-dimensional printing. In this process, the polymer composition can be incorporated into a print box that is easily adapted for use with a printer system. The print box may, for example, include a spool or other similar device carrying the polymer composition. For example, when supplied in the form of a filament, the spool may have a substantially cylindrical rim around which the filament is wound. Similarly, the spool may define a hole or shaft that allows it to be easily mounted to the printer during use. Any of a variety of three-dimensional printer systems may be employed in the present invention. A particularly suitable printer system is an extrusion-based system, which is generally referred to as a "fused deposition modeling" system. For example, the polymer composition may be supplied to a construction chamber of a print head including a platen and a gantry. The platen may be movable along a vertical z-axis based on a signal provided by a computer-operated controller. The gantry is a rail system that may be configured to move the print head in a horizontal xy plane in the construction chamber based on a signal provided by the controller. The print head is supported by the gantry and is configured to print the construction structure on the platen in a layer-by-layer manner based on a signal provided by the controller. For example, the print head may be a dual-tip extruder.

[0047] II. Film

[0048] As indicated above, the implantable device comprises at least one membrane layer positioned adjacent to the outer surface of the core. The number of membrane layers may 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 comprise only one membrane layer. For example, referring to Figure 1-2 , shows an embodiment of an implantable device 10, which includes a core 40 having a generally circular cross-sectional shape and being elongated so that the resulting device is generally cylindrical in nature. The core 40 defines an outer circumferential surface 61, and the membrane layer 20 is circumferentially disposed around the surface 61. Similar to the core 40, the membrane layer 20 also has a generally circular cross-sectional shape and is elongated so that it covers the entire length of the core 40. During use of the device 10, the drug compound can be released from the core 40 through the membrane layer 20 so that it exits from the outer surface 21 of the device.

[0049] Of course, in other embodiments, the device may include multiple film layers. Figure 1-2 In the device of , one or more additional film layers (not shown) may be disposed on the film layer 20 to help further control the release of the drug compound. In other embodiments, the device may be configured such that the core is located or sandwiched between separate film layers. For example, referring to Figure 3-4, shows an embodiment of an implantable device 100, which includes a core 140 having a generally circular cross-sectional shape and being elongated so that the resulting device is generally disc-shaped in nature. The core 140 defines an upper outer surface 161 and a lower outer surface 163, with the first film layer 120 located on the upper outer surface 161 and the second film layer 122 located on the lower outer surface 163. Similar to the core 140, the first film layer 120 and the second film layer 122 also have a generally circular cross-sectional shape, which generally covers the core 140. If necessary, the edges of the film layers 120 and 122 can also extend beyond the periphery of the core 140 so that they can be sealed together, thereby covering any exposed areas of the outer circumferential surface 170 of the core 140. During use of the device 100, the drug compound can be released from the core 140 through the first film layer 120 and the second film layer 122, so that it leaves the outer surfaces 121 and 123 of the device. Of course, if necessary, one or more additional film layers (not shown) may be disposed on the first film layer 120 and / or the second film layer 122 to help further control the release of the drug compound.

[0050] Regardless of the specific configuration adopted, one or more film layers generally include a film polymer matrix containing hydrophobic polymers and hydrophilic compounds, such as described above. The polymer matrix generally constitutes about 30% by weight to 100% by weight of the film layer, about 40% by weight to about 99% by weight in some embodiments, and about 50% by weight to about 90% by weight in some embodiments. As shown above, the weight ratio of hydrophobic polymers to hydrophilic compounds in the film polymer matrix can be about 0.8 to about 20, about 1 to about 16 in some embodiments, and about 1.2 to about 10 in some embodiments. This type of hydrophilic compound can for example constitute about 1% by weight to about 50% by weight of the film polymer matrix, about 2% by weight to about 40% by weight in some embodiments, and about 5% by weight to about 30% by weight in some embodiments, while the hydrophobic polymer generally constitutes about 50% by weight to about 99% by weight of the film polymer matrix, about 60% by weight to about 98% by weight in some embodiments, and about 70% by weight to about 95% by weight in some embodiments. In such embodiments, the hydrophilic compound can also constitute about 1% to about 50% by weight of the film layer, in some embodiments about 2% to about 40% by weight, and in some embodiments about 5% to about 30% by weight. Suitable hydrophilic compounds can include, for example, polymers, non-polymeric materials (e.g., glycerol, sugars, salts, peptides, etc.), etc. Examples of suitable hydrophilic polymers include, for example, sodium alginate, potassium alginate and calcium alginate, carboxymethyl cellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycols (e.g., polyethylene glycol), collagen, pectin, chitin, chitosan, poly-1-caprolactone, polyvinyl pyrrolidone, poly (vinyl pyrrolidone-co-vinyl acetate), polysaccharides, hydrophilic polyurethanes, polyhydroxyacrylates, dextran, xanthan gum, hydroxypropyl cellulose, methylcellulose, proteins, ethylene-vinyl alcohol copolymers, water-soluble polysilanes and silicones, water-soluble polyurethanes, etc., and combinations thereof. Particularly suitable hydrophilic polymers are polyalkylene glycols, such as those having a molecular weight of about 100 to 500,000 g / mol, in some embodiments about 500 to 200,000 g / mol, and in some embodiments about 1,000 to about 100,000 g / mol. Specific examples of such polyalkylene glycols include, for example, polyethylene glycol, polypropylene glycol, polybutylene glycol, polyepichlorohydrin, and the like.

[0051] When multiple film layers are used, it is generally desired that each film layer comprises a polymer matrix including a hydrophobic polymer and a hydrophilic compound. For example, the first film layer may comprise a first film polymer matrix and the second film layer may comprise 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 the hydrophobic polymer in one film layer may be the same or different from those used in another film layer. For example, in one embodiment, the first and second polymer matrices employ the same hydrophilic compound (e.g., hydrophilic polymer) and hydrophobic polymer (e.g., α-olefin copolymer). Similarly, the hydrophobic polymer used in one or more film layers may also be the same or different from the hydrophobic polymer employed in the core. For example, in one embodiment, the core and one or more film layers employ the same hydrophobic polymer (e.g., α-olefin copolymer). In other embodiments, one or more film layers may employ a hydrophobic polymer (e.g., α-olefin copolymer) having a lower melt flow index than the polymer employed in the core. In particular, this may further help control 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 one or more film layers 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 in one or more film layers may be, 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 measured 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 employed include those that may be named (For example 4030AC or 2861A) those available from Celanese.

[0052] As shown above, one or more film layers used in the device may optionally include a macromolecular drug compound dispersed in a polymer matrix, such as described above. The drug compound in one or more film layers may be the same or different from the drug compound used in the core. In any case, when such a macromolecular drug compound is used in a film layer, the film layer generally includes a drug compound that makes the ratio of the concentration (weight %) of the drug compound in the core to the concentration (weight %) of the drug compound in the film layer higher than 1, in some embodiments, about 1.5 or higher, and in some embodiments, about 1.8 to about 4. When used, the drug compound generally only constitutes about 1 weight % to about 40 weight % of the film layer, in some embodiments, about 5 weight % to about 35 weight %, and in some embodiments, about 10 weight % to about 30 weight %. Undoubtedly, in other embodiments, before being released from the core, the film layer generally does not contain such macromolecular drug compounds. When multiple film layers are used, each film layer may generally include a drug compound that makes the ratio of the weight percentage of the drug compound in the core to the weight percentage of the drug compound in the film layer higher than 1, in some embodiments, about 1.5 or higher, and in some embodiments, about 1.8 to about 4.

[0053] One or more film layers and / or the core may also optionally include one or more excipients as described above, such as radiocontrast agents, fillers, plasticizers, surfactants, crosslinking agents, flow aids, colorants (e.g., chlorophyll, methylene blue, etc.), antioxidants, stabilizers, lubricants, other types of antimicrobial agents, preservatives, etc. to enhance properties and processability. When employed, the optional one or more excipients typically constitute about 0.01% to about 60% by weight of the film layer, and in some embodiments about 0.05% to about 50% by weight, and in some embodiments about 0.1% to about 40% by weight.

[0054] One or more nonionic, anionic and / or amphoteric surfactants can also be used to help form uniform dispersions. When used, such one or more surfactants usually constitute about 0.05% by weight to about 8% by weight of the core, and in some embodiments about 0.1% by weight to about 6% by weight, and in some embodiments about 0.5% by weight to about 3% by weight. It is particularly suitable to generally have a hydrophobic base (e.g., a long-chain alkyl or alkylated aryl) and a hydrophilic chain (e.g., a chain containing ethoxy and / or propoxy moieties). Some suitable nonionic surfactants that can be used include, but are not limited to, ethoxylated alkylphenols, ethoxylated and propoxylated fatty alcohols, polyethylene glycol ethers of methyl glucose, polyethylene glycol ethers of sorbitol, ethylene oxide-propylene oxide block copolymers, fats (C8-C 18) 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, etc. The fat component 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. Sorbitan fatty acid esters (e.g., monoesters, diesters, triesters, etc.) that have been modified with polyoxyethylene are a group of particularly useful nonionic surfactants. These materials are typically prepared by adding 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 may be named (For example 80 or polyethylene (20) sorbitan monooleate) is commercially available.

[0055] One or more membrane layers can be formed using the same or different techniques as used to form the core, such as by hot melt extrusion, injection molding, solvent casting, dip coating, spraying, micro extrusion, cohesion, etc. In one embodiment, hot melt extrusion techniques can be used. The core and one or more membrane layers can also be formed separately or simultaneously. For example, in one embodiment, the core and one or more membrane layers are formed separately and then combined together using known bonding techniques, such as by stamping, heat sealing, adhesive bonding, etc.

[0056] III. Use of the device

[0057] The implantable device of the present invention can be used in various ways to prevent and / or treat the disease, disease or cosmetic state in the patient. Standard techniques can be used to implant the device subcutaneously, orally, or through the mucosa. The delivery route can be intrapulmonary, gastrointestinal, subcutaneous, intramuscular, or introduced into the central nervous system, intraperitoneal, or intra-organ delivery. If necessary, the device can be sealed in a package (e.g., sterile blister package) before use. The material and method of the sealed package can be changed as known in the art. For example, in one embodiment, the package can include a substrate, and the substrate includes any number of layers required to achieve the desired degree of protection properties, such as 1 or more, 1 to 4 layers in some embodiments, and 1 to 3 layers in some embodiments. Typically, the substrate contains a polymer film, such as those formed by 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., and combinations thereof. One or more sheets of film may be sealed together (e.g., heat sealed), such as at peripheral edges, to form a cavity in which the device may be stored. For example, a single film may be folded at one or more points and sealed along its periphery to define a cavity in which the device is located. To use the device, the package may be opened, such as by breaking the seal, and the device may then be removed and implanted in a patient.

[0058] The present invention may be better understood with reference to the following examples.

[0059] Test methods

[0060] Drug Release: The release of drug compounds (e.g., bromelain) can be measured using an in vitro method. More specifically, a sample of the implantable device can be placed in 150 ml of an aqueous sodium azide solution. The solution is sealed in a 250 ml UV-protected flask. Then the flask is placed in a temperature-controlled water bath and shaken continuously at 100rpm. In the release experiment, a temperature of 37°C is maintained to simulate in vivo conditions. Samples are taken out at regular time intervals by completely exchanging the sodium azide aqueous solution. Using a Cary1 split beam instrument, the concentration of the drug compound in the solution is determined via UV / Vis absorption spectroscopy. The amount (micrograms / hour) of the drug compound released at each sampling interval is calculated from the data and plotted over time (hours). In addition, the cumulative release ratio of the drug compound is also calculated as a percentage by dividing the amount of the drug compound released at each sampling interval by the total amount of the drug compound initially present, and then multiplying the value by 100. The percentage is then plotted over time (hours).

[0061] Examples 1-4

[0062] At different concentrations of hydrophobic polymer ( 4030AC) and a macromolecular biologic (bromelain) to form four (4) different types of core layers. To form the samples, bromelain powder was initially melt compounded into a Haake Rheomix 600p. 4030AC. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out discs with a diameter of 25 mm from the EVA-bromelain sheet to produce a core layer / monolithic bromelain implant containing bromelain.

[0063] Bromelain and The 4030AC content is given in Table 1.

[0064] Table 1

[0065]

[0066] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 5-6 middle.

[0067] Embodiment 5-7

[0068] Three (3) different types of core-membrane implantable devices were formed using a core layer containing 20 wt% hydrophobic polymer and 80 wt% biologic in combination with different concentrations of the components in the membrane layer. Bromelain powder was melt compounded into the membrane using a Haake Rheomix 600p. 4030AC to form the core layer. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out discs with a diameter of 23 mm from the EVA-bromelain sheet to produce a bromelain-containing core / monolithic bromelain implant. The bromelain was melt compounded using a Haake Rheomix 600p in the same manner as described above. 4030AC and VA64 was used to form the membrane layer, except that the resulting disc had a diameter of 25 mm. To form the core-membrane implant, a solvent bonding technique was used. That is, a small amount of toluene was applied to the sides of the disc using a paint brush, and then the sandwich layers were immediately bonded and pressed together. The pressure was maintained for 24 hours as the toluene evaporated. Thereafter, the core-membrane implant was formed using a solvent bonding technique applied using a plastic pipette. The high concentration toluene solution of 4030AC sealed the edges of the core layer. The edges were allowed to dry and drain the toluene for at least 48 hours. Table 2 shows the contents of the core and membrane layers used in each example.

[0069] Table 2

[0070]

[0071] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 7-8 middle.

[0072] Embodiment 8-13

[0073] Six (6) 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 different concentrations of components in the membrane layer. Bromelain powder was melt compounded into the membrane using a Haake Rheomix 600p. 4030AC to form the core layer. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out discs with a diameter of 23 mm from the EVA-bromelain sheet to produce a bromelain-containing core / monolithic bromelain implant. The bromelain was melt compounded using a Haake Rheomix 600p in the same manner as described above. 2861A and polyethylene glycol ("PEG") having a molecular weight of 100,000 g / mol were used to form the membrane layer, except that compounding occurred at a temperature of 170°C and the resulting disc had a thickness of 0.5 mm and a diameter of 25 mm. To form the core-membrane implant, a solvent bonding technique was used. That is, a small amount of toluene was applied to the sides of the disc using a paint brush, and then the sandwich layers were immediately bonded and pressed together. The pressure was maintained for 24 hours as the toluene evaporated. Thereafter, the core was bonded using a plastic pipette. The high concentration toluene solution of 4030AC sealed the edges of the core layer. The edges were allowed to dry and drain the toluene for at least 48 hours. Table 3 shows the contents of the core and membrane layers used in each example.

[0074] Table 3

[0075]

[0076] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 9-10 middle.

[0077] Examples 14-18

[0078] Five (5) 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 different concentrations of the components in the membrane layer. Bromelain powder was melt compounded into the membrane using a Haake Rheomix 600p. 4030AC to form the core layer. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out discs with a diameter of 23 mm from the EVA-bromelain sheet to produce a bromelain-containing core / monolithic bromelain implant. The bromelain was melt compounded using a Haake Rheomix 600p in the same manner as described above. 2861A and VA64 was used to form the membrane layer, except that compounding took place at a temperature of 170°C, the temperature used during pressing was 100°C, and the resulting disc had a thickness of 0.5 mm and a diameter of 25 mm. To form the core-membrane implant, a solvent bonding technique was used. That is, a small amount of toluene was applied to the sides of the disc using a paint brush, and then the sandwich layers were immediately bonded and pressed together. The pressure was maintained for 24 hours due to the evaporation of the toluene. Thereafter, the core was bonded using a plastic pipette. The high concentration toluene solution of 4030AC sealed the edges of the core layer. The edges were allowed to dry and drain the toluene for at least 48 hours. Table 4 shows the contents of the core and membrane layers used in each example.

[0079] Table 4

[0080]

[0081] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 11-12 middle.

[0082] Examples 19-20

[0083] Two (2) 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 different concentrations of the components in the membrane layer. Bromelain powder was melt compounded into the membrane using a Haake Rheomix 600p. 4030AC to form the core layer. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out discs with a diameter of 23 mm from the EVA-bromelain sheet to produce a bromelain-containing core / monolithic bromelain implant. The bromelain was melt compounded using a Haake Rheomix 600p in the same manner as described above. 4030AC, polyethylene glycol ("PEG") having a molecular weight of 100,000 g / mol, and bromelain powder were used to form the membrane layer, except that the resulting disc had a diameter of 25 mm. To form the core-membrane implant, a solvent bonding technique was used. That is, a small amount of toluene was applied to the sides of the disc using a paint brush, and then the sandwich layers were immediately bonded and pressed together. The pressure was maintained for 24 hours as the toluene evaporated. Thereafter, the membrane was sealed using a plastic pipette. The high concentration toluene solution of 4030AC sealed the edges of the core layer. The edges were allowed to dry and drain the toluene for at least 48 hours. Table 5 shows the contents of the core and membrane layers used in each example.

[0084] Table 5

[0085]

[0086]

[0087] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 13-14 middle.

[0088] Examples 21-23

[0089] Three (3) 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 different concentrations of the components in the membrane layer. Bromelain powder was melt compounded into the membrane using a Haake Rheomix 600p. 4030AC to form the core layer. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the bromelain powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out discs with a diameter of 23 mm from the EVA-bromelain sheet to produce a bromelain-containing core / monolithic bromelain implant. The bromelain was melt compounded using a Haake Rheomix 600p in the same manner as described above. 4030AC and polyethylene glycol ("PEG") having a molecular weight of 100,000 g / mol were used to form the membrane layer, except that compounding occurred at a temperature of 50°C, the temperature used during pressing was 80°C, and the resulting disc had a thickness of 0.5 mm and a diameter of 25 mm. To form the core-membrane implant, a solvent bonding technique was used. That is, a small amount of toluene was applied to the sides of the disc using a paint brush, and then the sandwich layers were immediately bonded and pressed together. The pressure was maintained for 24 hours as the toluene evaporated. Thereafter, the core was pressed using a plastic pipette. The high concentration toluene solution of 4030AC seals the edges of the core. Allow the edges to dry and drain the toluene for at least 48 hours.

[0090] Table 6

[0091]

[0092] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 15-16 middle.

[0093] Examples 24-27

[0094] Four (4) 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 different concentrations of the components in the membrane layer. 4030AC to form the core layer. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, the collagen powder was added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar. In order to prevent the molten EVA film from adhering to the surface of the press, a low-adhesion, temperature-resistant polyester foil ( RNK 23) was placed between the EVA blend and the press plate. After cooling, the polyester film was removed. A punch was used to punch out a disc with a diameter of 23 mm from the EVA-collagen sheet to produce a collagen-containing core layer / monolithic collagen implant. The implant was melt-compounded using a Haake Rheomix 600p in the same manner as described above. 4030AC and VA64 was used to form the membrane layer, except that compounding took place at a temperature of 50°C, the temperature used during pressing was 50°C, and the resulting disc had a thickness of 1.0 mm and a diameter of 25 mm. To form the core-membrane implant, a solvent bonding technique was used. That is, a small amount of toluene was applied to the sides of the disc using a paint brush, and then the sandwich layers were immediately bonded and pressed together. The pressure was maintained for 24 hours as the toluene evaporated. Thereafter, the core was bonded using a plastic pipette. The high concentration toluene solution of 4030AC sealed the edges of the core layer. The edges were allowed to dry and drain the toluene for at least 48 hours. Table 7 shows the contents of the core and membrane layers used in each example.

[0095] Table 7

[0096]

[0097] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 17-18 middle.

[0098] Examples 28-30

[0099] Three (3) 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 different concentrations of components in the membrane layer. Bromelain powder was melt compounded into the membrane using a DSM benchtop twin screw extruder with conical intermeshing screws. 4030AC is used to form the mandrel. First, 4030AC (1 mm fine powder) was dry blended with bromelain. The blended mixture was then fed into a 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. Using a Haake Rheomix 600p, VA64 powder is melted and mixed into 4030AC to form the film. First, use The 4030AC pellets were filled into the Rheomix 600p chamber and compounded at 50°C for 8 minutes. Compounding was performed in the Rheomix 600p using a roller rotor at 50 rpm. After 8 minutes, VA64 powder added 4030AC melt, and melt mixing was continued at 50°C for 3 minutes. After melt mixing, the blend was taken out of the Rheomix 600p and pressed into a 1 mm thick sheet using a hot press. The temperature during pressing was 50°C, the pressing time was 3 minutes, and the pressure was 100 bar.

[0100] To avoid melting 4030AC film is adhered to the surface of the press, and a low-adhesion, temperature-resistant polyester foil ( RNK 23) is placed 4030AC blend and the press plate. After cooling, the polyester film was removed. To form the core-film implant, a temperature bonding technique was used. That is, the film layers and the mandrel were heated to 55°C for 30 minutes. Then, a single film layer was manually attached to a single mandrel by applying gentle pressure while rolling the specimen for a long period of time. Thereafter, the film was bonded to the core using a plastic pipette. The high concentration toluene solution of 4030AC seals the joints between the ends of the cylinder and the ends of the membrane layer. Allow the edges and seams to dry and drain the toluene for at least 48 hours. Table 8 shows the contents of the core and membrane layer used in each example.

[0101] Table 8

[0102]

[0103] Once formed, the samples were tested for release rate as described above. The results are presented in Figure 19-20 middle.

[0104] Without departing from the spirit and scope of the present invention, these and other modifications and variations of the present invention may be practiced by those of ordinary skill in the art. In addition, it should be understood that the aspects of the various embodiments may be interchangeable in whole or in part. In addition, it will be appreciated by those of ordinary skill in the art that the foregoing description is by way of example only and is not intended to limit the present invention further described in the appended claims.

Claims

1. An implantable device for delivering a macromolecular drug compound, the device comprising: a core having an outer surface, wherein the core comprises a core polymer matrix, a drug compound having a molecular weight of at least about 0.5 kDa or greater dispersed within the core polymer matrix, the polymer matrix comprising a first ethylene-vinyl acetate copolymer; and a film layer adjacent to the outer surface of the core, wherein the film layer comprises a film polymer matrix, wherein the macromolecular drug compound is optionally dispersed within the film polymer matrix, wherein the film polymer matrix contains a second ethylene-vinyl acetate copolymer in combination with a hydrophilic compound, wherein the weight ratio of the second ethylene-vinyl acetate copolymer to the hydrophilic compound within the film polymer matrix is ​​from about 2.3 to about 99.

2. The implantable device of claim 1, wherein the device has a generally circular cross-sectional shape.

3. The implantable device of claim 2, wherein the device has a diameter of about 0.5 to about 50 millimeters.

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

5. The implantable device of claim 1, wherein the device is in the form of a disc.

6. The implantable device of claim 1, wherein the macromolecular drug compound comprises about 5% to about 60% by weight of the core and the core polymer matrix comprises about 40% to about 95% by weight of the core.

7. The implantable device of claim 1, wherein the device is capable of releasing the macromolecular drug compound for a period of about 5 days or longer.

8. The implantable device of claim 1, wherein after a period of 15 days, the device exhibits a cumulative release ratio of about 20% to about 70% of the macromolecular drug compound.

9. The implantable device of claim 1, wherein after a period of 30 days, the device exhibits a cumulative release ratio of about 40% to about 85% of the macromolecular drug compound.

10. The implantable device of claim 1, wherein the hydrophobic polymer of the core polymer matrix, the membrane polymer matrix, or both has a melt flow index of about 0.2 to about 100 g / 10 min as measured according to ASTM D1238-13 at a temperature of 190°C and a load of 2.16 kg.

11. The implantable device of claim 1, wherein the macromolecular drug compound is a protein, a peptide, an enzyme, an antibody, an interferon, an interleukin, a blood factor, a vaccine, a nucleotide, a lipid, or a combination thereof.

12. The implantable device of claim 1, wherein the ratio of the melt flow index of the first ethylene-vinyl acetate copolymer to the melt flow index of the second ethylene-vinyl acetate copolymer in the film layer is from about 1 to about 20, as measured in accordance with ASTM D1238-13 at a temperature of 190°C and a load of 2.16 kg.

13. The implantable device of claim 1, wherein the hydrophilic compound is a hydrophilic polymer.

14. The implantable device of claim 13, wherein the hydrophilic polymer comprises about 1 wt% to about 30 wt% of the membrane polymer matrix and the hydrophobic polymer comprises about 70 wt% to about 99 wt% of the membrane polymer matrix.

15. The implantable device of claim 13, wherein the hydrophilic polymer comprises sodium alginate, potassium alginate or calcium alginate, carboxymethyl cellulose, agar, gelatin, polyvinyl alcohol, polyalkylene glycol, collagen, pectin, chitin, chitosan, poly 1-caprolactone, polyvinyl pyrrolidone, poly(vinyl pyrrolidone-co-vinyl acetate), polysaccharide, hydrophilic polyurethane, polyhydroxyacrylate, dextran, xanthan gum, hydroxypropyl cellulose, methyl cellulose, protein, ethylene-vinyl alcohol copolymer, water-soluble polysilane, water-soluble silicone, water-soluble polyurethane, or a combination thereof.

16. The implantable device of claim 1, wherein the core, the membrane layer, or both comprise a radiocontrast agent.

17. The implantable device of claim 1, wherein the core defines an outer circumferential surface and the membrane layer is disposed circumferentially around the outer circumferential surface.

18. The implantable device of claim 1, wherein the core defines an upper outer surface and a lower outer surface, the membrane layer being disposed adjacent the upper outer surface.

19. The implantable device of claim 1, wherein the core, the film layer, or both are formed by hot melt extrusion.

20. A method of preventing and / or treating a disorder, disease and / or cosmetic condition in a patient, the method comprising subcutaneously implanting a device according to claim 1 in the patient.

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