Implantable device, formulation, and method for weight management

Abstract

The present disclosure relates to the field of patient treatment using an implantable delivery device for the long-term release of a therapeutic agent. In particular, the present disclosure relates to a device, formulation, and method for managing body weight.

Description

Technology Field Cross-reference regarding related applications

[0001] This application claims priority to U.S. provisional application No. 63 / 617,522 filed January 4, 2024 and No. 63 / 663,298 filed June 24, 2024, each of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0002] Many subjects, including human subjects as well as veterinary subjects, require long-term treatment with therapeutic agents. To improve compliance, many subjects can benefit from compliance provided by implantable devices that release the desired therapeutic agent at a desired rate over an extended period. In particular, weight management requiring permanent commitment can benefit from such options. The present disclosure meets these needs and provides other advantages.

[0003] In one embodiment, the present disclosure provides a device for managing the weight of an object, and the device is A capsule configured for transplantation and having a storage; Weight management agents placed in the storage; and It comprises a nanoporous membrane having multiple pores that provides a diffusion pathway for a weight management agent out of the reservoir, and the weight management agent is an incretin mimic.

[0004] In another embodiment, the present disclosure provides a formulation for managing the weight of a subject, the formulation is included in a device, and the device is A capsule configured for transplantation and having a storage; Weight management agents placed in the storage; and It comprises a nanoporous membrane having multiple pores that provides a diffusion pathway for a weight management agent out of the reservoir, and the weight management agent is an incretin mimic.

[0005] In another embodiment, the present disclosure provides a method for managing the weight of an object, and the method As a step of providing a device, the device A capsule configured for transplantation and having a storage; Weight management agents placed in the storage; and The method comprises a nanoporous membrane having a plurality of pores that provides a diffusion pathway for a weight management agent outside the storage, wherein the weight management agent is an incretin mimic; and a step of implanting a device into a target.

[0006] These and other purposes, aspects, and embodiments will become more apparent when read together with the following detailed description and drawings. Brief explanation of the drawing

[0007] FIG. 1a shows a diagram of a device according to the present disclosure having a single storage.

[0008] FIG. 1b shows a diagram of a device according to the present disclosure having two reservoirs and two nanoporous membranes.

[0009] Figure 2 shows the in vitro release rate of exenatide from an embodiment of the device of the present invention.

[0010] Figure 3 shows the effect on the body mass of a DIO mouse after implantation of the device of the present invention of Figure 2.

[0011] FIG. 4 shows the in vitro release rate of exenatide from an alternative embodiment of the device of the present disclosure.

[0012] Figure 5 shows the effect on the body mass of a Sprague Dolly rat after implantation of the device of the present disclosure of Figure 4. Specific details for implementing the invention

[0013] The present disclosure relates to the field of long-term treatment of a subject (e.g., for more than one month) using an implantable device that provides continuous delivery of a therapeutic agent.

[0014] Embodiments of the present disclosure include formulations and devices comprising one or more therapeutic agents, and optionally one or more stabilizers, release rate regulators, or other beneficial agents for the therapeutic agents. Additionally, embodiments of the present disclosure include methods for treating a subject using the devices and formulations of the present disclosure. definition

[0015] "Polypeptide" refers to a molecule having a backbone chain of two or more amino acid residues. Some polypeptides may have additional associated groups, such as metal ions in metalloproteins, organic small molecules as in heme proteins, or carbohydrate groups as in glycoproteins.

[0016] “Peptide” and “protein” refer to subgroups of polypeptides. In this disclosure, the definitions of peptide and protein follow the practice of the U.S. Food and Drug Administration (FDA), which defines peptide as a polypeptide having 40 or fewer amino acid residues and protein as a polypeptide having more than 40 amino acid residues.

[0017] Incretin mimics refer to agents that act like incretin hormones, such as glucagon-like peptide-1 (GLP-1). They bind to GLP-1 receptors to stimulate glucose-dependent insulin release and thus act as antihyperglycemic agents. Some incretin mimics include inhibitors of dipeptidyl peptidase-4 (DPP-4), which effectively increase circulating levels of GLP-1 type peptides. Some incretin mimics bind to one or more of the human GLP-1 receptor, human glucose-dependent insulin secretion-stimulating polypeptide (GIP) receptor, and / or human glucagon receptor. Some incretin mimics bind to human amylin receptors. Some incretin mimics are monoreceptor agonists. Some incretin mimics are bireceptor agonists. Some incretin mimics are trireceptor agonists.

[0018] "Formulation of a therapeutic agent" refers to the actual state in which the therapeutic agent is present in a product or an intermediate for the manufacture of a product, and includes the therapeutic agent, and optionally, any additional therapeutic agent used, any formulation excipient used, and any formulation solvent used.

[0019] A "membrane" refers to a permeable structure that allows the mass transport of molecules to occur from one side of the structure through the structure to the other.

[0020] "Porous membrane" refers to a membrane characterized by the presence of a two-phase system, wherein the membrane matrix material exhibits one phase, typically a continuous phase, which is infiltrated by open channels extending from one side of the membrane to the other, and is filled with a second phase, often a fluid phase, through which mass transport through the membrane can occur.

[0021] "Dense" or "non-porous membranes" refer to fluid-filled membranes without pores. In such membranes, mass transport can occur via a dissolution-diffusion mechanism, where the therapeutic agent dissolves in the membrane material itself and permeates the membrane by diffusing through it.

[0022] "Nanoporous membrane" and "nanopore membrane" are used interchangeably and refer to a porous membrane having a minimum diameter of less than 1,000 nanometers.

[0023] "Nanotube membrane" refers to a nanoporous membrane, where the pores are formed by an array of nanotubes.

[0024] "Titania nanotube membrane" refers to an array of titania nanotubes on a titanium substrate, wherein at least some of the titania nanotubes have both ends open and can allow diffusion from one side of the membrane to the other through the titania nanotubes.

[0025] The "molecular diameter" of a polymer refers to the diameter of the polymer's radius of rotation sphere, which is a physical measure of molecular size and is defined as twice the mass-weighted average distance from the center of the molecule to each mass element within the molecule.

[0026] "Stokes diameter" or "hydrodynamic diameter" refers to the dimensions of a molecule and its associated water molecules as they move through an aqueous solution, and is defined as the radius of an equivalent hard sphere diffusing at the same speed as the molecule being observed.

[0027] "Ion exchange resin" or IER refers to a polymer containing acidic or basic groups, or a combination thereof, which is made insoluble, for example, by crosslinking, and is capable of exchanging anions or cations, or a combination thereof, with a surrounding medium.

[0028] As used in this disclosure, “fluid” and “fluid form” refer to states of fluidable substances, including but not limited to gases, solutions, suspensions, emulsions, colloids, dispersions, etc.

[0029] "Fluid contact" refers to an object being in contact with a fluid.

[0030] "Neutral pH" refers to a pH range of 6.5 or higher to 7.5 or lower, or any number within that range.

[0031] The "administration" of a therapeutic agent refers to the act of injecting, implanting, or otherwise depositing the therapeutic agent by transdermally accessing the subject's body, such as in administration by injection or implantation means. The therapeutic agent may be contained within a drug delivery device, such as the device of FIG. 1a or FIG. 1b. The therapeutic agent may be delivered by the implantable device after the implantable device has been administered.

[0032] As used herein, the term “implant” broadly refers to any type of implanted or implantable object or device. Drug delivery devices or implants according to the present disclosure are not limited to any specific shape. The final shape and size of an implant in the body may vary and may differ depending on the therapeutic purpose. device

[0033] As illustrated in FIG. 1a, the device of the present disclosure comprises a capsule (101) suitable for implantation, and the capsule has a reservoir (102) suitable for holding therapeutic agents and stabilizers, release rate regulators, or other beneficial agents. In some embodiments, more than one reservoir exists. The capsule may be made of any suitable biocompatible material. In some embodiments, the capsule is made of a medical metal such as titanium or stainless steel, or of a medical polymer material such as silicon, polyurethane, polyacrylate, polyolefin, polyester, polyamide, etc. In some embodiments, the capsule is made of a plurality of materials. In some embodiments of the present 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 material and is, for example, a capsule having a cap having a membrane as a pathway for the release of a therapeutic agent, having a reservoir for holding a therapeutic agent and a stabilizer, a release rate regulator, or other beneficial agent, the cap may be attached to the reservoir by any suitable means such as welding, bonding, press-fitting, or the use of screw fastening means, or any combination thereof.

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

[0036] The device of the present disclosure has at least one membrane attached to a capsule and in fluid contact with a reservoir as described, and the membrane provides a pathway for mass transport of a therapeutic agent contained within the reservoir out of the reservoir and into the body of a subject to whom the capsule is implanted. In the present disclosure, “attached to a capsule” refers to a component being in a fixed position relative to the capsule and being connected directly or indirectly to the capsule using any suitable means including welding, bonding, press-fitting and the use of threaded means, or any combination thereof. In the case of the membrane, as described in U.S. Patent No. 9,814,867 and illustrated in FIG. 1a, the nanotube membrane is part of a nanotube array (103), some of which are still attached to a grown titanium substrate (104), and the substrate may be attached to the capsule. At least some of the nanotubes are open on both sides, as in (105) of FIG. 1a, to enable mass transport of the therapeutic agent out of the reservoir. The membrane may be attached to the capsule such that the substrate side faces the reservoir or faces away from the reservoir. The dimensions of the device may be determined based on the total amount of formulation to be contained in the reservoir and medically acceptable dimensional limits. In certain aspects, the size of the device may be from a diameter of about 0.2 cm to a length of about 2 cm, or from a diameter of about 0.25 cm to a length of about 2.5 cm. In other aspects, the size is from a diameter of about 4 mm to a length of about 40 mm. Other dimensions may be determined on a case-by-case basis.

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

[0038] Further descriptions of the device of the present disclosure including dimensions can be found in U.S. Patent Applications Publications US20220008345 and US20210246271, and U.S. Patents No. 9,814,867 and No. 9,770,412, which are incorporated herein by reference.

[0039] FIG. 1b is a diagram of a device according to the present disclosure having two storage units separated by an enclosure. Various identification numbers in FIG. 1b correspond to the same features of FIG. 1a, but with the letter b added. membrane

[0040] An embodiment of the present disclosure includes at least one membrane that provides a route for mass transport of a therapeutic agent out of the storage of the device of the present disclosure.

[0041] In the embodiments of the present disclosure, various types of membranes may be used.

[0042] The membranes of the present disclosure comprise dense and porous membranes; the porous membrane comprises a nanoporous membrane and a nanotube membrane.

[0043] Materials suitable for the membrane of the present disclosure include organic and inorganic materials, polymers, ceramics, metals, metal oxides, and combinations thereof. Materials suitable 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] The embodiments of the present disclosure are particularly useful as sustained delivery devices for therapeutic agents in which the release of the therapeutic agent is controlled by a nanoporous membrane.

[0046] Some embodiments of the present disclosure include titania nanotube membranes as described in U.S. Patent No. 9,814,867. The pore size of the membrane of the present disclosure can be controlled by a process as described in U.S. Patent No. 9,770,412.

[0047] Generally, the average pore size of the membrane of the present disclosure may be between 1 and 1,000 nanometers. In some embodiments, an average pore size greater than 1,000 nanometers may exist. In some embodiments, the average pore size is 1 to 5 nanometers. In some embodiments, the average pore size is 5 to 10 nanometers. In some embodiments, the average pore size is 10 to 50 nanometers. In some embodiments, the average pore size is 50 to 100 nanometers. In some embodiments, the average pore size is 100 to 1,000 nanometers. In some embodiments, a pore size of less than 1 nanometer may exist.

[0048] In some embodiments, the membrane pores have a diameter of the same order of size as the hydrodynamic diameter of a dissolved substance, such as a therapeutic agent, within the formulation. In some embodiments, the pores have a diameter smaller than the hydrodynamic diameter of the dissolved substance within the formulation. Due to the finite size of the pores, these membranes can act as size-blocking filters for the dissolved substance within the formulation of a drug delivery system.

[0049] In some embodiments, the membrane pores have a diameter ranging from 1 to 5 times the molecular diameter of the drug molecule diffusing through the aqueous phase, or 1, 2, 3, 4, or 5 times. In some embodiments, the membrane pores have a diameter as described in U.S. Patent No. 11,129,791. Under these conditions, it has been found that a drug release rate can be achieved that is not controlled by the concentration gradient between the reservoir and the environment in which the drug is released (e.g., non-Pickian or zero-order) as seen in typical Fickian diffusion, and can approach a more constant release rate over time.

[0050] The membrane pores are in fluid contact with the therapeutic agent within the reservoir, allowing molecules of the therapeutic agent to diffuse into and out of the pores and into the environment surrounding the device. The profile of the release rate over time can be any desired profile. In some embodiments, the profile is a decay profile following normal Pycian diffusion out of the reservoir. In some embodiments, the release rate profile is a non-Pycian profile, such as a constant rate or an approximate constant rate profile. A constant rate profile is sometimes referred to as a zero-order release rate profile. Some embodiments have a rapid increase in the drug release rate at the beginning of the profile. Some embodiments have a slow increase in the release rate at the beginning of the release rate profile.

[0051] The implantable drug delivery system of the present disclosure may have one or more membranes (see FIG. 1b). For example, the implantable drug delivery system may have one, two, three, four or more membranes. Membrane types include nanoporous membranes and non-porous membranes. Different nanoporous membranes may have the same or different pore diameters. When the implantable drug delivery system has more than one membrane having the same pore diameter, each membrane may provide a diffusion path for the therapeutic agent. Alternatively, the membranes may each have different pore diameters so that one or more of the membranes do not provide a diffusion path for the therapeutic agent. In some embodiments, when two membranes are present in the implantable drug delivery system, optionally only one membrane provides a diffusion path for the therapeutic agent.

[0052] Further descriptions of the membranes of the present disclosure can be found in U.S. Patents No. 9,814,867 and 9,770,412. remedy

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

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

[0055] The therapeutic agent of the present disclosure may exist in any desired state, including fluid and solid forms.

[0056] Any suitable therapeutic agent may be included in the embodiments of the present disclosure. For example, the therapeutic agent may be a small molecule drug 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 present disclosure, the therapeutic agent is a peptide or a protein. In some embodiments of the device, the therapeutic agent is an incretin mimic. Incretin mimics include liraglutide, semaglutide, dulaglutide, liraglutide, tirzepatide, albiglutide, lixisenatide, cotadutide, sitagliptin, saxagliptin, alogliptin, and linagliptin, danuglipron, orforglipron, permvidutide, cagrilintin, pramlintide, survodutide, mazdutide, amicriptin, and It includes, but is not limited to, amylin.

[0058] Exenatide (natural, recombinant, and synthetic, also known as exendin-4) refers to the compound with CAS number 141758-74-9; semaglutide (recombinant and synthetic) refers to the compound with CAS number 910463-68-2; liraglutide refers to the compound with CAS number 204656-20-2; dulaglutide refers to the compound with CAS number 923950-08-7; efpeglenatide refers to the compound with CAS number 1296200-77-5; tyrzepatide refers to the compound with CAS number 2023788-19-2; albiglutide refers to the compound with CAS number 782500-75-8; and lixisenatide refers to the compound with CAS number 320367-13-3; Retatrutide refers to the compound of CAS number 2381089-83-2; Framlintide refers to the compound of CAS number 196078-30-5; Surbodutide refers to the compound of CAS number 2805997-46-8; Cotadutide refers to the compound of CAS number 1686108-82-6; and Cagrisema (cagrilintide + semaglutide) refers to a formulation having the compound of CAS number 910463-68-2 and the compound of CAS number 1415456-99-3. These compounds may also include alternative pharmaceutical salts that retain the amino acid sequence.

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

[0060] The formulations of the present disclosure comprise at least one therapeutic agent disposed in a reservoir, and optionally one or more stabilizers, release rate regulators, or other beneficial agents. Beneficial agents include buffers, solubility regulators, surfactants, soluble high molecular weight and low molecular weight stabilizers, antioxidants, antimicrobial agents, etc. A list of potentially suitable inactive ingredients used in medicines currently marketed in the United States can be found on the U.S. Food and Drug Administration (FDA) website.

[0061] The therapeutic agents and stabilizers, release rate regulators, or other beneficial formulations of the present disclosure may be combined in any suitable combination for manufacturing the device of the present disclosure in any suitable state by any suitable means.

[0062] In some cases, the formulations of the present disclosure are solid formulations, such as crystallized or freeze-dried powders.

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

[0064] In some cases, the formulations of the present disclosure are mixed formulations such as suspensions and emulsions.

[0065] Any of the components of a formulation including not only therapeutic agents but also stabilizers, release rate regulators, or other beneficial agents may exist in any of the above states, such as a suspension of a stabilizer in a drug solution or a suspension of a drug in an emulsion of a release rate regulator.

[0066] The solvent of the present disclosure may be any of an aqueous, organic, or mixed aqueous-organic solvent.

[0067] A therapeutic agent, stabilizer, release rate controller, or other beneficial agent in a fluid or solid state may be combined with a therapeutic agent in a fluid or solid state. A therapeutic agent with a stabilizer, release rate controller, or other beneficial agent may be combined in a solid state in a first step and converted to a fluid state in a subsequent step. A therapeutic agent with a stabilizer, release rate controller, or other beneficial agent may be combined in a fluid state in a first step and converted to a solid state in a subsequent step. The combination of a therapeutic agent with a stabilizer, release rate controller, or other beneficial agent may be carried out by any suitable method including dry powder mixing and the preparation of a fluid mixture of the therapeutic agent with the stabilizer, release rate controller, or other beneficial agent. These options may be combined in any suitable combination and permutation.

[0068] Some embodiments of the present disclosure include therapeutic agents that require stabilization. In some embodiments, stabilization is provided by a pH adjuster. The stabilization mechanisms provided by embodiments of the present disclosure include chemical or physical mechanisms, and combinations of both. Reference also makes to U.S. Patent No. 10,479,868.

[0069] Some embodiments of the present disclosure include therapeutic agents requiring control of the release rate. In some embodiments, control of the release rate is provided by a pH regulator (see US20220008345). In some embodiments, control of the release rate is provided by a surfactant (see WO2023 / 235302).

[0070] In certain cases, 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 present disclosure provide a method for treating a disease or condition of a subject using the device and formulation of the present disclosure. Some embodiments of the present disclosure provide a method for managing body weight. Subjects include human and veterinary subjects. The method comprises providing a device of the present disclosure comprising a therapeutic agent and, optionally, one or more stabilizers, release rate regulators, or other beneficial agents, and implanting the device into a subject to treat a disease or condition or manage body weight.

[0072] The implantation can be performed by any means known to those skilled in the art, for example, by inserting the device subcutaneously using a hollow needle or a trocar.

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

[0074] In some embodiments, the incretin mimic is used for weight management. In some embodiments, the incretin mimic is exenatide or semaglutide or a combination. In some embodiments, after implantation into the subject, the incretin mimic is released at a rate of 10 micrograms to 500 micrograms per day, or 20 micrograms to 400 micrograms per day, or 30 micrograms to 300 micrograms per day.

[0075] In some embodiments, after implantation, the incretin mimic 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, the incretin mimic is released at an effective rate for more than 1 year.

[0076] In some embodiments of the treatment of a disease or condition, the implantation of the device of the present disclosure is repeated one or more times. In some embodiments, the frequency of implantation or administration is less than once a week, such as once every two weeks, once every three weeks, or once a month. The interval between repeated administrations may be longer than one month.

[0077] In some embodiments, treatment is repeated at a frequency of once a week to once a month, or once a month to once every three months, or once every three months to once every six months, or once every six months to once every 12 months, or once every 12 months to once every 24 months. For the purposes of this disclosure, the interval is defined to include its limits, such as exactly one week or exactly three months.

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

[0079] In some embodiments, the administration of the therapeutic agent is repeated. In some embodiments, the frequency of administration is less than once a week, for example, once every two weeks, once every three weeks, or once a month.

[0080] In some embodiments, administration of the therapeutic agent is repeated at a frequency of once a week to once a month, or once a month to once every three months, or once every three months to once every six months, or once every six months to once every 12 months, or once every 12 months to once every 24 months. For the purposes of this disclosure, the interval is defined to include its limits, such as exactly one week or exactly three months.

[0081] In some embodiments, the therapeutic agent is contained within an implantable device when administration takes place. This application refers to U.S. Patent Publications No. US 20220008345 and US 20210246271, and U.S. Patents No. 9,814,867, 9,770,412, 10,045,943, 10,479,868, 11,129,791 and WO2023 / 235302, each of which is incorporated herein by reference in its entirety. Examples

[0082] The device used in the exenatide example included a titanium capsule approximately 25 mm in length and 2.25 mm in diameter. A titanium substrate having a titanium oxide nanoporous membrane was welded to one end of the device. The nanoporous membrane had a diameter of 0.3 mm and consisted of approximately 6,000,000 nanopores. The membrane was manufactured as described in U.S. Patents No. 9814867 and 9770412. Twenty or eighty layers (see below) of titanium oxide were added to the membrane using atomic layer deposition (ALD) as described in U.S. Patent No. 9770412. A silicon diaphragm was inserted at the other end of the device. To fill the device with the formulation, the formulation was loaded into a filling device having a hollow needle penetrating the diaphragm. A vacuum was applied to the membrane of the device to lower the pressure inside the reservoir, and the formulation was injected into the reservoir by passing it through the needle and the diaphragm.

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

[0084] The in vitro release rate test of the device was performed by immersing the device in 3 mL of Bis-Tris buffered saline at pH 7.4 and incubating the vial at 37°C. At predetermined intervals, the amount of released drug in the release rate buffer was checked by high-performance liquid chromatography, and the device was transferred to a new release rate buffer. Example 1

[0085] One of the accepted animal models for studying weight management is the use of adult mice with diet-induced obesity (DIO) in 21- or 28-day transplant studies. (Gabery, S et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020 Mar 26; 5(6): e133429. Published online 2020 Mar 26).

[0086] In this embodiment, the effect of the embodiment of the present disclosure on weight management was investigated using this DIO model.

[0087] In the manufacture of the device, according to the method of PCT application US2021 / 019559, about 25% exenatide-acetate (w / w), 0.15 M Na + Approximately 56 mg of a formulation containing (as NaOH and NaCl) and a pH of about 5.5 was filled into the device. The membrane of this example had an ALD of 80 layers.

[0088] As described above, the in vitro release rates of multiple devices were measured in parallel with in vivo studies. The resulting release rates are shown in Fig. 2. In this embodiment, exenatide is released in a non-Pycian manner.

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

[0090] As can be seen in Figure 3, the body weight of the treated mice (lower trace) was about 20% lower than that of the control mice (upper trace). Example 2

[0091] As described in WO 2021 / 173770, a GLP toxicology study was conducted using a device similar to that of the above study, except for the addition of approximately 10 mg of stability-enhancing resin. It should be noted that, unlike the mouse model, the animals in this study were young Sprague Dolly rats that are still in a developmental stage and exhibiting significant growth. A control group with a placebo device was also included. Although this model was not explicitly developed to study weight loss, it was nevertheless able to yield useful results.

[0092] About 25% exenatide-acetate (w / w), 0.15 M Na according to the method of PCT application No. US2021 / 019559 + Approximately 45 mg of a formulation containing (as NaOH and NaCl) and a pH of about 5.5 was filled into the device. The membrane of this example had a 20-layer ALD.

[0093] As described above, the in vitro release rates of multiple devices were measured in parallel with in vivo studies. The resulting release rates are shown in Figure 4. The release of exenatide is non-Pycian.

[0094] Figure 5 shows the body mass profiles of treated rats (lower trace) versus placebo control groups (upper trace).

[0095] As can be seen in the graph, body mass increased in both groups, but a sustained decrease in body mass was observed in the treated rats compared to the control group.

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

Claims

Claim 1 A method for managing weight in a subject, comprising the step of providing a device, wherein the device comprises a capsule configured for implantation and having a reservoir, a weight management agent disposed within the reservoir, and a nanoporous membrane having a plurality of pores providing a diffusion path for the weight management agent outside the reservoir, wherein the weight management agent is an incretin mimic; and the step of implanting the device into the subject. Claim 2 The method according to claim 1, wherein the weight management agent is exenatide, semaglutide, tirzepatide, and retatrutide. Claim 3 A method according to claim 1 or 2, wherein the device further comprises one or more of a stabilizer and a release rate regulator. Claim 4 A method comprising a solvent in any one of claims 1 to 3. Claim 5 A method according to claim 4, wherein the concentration (w / w) of the weight management agent is 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. Claim 6 A method according to any one of claims 1 to 5, wherein the step of providing a weight management device suitable for implantation and the step of implanting said device into a subject are repeated at a frequency of less than once a week. Claim 7 A method according to any one of claims 1 to 6, wherein the device is implanted at a frequency of one of once a week to once a month, once a month to once every 3 months, once every 3 months to once every 6 months, once every 6 months to once every 12 months, and once every 12 months to once every 24 months. Claim 8 A device for managing the weight of a subject, wherein the device comprises a capsule configured for implantation and having a reservoir, a weight management agent disposed within the reservoir, and a nanoporous membrane having a plurality of pores providing a diffusion path for the weight management agent outside the reservoir; wherein the weight management agent is an incretin mimic. Claim 9 In paragraph 8, the device, wherein the weight management agents are exenatide, semaglutide, tyrzepatide, and retatrutide. Claim 10 A device according to claim 8 or 9, wherein the device further comprises one or more of a stabilizer and a release rate regulator. Claim 11 A device comprising a solvent further comprising any one of claims 8 to 10. Claim 12 A device according to claim 11, wherein the concentration (w / w) of the weight management agent is 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. Claim 13 A formulation for managing the weight of a subject, wherein the formulation is included in a device, the device comprises a capsule configured for implantation and having a reservoir, a weight management agent disposed within the reservoir, and a nanoporous membrane having a plurality of pores providing a diffusion path for the weight management agent outside the reservoir, and wherein the weight management agent is an incretin mimic. Claim 14 In paragraph 13, the formulations in which the weight management agents are exenatide, semaglutide, tyrzepatide, and retatrutide. Claim 15 A formulation according to claim 13 or 14, wherein the device further comprises one or more of a stabilizer and a release rate regulator. Claim 16 A formulation comprising a solvent in any one of claims 13 to 15. Claim 17 A formulation according to claim 16, wherein the concentration (w / w) of the weight management agent is 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. Claim 18 A method for managing weight in a subject, comprising the steps of providing 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 at a frequency of less than once a week. Claim 19 A method according to claim 18, wherein a weight management agent is administered at one of the following frequencies: once a week to once a month, once a month to once every three months, once every three months to once every six months, once every six months to once every twelve months, and once every twelve months to once every twenty-four months. Claim 20 In paragraph 18 or 19, the method wherein the weight management agent is an incretin mimic. Claim 21 In paragraph 18, the method wherein the incretin mimics are exenatide, semaglutide, tyrzepatide, and retatrutide. Claim 22 A method according to any one of claims 18 to 21, wherein a weight management agent is included in a device suitable for implantation. Claim 23 In claim 22, the method comprises a device suitable for implantation, a capsule configured for implantation, a reservoir, wherein a weight management agent is disposed within the reservoir, and the device further comprises a nanoporous membrane having a plurality of pores that provides a diffusion path for the weight management agent outside the reservoir.

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