Implantable devices, formulations and methods for body weight management

Abstract

The disclosure pertains to the field of treatment of patients with implantable delivery devices for long-term release of therapeutic agents. In particular, the disclosure pertains to devices, formulations, and methods to manage body weight.

Description

IMPLANTABLE DEVICES, FORMULATIONS AND METHODS FOR BODY WEIGHT MANAGEMENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US Provisional Patent Application Nos. 63 / 617,522, filed January 4, 2024, and 63 / 663,298, filed June 24, 2024, each of which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] Many subjects, human as well as veterinary, are in need of long-term treatment with therapeutic agents. In order to improve adherence, many subjects would benefit from the compliance provided by an implantable device releasing a desired therapeutic agent at a desired rate for an extended period of time. In particular, management of body weight, requiring a permanent commitment, would benefit from such an option. The present disclosure satisfies these needs and offers other advantages as well.BRIEF SUMMARY

[0003] In one embodiment, the present disclosure provides a device for managing body weight in a subject, the device comprising: a capsule configured for implantation and having a reservoir; a weight management agent disposed within the reservoir; and a nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir, wherein the weight management agent is an incretin mimetic.

[0004] In another embodiment, the present disclosure provides a formulation for managing body weight in a subject, the formulation contained in a device, the device comprising: a capsule configured for implantation and having a reservoir; a weight management agent disposed within the reservoir; anda nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir, wherein the weight management agent is an incretin mimetic.

[0005] In yet another embodiment, the present disclosure provides a method of managing body weight in a subject, comprising: providing a device, the device comprising: a capsule configured for implantation and having a reservoir; a weight management agent disposed within the reservoir; and a nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir, wherein the weight management agent is an incretin mimetic, and implanting the device in the subject.

[0006] These and other objects, aspects and embodiments will become more apparent when read with the detailed description and figures that follow.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 A represents a diagram of a device according to the disclosure with one reservoir.

[0008] FIG. IB represents a diagram of a device according to the disclosure with two reservoirs and two nanoporous membranes.

[0009] FIG. 2 represents the in vitro release rate of exenatide from an embodiment of devices of the invention.

[0010] FIG. 3 represents the effect on body mass of DIO mice after implantation of the devices of the invention from FIG. 2.

[0011] FIG. 4 represents the in vitro release rate of exenatide from an alternative embodiment of devices of the disclosure.

[0012] FIG. 5 represents the effect on body mass of Sprague Dawley rats after implantation of the devices of the disclosure from FIG. 4.DETAILED DESCRIPTION

[0013] The disclosure pertains to the field of long-term treatment (e.g., more than 1 month) of a subject with an implantable device providing a sustained delivery of a therapeutic agent.

[0014] Embodiments of the disclosure include devices and formulations including one or more therapeutic agents and, optionally, one or more stabilizing, release rate modifying, or otherwise beneficial agents for the therapeutic agent. Additionally, embodiments of the disclosure include methods of treatment of a subject with devices and formulations of the disclosure.Definitions

[0015] “Polypeptides” refer to molecules with a backbone chain of 2 or more amino acid residues. Some polypeptides may have additional associated groups, such as metal ions in metalloproteins, small organic molecules such as in heme proteins, or carbohydrate groups such as in glycoproteins.

[0016] “Peptides” and “Proteins” refer to subgroups of polypeptides. In this disclosure the definition of peptides and proteins follows the practice of the United States Food and Drug Administration, the FDA, which defines peptides as polypeptides with up to 40 amino acid residues, and proteins as polypeptides with more than 40 amino acid residues.

[0017] Incretin mimetics refers to agents that act like incretin hormones such as glucagon- like peptide- 1 (GLP-1). They bind to GLP-1 receptors and stimulate glucose dependent insulin release, therefore acting as antihyperglycemics. Some incretin mimetics include inhibitors of dipeptyl peptidase - (DPP-4), which effectively increase the circulating levels of GLP-1 type peptides. Some incretin mimetics bind to one or more of the human GLP-1 receptor, the human glucose-dependent insulinotropic polypeptide (GIP) receptor and / or the human glucagon receptor. Some incretin mimetics bind to the human amylin receptor. Some incretin mimetics are single receptor agonists. Some incretin mimetics are dual receptor agonists. Some incretin mimetics are triple receptor agonists.

[0018] “Formulation of a therapeutic agent” refers to the actual state in which a therapeutic agent is present in a product or in a product fabrication intermediate, and includes the therapeutic agent, plus, optionally, any used additional therapeutic agents, any used formulation excipients and any used formulation solvents.

[0019] “Membrane” refers to a permeable structure allowing mass transport of molecules from one side of the structure to the other through the structure.

[0020] “Porous membranes” refers to membranes characterized by the presence of a two- phase system, in which membrane matrix material represents one phase, typically acontinuous phase, which is permeated by open channels extending from one side of the membrane to the other, and filled with a second phase, often a fluid phase, through which mass transport through the membrane can take place.

[0021] “Dense” or “non-porous membranes” refers to membranes without fluid filled pores. In such membranes mass transport may take place by a dissolution-diffusion mechanism, in which therapeutic agents permeate the membrane by dissolving in the membrane material itself, and diffusing through it.

[0022] “Nanoporous membrane” and “nanopore membrane” are used interchangeably, and refer to porous membranes in which the pores have a smallest diameter of less than 1000 nanometer.

[0023] “Nanotube membrane” refers to a nanoporous membrane, wherein pores are formed by an array of nanotubes.

[0024] “ Titania nanotube membrane” refers to an array of titania nanotubes on a titanium substrate where at least a portion of the titania nanotubes are open at both ends and capable of allowing diffusion from one side of the membrane to the other through the titania nanotubes.

[0025] “Molecular diameter” of a polymer refers to the diameter of the sphere of gyration of the polymer, which is a physical measure of the size of a molecule, and is defined as two times the mass weighted average distance from the core of a molecule to each mass element in the molecule.

[0026] “ Stokes diameter” or “hydrodynamic diameter” refers to the dimension of a molecule plus its associated water molecules as it moves through an aqueous solution, and is defined as the radius of an equivalent hard sphere diffusing at the same rate as the molecule under observation.

[0027] “Ion exchange resin” or IER refers to a polymer comprising acidic or basic groups, or a combination thereof, made insoluble, for instance by cross-linking, and capable of exchanging anions or cations, or a combination thereof, with a medium surrounding it.

[0028] “Fluid” and “fluid form” as used in this disclosure refers to flowable states of matter and includes, but is not limited to gases, solutions, suspensions, emulsions, colloids, dispersions and the like.

[0029] “Fluid contact” refers to an entity being in contact with a fluid.

[0030] “Neutral pH” refers to a pH range between 6.5 and 7.5 inclusive, or any number in between the range.

[0031] Administration” of a therapeutic agent, as in administration by an injectable or implantable means, refers to the act of percutaneously accessing the body of a subject and injecting or implanting, or otherwise depositing, the therapeutic agent. The therapeutic agent may be contained within a drug delivery device such as the device of FIG. 1A or IB. The therapeutic agent may be delivered by an implantable device, once the implantable device is administered.

[0032] The term “implant”, as used herein, refers widely to any type of implanted or implantable object or device. The drug delivery device or implant according to this disclosure is not limited to any particular shape. The final shape and size of the implant in the body can vary and may depend on the purpose of the treatment.Devices

[0033] As illustrated in Fig. 1 A, devices of the disclosure include a capsule 101 suitable for implantation, wherein the capsule has a reservoir 102 suitable for holding a therapeutic agent and a stabilizing, release rate modifying, or otherwise beneficial agent. In some embodiments more than one reservoir is present. The capsule may be made of any suitable biocompatible material. In some embodiments the capsule is made of a medical grade metal, such as titanium or stainless steel, or of a medical grade polymeric material, such as silicone, polyurethane, polyacrylate, polyolefin, polyester, polyamide and the like. In some embodiments the capsule is made of multiple materials. In some embodiments of the disclosure the capsule is made of titanium.

[0034] In some embodiments the capsule is made of a single piece of material. In some embodiments the capsule is made of multiple pieces of materials, for instance a capsule having a reservoir for holding a therapeutic agent and a stabilizing, release rate modifying, or otherwise beneficial agent and having a cap holding a membrane as a pathway for release of the therapeutic agent, wherein the cap can be attached to the reservoir by any suitable means, such as welding, gluing, press fitting or using threaded means, or any combination of these.

[0035] The capsule may have any suitable size or shape. In some embodiments of the disclosure the capsule is cylindrical, facilitating implantation or administration into the body by means of a tubular implantation device, such as a needle or trocar.

[0036] Devices of the disclosure have at least one membrane, as described in this disclosure, attached to the capsule and in fluid contact with the reservoir, wherein the membrane provides a pathway for mass transport of a therapeutic agent included within the reservoir out of that reservoir and into the body of a subject into which the capsule has been implanted. In this disclosure “attached to the capsule” refers to a component being fixed in place with respect to the capsule, and connected to the capsule directly or indirectly, by using any suitable means, including by welding, gluing, press-fitting and by using threaded means, or by any combination of these. In the case of membranes as described in US Patent No. 9,814,867, and as illustrated in FIG. 1A, the nanotube membranes are part of an array of nanotubes 103, some of which are still attached to the titanium substrate 104 from which they were grown, and the substrate may be attached to the capsule. At least some of the nanotubes are open on both sides, 105 in FIG. 1 A, to allow for mass transport of a therapeutic agent out of the reservoir. The membranes may be attached to the capsule with the substrate side facing into the reservoir or facing away from the reservoir. The dimensions of the device may be determined based on total amount of formulation to be included in the reservoir, and on medically acceptable dimension limits. In certain aspects, the size of the device may be about 0.2 cm in diameter to about 2 cm in length, or about 0.25 cm in diameter to about 2.5 cm in length. In other aspects, the size is about 4 mm in diameter to about 40 mm in length. Other dimensions may be determined on a case-by-case basis.

[0037] In certain instances, the device has a reservoir capacity with a volume of about 10 microliters to about 10 milliliters. In certain instances, the reservoir has a volume of about 10 pL to about 100 pL such as 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, or 100 pL. In other instances, the reservoir is about 25-60 pL or about 30-50 pL, or even about 30-45 pL. In other instances, the reservoir is about 100-500 microliters, 150-450 microliters, or about 150- 350 microliters, such as about 250 microliters.

[0038] Further descriptions of devices of the disclosure, including dimensions, may be found in US patent application Pubs. US20220008345 and US20210246271, and US Patents Nos. 9,814,867 and 9,770,412, incorporated herein by reference.

[0039] FIG IB is a diagram of a device according to the disclosure with two reservoirs separated by an enclosure. The various identifying numbers in FIG. IB corresponding to the same features in FIG. 1 A but appended with the letter b.Membranes

[0040] Embodiments of the disclosure include at least one membrane providing a pathway for mass transport of a therapeutic agent out of a reservoir of a device of the disclosure.

[0041] A wide variety of membranes can be used in embodiments of the present disclosure.

[0042] Membranes of the disclosure include dense and porous membranes; porous membranes include nanoporous membranes and nanotube membranes.

[0043] Suitable materials for membranes of the disclosure include organic and inorganic materials, polymers, ceramics, metals, metal oxides and combinations thereof. Suitable materials for the membrane include silicon, silica, titanium and titania.

[0044] In some embodiments, the membrane is a nanoporous membrane. In some embodiments the membrane is a nanotube membrane. In some embodiments the membrane is a titania nanotube membrane.

[0045] Embodiments of the disclosure are particularly useful as sustained delivery devices for therapeutic agents, in which the release of the agents is controlled by a nanoporous membrane.

[0046] Some embodiments of the disclosure comprise a titania nanotube membrane, such as described in US Patent No. 9,814,867. The pore size of membranes of the disclosure can be controlled by processes such as described in US Patent No. 9,770,412.

[0047] Generally, average pore sizes of membranes of the disclosure may be between 1 and 1000 nanometer. In some embodiments, average pore sizes larger than 1000 nanometer may be present. In some embodiments the average pore size is from 1 to 5 nanometer. In some embodiments the average pore size is from 5 to 10 nanometer. In some embodiments the average pore size is from 10 to 50 nanometer. In some embodiments the average pore size is from 50 to 100 nanometer. In some embodiments the average pore size is from 100 to 1000 nanometer. In some embodiments pore sizes of less than 1 nanometer may be present.

[0048] In some embodiments the membrane pores have a diameter of the same order of magnitude as the hydrodynamic diameter of dissolved substances, such as a therapeutic agent in a formulation. In some embodiments, the pores have a diameter smaller than hydrodynamic diameter of dissolved substances in a formulation. Because of the finite size of the pores, such membranes may act as a size cut-off filter for dissolved substances in the formulations of the drug delivery systems.

[0049] In some embodiments, the membrane pores have diameters in a range of 1-5 times or 1, 2, 3, 4, or 5 times the molecular diameter of the drug molecules diffusing through their aqueous phase. In some embodiments the membrane pores have diameters, as described in US Patent No. 11, 129,791. It has been shown that under those conditions drug release rates may be achieved that are not controlled by a concentration gradient between the reservoir and the environment into which the drug is released as would be seen in typical Fickian diffusion (e.g., non-Fickian or zero order), and that may approach a more constant release rate over time.

[0050] The membrane pores are in fluid contact with the therapeutic agent in the reservoir, such that molecules of the therapeutic agent are able to diffuse into and out of the pores and into an environment surrounding the device. The profile of the release rate over time may be any desired profile. In some embodiments the profile is a declining profile, in accordance with regular Fickian diffusion out of the reservoir. In some embodiments the release rate profile is non-Fickian, like a constant rate or near-constant rate profile. Constant rate profiles are sometimes referred to as zero-order release rate profiles. Some embodiments have a spike in drug release rate at early time points in the profile. Some embodiments have slow ramp up of release rates at early time points in the release rate profile.

[0051] The implantable drug delivery system of the present disclosure can have one or more membranes (See, FIG. IB). For example, the implantable drug delivery system can have 1, 2, 3, 4, or more membranes. Membrane types include nanoporous and non-porous membranes. Different nanoporous membranes can have the same or different pore diameters. When the implantable drug delivery system has more than one membrane each with the same pore diameter, each membrane can provide a diffusion pathway for the therapeutic agent. Alternatively, the membranes can each have different pore diameters such that one or more of the membranes does not provide a diffusion pathway for the therapeutic agent. In some embodiments, when two membranes are present in the implantable drug delivery system, only one membrane provides a diffusion pathway for the therapeutic agent.

[0052] Further descriptions of membranes of the disclosure may be found in US Patents Nos. 9,814,867 and 9,770,412.Therapeutic agents

[0053] Some embodiments of the disclosure include low molecular weight therapeutic agents, sometimes referred to as “small molecule drugs”. Some embodiments of thedisclosure include high molecular weight therapeutic agents, like peptides and proteins, carbohydrates and nucleic acids, and combinations thereof, like glycoproteins.

[0054] Some embodiments of the disclosure include more than one type of therapeutic agent.

[0055] Therapeutic agents of the disclosure may be present in any desired state, including fluid and solid forms.

[0056] Any suitable therapeutic agent can be incorporated into embodiments of the disclosure. For example, the therapeutic agent can be a small molecule drug, such as one having a molecular weight of less than about 1000 g / mol, or less than about 750 g / mol, or less than about 500 g / mol.

[0057] In some embodiments of the disclosure the therapeutic agent is a peptide or protein. In some embodiments of the device the therapeutic agent is an incretin mimetic. Incretin mimetics include, but are not limited to, liraglutide, semaglutide, dulaglutide, liraglutide, tirzepatide, albiglutide, lixisenatide, cotadutide, sitagliptin, saxagliptin, alogliptin, and linagliptin, danuglipron, orforglipron, permvidutide, cagrilintin, pramlintide, survodutide, mazdutide, amycriptin and amylin.

[0058] Exenatide (natural, recombinant and synthetic, also called exendin-4) refers to the compound with CAS No. 141758-74-9; Semaglutide (recombinant and synthetic) refers to the compound with CAS No. 910463-68-2; Liraglutide refers to the compound with CAS No. 204656-20-2; Dulaglutide refers to the compound with CAS No. 923950-08-7; Efpeglenatide refers to the compound with CAS No. 1296200-77-5; Tirzepatide refers to the compound with CAS No. 2023788-19-2; Albiglutide refers to the compound with CAS No. 782500-75- 8; Lixisenatide refers to the compound with CAS No. 320367-13-3; Retatrutide refers to the compound with CAS No. 2381089-83-2; Pramlintide refers to the compound with CAS No. 196078-30-5; Survodutide refers to a compound with CAS No. 2805997-46-8; Cotadutide refers to a compound with CAS No. 1686108-82-6; and Cagrisema (cagrilintide+semaglutide) refers to formulation having a compound with CAS No. 910463- 68-2 and a compound with CAS No. 1415456-99-3. These compounds may also include alternative pharmaceutical salts, which maintain their amino acid sequences.

[0059] In some embodiments, the amount of polypeptide therapeutic agent present is from about 10 pg to about 50 mg, such as 100 pg, 200 pg, 300 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, or 50 mg or more.Formulations

[0060] Formulations of the disclosure include at least one therapeutic agent and, optionally, one or more stabilizing, release rate modifying, or otherwise beneficial agents, disposed within the reservoir. Beneficial agents include buffering agents, solubility modifiers, surfactants, soluble high and low molecular weight stabilizers, anti-oxidants, antimicrobials and the like. A list of potentially suitable inactive ingredients used in currently marketed pharmaceutical products in the US can be found on the website of the United States Food and Drug Administration (FDA).

[0061] Therapeutic agents and stabilizing, release rate modifying, or otherwise beneficial agents in this disclosure may be combined in any suitable combination in preparing devices of the disclosure, by any suitable means, and in any suitable state.

[0062] In some instances, formulations of the disclosure are solid formulations, such as crystallized or lyophilized powders.

[0063] In some instances, formulations of the disclosure are fluid or liquid formulations, such as true solutions.

[0064] In some instances, formulations of the disclosures are mixed formulations, such as suspensions and emulsions.

[0065] Any of the components of the formulation, therapeutic agents as well as stabilizing, release rate modifying or otherwise beneficial agents can be in any of the above states, such as a suspension of stabilizer in a solution of a drug, or a suspension of a drug in an emulsion of a release rate modifying agent.

[0066] Solvents of the disclosure may be any of aqueous, organic, or mixed aqueous- organic solvents.

[0067] Therapeutic agents, stabilizing, release rate modifying, or otherwise beneficial agents in a fluid or solid state may be combined with therapeutic agents in a fluid or solid state. Stabilizing, release rate modifying, or otherwise beneficial agents and therapeutic agents may be combined in their solid states in a first step, and brought into a fluid state in alater step. Stabilizing, release rate modifying, or otherwise beneficial agents and therapeutic agents may be combined in fluid states in a first step, and brought into a solid state in a later step. Combination of the therapeutic agent and the stabilizing, release rate modifying, or otherwise beneficial agent may be performed by any suitable method, including dry powder mixing and preparing a fluid mixture of the therapeutic agent and the stabilizing, release rate modifying, or otherwise beneficial agent. These options may be combined in any suitable combination and permutation.

[0068] Some embodiments of the disclosure comprise a therapeutic agent in need of stabilization. In some embodiments stabilization is provided by pH-controlling agents.Stabilization mechanisms provided by embodiments of the disclosure include chemical or physical mechanisms, as well as combinations of both. See also US Patent No. 10,479,868.

[0069] Some embodiments of the disclosure comprise a therapeutic agent in need of release rate modification. In some embodiments release rate modification is provided by pH- controlling agents. (See US20220008345) In some embodiments release rate modification is provided surfactants. (See WO2023 / 235302).

[0070] In certain instances, the formulation is about 1 mg to about 800 mg, about 50 mg to about 400 mg, or about 100 to about 300 mg, or about 150 to about 250 mg.Treatment methods

[0071] Some embodiments of the disclosure provide methods of treating a disease or condition in subjects using devices and formulations of the disclosure. Some embodiments of the disclosure provide methods to manage body weight. Subjects include human and veterinary subjects. The methods include providing a device of the disclosure including a therapeutic agent and, optionally, one or more stabilizing, release rate modifying, or otherwise beneficial agents and implanting the device in the subject, thereby treating the disease or condition or managing the body weight.

[0072] The implantation can be performed by any means known to one of skill in the art, for instance through subcutaneous insertion of the device using a hollow needle or trocar.

[0073] In some embodiments the therapeutic agent is an incretin mimetic.

[0074] In some embodiments the incretin mimetic is used to manage body weight. In some embodiments the incretin mimetic is exenatide or semaglutide or a combination. In someembodiments, after implantation in a subject, an incretin mimetic is released at rate between 10 microgram per day and 500 microgram per day, or between 20 microgram per day and 400 microgram per day, or between 30 microgram per day and 300 microgram per day.

[0075] In some embodiments, after implantation, an incretin mimetic is released at an effective rate for at least 1 month, or at least 2 months, or at least 3 months, or at least 6 months, or at least 1 year. In some embodiments an incretin mimetic is released at an effective rate for more than 1 year.

[0076] In some embodiments of treatment of a disease or condition the implantation of devices of the disclosure is repeated one or more times. In some embodiments the frequency of implantation or administration is less frequent than once a week, such as once every 2 weeks, or once every 3 weeks, or once every month. The interval between repeat administrations can be longer than 1 month.

[0077] In some embodiments the treatment is repeated with a frequency that is between once a week and once a month, or between once a month and once every 3 months, or between once every 3 months and once every 6 months, or between once every 6 months and once every 12 months, or between once every 12 months and once every 24 months. For the purpose of this disclosure, the intervals are defined as including their limits, such as exactly one week, or exactly 3 months.

[0078] In some embodiments the therapeutic agent is contained within an implantable device when administration occurs.

[0079] In some embodiments the administration of the therapeutic agent is repeated. In some embodiments the frequency of administration is less frequent than once a week, such as once every 2 weeks, or once every 3 weeks, or once every month.

[0080] In some embodiments the administration of the therapeutic agent is repeated with a frequency that is between once a week and once a month, or between once a month and once every 3 months, or between once every 3 months and once every 6 months, or between once every 6 months and once every 12 months, or between once every 12 months and once every 24 months. For the purpose of this disclosure, the intervals are defined as including their limits, such as exactly one week, or exactly 3 months.

[0081] In some embodiments the therapeutic agent is contained within an implantable device when administration occurs.This application references US Patent Application Publication Nos. US 20220008345 and U.S. 20210246271, and U.S. Patent Nos. 9,814,867, 9,770,412, 10,045,943, 10,479,868, 11,129,791 and WO2023 / 235302, which are each incorporated herein by reference in their entireties.Examples

[0082] The devices that were used for the exenatide examples included titanium capsules of approximately 25 mm length and 2.25 mm diameter. A titanium substrate with a titanium oxide nanoporous membrane was welded to one end of the device. The nanoporous membrane had a diameter of 0.3 mm and was composed of about 6,000,000 nanopores. The membranes were manufactured as described in US patent Nos. 9814867 and 9770412. Using Atomic Layer Deposition (ALD) 20 or 80 (See below) layers of titanium oxide were added to the membranes, as described in US patent No. 9770412. A silicone septum was inserted at the other end of the device. In order to fill the devices with formulations, the formulations were loaded into a filler apparatus with a hollow needle to pierce the septum. A vacuum was applied to the membrane of the device to reduce the pressure inside the reservoir, and the formulation was injected through the septum into the reservoir through the needle.

[0083] The formulations used are specified in the examples below.

[0084] In vitro release rate testing of the devices was performed by submerging them in 3 mL of Bis-Tris buffered saline at pH 7.4 and incubating the vials at 37°C. At predetermined intervals the release rate buffers were examined for released amounts of drug by High Performance Liquid Chromatography, and the devices were transferred to fresh release rate buffer.Example 1

[0085] One of the accepted animal models to study weight management is the use of adult mice with Diet-Induced Obesity (DIO) in a 21-day or 28-day implantation study. (Gabery, S et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020 Mar 26; 5(6): el33429. Published online 2020 Mar 26).

[0086] In this example, the effectiveness of embodiments of the disclosure in managing weight was investigated using this DIO model.

[0087] In the preparation of the devices, about 56 mg of a formulation containing approximately 25% exenatide-acetate (w / w), 0.15 M Na+(As NaOH and NaCl) and a pH of approximately 5.5 was filled into the device as per methods in PCT Application No. US2021 / 019559. The membranes in this example had 80 layers of ALD.

[0088] The in vitro release rates of a number of devices were measured in parallel with the in vivo study, as described above. The resulting release rates are represented in FIG. 2. In this example, the exenatide is released in a non-Fickian manner.

[0089] The devices were implanted in 7 mice in a diet-induced obesity (DIO) mouse model, and the body weight was followed over 28 days. 7 mice with placebo devices were included as controls.

[0090] As can be seen in FIG. 3, weights in the treated mice (lower trace) were about 20% lower than in control mice (upper trace).Example 2

[0091] A GLP toxicology study was performed with devices similar to the study above, but with addition of about 10 mg of a stability enhancing resin, as described in WO 2021 / 173770. It should be noted that, contrary to the mouse model, the animals in this study were juvenile Sprague Dawley rats, still in their developmental phase and thus exhibiting significant growth. A control group with a placebo device was included as well.While this model was not explicitly developed to study weight loss, useful results could be obtained nevertheless.

[0092] About 45 mg of a formulation containing approximately 25% exenatide-acetate (w / w), 0.15 M Na+(As NaOH and NaCl) and a pH of approximately 5.5 was filled into the device as per methods in PCT Application No. US2021 / 019559. The membranes in this example had 20 layers of ALD.

[0093] The in vitro release rates of a number of devices were measured in parallel with the in vivo study, as described above. The resulting release rates are represented in FIG. 4. The release of exenatide is non-Fickian.

[0094] FIG. 5 shows the body mass profile of treated rats (lower trace) vs the placebo control (upper trace).

[0095] As can be seen in the graph, while body mass did increase in both groups, a sustained reduction in body mass compared to the control group was observed in the treated rats.

[0096] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A method of managing body weight in a subject, comprising providing a device, the device comprising a capsule configured for implantation and having a reservoir; a weight management agent disposed within the reservoir; and a nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir, wherein the weight management agent is an incretin mimetic; and implanting the device in the subject.

2. The method of claim 1, wherein the weight management agent is exenatide, semaglutide, tirzepatide and retatrutide.

3. The method of any one of claims 1-2, wherein the device further includes one or more of a stabilizing agent and a release rate modifying agent.

4. The method of any one of claims 1-3, further comprising a solvent.

5. The method of claim 4, wherein the concentration (w / w) of the weight management agent is one of at least 1.1 %, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25% and at least 30% w / w.

6. The method of any one of claims 1-5, wherein the steps of providing a device for weight management suitable for implantation and implanting the device in the subject are repeated with a frequency of less frequent than once a week.

7. The method of any one of claims 1-6, wherein a device is implanted with a frequency that is one of: between once a week and once a month, and between once a month and once every 3 months, and between once every 3 months and once every 6 months, and between once every 6 months and once every 12 months, and between once every 12 months and once every 24 months.

8. A device for managing body weight in a subject, the device comprising: . a capsule configured for implantation and having a reservoir; a weight management agent disposed within the reservoir; anda nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir; wherein the weight management agent is an incretin mimetic.

9. The device of claim 8, wherein the weight management agent is exenatide, semaglutide, tirzepatide and retatrutide.

10. The device of any one of claims 8-9, wherein the device further includes one or more of a stabilizing agent and a release rate modifying agent.

11. The device of any one of claims 8-10, further comprising a solvent.

12. the device of claim 11, wherein the concentration (w / w) of the weight management agent is one of at least 1.1 %, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25% and at least 30% w / w.

13. A formulation for managing body weight in a subject, the formulation contained in a device, the device comprising: a capsule configured for implantation and having a reservoir; a weight management agent disposed within the reservoir; and a nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir, wherein the weight management agent is an incretin mimetic.

14. The formulation of claim 13, wherein the weight management agent is exenatide, semaglutide, tirzepatide and retatrutide.

15. The formulation of any one of claims 13-14, wherein the device further includes one or more of a stabilizing agent and a release rate modifying agent.

16. The formulation of any one of claims 13-15, further comprising a solvent.

17. The formulation of claim 16, wherein the concentration (w / w) of the weight management agent is one of at least 1.1 %, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25% and at least 30% w / w.

18. A method of managing body weight in a subject, comprisingproviding a weight management agent, administering the weight management agent to the subject, and repeating the step of administering the weight management agent to the subject with a frequency of less frequent than once a week.

19. The method of claim 18, wherein the weight management agent is administered with a frequency that is one of: between once a week and once a month, and between once a month and once every 3 months, and between once every 3 months and once every 6 months, and between once every 6 months and once every 12 months, and between once every 12 months and once every 24 months.

20. The method of any one of claims 18 and 19, wherein the weight management agent is an incretin mimetic.

21. The method of claim 18, wherein the incretin mimetic is exenatide, semaglutide, tirzepatide and retatrutide.

22. The method of any one of claims 18-21, wherein the weight management agent is contained within a device suitable for implantation.

23. The method of claim 22, wherein the device suitable for implantation comprises: a capsule configured for implantation; a reservoir; wherein the weight management agent disposed within the reservoir; and wherein the device further comprises a nanoporous membrane with a plurality of pores providing a diffusion path for the weight management agent out of the reservoir.

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