Controlled Release Devices

Abstract

The present invention relates to an implantable and / or injectable device made of a biodegradable material comprising two hollow volumes, said device comprising a cylinder (60) having a top (61) and a bottom (62), said cylinder having open upper (63) and lower (64) ends through which a first hollow volume (65) and a second hollow volume (66) are accessed, respectively, said first hollow volume (65) and second hollow volume (66) being separated from each other by a partition (67), and wherein the thickness (70) of the side wall (68) of the first hollow volume (65) is smaller than the thickness (71) of the side wall (69) of the second hollow volume (66). The invention further relates to methods for manufacturing, loading with at least one active agent, and closing said device, and to the use of said device loaded with at least one active agent for the treatment and / or prevention of conditions requiring repeated, programmed administration over time.

Description

[Technical Field]

[0001] The present invention relates to a biodegradable device that can be injected and / or implanted into the human or animal body and that contains at least one active agent, which device allows for the programmed release of the active agent, where "programmed release" is understood to mean the release of predetermined doses, i.e., metered amounts, of said at least one active agent at discrete, predetermined times.

[0002] The invention further relates to methods for manufacturing, filling and closing the device.

[0003] Finally, the use of the above device for the treatment of conditions requiring repeated and programmed administration of at least one active agent is claimed. [Background technology]

[0004] prior art A range of conditions are known that require repeated programmed treatment, i.e., treatment that is repeated and at predetermined times and doses.

[0005] For example, the preferred treatment for macular disorders (the most common type of which is age-related macular degeneration (AMD)) consists of intravitreal injections of drugs, primarily those that inhibit endothelial growth factors (anti-VEGF drugs). A prerequisite for the effectiveness of the treatment is that the tissue should be regularly exposed to the anti-VEGF drugs.

[0006] Treatment with repeated injections presents compliance difficulties for patients and represents a significant cost to the health service.

[0007] WO 2011 / 097634 describes an intraocular implant for the release of two drug doses at two separate times, where the implant is activated by a laser to destroy and allow release at predetermined times.

[0008] The implants described in WO 2009 / 097468 also have an externally controlled release, and activation of the implant is actually obtained by means of a light source.

[0009] U.S. Patent Application Publication No. 2005 / 244465 describes an intraocular implant with a sandwich structure, in which a central portion contains a drug and two outer layers are made of a polymer material. The geometric parameters of the sandwich structure, in conjunction with the properties of the polymer material, regulate the release of the drug over time. The exemplified solution has the disadvantage that biodegradable polymer materials are used for production, resulting in the release of undesirable products that cause eye deterioration. Summary of the Invention

[0010] The present invention relates to a programmed release device that solves structural design problems that current state of the art devices cannot solve. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 shows in views A to F the steps for the assembly of an embodiment of an implantable and / or injectable device according to the invention which is a cylinder: (A) providing an innermost open hollow body and filling it; (B) closing the innermost hollow body; (C) providing a further open hollow body and filling it; (D) inserting the innermost hollow body inside a further hollow body; (E) providing an outermost hollow body and filling it; (F) inserting a further hollow body inside the outermost hollow body. [Figure 2] FIG. 2 shows a vertical cross-sectional view of an embodiment of an implantable and / or injectable device according to the present invention. [Figure 3] FIG. 3 shows a vertical section through a hollow body contained in a further embodiment of the device according to the invention, with a conical engaging closure. [Figure 4] FIG. 4 shows in views A and B a further embodiment of the closure of the device according to the invention. [Figure 5]Figure 5 shows, in figures A to F, the assembly steps of an embodiment of an implantable and / or injectable device according to the invention: (A) providing an innermost open hollow body and filling it; (B) closing the innermost hollow body; (C) providing a further open hollow body and filling it; (D) inserting the innermost hollow body inside a further hollow body; (E) providing an outermost hollow body and filling it; (F) inserting a further hollow body inside the outermost hollow body. [Figure 6] FIG. 6 shows a further embodiment of a device according to the invention: (A) vertical cross section; (B) perspective view; (C) top, front, and bottom views. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to an implantable and / or injectable device comprising at least two hollow bodies inserted one inside the other, the at least two hollow bodies being made of biodegradable material. The at least two hollow bodies define i) a volume within the innermost hollow body, referred to as the "core," and ii) one or more volumes, referred to as "annular spaces," located between the innermost hollow body and the outer hollow body. The core and the at least one annular space are designed to accommodate a dose of an active agent. The hollow bodies comprise cylinders.

[0013] In a preferred embodiment, the surface of the hollow body is an impermeable continuous surface that becomes permeable over time after implantation and / or injection of the device. Each side or wall of the cylinder is an impermeable continuous surface, and preferably at least one or both of the bases of the cylinder are also impermeable continuous surfaces that become permeable over time after implantation and / or injection of the device.

[0014] The number of hollow bodies inserted one inside the other to form an implantable device determines the therapeutic content. For example, an implantable device formed by two hollow bodies inserted one inside the other, and thus by two biodegradable layers, can release two doses of an active agent after implantation. An implantable device formed by three hollow bodies inserted one inside the other can release three doses of an active agent after implantation. An additional dose of the active agent can be administered during injection and / or implantation of the device, and the additional dose is administered simultaneously and not included in the injection and / or implantation of the device. Embodiments are envisioned that include up to 20 hollow bodies inserted one inside the other, preferably up to 10, or up to 5, preferably three hollow bodies inserted one inside the other.

[0015] With reference to Figures 1, 2 and 5, a device 1 comprising three hollow bodies inserted one inside the other will now be described in detail, purely by way of non-limiting example.

[0016] 1, 2, and 5F show vertical cross-sections of device 1, showing innermost hollow body 2 inserted inside intermediate hollow body 3, which in turn is inserted inside outer hollow body 4. The inner hollow body defines core 5, intermediate hollow body 3 defines annular space 6, and outer hollow body 4 defines annular space 7. Hollow bodies 2, 3, and 4 include, for example, cylinders with circular or elliptical bases or regular or irregular polygonal bases, e.g., triangular, square, or pentagonal bases, with a preferred embodiment being a cylinder with a circular base. For purposes of this specification, each of the hollow bodies is defined as a cylinder 2, 3, 4, which may be a prism with a triangular, square, pentagonal, n-gonal, elliptical, or circular base, and, with reference to FIGS. 1 and 5, includes a base support 8, 9 at one of the bases, which may be triangular, square, n-gonal, elliptical, or circular. The base supports 8, 9 have areas A, A' that are equal to or greater than the area of ​​the bases 29, 30 of the cylinders into which the hollow bodies are inserted, and can be inserted into any further hollow bodies into which the hollow bodies are inserted, or, referring to the embodiment shown in FIG. 5, the area A of the base support 8 is equal to or greater than the area of ​​the base 29 of the cylinder forming hollow body 3, such that once inserted, the base support 8 acts as a lid for hollow body 3 and can be inserted into the cylinder forming hollow body 4, as shown in FIG. 5D. The areas A, A' of the base supports 8, 9 are greater than the base areas 28, 29 of the cylinders 2, 3 to which the base supports 8, 9 are joined, and therefore the base supports 8, 9 protrude from the cylinders to which they are joined, and are equal to or greater than the area of ​​the bases 29, 30 of cylinders 3 and 4 into which cylinders 2, 3 are inserted, respectively, as shown in FIGS. 5B and 5C. In other words, the area A of the base support 8 of cylinder 2 is larger than the base area 28 of cylinder 2 and is the same as or larger than the area of ​​the base 29 of cylinder 3, so that when the base support 8 is inserted inside cylinder 3, it can act as a lid and area A can be inserted into a further cylinder 4.Referring to the embodiment shown in Figure 5A, the innermost hollow body 2 has a base support 8 with area A, the intermediate hollow body 3 (see Figure 5C) is a cylinder with a base with area A and a base support 9 with area A', and the outermost hollow body 4 (see Figure 5E) is a cylinder with base area A'.

[0017] In a preferred embodiment, the base supports 8, 9 are circular.

[0018] In an even more preferred embodiment, referring to Figure 1, the hollow bodies 2, 3, and 4 are cylinders with circular bases. In this embodiment, each of the hollow bodies 2, 3 forming the implantable / injectable device, except for the outermost hollow body 4, characteristically consists of a cylinder having a circular base support 8, 9 with a radius r, r', the length of the radii r, r' of the base supports 8, 9 being equal to or longer than the length of the base radius of the cylinder into which the hollow body is inserted and shorter than the length of the base radius of any additional hollow bodies into which the hollow body is inserted. In other words, referring to the embodiment shown in Figure 1, the radius r of the base support 8 is equal to or longer than the length of the base radius of the cylinder forming hollow body 3 and shorter than the length of the base radius of the cylinder forming hollow body 4. The lengths of the radii r, r' of the base supports 8, 9 are greater than the length of the base radius of the cylinders 2, 3 to which the base support is connected and smaller than the length of the base radius of the cylinders 3, 4 into which the cylinders 2, 3 are inserted, respectively. Referring to the embodiment shown in Figure 2, the innermost hollow body 2 has a base support 8 with a radius r. The middle hollow body 3 is a cylinder with a base radius of length r and a base support 9 with a radius r'. The outermost hollow body 4 is a cylinder with a base radius of length r'.

[0019] In the device, the requirements regarding the dimensions of the base support and base area are replicated for each of the further hollow bodies that form part of it.

[0020] The geometry of the device according to the invention advantageously solves the technical problem of assembling and filling devices comprising bodies inserted inside one another, with dimensions suitable for implantable and / or injectable devices. The advantages arising from the above structure will become apparent from the process leading to the assembly of the implantable / injectable device.

[0021] The hollow bodies 2, 3 and 4 are made from a biodegradable material, preferably magnesium or a magnesium alloy. Magnesium alloys, such as aluminum, lithium, calcium, zinc or manganese alloys, form a particularly preferred embodiment.

[0022] In a preferred embodiment, the device is made of the magnesium alloy JDBM, which is an alloy of Mg-2.5Nd-0.2Zn-0.4Zr (wt%, JDBM) with good mechanical and corrosion resistance properties. Alternatively, the alloy is JBDM-2, Mg-2.2Nd-0.1Zn-0.4Zr (wt%, denoted as JDMB-2).

[0023] The advantages obtained by using magnesium compounds in implantable and / or injectable devices relate to complete resorption due to limited corrosion resistance in moist environments and high biocompatibility of the corrosion products.

[0024] The thickness of the magnesium layer forming the hollow body determines its degree of decomposition, with greater thickness corresponding to longer decomposition times.

[0025] The device according to the present invention is impermeable and becomes permeable over time after implantation and / or injection of the device. In a preferred embodiment, this permeability is achieved by dissolution of the wall of the outermost hollow body. This dissolution occurs over time and after injection and depending on the thickness of the wall, resulting in the release of the active agent contained in the outermost hollow body. After the wall of the inserted hollow body is subsequently exposed to the implantation and / or injection environment, degradation of the wall of the inserted hollow body inside the outermost hollow body occurs, releasing the amount of active agent contained therein.

[0026] In one embodiment, the wall thickness of the hollow bodies is the same for each of the hollow bodies. In an alternative embodiment, which is advantageously applied when the active agent is a liquid, the wall thickness of the hollow bodies varies, increasing in the direction from the outermost hollow body to the innermost hollow body.

[0027] In preferred embodiments, the degradation time of each hollow body is 2 weeks, or 3 weeks, or 4 weeks, or 6 weeks, or 8 weeks, or 10 weeks, or 12 weeks.

[0028] In one embodiment, the core 5 and the one or more annular spaces 6, 7 have the same volume as each other. In an alternative embodiment, they have different volumes from each other.

[0029] In one embodiment, the implantable and / or injectable device comprises a cylinder, which for ophthalmic applications has a height of about 10 mm or about 5 mm and a circular base diameter or the diameter of a circle that the base can be inscribed in is equal to about 0.8 mm, 0.7 mm, or 0.6 mm. If the device is intended for non-ophthalmic applications, the cylinder has a height of 40 mm or less and a circular base diameter or the diameter of a circle that the base can be inscribed in is 4 mm or less.

[0030] The present invention further relates to methods for manufacturing, filling and closing implantable and / or injectable devices for the controlled release of active agents.

[0031] The method, with reference to FIG. 1, includes the following steps: a) providing single-open hollow bodies 2, 3, 4, each hollow body 2, 3, 4 being cylindrical and having side walls 11, 12, 13 and a base 28, 29, 30, each of said open hollow bodies which will form the inserted hollow bodies 2, 3 having a base support 8 on the base 28 and a base support 9 on the base 29 with areas A, A', the areas of the base supports 8, 9 being equal to or greater than the area of ​​the base of the cylinder 3, 4 into which the hollow body 2, 3 will be inserted and smaller than the area of ​​the base of the further cylinder 4 into which the hollow body 3 will be inserted. In other words, the area A of the base support 8 is greater than the area of ​​the base 28 of the cylinder to which it is joined, and the outermost hollow body 4 has a base 10 and does not require a base support; b) filling the innermost internal volume of the hollow body, called core 5, with at least one active agent; c) closing the innermost hollow body 2 with a lid, which is the upper end 14 of the cylinder forming the innermost hollow body 2; d) filling the hollow body 3 with at least one active agent; e) inserting the innermost hollow body 2 inside the hollow body 3, wherein the upper end 14 of the innermost hollow body 2 rests on the base 29 of the hollow body 3 and the base support 8 of the hollow body 2 forms the upper end of the hollow body 3; f) filling the hollow body 4 with at least one active agent; g) inserting the hollow body 3 into which the innermost hollow body 2 is inserted into the hollow body 4, wherein the base support 9 of the hollow body 3 forms the upper end of the hollow body 4; h) Repeating steps f and g for each additional hollow body included in said device.

[0032] In a preferred embodiment, the base support has a circular shape.

[0033] In an even more preferred embodiment, the hollow body is a cylinder having a circular base. In particular, when the hollow body is a cylinder and the base support is circular, the method comprises: a) providing single-open hollow bodies 2, 3, 4, each hollow body 2, 3, 4 having a cylindrical shape and including side walls 11, 12, 13 and a bottom end 28, 29, 30, each of the open hollow bodies that will form the inserted hollow bodies 2, 3 having a base support 8, 9 with a radius r, r', the length of the radius r, r' of the base support 8, 9 being equal to or greater than the base radius of the cylinder 3, 4 into which the hollow body 2, 3 will be inserted, and less than the base radius of the further cylinder 4 into which the hollow body 3 will be inserted. In other words, r is greater than the base radius of the cylinder to which the base is connected. For the outermost hollow body 4, the base 30 has a radius r', the length of which is equal to the base radius of the cylinder forming the outermost hollow body 4 and to the radius of the base support 9; b) filling the innermost internal volume of the hollow body, called core 5, with at least one active agent; c) closing the innermost hollow body 2 with a lid, which is the upper end 14 of the cylinder forming the innermost hollow body 2, wherein the upper end 14 has the same radius as the base radius of the cylinder forming the innermost hollow body 2; d) filling the hollow body 3 with at least one active agent; e) inserting the innermost hollow body 2 inside the hollow body 3, wherein the upper end 14 of the innermost hollow body 2 rests on the lower end 29 of the hollow body 3 and the base support 8 of the hollow body 2 forms the upper end of the hollow body 3; f) filling the hollow body 4 with at least one active agent; g) inserting the hollow body 3 into which the innermost hollow body 2 is inserted into the hollow body 4, wherein the base support 9 of the hollow body 3 forms the upper end of the hollow body 4; h) Repeating steps f and g for each additional hollow body included in said device.

[0034] In one embodiment, the lower ends 28, 29, 39 and base supports 8, 9 are integral with the side walls 11, 12, 13, respectively.

[0035] In a further embodiment, the lower ends 28, 29, 39 and base supports 8, 9 are separated from the side walls 11, 12, 13, respectively.

[0036] In a preferred embodiment, at least one lower end 28, 29, 30 and the base support 8, 9 have at least one through-hole that opens into the empty volume, i.e., the core 5 or the annular space 6, 7. The at least one through-hole is for filling the hollow body, so-called bubble removal. Once filled, the through-hole is appropriately sealed, for example with an adhesive as described below, or with a drop of biodegradable material itself.

[0037] The method according to the invention advantageously allows for the dispensing of at least one active agent into the volumes 5, 6, 7 without leaving any empty space therein. Preferably, the volumes in the tubes are filled with at least one active agent until they are completely filled. Inserting the inner hollow body 2, 3 inside the immediately outer hollow body 3, 4 has the effect that excess active agent is expelled, leaving the volumes 6, 7 completely filled.

[0038] Advantageously, the provision of a first hollow body with a base support whose area is greater than the base of the cylinder forming it and is the same as the area of ​​the base of the cylinder forming the hollow body into which it is inserted facilitates its alignment, i.e. favors a uniform distribution of the empty volume created between the outermost cylinder and the inserted cylinder.

[0039] The above method does not impose any limitations on the total number of layers and can therefore be repeated for any number of hollow bodies, and therefore volumes, that form the final device, depending on the application and clinical requirements.

[0040] This method does not impose any restrictions on the volume of a single empty space, and therefore it is possible to have configurations with the same volume of drug to be released, and other configurations with different drug volumes, obviously depending on the clinical treatment.

[0041] The method according to the invention makes it possible, due to the geometric design of the system, to advantageously fill it with dimensions such that hollow bodies inserted one inside the other can be poured and / or embedded, also for ophthalmic applications.

[0042] The two hollow bodies, one inserted inside the other, are joined together by means of welding, gluing with surgical adhesive, or an interference or friction fit joint using methods known to those skilled in the art.

[0043] In a preferred embodiment, the welding method involves laser microwelding, using very high concentrations of energy delivered in a very short time to cause rapid melting of the metal, minimizing heat load and producing small welds that are cleaner, deeper, and of superior quality compared to those obtained using conventional welding methods. In this embodiment, welding may be performed by means of a standard, very low-power Nd:Yag laser, providing spot welds of 0.1-0.2 mm in a controlled, argon-based inert atmosphere. Advantageously, this method guarantees high working speed, cleanliness, precision, minimal heat load, optimal weld appearance, very high mechanical strength, and the ability to control the penetration depth.

[0044] The surgical adhesive is selected from the group comprising surgical adhesives based on urethanes, polyurethane adhesives, cyanoacrylate synthetic adhesives such as 2-octyl cyanoacrylate and n-butyl cyanoacrylate, fibrin-based adhesives, gelatin, and synthetically obtained cross-linked gelatins such as gelatin-resorcinol-formaldehyde, or cross-linked gelatins obtained by enzymatic cross-linking such as mTG gelatin or photocross-linked gelatin, albumin-based adhesives, dextran, chitosan, PEG, or two-component adhesives consisting of a solution of purified bovine albumin serum and glutaraldehyde.

[0045] By way of example only, an interference fit joint may include a connecting member such as a spline, with protrusions and recesses formed in the axial direction along the portion of the cylinder that forms the hollow body, and the base that is inserted inside the cylinder portion also having protrusions and recesses in the axial direction.

[0046] By way of example only, a friction fit joint may be a cone type joint such as that shown in Figure 3, where the portion of the cylinder 2 forming the hollow body is tapered and the base 14, which is also tapered, is inserted into the tapered region.

[0047] An example of an interference fit joint is shown in Figure 4. One end of the cylinder 2 forming the hollow body has at least two L-shaped grooves 20 (Figure A) that cooperate with at least two protrusions 21 (Figure B) present on the lid 14. The at least two protrusions cooperate with the grooves to lock the lid into the hollow body.

[0048] In a further embodiment, an implantable and / or injectable device as described above is claimed, filled with at least one active agent.

[0049] In one embodiment, the at least one active agent is the same active agent contained in each empty volume of the device. Alternatively, each empty volume is filled with a different active agent. Alternatively, each empty volume is filled with a mixture of at least two active agents.

[0050] The active agent is in solid form, such as a powder or granules, or in liquid or gel form.

[0051] The at least one active agent is introduced neat or otherwise free or dispersed in a suitable dispersant or solvent known to those skilled in the art.

[0052] The present invention also relates to implantable and / or injectable devices obtainable according to the above method.

[0053] The present invention further relates to an implantable and / or injectable device comprising two hollow volumes. The device comprises a cylinder. Referring to FIG. 6, the device comprises a cylinder 60 having a top 61 and a bottom 62. The cylinder has an upper end 63 and a lower end 64 that are open. A first hollow volume 65 and a second hollow volume 66 are respectively accessible through the openings at the upper and lower ends, whereby the first hollow volume 65 is not in communication with the second hollow volume 66.

[0054] The first and second hollow volumes 65 and 66 are designed to contain an effective dose.

[0055] The first and second hollow volumes 65 and 66 are separated from one another by a partition 67, and are characterized in that a thickness 70 of a side wall 68 of the first hollow volume 65 is less than a thickness 71 of a side wall 69 of the second hollow volume 66. The partition 67 is impermeable to at least one active agent contained within the first and second hollow volumes.

[0056] The upper and lower ends 63, 64 are suitably closed with base supports (not shown) having substantially the same shape and area as the base of the cylinder 60.

[0057] Side walls 68 and 69 and the base support are impermeable, continuous surfaces that become permeable over time after implantation and injection of the device. The different thicknesses of the side walls of the first and second hollow volumes are such that the time for dissolution of the side walls, and therefore the time for outward opening of the first and second volumes, is different, such that the first hollow volume having a thinner side wall will open outward first compared to the second hollow volume having a thicker side wall.

[0058] In one embodiment, the first and second hollow volumes have the same volume. In a further embodiment, the first and second hollow volumes have different volumes.

[0059] The device is made of a biodegradable material, preferably magnesium or a magnesium alloy, with magnesium alloys such as aluminum, lithium, calcium, zinc or manganese alloys constituting a particularly preferred embodiment.

[0060] In a preferred embodiment, the device is made of the magnesium alloy JDBM, which is an alloy of Mg-2.5Nd-0.2Zn-0.4Zr (wt%, JDBM) with good mechanical and corrosion resistance properties. Alternatively, the alloy is JBDM-2, Mg-2.2Nd-0.1Zn-0.4Zr (wt%, denoted as JDMB-2).

[0061] In one embodiment, when the implantable and / or injectable device is for ophthalmic use, the device is cylindrical and has a height of about 10 mm or about 5 mm, and the diameter of the circular base is about 0.8 mm, 0.7 mm, 0.6 mm, or 0.5 mm. When the device is an injectable device and a standard needle is used for injection, the diameter of the circular base is 0.5 mm. For example, the thickness 70 of the sidewall 68 of the first hollow volume 65 is equal to about 0.075 mm, and the thickness 71 of the sidewall 69 of the second hollow volume 66 is equal to about 0.150 mm. In one embodiment, the first hollow volume has a height of about 1.5 mm, and the second hollow volume has a height of about 3 mm. In this embodiment, the first hollow volume and the second hollow volume have substantially the same volume.

[0062] Furthermore, the present invention relates to a method for manufacturing an implantable and / or injectable device according to this embodiment for the controlled release of an amount of an active agent.

[0063] The method includes: - Providing cylinders made of biodegradable materials; - drilling the upper and lower ends of said cylinder using drill bits having different diameters, operating in such a way as to leave a partition separating a first hollow volume obtained by drilling the upper end from a second hollow volume obtained by drilling the lower end; - filling the first and second hollow volumes with at least one active agent; - closing the first hollow volume and the second hollow volume with a base support.

[0064] In one embodiment, the drilling is a mechanical micro-drilling process performed similarly to conventional mechanical micro-drilling, but with very small diameter (<1 mm) drill bits, using a very precise and stable machine that limits runout of the rotating bit and has a high performance spindle that ensures high rotational speeds to compensate for the very small dimensions of the tool and ensure adequate peripheral cutting.

[0065] In a further embodiment, the micro-drilling is performed by means of electrical discharge machining or plunge spark machining.

[0066] The present invention also relates to a programmed release implantable / injectable device according to the present invention for use in the treatment of a condition requiring repeated and programmed administration of at least one active agent over time, for example every 2 weeks, or every 3 weeks, or every 4 weeks, or every 6 weeks, every 8 weeks, every 10 weeks, or every 12 weeks.

[0067] In a preferred embodiment, the condition is an ocular condition and the device can be injected into the posterior eye chamber. By way of example, the ocular condition is selected from exudative age-related macular degeneration, diabetic macular edema, diabetic retinopathy, macular edema from retinal venous occlusion, and myopic macular degeneration, and the at least one active agent is an anti-VEGF drug.

[0068] In further embodiments, the condition is an ocular condition requiring treatment with an active agent other than an anti-VEGF drug, such as macular edema (wherein at least one active agent is cortisone and / or at least one NSAID), or inflammatory macular edema (wherein at least one active agent is cortisone and / or at least one immunosuppressant).

[0069] In one embodiment, the ocular condition is atrophic (or dry) age-related macular degeneration, and the at least one active agent is selected from the group comprising, for example, anti-complement inhibitors such as Pot-4, JPE1375, ARC1905, APL-2, Zimura, Eculizumab, immunomodulators such as glatiramer acetate, antioxidants such as OT-551, fenretinide and / or ciliary neurotrophic factor, brimonidine, doxycycline.

[0070] For example, the at least one active agent is selected from the group consisting of adPEDF.11, AGN211745, Zybrestat, Sirolimus, ATG003, Bevacizumab, Ranibizumab, Pegaptanib, Aflibercept, Brolocizumab, Faricimab, Combercept, Abicipar, VEGF Trap, Vatalanib, Pazopanib, TG101095 / The inhibitor is selected from the group including TG100801, AL-39324, AG013958, JSM6427, PF-04523655 (REDD14NP), ciliary neurotrophic factor, fenretinide, OT-551, POT-4, glatiramer acetate, anti-FGF2, tyrosine kinase inhibitors (such as sunitinib), anti-angiopoietin-2 (such as RG7716), antibodies (such as anti-endoglin), and tissue factor target protein (such as ICON-1).

[0071] In a further embodiment, the condition is hypercholesterolemia and the at least one active agent is evolocumab, used alone or in combination with other lipid-lowering drugs. The device according to the invention is particularly interesting for use in the treatment of homozygous familial hypercholesterolemia, a rare genetic disorder in which LDL cholesterol levels are elevated above normal from birth, and requires subcutaneous administration of evolocumab at least once, preferably twice monthly. The subcutaneously implanted device according to the invention advantageously solves the problem of repeated injections.

[0072] In a further embodiment, the condition is arterial hypertension.The subcutaneously implanted device according to the invention is filled with one or more active agents selected from the group comprising ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics, alpha blockers, beta blockers, alpha-beta blockers, centrally acting sympatholytic agents, renin-angiotensin-aldosterone system inhibitors.

[0073] In a further embodiment, the device is used for post-surgical prophylaxis, for example, during open surgery or laparoscopy, in which the device is configured to release an active agent, such as an anti-inflammatory drug, a cortisone-based drug, an antibiotic, antimetabolite, or an anti-cancer drug, in a programmed manner.

[0074] In a further embodiment, the device is intended for use in the treatment and / or prevention of migraine headaches, and the device is filled with a monoclonal antibody that is an inhibitor of the calcitonin gene-related peptide (Cgrp) receptor (e.g., Erenumab).

[0075] In a further embodiment, the use of the programmed release device as a contraceptive is claimed herein, in which the device is implanted intravaginally and / or subcutaneously and, in addition to its use as a contraceptive, is used to treat gynecological and hormonal disorders. [Explanation of symbols]

[0076] 1 device 2,3,4 Cylinder-shaped hollow body 5 Core (hollow volume) 6,7 Annular space (hollow volume) 11,12,13 Side wall 8,9 Base support 14 Lid 28,29,30 base 60 cylinders 61 Top 62 Bottom 63 Top 64 Bottom end 65 First hollow volume 66 Second hollow volume 67 Bulkhead 68,69 side wall

Claims

1. An implantable and / or injectable device made of biodegradable materials, comprising: The device comprises a cylinder (60) as a hollow body, a partition (67) and two base supports, the cylinder (60) comprising a top (61) and a bottom (62); The upper (63) and lower (64) ends of the cylinder are closed by the two base supports, the top (61) includes a first hollow volume (65) that is closed and can be filled with one or more activators, and the bottom (62) includes a second hollow volume (66) that is closed and can be filled with one or more activators, the first hollow volume (65) and the second hollow volume (66) being separated from each other by the partition (67); the base support has substantially the same shape and area as the base of the cylinder (60); the cylinder has side walls surrounding the two hollow volumes, and the thickness (70) of the side wall (68) surrounding the first hollow volume (65) is smaller than the thickness (71) of the side wall (69) surrounding the second hollow volume (66); each side wall (68, 69) of the cylinder and the septum (67) are impermeable continuous surfaces that become permeable over time after implantation and / or injection of the device; The one or more active agents are released after degradation of the side wall of the cylinder. A device characterized in that

2. The device of claim 1 , wherein the base support has a circular shape.

3. The device of claim 2 , wherein the hollow body is a cylinder having a circular base.

4. 3. A device according to claim 2, wherein the length of the radii r, r' of the base supports (8, 9) is the same as the length of the base radius of a cylinder into which the hollow body is to be inserted.

5. The device according to any one of claims 1 to 4, wherein the cylinder of biodegradable material is made of magnesium or a magnesium alloy.

6. 6. The device of claim 1, wherein the device has a height of about 10 mm or about 5 mm and the diameter of the circular base or the diameter of a circle that can be inscribed around the base is equal to about 0.8 mm, 0.7 mm, 0.6 mm or 0.5 mm, or the device has a height of 40 mm or less and the diameter of the circular base or the diameter of a circle that can be inscribed around the base is 4 mm or less.

7. 7. The device of any one of claims 1 to 6, wherein the base of at least one or both of the cylinders is also an impermeable continuous surface, which becomes permeable over time after implantation and / or injection of the device.

8. The device of any one of claims 1 to 7, wherein the closed hollow volume is filled with one or more active agents.

9. 10. A method for manufacturing, filling and closing an implantable and / or injectable device according to claim 1 for controlled release of an active agent, said method comprising the steps of: a) providing a cylinder made of a biodegradable material; b) drilling holes at the upper and lower ends of the cylinder using drill bits having different diameters at the upper and lower ends, operating in such a way as to leave a partition separating a first hollow volume obtained by drilling the upper end from a second hollow volume obtained by drilling the lower end; c) filling said first and second hollow volumes with at least one active agent; d) enclosing said first hollow volume and said second hollow volume with a base support.

10. 9. An implantable / injectable device as claimed in claim 8 for the controlled release of quantified amounts for use in the treatment and / or prevention of conditions requiring repeated programmed administration of at least one active agent over time, preferably every 2 weeks, or every 3 weeks, or every 4 weeks, or every 8 weeks, or every 10 weeks or every 12 weeks.

11. 11. The device for use according to claim 10, wherein the condition is selected from the group consisting of ophthalmic conditions, hypercholesterolemia, arterial hypertension, migraine headaches, and gynecological and hormonal disorders.

12. 12. The device for use according to claim 11, wherein the ocular condition is selected from the group consisting of exudative age-related macular degeneration, diabetic macular edema, diabetic retinopathy, macular edema due to retinal vein occlusion, and atrophic (or dry) age-related macular degeneration.

13. The device for use according to claim 11, wherein said hypercholesterolemia is homozygous familial hypercholesterolemia.

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