Implantable devices for sustained delivery of opioid antagonists and methods for treating inflammatory, neuroinflammatory and metabolic disorders

Abstract

Described herein are diffusion-based implantable devices for delivering opioid antagonists, such as naltrexone. The device is in the shape of a cylinder or a disc and is matched with a biocompatible membrane. These devices are filled with a compressed formulation of the opioid antagonist and optionally a binder. When an aqueous fluid is introduced into the device, the compressed formulation erodes along an axis at a constant rate to release the opioid antagonist from the device at a constant rate. The rate is selected in the range of about 0.02-2.00 mg / day for use in the treatment of inflammatory, neuroinflammatory, or metabolic disorders.

Description

Technical Field

[0001] The subject matter described herein relates to implantable devices comprising opioid antagonist compositions suitable for treating inflammatory, neuroinflammatory, and metabolic disorders. Background Art

[0002] Opioid antagonists, which comprise a class of drugs including naltrexone, naloxone, and nalmefene, have been widely used to treat opioid use disorder (OUD) and alcoholism since the 1970s. Most of these drugs are effective, but are rapidly metabolized and cleared after oral administration. For example, when administered as a supportive treatment for opioid use disorder, a typical oral dose of naltrexone is 50 mg / day, with an average bioavailability of 5-40%, and a plasma half-life of approximately 4 hours. This pulse approach to dosing does not maintain constant plasma levels of the drug, but it does maintain a high degree of μ and κ opioid receptor occupancy over time. Therefore, such a dose is suitable for protecting patients from the euphoric effects of opioid receptor agonists such as morphine, heroin, and oxycodone.

[0003] Although naltrexone, naloxone, nalmefene and similar drugs were developed as antidotes and preventives for the treatment of opioid overdose and opioid use disorder, recent studies have shown that they can also be used to treat a variety of inflammatory, neuroinflammatory, gastrointestinal and metabolic disorders. These diseases include psoriasis, fibromyalgia, HIV-associated neurological and neurocognitive disorders, Crohn's disease, multiple sclerosis and cachexia. It is speculated that naltrexone-like opioid antagonists can act as immunomodulators in these cases - specifically, by antagonizing Toll-like receptor 4 (TLR4) signaling, thereby reducing the production of downstream cytokines and proinflammatory agents (such as IL-1, TNF-α and interferon-β). In contrast, long-term activation of TLR4 - for example, by long-term use of traditional opioids such as morphine, or by low levels of HIV in CNS reservoirs - is associated with the emergence of neuropathic pain and cognitive deficits.

[0004] TLR4 is expressed in a variety of cell and tissue types, including microglia in the CNS, epithelial cells in the gastrointestinal tract, and in a variety of cancers. TLR4 overexpression is thought to be pro-inflammatory and pro-oncogenic, and expression levels are positively correlated with the proliferation rate of tumor cell lines. For example, a breast cancer cell line (MDA-MB-231) that expresses high basal levels of TLR4 was found to be less invasive after TLR4 knockdown.

[0005] Although opioid antagonists and closely related molecules were not originally developed as anti-inflammatory agents, they have been found to antagonize TLR4 signaling, including (+)-naltrexone, (-)-naltrexone, (+)-naloxone, (-)-naloxone, and (-)-nalmefene. There is also clinical evidence that therapeutically effective levels of binding of the levorotatory isomers of naltrexone, naloxone, and nalmefene to TLR4 in patients with OUD can be achieved with oral doses much smaller than those required to block μ and κ opioid receptors. For example, "low-dose naltrexone" (LDN) therapy refers to the oral administration of naltrexone (usually (-)-naltrexone) at a dose of approximately 0.5-5 mg / day to treat a range of inflammatory disorders. This corresponds to approximately 1-10% of the oral dose typically administered to treat OUD. However, as discussed above, naltrexone is rapidly metabolized and cleared following oral administration; thus, a significant portion of any oral dose is "wasted" because plasma levels must be well above the minimum effective plasma concentration to maintain a therapeutic effect throughout the 24-hour plasma clearance period (equivalent to approximately 6 half-lives of naltrexone).

[0006] Naltrexone, naloxone, and similar drugs exist in a variety of dosage forms, but most are not ideal for treating inflammatory or metabolic disorders at low drug concentrations. For example, (-)-naltrexone is commonly given as a tablet (50 mg hydrochloride, daily; ) or long-acting injection (380 mg base, given monthly; ) are provided to patients in the form of . Dosage forms currently under development include the O'Neil Long-Acting Naltrexone Implant (OLANI), a subcutaneous implant composed of erodible particles (total mass 1.8 g, designed to deliver approximately 1.0 g of naltrexone over a 6-month treatment period). These dosage forms were developed explicitly for the treatment of alcoholism and OUD and typically produce very high and uneven plasma levels over time. In addition, in the case of OLANI, the large amount of naltrexone required to treat OUD patients over a 6-month period results in the large size of the implant and the invasiveness of the implantation procedure.

[0007] Although many factors affect the release kinetics of tablets and erodible long-acting drug delivery systems, an important factor may be related to the physical surface area of ​​dosage form changes over time. In general, if non-porous objects are immersed in a certain volume of fluid and allowed to dissolve, the surface area of ​​solid objects should be gradually reduced. In addition, if it is assumed that the fluid outside the object can not be saturated (for example, if the fluid volume is very large, or if the fluid is a part of an open system), and if the absolute dissolution rate of the object is roughly proportional to its surface area, its instantaneous dissolution rate should also be reduced over time. If the object in question is an erodible particle or agglomerate containing a dispersed drug, and fluid is a buffered biological fluid (such as interstitial fluid), the speed of drug delivery in its environment should also be reduced over time.

[0008] In summary, naltrexone and related opioid receptor antagonists show the prospect of being reused drugs for treating inflammatory and metabolic disorders, but existing commercial dosage forms are not optimal for these applications. Since these drugs were originally designed for the treatment of alcoholism and OUD, existing oral and long-acting preparations are customized to provide relatively high doses of these drugs in a pulsatile or uneven manner over time. Patients seeking to alleviate chronic inflammatory and metabolic disorders can benefit from a much lower daily dose rate of the drug over a long period of time. In addition, patients with inflammatory comorbidities and / or high pill burdens (e.g., late AIDS patients or patients with cachexia) can benefit from extremely long-acting anti-inflammatory agents that do not require frequent administration. A solution can be in the form of a subcutaneous, non-erodible implant that releases an opioid antagonist (e.g., naltrexone) from an internal reservoir through the control and slow dissolution of a solid formulation.

[0009] For example, in one version of such a device, a hollow cylinder or disc is tightly packed with a solid formulation of an opioid antagonist drug, such as (+)-naltrexone, (-)-naltrexone, (+)-naloxone, (-)-naloxone, (+)-nalmefene, (-)-nalmefene, and sealed at one or both circular ends with a membrane. The formulation may contain in whole or in part 1.) a free base form of an opioid antagonist (such as naltrexone), or 2.) a salt form of an opioid antagonist (such as naltrexone) formed by reaction of the drug (as a base) with a pharmaceutically acceptable acid. When the membrane and formulation are wetted, the shell of the reservoir restricts diffusion in two dimensions (i.e., the shell contacts the formulation and restricts intrusion of the fluid), while the membrane promotes fluid contact and diffusion of the drug along the third dimension. In other words, the solid preferentially dissolves at a constant rate along a single axis corresponding to the height of the cylinder or the thickness of the disc, rather than isotropically. In this case, the drug release kinetics may approach zero order. In other cases, the output of the device may be limited by the surface area and porosity of the membrane surface rather than the dissolution rate of the formulation. For example, a cylindrical implantable device may have a small diameter of about 1-5 mm to minimize patient discomfort and limit the membrane surface area so that the diffusion rate of the drug through the circular membrane is less than the rate at which the drug formulation dissolves in the device. The output rate can be additionally adjusted by placing the membrane at both ends of the device (to increase the output) or at a single end of the device (to reduce the output). The target output rate (e.g., expressed in mg drug / day / device) must provide sufficient patient exposure after implantation to provide a therapeutic effect (e.g., reduce inflammation) throughout a longer treatment period (e.g., 1-24 months). At the same time, the device must be loaded with enough drug bolus to support its target output rate and surgical period, but the device cannot be too large to avoid being difficult to implant or remove, or causing discomfort to the wearer. The problem of output rate and device size becomes complicated by the limited water solubility of many opioids in aqueous fluids; depending on the device design, the pure drug may or may not dissolve at a high enough rate to drive diffusion through one or more membranes with limited surface area. For example, naltrexone has a reported water solubility of 667 mg / L at 25°C; this is substantially higher than the reported solubility of nalmefene and buprenorphine, two other drugs used to treat opioid use disorder (values ​​of 140 mg / L and 168 mg / L, respectively). To achieve adequate diffusion rates from implants made with these less soluble drugs, it may be necessary to 1.) increase the membrane surface area of ​​the device by increasing the volume or changing the shape, or 2.) add excipients that enhance the solubility of the drug within the device, but at the expense of reducing the drug load or (again) increasing the overall device volume. There is also the question of whether the added excipients will remain stable within the device over time.For example, many salt forms of opioid antagonists have greater solubility in water than the free base form of the drug; for example, naltrexone hydrochloride has an estimated water solubility of 100 g / L at 25°C. In addition to the fact that such salts may dissolve too quickly to be useful in sustained-release applications, these salt forms are also susceptible to hydrolysis and other forms of chemical degradation, and the rate of drug decomposition may depend on other characteristics of the device, such as the rate at which physiological buffer substances diffuse into the device from its operating environment. These factors illustrate the complexity of pairing a drug composition with a particular device design, particularly one that relies on diffusion to release the drug from an internal reservoir. Formulation-device pairing is needed to address these and other complications associated with the sustained and controlled delivery of opioid antagonists for anti-inflammatory and immunomodulatory applications. Summary of the invention

[0010] The following aspects and embodiments thereof described and illustrated below are intended to be exemplary and illustrative, not limiting in scope.

[0011] In one aspect, a device comprising a composition consisting of an opioid antagonist is provided. The device has an elongated shape with an internal reservoir, and it has a first end and a second end. The membrane is located at one or both ends. In one embodiment, the device is sized to have a length of less than or equal to about 8 cm and an internal reservoir diameter of about 8 mm. In another embodiment, the device has a size of less than or equal to about 5 cm in length and an internal reservoir diameter of about 5 mm.

[0012] The walls of the provided device are made of a biocompatible, non-erodible material such as stainless steel or titanium.

[0013] In one embodiment, the internal reservoir of the device contains a composition consisting of an opioid antagonist in the form of a compacted solid comprising, consisting essentially of, or consisting of an opioid antagonist, preferably in the form of a solid or compacted solid. In another embodiment, the composition consists of an opioid antagonist as a suspension or solution or solid form. In another embodiment, the opioid antagonist is prepared as a solid solution or dispersion within a wettable solid matrix.

[0014] In one embodiment, the membrane at one or both ends of the device is circular.In one embodiment, the device has a cylindrical shape.

[0015] In one embodiment, the opioid antagonist is naltrexone base.

[0016] In another embodiment, the opioid antagonist is a stereoisomer or racemic mixture of naloxone, nalmefene, nalorphine, nalodeine, levallorphan, xorphanol, oxilorphan, samidorphan, 6-β-naltrexol, methylnaltrexone, diprenorphine or cyprodime.

[0017] In one embodiment, the composition comprising an opioid antagonist is formed into a certain shape, such as a tablet, a pellet or a stick, which is sized for placement in the internal reservoir of the device. In one embodiment, the shape is a compressed shape.

[0018] In another embodiment, the opioid antagonist composition is formulated into a pellet or stick having an outer diameter greater than or equal to about 95%, 96%, 97%, 98%, or 99% or 99.5% of the inner diameter of the internal reservoir of the device.

[0019] In yet another embodiment, the composition comprising an opioid antagonist further comprises a binder. Exemplary binders include lactose, maltose, hydroxypropylcellulose, polyvinyl pyrrolidone, gelatin, dextran, alginate, maltodextrin and polyethylene glycol. In one embodiment, the binder is conducive to the composition being manufactured into a compressed shape, such as a sheet, a pellet or a rod. In one embodiment, the compressed shape has a diameter greater than or equal to about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% or 99.5% of the internal diameter of the internal storage depot of the device.

[0020] In one embodiment, the composition comprising an opioid antagonist does not contain an organic acid. In one embodiment, the organic acid (i) has a water solubility of less than about 20 g / L at room temperature, (ii) maintains the pH of the suspension between 3-6.5 for at least about 30 days in the environment in which it is used, and / or (iii) has a molecular weight of less than or equal to 500 grams per mole. That is, in one embodiment, the composition comprising an opioid antagonist does not contain the following organic acids: (i) has a water solubility of less than about 20 g / L at room temperature, (ii) maintains the pH of the suspension between 3-6.5 for at least about 30 days in the environment in which it is used, and (iii) has a molecular weight of less than or equal to 500 grams per mole.

[0021] In another embodiment, the composition comprising the opioid antagonist is prepared so that the opioid antagonist is frozen in a solid solution or dispersed in a wettable solid matrix. The solid matrix has a melting point greater than or equal to about 40°C. Suitable matrix materials include polyvinyl pyrrolidone, polyethylene glycol, methylcellulose, fatty acids or fatty alcohols containing at least 12 carbon atoms, dicarboxylic acids containing at least 8 carbons, or any mixture thereof. The solid matrix can be cast or manufactured into a compressed or extruded shape, such as a sheet, pellet or rod, having a diameter greater than or equal to about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% of the inner diameter of the device.

[0022] In one embodiment, the composition comprising an opioid antagonist includes one or more stabilizing excipients. Such excipients include metal chelators, such as salts of ethylenediaminetetraacetic acid; buffers, such as phosphates, carboxylates, or amino acids; and antioxidants, such as ascorbic acid, ascorbic acid esters, tocopherols, tocopherol esters, cysteine, cysteine ​​esters or amides, methionine, methionine esters or amides, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA).

[0023] In another embodiment, the composition comprising an opioid antagonist comprises a component for dissolving the composition. In one embodiment, the component is a sugar, such as sucrose or mannitol. In another embodiment, the composition comprising a component for dissolving the composition is in the form of a solid, a compacted pill or stick, or a compressed powder. In another embodiment, the composition is formulated to promote the dissolution of a solid, compacted tablet, pill, stick, or compressed solid shape into an aqueous solution when hydrated in the internal reservoir of the device. In one embodiment, the composition is formulated as a lyophilized powder. In one embodiment, the composition is a lyophilized composition consisting of an opioid antagonist and sugar.

[0024] In one embodiment, the device is provided with a composition in a dry state in an internal reservoir. In another embodiment, the device is provided with a composition in a hydrated state in an internal reservoir. In yet another embodiment, the device is provided with a composition as a dry compressed solid in an internal reservoir, and the compressed solid is wetted or moistened by an aqueous fluid introduced before or during use, and the opioid antagonist is partially or completely dissolved in the aqueous fluid. For example, after the device is implanted in a subject, body fluids will enter the device to produce an aqueous phase in the internal reservoir, and the aqueous phase contains the dissolved opioid antagonist. The aqueous phase may also contain undissolved opioid antagonists. Exemplary aqueous fluids include biocompatible fluids, such as sterile water, 0.9% saline, and phosphate buffered saline. In one embodiment, the compressed solid is shaped to meet the size of the internal reservoir of the device. In one embodiment, the compressed solid has a sheet-like, pill-like, or rod-like shape.

[0025] In another embodiment, the device has a cylindrical or disk-like geometry.

[0026] In yet another embodiment, the device is configured for subcutaneous implantation in a human or other vertebrate.

[0027] In another embodiment, the device contains a single circular membrane or two circular membranes mounted in parallel at the ends of the device. The total diffusion area of ​​the membrane is preferably between about 1 mm 2 With 50mm 2 between.

[0028] In another embodiment, the device membrane is selected from an inert fluoropolymer, such as polyvinylidene fluoride (PVDF); a sintered metal, such as stainless steel or titanium; or a ceramic, such as alumina, titania, or silica.

[0029] In yet another embodiment, the device is loaded with a sufficient amount of an opioid antagonist composition to provide a selected opioid antagonist plasma level for achieving a therapeutic effect during a surgical period of greater than or equal to about 1 month. In one embodiment, the device comprises a composition consisting of naltrexone in an amount that produces an average plasma level of the active portion of naltrexone (defined as naltrexone and its active metabolite 6-β-naltrexol) between about 0.01-0.50 ng / mL, between about 0.05-0.5 ng / mL, between about 0.08-0.5 ng / mL, or between about 0.1-0.5 ng / mL after subcutaneous implantation in a human subject for a surgical period of greater than or equal to about one month. In one embodiment, the device comprises a composition consisting of naltrexone in an amount that produces a mean plasma level of the active portion of naltrexone (defined as naltrexone and its active metabolite 6-β-naltrexol) of at least about 0.01 ng / mL, 0.02 ng / mL, 0.03 ng / mL, 0.04 ng / mL, 0.05 ng / mL, 0.06 ng / mL, 0.07 ng / mL, 0.08 ng / mL, 0.09 ng / mL, or 0.1 ng / mL and less than 0.50 ng / mL following subcutaneous implantation in a human subject for a surgical period of greater than or equal to about one month.

[0030] In another embodiment, the composition in the internal reservoir of the device is hydrated in the presence of a sterile or filtered aqueous solution to form an aqueous phase within the internal reservoir of the device, which contains at least some of the opioid antagonist in dissolved form. In another embodiment, the composition in the internal reservoir of the device is hydrated in the presence of a sterile or filtered aqueous solution to form an aqueous phase within the internal reservoir of the device, which contains at least a portion of the opioid antagonist in suspended form.

[0031] In another embodiment, the opioid antagonist is released from the device at a rate that provides a therapeutic effect during the treatment period.

[0032] In another embodiment, multiple devices are administered to the subject, preferably 1-6, 1-5, 1-4, 2-6, 2-5, 2-4 or 2-3 devices. In one embodiment, multiple devices are administered to achieve a target opioid antagonist concentration in plasma, such as a naltrexone active moiety concentration of 0.01-0.50 ng / mL, about 0.05-0.5 ng / mL, about 0.08-0.5 ng / mL or about 0.1-0.5 ng / mL. In one embodiment, multiple devices are administered to achieve a target opioid antagonist concentration in plasma, such as a naltrexone active moiety concentration of at least about 0.01 ng / mL, 0.02 ng / mL, 0.03 ng / mL, 0.04 ng / mL, 0.05 ng / mL, 0.06 ng / mL, 0.07 ng / mL, 0.08 ng / mL, 0.09 ng / mL or 0.1 ng / mL and less than 0.50 ng / mL. In one embodiment, the device is administered by implantation, and in another embodiment, the device is implanted subcutaneously.

[0033] In another aspect, a method for sustained, controlled delivery of a small molecule opioid antagonist is provided, wherein the method comprises providing a device comprising a composition described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

[0034] In an embodiment, a method for treating a disorder selected from psoriasis, fibromyalgia, HIV-associated neurological and neurocognitive disorders, Crohn's disease, multiple sclerosis, complex regional pain syndrome, Hailey-Hailey disease, insulin resistance, pain cachexia is provided.

[0035] In another aspect, a method of providing maintenance therapy to treat a chronic inflammatory, neuroinflammatory or metabolic disorder is provided, wherein the method comprises providing a device comprising a composition as described herein. In some embodiments, the method further comprises administering the device, such as by subcutaneous implantation.

[0036] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.

[0037] Other embodiments of the methods, devices, compositions, etc. of the present invention will be apparent from the following description, drawings, examples, and claims. It will be understood from the foregoing and following descriptions that each and every feature described herein and each and every combination of two or more such features are included within the scope of the present disclosure, provided that the features included in such combinations are not mutually contradictory. In addition, any feature or combination of features may be expressly excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1A-1B is in assembled form ( Figure 1A ) and in unassembled form ( Figure 1B ) is an illustration of a drug delivery device.

[0039] Figures 1C-1F A portion of a first exemplary drug delivery device is shown, showing a cross-sectional view of the end cap assembly when fully assembled ( Figure 1C ) and exploded views ( Figure 1D ), and an isometric view when assembled ( Figure 1E ). Figure 1F An exploded view of the cap assembly alone is shown. The numbered elements of the subassembly are 1 = cap, 2 = porous membrane, 3 = seal, 4 = retaining ring and 5 = drug device reservoir.

[0040] Figure 1G-1K A portion of a second exemplary drug delivery device is shown, showing a cross-sectional view of the end cap assembly when fully assembled ( Figure 1G ) and exploded views ( Figure 1H ), and an isometric view when assembled ( Fig. 1I ). Figures 1J-1K The cap assembly alone is shown in assembled and exploded views. The numbered elements of the subassemblies are 1 = cap, 2 = porous membrane, 3 = seal, 4 = drug delivery device reservoir, and 5 = retaining ring.

[0041] Figure 2 is a graph showing the in vitro cumulative release of naltrexone base (in mg) as a function of time (in days) from two groups of devices (n=3 per group) containing a composition of naltrexone base. The devices in the first group were filled with approximately 325 mg of naltrexone base in the form of a fine powder. The devices in the second group were filled with approximately 570 mg of a tablet consisting of naltrexone base combined with 5% polyvinylpyrrolidone (40 kD) and 2% stearic acid.

[0042] Figure 3is a graph showing naltrexone plasma levels (in ng / mL) as a function of time (in days) in rats implanted with a single device containing a composition of naltrexone base. One group of rats (n=5) received a device loaded with approximately 325 mg of finely powdered naltrexone base. A second group of rats (n=3) received a device loaded with approximately 570 mg of a tablet consisting of naltrexone base combined with 5% polyvinylpyrrolidone (40 kD) and 2% stearic acid (by mass). DETAILED DESCRIPTION

[0043] definition

[0044] Various aspects will now be described more fully below. However, these aspects may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; on the contrary, these embodiments are provided so that this disclosure will be thorough and complete and fully convey its scope to those skilled in the art.

[0045] When a range of values ​​is provided, it is intended that each intervening value between the upper and lower limits of the range and any other stated or intervening value in the stated range is encompassed within the disclosure. For example, if a range of 1 mg to 8 mg is stated, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg are also expressly disclosed, as well as a range of values ​​greater than or equal to 1 mg and a range of values ​​less than or equal to 8 mg.

[0046] Unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more of the same or different polymers, reference to "an excipient" includes a single excipient as well as two or more of the same or different excipients, and so forth.

[0047] When immediately preceding a numerical value, the word "about" means a range of plus or minus 10% of the value, e.g., "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc., unless the context of the present disclosure indicates otherwise or is inconsistent with such an interpretation. For example, in a numerical list such as "about 49, about 50, about 55," "about 50" means a range extending to less than half of the interval between the previous value and the subsequent value, e.g., greater than 49.5 to less than 52.5. In addition, the phrases "less than about" a value or "greater than about" a value should be understood according to the definition of the term "about" provided herein.

[0048] The disclosed compositions can comprise, consist essentially of, or consist of the disclosed components.

[0049] All percentages, parts and ratios are based upon the total weight of the composition and all measurements made are at about 25°C, unless otherwise specified.

[0050] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, salts, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or other mammals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in mammals (e.g., animals), and more particularly, for use in humans.

[0051] The term "treating" as used herein refers to a method of administering a small molecule that reduces the intensity or frequency of symptoms of a medical condition (e.g., inflammatory, neuroinflammatory, and metabolic disorders, such as psoriasis, fibromyalgia, HIV-associated neurological and neurocognitive disorders, Crohn's disease, multiple sclerosis, complex regional pain syndrome, Hailey-Hailey disease, insulin resistance, pain, and / or cachexia) in a subject relative to a subject who has not received the compound or composition. This can include reversing, reducing, or preventing the symptoms, clinical signs, and underlying pathology of a condition in a manner that improves or stabilizes the condition of the subject.

[0052] Less than the entirety of the disclosure may be claimed for any reason by reserving the right to limit or exclude any individual member of any such group that may be claimed by range or in any similar manner, including any subrange or combination of subranges within said group. In addition, less than the entirety of the disclosure may be claimed for any reason by reserving the right to provide limitations or exclusions to any individual substituent, analog, compound, ligand, structure, or group thereof, or any member of a claimed group.

[0053] Throughout this disclosure, various patents, patent applications and publications are cited. The disclosures of these patents, patent applications and publications are incorporated into this disclosure in their entirety by reference in order to more fully describe the state of the art in this area known to those skilled in the art as of the date of this disclosure. If there is any inconsistency between the cited patents, patent applications and publications and this disclosure, the present disclosure shall prevail.

[0054] For convenience, certain terms used in the specification, examples and claims are collected here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0055] Device and composition

[0056] In an exemplary embodiment, the device comprises a composition (or formulation) comprising an opioid antagonist, such as naltrexone base or a pharmaceutically acceptable salt form of naltrexone, and optionally a binder. The composition can be compressed, cast, molded, or extruded to form a solid, compressed shape. In one embodiment, the compressed shape is in the form of a tablet, a pill, or a rod. It is understood that a tablet is a disc-shaped object; a pill is a spherical or oval object, and a rod has a cylindrical, slightly elongated shape. In one embodiment, the compressed shape has a density of more than 1.00 g / cm 3 In one embodiment, the pill or stick is non-porous. In another embodiment, the composition is cast, molded or compressed to form a density of about 1.00 g / cm 3 -1.20g / cm 3 The density of tablets, pills or sticks is between.

[0057] The composition may include an optional binder having a melting point greater than or equal to about 40° C. Examples include, but are not limited to, common tableting excipients including lactose, maltose, mannitol, trehalose, hydroxypropylcellulose, polyvinyl pyrrolidone, and polyethylene glycol. Other binders include fatty (aliphatic) acids or fatty alcohols containing a minimum of 12 carbon atoms, dicarboxylic acids containing a minimum of 8 carbons such as suberic acid or sebacic acid, or any mixture thereof.

[0058] In one embodiment, the composition comprising an opioid antagonist includes one or more stabilizing excipients. Such excipients include metal chelators, such as salts of ethylenediaminetetraacetic acid; buffers, such as phosphates, carboxylates, or amino acids; and antioxidants, such as ascorbic acid, ascorbic acid esters, tocopherols, tocopherol esters, cysteine, cysteine ​​esters or amides, methionine, methionine esters or amides, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA).

[0059] The pill or stick is made so that the diameter of the pill or stick is substantially equal to the inner diameter of the internal reservoir of the device. In one embodiment, the diameter of the pill or stick is ≥ 95%, 96%, 97%, 98% or 99% of the inner diameter of the internal reservoir of the device. The composition may further comprise a lubricant.

[0060] The compressed shape is prepared and loaded into the device as a solid, but is capable of dissolving in the presence of an aqueous fluid to produce an aqueous phase containing a dissolved and / or suspended opioid antagonist (such as naltrexone) within the internal reservoir of the device.

[0061] As described above, when combined with an aqueous fluid, the formulations described herein provide a mixture of an aqueous phase containing an opioid antagonist and a non-aqueous phase. When paired with a device, the aqueous phase formed in the device is in direct or indirect contact with the porous membrane. This allows the dissolved opioid antagonist to diffuse from the interior of the device into the environment of use. In one embodiment, this diffusion occurs for a period of time, preferably at least about two weeks to about twelve months, or at least about four weeks to six months.

[0062] In one embodiment, the delivery device is cylindrical or disc-shaped in shape, with a size less than or equal to about 8 mm in outer diameter and about 8 cm in length. In another embodiment, the length of the device is less than or equal to about 5 cm, and the outer diameter of the device is less than or equal to about 5 mm. The walls of the device reservoir are made of non-erodible and / or biocompatible materials (such as titanium or surgical stainless steel), and one or both ends of the flat, circular, parallel ends of the device may include a porous partition or a porous membrane. In one embodiment, the device is sized to facilitate subcutaneous placement in a human subject; for example, a cylindrical implant can be made to be deposited in the subcutaneous space by a surgical trocar or an implanter tool.

[0063] A porous membrane or separator mounted on one or both ends of the device for fluid communication with the device reservoir, the porous membrane or separator being composed of a biocompatible material such as polyvinylidene fluoride, sintered titanium or stainless steel, or a ceramic such as alumina, titanium dioxide, or silicon dioxide. In a preferred embodiment, the total diffusion membrane surface area of ​​each device is between about 1 mm 2 With 50mm 2 In preferred embodiments, the porous separator has a porosity of greater than or equal to about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%, and a pore size between about 0.05-0.75 microns, between about 0.1 and 0.45 microns, or between about 0.1 and 0.30 microns.

[0064] The internal volume of the implantable device is sufficient to accommodate an amount of opioid antagonist formulation sufficient to be administered to a human subject during the expected treatment period. The treatment period can be about 1 to 12 months, and preferably greater than about 2 months, 3 months, 4 months or 6 months, and optionally less than about 14 months or about 12 months. In a preferred embodiment, the device has an internal volume between about 500 μL and 1000 μL.

[0065] The internal diameter of the implantable drug delivery device is constant over its entire length, and in one embodiment, the diameter of the internal reservoir is no more than 5% larger than the diameter of the solid compressed shape (e.g., tablet, pill, or rod) placed in the internal reservoir. In other embodiments, the diameter of the internal reservoir is 5%, 4.4%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or 0.5% larger than the diameter of the solid compressed shape placed in the internal reservoir. This configuration only allows a small amount of fluid to penetrate between the wall of the internal reservoir and the curved outer surface of the compressed shape. Limited fluid volume limits the number of diffusion paths of particles leaving from the curved surface of the compressed shape relative to the particles leaving from the orthogonal flat end of the compressed shape aligned with the porous membrane (and therefore limits the absolute diffusion rate).

[0066] The compressed shape in the device can be hydrated in situ when the device is implanted subcutaneously, or more preferably, the compressed shape can be hydrated to the reservoir by a liquid (e.g., physiological buffer, isotonic saline, phosphate buffered saline or propylene glycol aqueous solution) introduced by a clinician immediately before subcutaneous implantation. The reservoir can be prepared in an auxiliary container (e.g., a lyophilized vial sealed with a soft rubber septum) and sealed under vacuum to facilitate the process. The liquid can be provided as part of a kit, which includes a vial carrying a drug delivery device and a second vial carrying a hydration liquid.

[0067] Examples of drug delivery devices are Figure 1A-1B Available in. Figure 1A The device 10 is shown assembled and ready for implantation in an anatomical compartment of a subject, such as beneath the skin or in the peritoneal cavity. The device is comprised of a non-erodible housing member 12 defining an interior compartment or reservoir 14. The reservoir contains a composition or formulation described herein. The housing member 12 has a first end 16 and a second end 18. The first end 16 is sealed with a liquid-tight end cap 20, which is provided at the Figure 1B , which shows the device 10 in an unassembled form. The end cap 20 may optionally include a porous membrane or semi-permeable membrane or porous separator 22. The second end 18 is fitted with a porous membrane, semi-permeable membrane or porous separator 24.

[0068] Figure 1C-1K An end cap and end cap assembly portion of an exemplary drug delivery device are shown. Figures 1C-1F The numbered elements of the subassembly shown are 1 = cap, 2 = porous membrane, 3 = seal, 4 = retaining ring, and 5 = drug device reservoir. Figure 1G-1K The numbered elements of the subassembly shown are 1 = cap, 2 = porous membrane, 3 = seal, 4 = drug delivery device reservoir, and 5 = retaining ring.

[0069] In one embodiment, the interior of the device contains a solid formulation containing an opioid antagonist, such as naltrexone base or a pharmaceutically acceptable salt thereof, and (optionally) a binder, such as lactose, maltose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, a fatty acid or fatty alcohol containing at least 12 carbon atoms, a dicarboxylic acid containing at least 8 carbon atoms, or any mixture thereof, such that the melting point of the formulation is greater than or equal to 40° C. In one embodiment, the solid is compressed into a macroscopically non-porous shape, such as a tablet, rod, or pellet, the diameter of which is at least about 95% of the inner diameter of the device. In one embodiment, the density of the tablet, rod, or pellet is greater than or equal to 1.00 g / cm 3 , or between about 1.00 g / cm 3 With 1.20g / cm 3 The preparation may optionally contain a lubricant such as stearic acid, magnesium stearate, stearin, calcium stearate, sodium lauryl sulfate, glyceryl behenate, sodium benzoate, talc, and the like.

[0070] As used herein, the terms "porous membrane" and "porous partition" mean a structural member having a plurality of pores in the nanometer or micrometer (μm) range, preferably in the range of 0.1-0.45 μm. The drug is eluted from the interior of the device by diffusion through the partition; it allows dissolved naltrexone (or similar opioid antagonists, such as naloxone) to leave the device, but retains the undissolved drug composition in a solid state. To deliver a therapeutic dose from the device of the present invention, the total surface area of ​​the porous partition incorporated into each device is 1 mm 2 Up to 50mm 2 The drug delivery device is described in US Patent 2011 / 0106006, which is incorporated herein by reference. In a preferred embodiment, the membrane / separator has a porosity greater than or equal to 70%. In another embodiment, the membrane / separator has a porosity greater than or equal to 50%.

[0071] Taking naltrexone base as an example, a study was conducted to evaluate the release rate and release kinetics sequence of drug delivery devices containing solid formulations of opioid antagonists. As described in Example 1, two groups of cylindrical drug delivery devices were prepared. For Group 1: inner diameter (ID), 4.3mm; outer diameter (OD), 5.00mm; internal volume, 474μL; length, 40mm. For Group 2: ID, 4.5mm; OD, 5.00mm; internal volume, 650μL; length, 42.2mm. All device reservoirs and caps were made of titanium, and the ends of all devices were covered with a circular 0.1μm polyvinylidene fluoride membrane (DURAPORE TM, Millipore, Inc.) cap. The total diffusion area for each device in the first group was calculated to be approximately 19.4 mm 2 , and the second group is about 21.6mm 2 The devices in the first group were loaded with approximately 325 mg of naltrexone base as a fine powder. The devices in the second group were loaded with approximately 570 mg of tablets consisting of 93% naltrexone base, 5% polyvinylpyrrolidone (40 kD), and 2% stearic acid (by mass) as a lubricant. Tablets were prepared by grinding the various powders together and then by tableting on a single punch tablet press equipped with a custom 4.35 mm diameter die. Compression parameters were adjusted to produce approximately 1.09 g / cm 3 In one embodiment, the tablet has a density of at least about 0.75 g / cm 3 , at least about 0.80 g / cm 3 , at least about 0.85 g / cm 3 , at least about 0.90 g / cm 3 , at least about 0.95 g / cm 3 , at least about 1.0 g / cm 3 , at least about 1.05 g / cm 3 , at least about 1.10 g / cm 3 , or at least about 1.15 g / cm 3 density.

[0072] Prior to in vitro or in vivo testing, the drug delivery devices were sealed in lyophilized vials under vacuum and hydrated with 0.9% saline. Figure 2 Results of in vitro testing are shown, where the cumulative release of naltrexone (mg) for each device group is plotted against time (days). Data from drug delivery devices filled with naltrexone powder compositions are shown as blue circles; data from devices filled with tablet naltrexone compositions are shown as orange squares. After hydration at t=0, the devices (n=3) were incubated at 37°C in jars containing phosphate-buffered saline as the receiving buffer. Buffer changes were performed regularly for each group, and the drug content of the retention buffer samples was quantified by reverse phase HPLC. Figure 2 As can be seen, over a period of about 6 months, the compressed solid composition comprising naltrexone provided 2 =0.994) naltrexone eluted from the device at an average rate of 0.5-0.6 mg / day.

[0073] Figure 3A graph of plasma concentrations of naltrexone (ng / mL) as a function of time (days) is shown in rats implanted with devices loaded with fine powdered naltrexone base (n=5) or tableted naltrexone compositions (n=3). Plasma samples were taken from these animals periodically, frozen, and then analyzed using an LC / MS method to quantify plasma levels of naltrexone. The data were then normalized to the initial body weight of each animal to account for weight gain over the course of the study. Plasma levels were found to remain relatively constant between 10 ng / mL and 15 ng / mL for at least 5 months.

[0074] It is contemplated that drug delivery devices such as those described herein may be implanted in any suitable implantation site using methods and devices well known in the art. As described below, an "implantation site" is a site in which a drug delivery device is introduced and positioned in a subject. Implantation sites include, but are not limited to, subdermal, subcutaneous, intramuscular, or other suitable sites in the subject's body. Because it is convenient to implant and remove a drug delivery device, a subcutaneous implantation site is preferred. Exemplary subcutaneous delivery sites include below the skin of the abdomen, arms, shoulders, neck, back, or legs. The site in the body cavity is also a suitable implantation site. Methods for implanting or otherwise positioning a drug delivery device for subcutaneous delivery of a drug are well known in the art. Typically, the placement of a drug delivery device will be accomplished using methods and tools well known in the art, and is performed under aseptic conditions, and at least some local or general anesthesia is applied to the subject.

[0075] Treatment

[0076] In other aspects, methods of treatment using the compositions and devices described herein are contemplated. In one embodiment, a method for sustained, controlled delivery of an opioid antagonist is contemplated, wherein a device paired with a composition described herein is provided.

[0077] In one embodiment, the composition is a dry preparation, such as a powder, tablet, pill or stick. The dry preparation is placed in the internal storage of the device. A porous partition or membrane is fixed to the device, and in one embodiment, is fixed to one or both ends of the device, wherein the internal storage of the device is connected to the environmental fluid outside the device via a porous partition / membrane. If necessary, the device can be placed in a glass bottle and sealed under a vacuum with a pressure range of 0.02Torr to 100Torr. The bottled device is packaged, distributed and stored in a dry form. In one embodiment, before the implantation device, an aqueous medium (such as 0.9% saline or water for injection) is introduced into a vial. Vacuum draws aqueous fluid into the vial and into the void space in the device storage (that is, the internal storage volume is not occupied by solid, dry preparations). The liquid wets the membrane and the preparation, and forms a diffusion path for the dissolved drug; the diffusion of the drug through the membrane occurs immediately after hydration. Undissolved drugs are retained in the internal storage of the device. However, when the dissolved drug diffuses from the device, the undissolved drug enters the solution and can diffuse through the partition.

[0078] The preferred implant site of the device is the subcutaneous tissue of the abdomen or arm. For example, the implantation is accomplished using an implanter tool and other instruments provided in a surgical kit. After implantation, the device elutes sufficient drug in the body to achieve a plasma concentration sufficient for treatment for at least about 1 month and up to 3 months, 4 months, 6 months, or 12 months. For example, when the opioid antagonist is naltrexone base, the target plasma concentration is about 0.01-0.50 ng / mL, lasting at least 1 month and up to 12 months, because the level of exposure is expected to correspond to the average plasma level obtained from oral naltrexone, which is about 1 / 10 of the level used to treat opioid use disorder. In another example, when the opioid antagonist is naltrexone base, the target plasma concentration is at least about 0.01 ng / mL, 0.02 ng / mL, 0.03 ng / mL, 0.04 ng / mL, 0.05 ng / mL, 0.06 ng / mL, 0.07 ng / mL, 0.08 ng / mL, 0.09 ng / mL, or 0.1 ng / mL and less than 0.50 ng / mL for at least 1 month and up to 12 months, as this exposure level is expected to correspond to the average plasma level obtained from oral naltrexone, which is a dose of approximately 1 / 10 of the level used to treat opioid use disorder. In other embodiments, the device contains an amount of opioid antagonist to provide a therapeutic blood (plasma or serum or blood) concentration lasting between 1-36 months, 1-24 months, 1-12 months, 1-8 months, 1-6 months, 1-4 months, 1-3 months, 2-36 months, 2-24 months, 2-12 months, 2-10 months, 2-8 months, 2-6 months, 2-4 months, 3-36 months, 3-24 months, 3-12 months, 3-10 months, 3-9 months, 3-8 months, 3-6 months or 3-4 months. For example, by balancing the shape and size of the device, the mass of the loaded drug, the porosity and diffusion surface area of ​​the porous partition, and the number of implanted devices, sufficient output of the opioid antagonist from the device can be achieved.

[0079] In one embodiment, a device having an internal volume of between about 500-1000 μL contains a composition of naltrexone or a pharmaceutically acceptable salt thereof. The amount of opioid antagonist within the device is sufficient to provide therapeutically relevant plasma levels of naltrexone and its active metabolite 6-β-naltrexol for a period of at least about 1 month, at least about 2 months, at least about 3 months, or for a period of 1-36 months, 1-24 months, 1-18 months, 1-12 months, 1-6 months, 1-3 months, or 2-36 months, 2-24 months, 2-28 months, 2-12 months, 2-6 months, or 2-3 months. In another embodiment, the amount of opioid antagonist within the device is sufficient to provide therapeutically relevant plasma levels of naltrexone (excluding its active metabolite 6-β-naltrexol) for a period of at least about 1 month, at least about 2 months, at least about 3 months, or for between 1-36 months, 1-24 months, 1-18 months, 1-12 months, 1-6 months, 1-3 months, or 2-36 months, 2-24 months, 2-28 months, 2-12 months, 2-6 months, or 2-3 months.

[0080] In another embodiment, methods for maintaining therapeutic plasma levels of naltrexone, naloxone, or a similar opioid receptor antagonist are contemplated to reduce the frequency or intensity of symptoms associated with a chronic inflammatory, neuroinflammatory, or metabolic disorder over a period of time.

[0081] III. Examples

[0082] The following examples are illustrative in nature and are not intended to be limiting in any way.

[0083] Example 1

[0084] A dissolution-based device for constant rate delivery of naltrexone—in vitro evaluation

[0085] Tablets consisted of naltrexone base (93% by mass), polyvinylpyrrolidone (average molecular weight 40 kD; 5% by mass), and stearic acid (2% by mass) as a lubricant and were prepared by simply grinding the powders together and then pressing them on a single punch tablet press (Vanguard Model CP-501; Spring, TX) equipped with a custom 4.35 mm diameter die. Compression parameters were adjusted to produce approximately 1.09 g / cm 3 These were used to fill cylindrical drug delivery devices (4.50 mm ID, 5.00 OD, 42.2 mm length, 650 μL internal volume) made of titanium and filled with two circular parallel 0.1 μm polyvinylidene fluoride Membrane (total diffusion area per device 21.6mm 2) capped. All devices were vacuum backfilled with 0.9% saline and transferred to jars containing phosphate buffered saline (volume of approximately 100 mL). The sealed jars were then incubated at 37°C. The receiving buffer was replaced regularly (minimum once a week) and a small aliquot (approximately 500 μL) of the retained liquid was analyzed by high pressure liquid chromatography (HPLC) to quantify the drug. The release of naltrexone from this device configuration is shown in Figure 2 Medium (orange square symbol).

[0086] The in vitro release profile of a powder formulation of naltrexone base was also measured. The device was made of titanium and had the following dimensions: ID, 4.3 mm; OD, 5.00 mm; internal volume, 474 μL; length, 40 mm. Each device reservoir was loaded with approximately 325 mg of fine naltrexone base powder and then filled with two circular parallel 0.1 micron polyvinylidene fluoride. Membrane (total diffusion area per device was 19.4 mm 2 ) cap. The in vitro release rate was measured as above. The release of naltrexone from this device configuration is also shown in Figure 2 Medium (blue circular symbol).

[0087] Example 2

[0088] A dissolution-based device for constant rate delivery of naltrexone—in vivo evaluation

[0089] The drug delivery device was prepared as described in Example 1. Tablets consisting of naltrexone base (93% by mass), polyvinylpyrrolidone (average molecular weight 40 kD; 5% by mass), and stearic acid (2% by mass) were prepared by simply grinding the powders together and then pressing them on a single punch tablet press (Vanguard Model CP-501; Spring, TX) equipped with a custom 4.35 mm diameter die. The compression parameters were adjusted to produce approximately 1.09 g / cm 3 These were used to fill cylindrical drug delivery devices (4.50 mm ID, 5.00 OD, 42.2 mm length, 650 μL internal volume) with two circular parallel 0.1 μm polyvinylidene fluoride Membrane (total diffusion area per device was 21.6 mm 2) cap. The average fill weight was approximately 570 mg of formulation per device. The devices were sealed in lyophilized vials under vacuum and terminally sterilized. The devices were vacuum backfilled with 0.9% saline and implanted individually into rats (n=3). Plasma samples were regularly obtained from these animals, frozen, and then analyzed using LC / MS methods to quantify the plasma levels of naltrexone over time. The data were then normalized to the initial weight of each animal to account for weight gain during the study. Plasma levels were found to remain relatively constant between 10 ng / mL and 15 ng / mL within 5 months after implantation ( Figure 3 , orange square symbol).

[0090] As also described in Example 1, the devices were made of titanium and had the following dimensions: ID, 4.3 mm; OD, 5.00 mm; internal volume, 474 μL; length, 40 mm. Each device reservoir was loaded with approximately 325 mg of naltrexone base fine powder and then filled with two circular parallel 0.1 micron polyvinylidene fluoride. Membrane (total diffusion area per device was 19.4 mm 2 ) cap. The devices were sealed in lyophilized vials under vacuum and terminally sterilized. The devices were vacuum backfilled with 0.9% saline and implanted individually into rats (n=3). Plasma samples were taken from these animals regularly, frozen, and then analyzed using LC / MS methods to quantify plasma levels of naltrexone over time. The data were then normalized to the initial weight of each animal to account for weight gain during the study. Plasma levels were found to remain relatively constant between 10 ng / mL and 15 ng / mL for approximately 5 months after implantation ( Figure 3 , blue circular symbol).

Claims

1. A device for delivering an opioid antagonist, the device comprising: a device having an internal reservoir having an inner diameter, a first end, and a second end, the device being sized for implantation in a subject; a porous partition secured to the device; and A formulation comprising an opioid antagonist in the internal reservoir, wherein the formulation does not include an organic acid.

2. The device according to claim 1, wherein the preparation is a solid preparation.

3. The device according to claim 2, wherein the solid formulation is a powder.

4. The device according to claim 3, wherein the powder is compressed.

5. The device according to claim 4, wherein the compressed powder has a compressed shape of a tablet, a pellet or a stick.

6. The device of claim 5, wherein the compressed shape has a diameter equal to or greater than 80% of the inner diameter of the internal reservoir.

7. The device of claims 4 to 6, wherein the opioid antagonist is combined with a binder.

8. The device according to claim 7, wherein the binder used to formulate the opioid antagonist is lactose, maltose, mannitol, trehalose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, a fatty (aliphatic) acid or alcohol containing at least 12 carbon atoms, a dicarboxylic acid containing at least 8 carbons, or any combination thereof.

9. The device of claims 2 to 8, wherein the opioid antagonist is combined with one or more stabilizing excipients.

10. The device of claim 9, wherein the stabilizing excipient comprises a metal chelator such as a salt of ethylenediaminetetraacetic acid; a buffer such as a phosphate, a carboxylate or an amino acid; and an antioxidant such as ascorbic acid, an ascorbic acid ester, tocopherol, a tocopherol ester, cysteine, a cysteine ​​ester or amide, methionine, a methionine ester or amide, butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA).

11. The device of any one of claims 2 to 10, wherein the solid formulation has a melting point greater than or equal to about 40°C. 12 . The device according to claim 2 , wherein the porous separator is a polyvinylidene fluoride porous membrane.

13. The device of any one of claims 2 to 11, wherein the porous separator is a sintered metal disk comprising titanium or stainless steel.

14. The device according to any one of claims 2 to 11, wherein the porous separator is a porous ceramic membrane composed of aluminum oxide, titanium dioxide or silicon dioxide.

15. The device according to any preceding claim, wherein the porous partition has a thickness of about 1-50 mm. 2 The surface area between them is available for diffusion.

16. The apparatus of any preceding claim, wherein the porous separator has a porosity greater than or equal to about 70% and one or more pores having a pore size between about 0.1-0.45 microns.

17. The device of any preceding claim, wherein the device is less than or equal to about 8 mm in diameter and less than or equal to about 8 cm in length, or wherein the device has a diameter between about 2-8 mm and a length between about 2-8 cm.

18. The device of any one of claims 1 to 17, wherein the device is less than or equal to 5 mm in diameter and less than or equal to 5 cm in length, or wherein the device has a diameter between about 2-5 mm and a length between about 2-5 cm.

19. The device of any one of claims 1 to 18, configured for subcutaneous implantation.

20. The device of claim 19 configured for subcutaneous implantation using a trocar.

21. The device of any one of claims 1 to 20, wherein the opioid antagonist is naltrexone base.

22. The device of any one of claims 1 to 20, wherein the opioid antagonist is a pharmaceutically acceptable salt of naltrexone.

23. The device according to any one of claims 1 to 20, wherein the opioid antagonist is a stereoisomer or a racemic mixture of naloxone, nalmefene, nalorphine, nalodine, levallorphan, zolphanol, oxymorphan, samidorphine, 6-β-naltrexol, methylnaltrexone, diprenorphine or cyprodime.

24. The device of any one of claims 1 to 20, wherein the opioid antagonist is in the form of a pharmaceutically acceptable salt of naloxone, nalmefene, nalorphine, nalodine, levallorphan, zolphanol, oxymorphan, samidorphine, 6-β-naltrexol, methylnaltrexone, diprenorphine or a stereoisomer of cyprodime.

25. An apparatus according to any preceding claim, wherein the porous partition is fixed to the first end or the second end or both.

26. The device of any preceding claim, wherein the amount of the opioid antagonist maintains a therapeutically effective plasma level of the opioid antagonist for at least about 1 month.

27. A device according to any preceding claim for use in treating an inflammatory, neuroinflammatory or metabolic disorder such as psoriasis, fibromyalgia, HIV-associated neurological and neurocognitive disorders, Crohn's disease, multiple sclerosis, complex regional pain syndrome, Hailey-Hailey disease, insulin resistance, pain and / or cachexia.

28. A method for in vivo delivery of an opioid antagonist, the method comprising: There is provided an apparatus according to any one of claims 1 to 27, and The device is implanted into a subcutaneous space of a human subject, whereby the implantation causes aqueous fluid in the subcutaneous space to enter the device to hydrate the formulation.

29. A method for in vivo delivery of an opioid antagonist, the method comprising: There is provided an apparatus according to any one of claims 1 to 27, and Prior to implanting the device into the subcutaneous space of a human subject, the device is contacted with an aqueous fluid to wet the device membrane and the formulation.

30. The method of claim 29, wherein the aqueous fluid is isotonic saline, sterile water, or phosphate buffered saline.

31. The method of any one of claims 28 to 30, wherein the implanting or contacting produces an aqueous phase within the internal reservoir, and the aqueous phase comprises a dissolved opioid antagonist.

32. A method for treating an inflammatory, neuroinflammatory or metabolic disorder, such as psoriasis, fibromyalgia, HIV-associated neurological and neurocognitive disorders, Crohn's disease, multiple sclerosis, complex regional pain syndrome, Hailey-Hailey disease, insulin resistance, pain and / or cachexia, the method comprising: A device according to any one of claims 1 to 27 is provided, The device is administered to a human subject by subcutaneous implantation, wherein the administration provides delivery of the opioid antagonist in an amount that provides therapeutic blood levels for a period of between about 1-36 months.

33. The method of claim 32, wherein the opioid antagonist is naltrexone base and naltrexone is administered in an amount that provides a plasma level of the active moiety of naltrexone (defined as naltrexone and its active metabolite 6-β-naltrexol) greater than about 0.01-0.50 ng / mL over the time period.

34. The method of claim 32, wherein the opioid antagonist is naltrexone base and naltrexone is administered in an amount to provide a plasma level of naltrexone (excluding its active metabolite 6-β-naltrexol) greater than about 0.01-0.50 ng / mL over the time period.

35. The method of any one of claims 32 to 34, further comprising contacting the device with an aqueous fluid to wet the device membrane and the formulation prior to said administering.

36. The method of claim 35, wherein providing comprises providing the device in a container under vacuum, and introducing the aqueous fluid into the container.

37. The method of any one of claims 32 to 36, wherein providing and administering comprises providing 1 to 4 devices and administering 1 to 4 devices.

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