Formulations, devices, and methods for GLP-1 agonists

Abstract

The present disclosure provides formulations, methods, and implantable devices that improve patient compliance by releasing a desired therapeutic agent, such as semaglutide, over an extended period of time, for example, one year or more, at a semaglutide concentration (w / w) greater than 1%, such as from about 1.1% w / w to about 35% w / w.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Nos. 63 / 437,541, filed January 6, 2023, and 63 / 523,458, filed June 27, 2023, the teachings of which are incorporated herein by reference in their entirety and for all purposes. [Background technology]

[0002] Many subjects, both humans and animals, require long-term treatment with therapeutic agents. To improve adherence or compliance, many subjects would benefit from the adherence provided by an implantable device that releases a desired therapeutic agent at a desired rate over an extended period of time. Despite many years of research, there remains a need for the development of such devices, and in particular, methods for controlling the release rate of a therapeutic agent from such devices upon implantation into a subject.

[0003] In view of the above, the present disclosure provides formulations, methods, and implantable devices that improve patient compliance by releasing desired therapeutic agents over an extended period of time, even for a year or more, as well as by providing other benefits. Summary of the Invention

[0004] Quick Overview The present disclosure provides implantable drug delivery devices and relates to the long-term treatment of subjects using the implantable devices that provide sustained delivery of one or more therapeutic agents, such as incretin mimetics, at a controlled rate. The compositions, implantable drug delivery systems, and methods of using the therapeutic agents are useful for treating diseases such as diabetes and for administration to subjects in need of treatment with the therapeutic agents.

[0005] In certain aspects, embodiments include a formulation having a solvent, the formulation comprising semaglutide having a concentration, wherein the semaglutide concentration (w / w) is greater than about 1%, such as 1.1%, to about 35% w / w or more.

[0006] In certain aspects, embodiments include formulations wherein the semaglutide concentration (w / w) is one of at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, and at least 30% (w / w).

[0007] In certain aspects, embodiments include formulations of semaglutide, wherein the pH of the formulation is between 6 and 10.

[0008] In certain aspects, embodiments include formulations of semaglutide that are substantially free of additional pharmaceutical excipients.

[0009] In certain aspects, embodiments include formulations of semaglutide in which a tonicity agent is present.

[0010] In certain aspects, embodiments include formulations of semaglutide wherein the tonicity agent is an agent other than sodium chloride. The concentration of the tonicity agent may be from about 0.1% to about 10% w / w.

[0011] In certain aspects, embodiments include formulations of semaglutide wherein the tonicity agent is potassium chloride.

[0012] In certain aspects, embodiments include formulations of semaglutide wherein the solvent is water.

[0013] In certain aspects, embodiments include formulations of semaglutide wherein the solvent is an organic solvent or an aqueous-organic solvent mixture.

[0014] In certain aspects, embodiments include formulations of semaglutide in which additional pharmaceutical excipients are present.

[0015] In certain aspects, embodiments include formulations of semaglutide wherein the additional pharmaceutical excipient is one or more of an antimicrobial agent, a surfactant, an antioxidant, a free radical scavenger, and a peptide stabilizer.

[0016] In certain aspects, embodiments include formulations of semaglutide wherein the peptide stabilizer is one or more selected from the group of cyclodextrins and / or amino acids.

[0017] In certain aspects, embodiments include formulations of semaglutide wherein the cyclodextrin is hydroxypropyl alpha cyclodextrin.

[0018] In certain aspects, embodiments include formulations of semaglutide wherein the amino acid is histidine.

[0019] In a particular aspect, an embodiment includes a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a liquid formulation of semaglutide having a solvent and a concentration of semaglutide disposed within the reservoir; wherein the semaglutide concentration (w / w) is greater than about 1%.

[0020] In certain aspects, embodiments include a device for the sustained release of semaglutide, wherein the semaglutide concentration (w / w) is one of at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, and at least 30%.

[0021] In certain aspects, embodiments include a device for the sustained release of semaglutide, wherein the pH is from about 6 to about 10.

[0022] In certain aspects, embodiments include a device for the sustained release of semaglutide that is substantially free of additional pharmaceutical excipients.

[0023] In certain aspects, embodiments include a device for the sustained release of semaglutide in the presence of a tonicity agent.

[0024] In certain aspects, embodiments include a device for the sustained release of semaglutide, wherein said tonicity agent is an isotonicity agent other than sodium chloride.

[0025] In a particular aspect, an embodiment comprises a device for the sustained release of semaglutide, wherein said tonicity agent is potassium chloride.

[0026] In certain aspects, embodiments include a device for the sustained release of semaglutide, wherein the solvent is water.

[0027] In certain aspects, embodiments include a device for the sustained release of semaglutide, wherein the solvent is an organic solvent or an aqueous-organic solvent mixture.

[0028] In certain aspects, embodiments include devices for the sustained release of semaglutide in which an additional pharmaceutical excipient is present.

[0029] In certain aspects, embodiments include a device for the extended release of semaglutide, wherein the additional pharmaceutical excipient is one or more selected from the group of antimicrobial agents, surfactants, antioxidants, free radical scavengers, and peptide stabilizers.

[0030] In a particular aspect, an embodiment comprises a device for the sustained release of semaglutide, wherein the peptide stabilizer is one or more selected from the group of cyclodextrins and amino acids.

[0031] In a particular aspect, an embodiment comprises a device for the sustained release of semaglutide, wherein said cyclodextrin is hydroxypropyl alpha cyclodextrin.

[0032] In a particular aspect, the embodiment comprises a device for the sustained release of semaglutide, wherein said amino acid is histidine.

[0033] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed in the reservoir; wherein the semaglutide concentration (w / w) is greater than about 1%.

[0034] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and a concentration of semaglutide disposed within the reservoir; wherein the semaglutide concentration (w / w) is one of at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, and at least 30%.

[0035] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the pH is from about 6 to about 10.

[0036] In particular aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein there are substantially no additional pharmaceutical excipients.

[0037] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein a tonicity agent is present.

[0038] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the tonicity agent is an isotonicity agent other than sodium chloride.

[0039] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the tonicity agent is potassium chloride.

[0040] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the solvent is water.

[0041] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the solvent is an organic solvent or an aqueous-organic solvent mixture.

[0042] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; and wherein additional pharmaceutical excipients are present.

[0043] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the additional pharmaceutical excipient is one or more of an antimicrobial agent, a surfactant, an antioxidant, a free radical scavenger, and a peptide stabilizer.

[0044] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the peptide stabiliser is one or more of the group of cyclodextrins and amino acids.

[0045] In certain aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the cyclodextrin is hydroxypropyl alpha cyclodextrin.

[0046] In particular aspects, embodiments include methods of treating a subject with semaglutide comprising providing a device for the sustained release of semaglutide, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a device for the liquid sustained release of semaglutide having a solvent and having a concentration of semaglutide disposed within the reservoir; wherein the amino acid is histidine.

[0047] In certain aspects, embodiments of the present disclosure provide that excipients in the formulation modulate the release rate of the pharmaceutical agent. Modulation of the release rate by surfactants is disclosed in PCT / US2023 / 023845, filed May 30, 2023, and is incorporated herein by reference. It has now been found that other excipients can also modulate the release rate. For example, it has been found that the presence of hydroxypropyl alpha-cyclodextrin flattens the release rate profile of semaglutide. In general, flattening the long-term release rate profile of a therapeutic agent is considered desirable.

[0048] Cyclodextrins are beaker-shaped oligosaccharides with a hydrophobic interior and a hydrophilic exterior. They are typically used to encapsulate small hydrophobic molecules, much smaller than GLP-1 analogs, to improve their aqueous solubility. The most common cyclodextrins are α-, β-, and γ-cyclodextrin. They are often derivatized with hydroxypropyl groups to improve their aqueous solubility.

[0049] These and other aspects, objects, and advantages will become more apparent from a review of the drawings and detailed description that follow. [Brief explanation of the drawings]

[0050] [Figure 1] FIG. 1 depicts a device of the present disclosure.

[0051] [Figure 2] FIG. 2 depicts the release rate profile for the first embodiment of the present disclosure.

[0052] [Figure 3] FIG. 3 depicts the release rate profile for the second embodiment of the present disclosure.

[0053] [Figure 4] FIG. 4 depicts the release rate profile for a third embodiment of the present disclosure.

[0054] [Figure 5] FIG. 5 depicts the release rate profile for certain embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0055] Detailed Description of the Invention definition The term "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, small organic molecules such as hemoproteins, or carbohydrate groups such as glycoproteins.

[0056] The terms "peptide" and "protein" refer to subgroups of polypeptides. In this disclosure, the definitions of peptide and protein follow the convention of the U.S. Food and Drug Administration (FDA), where a peptide is defined as a polypeptide having up to 40 amino acid residues and a protein is defined as a polypeptide having more than 40 amino acid residues.

[0057] The term "incretin mimetic" refers to agents that act like incretin hormones, such as glucagon-like peptide-1 (GLP-1). They bind to the GLP-1 receptor and stimulate glucose-dependent insulin release, thus acting as hypoglycemic agents. Incretin mimetics also suppress appetite and inhibit glucagon secretion. They delay gastric emptying, thereby preventing postprandial spikes in blood glucose levels. In addition, incretin mimetics also encompass compounds that possess GLP-1 agonism as well as other complementary antagonistic or agonistic properties, including GLP and / or glucagon antagonism.

[0058] The term "formulation of a therapeutic agent" refers to the actual state in which the therapeutic agent is present in a product or a product manufacturing intermediate, and includes, in addition to the therapeutic agent, any additional therapeutic agents used, any formulation excipients used, and any formulation solvents used, as appropriate.

[0059] The term "membrane" refers to a permeable structure that allows the mass transport of molecules through the structure from one side to the other.

[0060] The term "porous membrane" refers to a membrane characterized by the presence of a two-phase system in which the membrane matrix material represents one phase, typically the continuous 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, which allows mass transport across the membrane.

[0061] The terms "dense" or "non-porous membrane" refer to a membrane that is fluid-filled and lacks pores. In such membranes, mass transport can occur by a solution-diffusion mechanism, where the therapeutic agent permeates the membrane by dissolving in the membrane material itself and diffusing through it.

[0062] The terms "nanoporous membrane" and "nanopore membrane" are used interchangeably and refer to a porous membrane in which the pores have a minimum diameter of less than 1000 nanometers.

[0063] The term "nanotube membrane" refers to a nanoporous membrane in which the pores are formed by an array of nanotubes.

[0064] The term "titania nanotube film" 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, allowing diffusion through the titania nanotubes from one side of the film to the other. In certain examples, the titania nanotube film has two faces or sides. The first face or side has the array of titania nanotubes and is the second face or side of the titanium substrate. In certain embodiments, the array of titania nanotubes is grown on the titanium substrate by electrochemical anodization.

[0065] The term "molecular diameter" of a polymer refers to the diameter of a sphere of rotation of the polymer, which is a physical measure of the size of a molecule and is defined as twice the mass-weighted average distance from the core of the molecule to each mass element within the molecule.

[0066] The term "Stokes diameter" or "hydrodynamic diameter" refers to the dimension of a molecule and 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 being observed.

[0067] As used in this disclosure, the terms "fluid" and "fluid form" refer to a flowable state of matter, including, but not limited to, gases, solutions, suspensions, emulsions, colloids, dispersions, and the like.

[0068] The term "fluid contact" refers to an entity in contact with a fluid.

[0069] The term "neutral pH" refers to a pH between 6.5 and 7.5, such as 7. Embodiment

[0070] Embodiments of the present disclosure include devices, formulations, and methods for controlling the release rate of one or more therapeutic agents from such devices. Additionally, embodiments of the present disclosure include methods of treating a subject using the disclosed devices and formulations. U.S. Patent Application Publication Nos. 20210246271 and 20220008345 are incorporated by reference in their entireties into this disclosure. device

[0071] As shown in FIG. 1 , the device of the present disclosure includes a capsule 100 suitable for implantation, the capsule having a reservoir 110 suitable for holding a therapeutic agent and, optionally, a pH control agent. In some embodiments, there are two or more reservoirs. The capsule can be made from any suitable biocompatible material. In certain embodiments, the capsule is made from a medical-grade metal, such as titanium or stainless steel, or a medical-grade polymeric material, such as silicone, polyurethane, polyacrylate, polyolefin, polyester, or polyamide. In embodiments, the capsule is made from multiple materials. In some embodiments of the present disclosure, the capsule is made from titanium.

[0072] The device of the present disclosure has at least one membrane (120) attached to the capsule and in fluid contact with the reservoir, as described herein, where the membrane provides a pathway for mass transport of the therapeutic agent contained within the reservoir out of the reservoir and into the body of a subject in which the capsule is implanted. In this disclosure, "attached to the capsule" refers to a component that is fixed in place relative to the capsule and directly or indirectly connected to the capsule using any suitable means, including welding, gluing, press-fitting, and threading, or any combination thereof. In the case of the membrane described in U.S. Pat. No. 9,814,867, as shown in FIG. 1, the nanotube membrane is part of an array of nanotubes 121, some of which are still attached to the titanium substrate 130 on which they were grown, and the substrate may be attached to the capsule. At least some of the nanotubes are open on both sides, allowing mass transport of the therapeutic agent from the reservoir and, when implanted, out of the reservoir and into the subject. In one embodiment, the membrane 120 is a titania nanotube membrane 120 having two faces or sides: a first face or side having an array of titania nanotubes 121, and a second face or side being a titanium substrate 130. Figure 1 shows the membrane attached to a capsule, with the titanium substrate 130 facing the reservoir of the device. The device is configured to be implanted into a subject. film

[0073] Embodiments of the present disclosure include at least one membrane that provides a pathway for mass transport of a therapeutic agent from a reservoir of a device of the present disclosure.

[0074] A wide variety of membranes can be used in embodiments of the present disclosure. Membranes of the present disclosure include dense and porous membranes; porous membranes include nanoporous membranes and nanotube membranes.

[0075] Materials suitable for the membranes 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. 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.

[0076] Embodiments of the present disclosure are particularly useful as sustained delivery devices for therapeutic agents, where the release of the agent is controlled by a nanoporous membrane.

[0077] The fabrication of one such membrane of the present disclosure is described in U.S. Pat. No. 9,814,867, and control of the inner diameter of the nanopores in such membranes is described in U.S. Pat. No. 9,770,412, both of which are incorporated herein by reference. Release rate control

[0078] The devices of the present disclosure have the ability to release therapeutic agents contained within reservoirs through the nanopores in the membrane at a controlled rate. In some cases, the release rate of the therapeutic agent is a non-Fickian release rate, i.e., a release rate that is not proportional to a concentration gradient driving the release, such as zero-order release. Examples of non-Fickian release rates through nanoporous membranes are described in U.S. Pat. No. 9,814,867, which is incorporated herein by reference. In some cases, the therapeutic agents disclosed herein undergo a "sustained release" or "sustained release," in which the device maintains drug release over an extended period of time at a non-Fickian release rate, such as a zero-order release rate.

[0079] The exact mechanism by which the membrane nanopores control the release rate is not understood in detail. One hypothesis is that interactions between diffusing molecules of the therapeutic agent and the inner wall of the nanotube may play a role in this release mechanism. manufacturing

[0080] Methods for manufacturing the device and formulation are described in U.S. Patent Application Publication Nos. 20210246271 and 20220008345, which are incorporated herein by reference. Therapeutic Agents and Formulations

[0081] Therapeutic agents suitable for embodiments of the present disclosure are described in U.S. Patent Application Publication Nos. 20210246271 and 20220008345, which are incorporated herein by reference. In some embodiments, the therapeutic agent is a peptide or protein. In some embodiments, the peptide or protein is an incretin mimetic, such as a GLP-1 agonist. In some embodiments, the incretin mimetic is semaglutide.

[0082] Semaglutide is a human GLP-1 receptor agonist (or GLP-1 analogue). The peptide backbone can be produced by yeast fermentation. The lysine at position 26 of semaglutide is modified to include a hydrophilic spacer and a C18 fatty diacid. In addition, semaglutide is modified at position 8 to provide stability against degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). A small modification is made at position 34 to ensure the addition of only one fatty diacid. The molecular formula is C 187 H 291 N 45 O 59 and has a molecular weight of 4113.58 g / mol. Semaglutide has the following structure: [ka]

[0083] See, for example, the European Medicines Agency dossier dated December 14, 2017, which is the review report for OZEMPIC® (incorporated herein by reference). The EMA review report dossier describes semaglutide as a long-acting analog of human glucagon peptide-1, i.e., Aib8, an Arg34-GLP-1(7-37) analog substituted at the ε-amino group of the lysine residue at position 26 with an (S)-22,40-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetracontan-1-oyl side chain. The side chain consists of two 8-amino-3,6-dioxaoctanoic acid (ADO) spacers, one γ-glutamic acid (Glu) spacer, and a fatty diacid (1,18-octadecanedioic acid). Semaglutide is produced using recombinant DNA technology and chemical modification in yeast (Saccharomyces cerevisiae).

[0084] Many peptides and proteins tend to form aggregates when in solution. This tendency tends to increase with increasing concentration. These aggregates can be permanent or reversible, covalently or non-covalently bound, soluble or insoluble, and disordered or organized, such as beta sheets or fibrils. In many cases, these aggregates are undesirable, for example, when they are irreversible and lose pharmaceutical activity, or when they cause adverse effects, such as excessive viscosity increases in the formulation.

[0085] These aggregates are well known and well studied in the literature and represent a significant obstacle in the preparation of highly concentrated formulations of peptides and proteins. Many formulation approaches have been described in the literature, often involving excipients such as surfactants.

[0086] Semaglutide (CAS#910463-68-2) is an incretin mimetic and is structurally similar to GLP-1. Semaglutide is known to have a tendency to aggregate, forming fibrils as well as irregular high molecular weight species. As discussed below, other incretin mimetics are usefully employed in the present disclosure.

[0087] Typically, pharmaceutical formulations of semaglutide do not exceed 1% (w / w) or 10 mg / ml (U.S. Patent No. 11,318,191, incorporated herein by reference). However, it has now been surprisingly found that significantly higher concentrations can be prepared and used in pharmaceutical applications without undue loss or even degradation due to such aggregation phenomena. Formulations of up to 25% w / w have been prepared and tested for pharmaceutical usefulness. A literature-cited measure of stability in this regard is 80% retention (or less than 20% loss) of the pure GLP-1 analogue after 3 months of static storage at 25°C (U.S. Patent No. 10,888,605). In other words, a formulation of an incretin mimetic (e.g., semaglutide) possesses chemical stability if the covalent bond is intact in at least 80% (w / v) of the incretin mimetic compound after 3 months of storage at 25°C.

[0088] Embodiments of the disclosure include formulations having more than 1% semaglutide that meet this stability criterion, such as at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 20%, or at least 30% semaglutide. All percentages are on a w / w basis. In some cases, the concentration range of semaglutide is 1.1% to about 35% w / w or 12% to about 35% w / w.

[0089] In some embodiments, semaglutide is present with a counterion. In some embodiments, the counterion is acetate or another pharmaceutically acceptable salt. In some embodiments, high concentrations of semaglutide are achieved by adding a basic pH adjuster (e.g., NaOH) to the dissolution medium before adding semaglutide. Such a dissolution process significantly reduces viscosity and improves ease of mixing.

[0090] Those skilled in the art will appreciate that the therapeutic agent can be a different incretin mimetic other than semaglutide, including, for example, liraglutide, semaglutide, dulaglutide, liraglutide, tirzepatide, exenatide, albiglutide, lixisenatide, cotadutide, sitagliptin, saxagliptin, alogliptin, and linagliptin.

[0091] In some embodiments, the concentration of the incretin mimetic is at least 1.1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% w / w.

[0092] In some embodiments, the solvent is purified water. In some embodiments, a co-solvent such as polyethylene glycol or propylene glycol is present. In some embodiments, the co-solvent is present in a mixed solvent, i.e., a miscible aqueous solvent, at up to 50% w / w. In other specific embodiments, the co-solvent is present at about 1% to about 50%, e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or about 50%. Other solvents include organic solvents such as acetone, ethanol, methanol, 2-propanol, ethyl acetate, isopropyl acetate, methyl ethyl ketone, 1-butanol, tert-butanol, and the like.

[0093] In some embodiments, no additional pharmaceutical excipients are present in addition to the counterions and solvents or co-solvents described above.

[0094] In some embodiments, additional pharmaceutical excipients are present.

[0095] In some embodiments, a pH-adjusting excipient or component is present, such as an acid, base, or buffer system. In some embodiments, the pH is 6-10, e.g., 6, 7, 8, 9, or 10, and values ​​therebetween. In some embodiments, the pH is 7-9. In some embodiments, the pH is 7-8. In some embodiments, the pH-adjusting component is a non-soluble component, e.g., an acidic or basic ion exchange resin. In some embodiments, the formulations of the present disclosure include a buffer, e.g., phosphate buffer, TRIS, or no buffer. In some embodiments, the phosphate buffer is a sodium phosphate buffer, e.g., disodium hydrogen phosphate.

[0096] In some embodiments, a tonicity agent, such as a salt or other cosolute, is present. In some embodiments, the tonicity agent is an inorganic compound, such as, but not limited to, NaCl, KCl, or CaCl. In some embodiments, the tonicity agent is an organic compound, such as, but not limited to, Na, K, or Ca salts of organic acids, or a non-ionic compound, such as, but not limited to, a sugar, alcohol, or sugar alcohol. Non-limiting examples of tonicity agents include dextrose, glycerin, and mannitol. Generally, the tonicity agent may be present at about 0.1% to about 10% w / w.

[0097] In some embodiments, a surfactant is present. The addition of a surfactant(s) can significantly enhance the release rate of a therapeutic agent from an implantable device of the present disclosure into the environment of use. Any type of pharmaceutically acceptable surfactant may be used in embodiments of the present disclosure, including, but not limited to, natural and synthetic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants, and nonionic surfactants.

[0098] Nonionic surfactants include fatty alcohol ethoxylates, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, alkylphenol ethoxylates, nonoxynol, Triton® X-100, fatty acid ethoxylates, ethoxylated amines and / or fatty acid amides, polyethoxylated tallow amine, cocamide monoethanolamine, cocamide diethanolamine, end-blocked ethoxylates, poloxamers, fatty acid esters of polyhydroxy compounds, fatty acid esters of glycerol, glycerol monostearate, glycerol monolaurate, fatty acid esters of sorbitol, Spans, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, Tweens, Tween® 20, Tween® 40, Tween® 60, Tween® 80, fatty acid esters of sucrose, alkyl polyglucosides, alkyl polyglycosides, decyl glucoside, lauryl glucoside, octyl glucoside.

[0099] Some embodiments of the present disclosure include two or more surfactants.

[0100] The mechanism of release rate enhancement by surfactants is unclear and may or may not be related to the critical micelle concentration (CMC) of the surfactants or the level at which they can reduce surface tension.

[0101] In some embodiments, an antioxidant or free radical scavenger is present.

[0102] In some embodiments, a peptide stabilizer is present. In some cases, the stabilizer is a surfactant. In some embodiments, the stabilizer is a complexing agent such as hydroxypropyl alpha cyclodextrin, hydroxypropyl beta cyclodextrin, hydroxypropyl gamma cyclodextrin, alpha cyclodextrin, beta cyclodextrin, or gamma cyclodextrin. In some embodiments, the stabilizer is an antioxidant or a free radical scavenger.

[0103] In some embodiments, the cyclodextrin is present at about 1% to about 20% w / w, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% w / w, or about 1% to about 15%, such as about 10%.

[0104] In some embodiments, the formulation is contained within a reservoir of a device of the present disclosure.

[0105] Some embodiments of the present disclosure include methods of treating a subject in need of treatment with a formulation or device of the present disclosure.

[0106] Formulations of the present disclosure are stable, with minimal or no loss due to aggregation or degradation of the active ingredient(s), for example, semaglutide or other incretin memetics. In some cases, formulations having semaglutide concentrations of greater than 1% w / w up to 35% w / w are stable for 1 month up to 2 years, for example, up to about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, and / or 24 months or so. In some cases, the formulations are stable for more than 2 years.

[0107] Advantageously, these stability characteristics allow for long-term implantation of the disclosed devices, in some cases extending the period of time for which the devices are implanted up to one or even two years, and delivering effective and effective medical treatment for a variety of conditions.

[0108] In some embodiments, the formulations, methods, and devices are used in medical indications and treatments such as the treatment or prophylactic treatment of diabetes, hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, gestational diabetes, and / or lowering HbA1c. Such indications include slowing the progression or prophylactic treatment of diabetic disease, or slowing the progression of impaired glucose tolerance in insulin-dependent type 2 diabetes, and / or slowing the progression of non-insulin dependent type 2 diabetes.

[0109] "Diabetes" or "diabetes mellitus" refers to a group of metabolic disorders characterized by prolonged high blood sugar levels. Diabetes includes type 1 diabetes, which results from insufficient insulin production, and type 2 diabetes, which results from insulin resistance in which cells no longer respond to insulin and progress to insulin deficiency. Other forms of diabetes are known to those skilled in the art.

[0110] Applications also include, for example, the prevention, prophylactic treatment, or treatment of eating disorders such as obesity by reducing food intake, reducing weight, suppressing appetite, or inducing satiety; the treatment, prophylactic treatment, or prevention of binge eating disorder, bulimia, and / or obesity induced by the administration of antipsychotic drugs or steroids; the attenuation of gastric motility; and / or the slowing of gastric emptying. In some cases, applications are as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

[0111] Suitable dosages for treating diabetes or obesity can provide any suitable mean steady-state plasma concentration of the therapeutic agent in a subject. For example, the mean steady-state plasma concentration can be from 10 pg / ml to 10,000 ng / ml. In some embodiments, the mean steady-state plasma concentration of semaglutide can be from 10 to 300 ng / mL, or from 65.0 ng / mL to 123.0 ng / mL, or from 111.1 ng / mL to 222.1 ng / mL.

[0112] In certain embodiments, the semaglutide concentration is sufficient to achieve a mean or minimum circulating plasma level of semaglutide of at least 100 ng / mL for at least about 1 month, at least about 3 months, or at least about 6 months, at least about 8 months, at least about 12 months, at least about 18 months or at least about 24 months or more.

[0113] The therapeutic agent may be an incretin mimetic, or a GLP-1 analog or GLP-1 agonist, which refers to a drug that acts like an incretin hormone such as glucagon-like peptide-1 (GLP-1). They bind to the GLP-1 receptor and stimulate glucose-dependent insulin release, thus acting as a hypoglycemic agent. Examples of incretin mimetics include liraglutide, semaglutide, dulaglutide, liraglutide, tirzepatide, exenatide, albiglutide, lixisenatide, cotadutide, sitagliptin, saxagliptin, alogliptin, and linagliptin.

[0114] In certain embodiments, the incretin mimetic is present at a concentration of about 1%, such as at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 20%, or at least 30%.

[0115] In some embodiments, a peptide stabilizer is present. In some cases, the stabilizer is a surfactant. In some embodiments, the stabilizer is a complexing agent such as hydroxypropyl alpha cyclodextrin, hydroxypropyl beta cyclodextrin, hydroxypropyl gamma cyclodextrin, alpha cyclodextrin, beta cyclodextrin, or gamma cyclodextrin. In some embodiments, the stabilizer is an antioxidant or a free radical scavenger.

[0116] In some embodiments, the cyclodextrin is present at about 1% to about 20% w / w, or about 1% to about 15%, such as about 10%.

[0117] In one embodiment, the therapeutic agent is a dual glucagon-like peptide-1 and glucagon receptor agonist, such as cotadutide or liraglutide.

[0118] Provided herein are methods for improving glycemic control, reducing weight, and treating type 2 diabetes mellitus (T2DM) in a human patient, comprising administering a GLP-1 / glucagon agonist peptide such as cotadutide. The chemical formula of cotadutide is CHN0, which has a molecular weight of 3728.09, a CAS number of 1686108-82-6, and the following sequence: HSQGTFTSDX10SEYLDSERARDFVAWLEAGG-ACID, {wherein X 10 = a lysine with a palmitoyl group attached to the epsilon nitrogen by a gamma glutamate linker (i.e., K(gE-palm)).

[0119] The chemical formula of liraglutide is CHN, with a molecular weight of 3751.20, a CAS number of CAS 204656-20-2, and the following sequence: HAEGTFTSDVSSYLEGQAA-[Lys([Palm]-[g-Glu]-]-EFIAWLVRGRG-acid] with the addition of glutamic acid spaced palmitic acid to the epsilon-amino group of lysine at position 26.

[0120] In one embodiment, the therapeutic agent is LY3437943, which is a novel triple agonist peptide of the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R).

[0121] The therapeutic agent can be administered by any method known to those skilled in the art. For example, the therapeutic agent can be administered by an implantable drug delivery system of the present invention. In some embodiments, the present invention provides a method of administering a therapeutic agent to a subject in need thereof, comprising implanting an implantable drug delivery system of the present invention containing a pharmaceutical composition of the present invention comprising a therapeutic agent and a polymeric buffer comprising a polymer functionalized with multiple acidic or multiple basic groups, wherein the therapeutic agent elutes from the implantable drug delivery system, thereby administering the therapeutic agent. [Example]

[0122] The following examples are offered to illustrate, but not to limit, the claimed invention. Example 1:

[0123] Release rate and stability of 25% semaglutide formulations with cyclodextrins Preparation of formulations

[0124] A 0.7 ml solution containing 10% (w / w) cyclodextrin and 0.6% (w / w) NaCl in water for injection (WFI) was prepared in a polypropylene centrifuge tube. Approximately 400 mg of powdered semaglutide was added. The drug was dissolved by prolonged vortex mixing. During the mixing process, the formulation foamed significantly, significantly hindering mixing. To facilitate mixing, the solution was centrifuged in a small tabletop centrifuge several times during the process. This removed foam and greatly improved the mixing process. When mixing was complete, a viscous and clear solution was obtained after the final centrifugation.

[0125] To bring the solution to pH 7.4, approximately 91 microliters of 1N NaOH was added in multiple steps, with mixing, centrifugation, and pH measurement after each step. Some loss of formulation to the pH probe was experienced. The viscosity of the solution decreased significantly during the pH adjustment process. At the end of the process, the volume was adjusted to 1.5 mL, followed by mixing and centrifugation.

[0126] The solution was sterile filtered by filtration using a 1 mL syringe and a small Pall syringe filter (PN4602). Filling the reservoir

[0127] Release rate studies were performed using clear polycarbonate devices instead of titanium to allow visual inspection for visible aggregates such as fibrils or randomly precipitated aggregates.

[0128] Briefly, a polycarbonate capsule with an internal reservoir volume of approximately 50 microliters was fitted with a silicone septum at one end and a titanium screw cap at the other end, which held a titania nanotube membrane. To load the formulation into the device, a vacuum was applied to the reservoir through the membrane, and then the formulation was injected into the reservoir by piercing the septum with the needle of a syringe filled with the formulation, which was attached to a pump system that delivered the formulation. Release rate testing

[0129] In vitro release rate experiments were carried out in 4 mL HPLC vials containing 3 mL of PBS at pH 7.4. The vials were incubated in an incubator at 37°C. Microbial Control

[0130] 0.3% sodium azide was added as an antimicrobial agent to all formulations and in vitro release rate buffers to allow for long-term release rate experiments without the need for strict sterility. Example 2

[0131] Release rate and stability of 15% w / w semaglutide formulations with cyclodextrins

[0132] The same process was carried out according to Example 1, but using approximately 240 mg of semaglutide and 54 microliters of 1 N NaOH. result

[0133] As can be seen in Figures 2 and 3, in Examples 1 and 2, continuous release of the therapeutic agent was observed for more than 77 days. Figure 2 shows 25% w / w semaglutide with 10% w / w cyclodextrin. Figure 3 shows 15% w / w semaglutide and 10% w / w cyclodextrin. Each trace in the figures represents a separate measurement from a separate vial. At the end of the period, the device was turned off, disassembled, and the internal composition measured.

[0134] [Table 1]

[0135] The starting purity of the semaglutide received was 94%. Therefore, the total loss in purity over 77 days is approximately 7-8%. A purity loss of 7-8% over 75 days is well within the acceptable limit of a 20% loss over three months.

[0136] Mass balance figures indicate that negligible amounts of drug were lost in the form of degradants not detectable by HPLC, such as fibrils. Example 3

[0137] Release rate and stability of a 15% w / w semaglutide formulation without cyclodextrin Preparation of formulations

[0138] A 0.7 ml solution containing 0.6% (w / w) NaCl in water for injection (WFI) was prepared in a polypropylene centrifuge tube. Forty-five microliters of 1 N NaOH was added.

[0139] After mixing the materials, 240 mg of semaglutide was added. It was found that adding some NaOH to the solvent before adding the therapeutic agent significantly reduced the viscosity, thereby improving ease of mixing.

[0140] The drug dissolution process was similar to that of Example 1, except that the mixing process was greatly facilitated after adding some 1N NaOH before adding the therapeutic agent.

[0141] Device loading and release rate testing were identical to Example 1. result

[0142] Figure 4 shows 15% w / w semaglutide in continuous and ongoing drug release for over 300 days. Each trace in the figure represents a separate measurement of a separate vial.

[0143] Two devices of the formulation were stopped at 336 days, and the purity and total recovery were determined. The purities were 64% and 61%. The mass balance of both devices was 98%, suggesting that negligible amounts of drug were lost in the form of fibrils and other degradants not detectable by HPLC. Example 4

[0144] Comparison of the release rate profiles of the formulations described in Examples 2 and 3 (see Figure 5). Group 1, 15% (w / w) semaglutide with 10% (w / w) hydroxypropyl alpha cyclodextrin, is represented by a slower release rate profile. Group 3, (15% semaglutide with no cyclodextrin whatsoever) is represented by a higher and steeper decline profile.

[0145] All publications, patents, and patent applications cited herein are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Although the foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the present disclosure that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

Claims

1. A liquid pharmaceutical formulation having a solvent, the formulation comprising semaglutide having a concentration, wherein the semaglutide concentration (w / w) is greater than about 1%.

2. 2. The formulation of claim 1, wherein the semaglutide concentration (w / w) is at least 1.1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or at least 35%.

3. 3. The formulation of claim 1, wherein the pH of the formulation is from about 6 to about 10.

4. 4. The formulation of any one of claims 1 to 3, which is substantially free of additional pharmaceutical excipients.

5. 4. The formulation of any one of claims 1 to 3, wherein an isotonicity agent is present in the formulation.

6. 6. The formulation of claim 5, wherein the tonicity agent is other than sodium chloride.

7. 6. The formulation of claim 5, wherein the tonicity agent is potassium chloride.

8. The formulation according to any one of claims 1 to 7, wherein the solvent is water.

9. The formulation according to any one of claims 1 to 7, wherein the solvent is an organic solvent or an aqueous-organic solvent mixture.

10. The formulation of any one of claims 1 to 3, wherein additional pharmaceutical excipients are present.

11. 11. The formulation of claim 10, wherein the additional pharmaceutical excipient is one or more selected from the group consisting of antimicrobial agents, surfactants, antioxidants, free radical scavengers, and peptide stabilizers.

12. 12. The formulation of claim 11, wherein the peptide stabilizer is one or more selected from the group consisting of cyclodextrins and amino acids.

13. 13. The formulation of claim 12, wherein the cyclodextrin is hydroxypropyl alpha cyclodextrin.

14. 13. The formulation of claim 12, wherein the amino acid is histidine.

15. 1. A device for the extended release of semaglutide comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a liquid formulation of semaglutide having a solvent and a concentration of semaglutide disposed in the reservoir; wherein the semaglutide concentration (w / w) is greater than about 1%.

16. 16. The device of claim 15, wherein the semaglutide concentration (w / w) 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% or about 35%.

17. The device of any one of claims 15 to 16, wherein the pH is from about 6 to about 10.

18. 18. The device of any one of claims 15 to 17, which is substantially free of additional pharmaceutical excipients.

19. The device according to any one of claims 15 to 17, wherein a tonicity agent is present.

20. 20. The device of claim 19, wherein the tonicity agent is other than sodium chloride.

21. 20. The device of claim 19, wherein the tonicity agent is potassium chloride.

22. The device of any one of claims 15 to 21, wherein the solvent is water.

23. The device according to any one of claims 15 to 21, wherein the solvent is an organic solvent or an aqueous-organic solvent mixture.

24. 18. The device according to any one of claims 15 to 17, wherein additional pharmaceutical excipients are present.

25. 25. The device of claim 24, wherein the additional pharmaceutical excipient is one or more selected from the group consisting of antimicrobial agents, surfactants, antioxidants, free radical scavengers, and peptide stabilizers.

26. 26. The device of claim 25, wherein the peptide stabilizer is one or more selected from the group consisting of cyclodextrins and amino acids.

27. 27. The device of claim 26, wherein the cyclodextrin is hydroxypropyl alpha cyclodextrin.

28. 27. The device of claim 26, wherein the amino acid is histidine.

29. 1. A method of treating a subject in need of treatment with semaglutide, said method comprising: To provide a device for the sustained release of semaglutide; wherein the device comprises: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a liquid formulation of semaglutide having a solvent and a concentration of semaglutide disposed in the reservoir; wherein the semaglutide concentration (w / w) is greater than 1%.

30. 30. The method of claim 29, wherein the semaglutide concentration (w / w) 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% or about 35% w / w.

31. 31. The method of any one of claims 29 to 30, wherein the pH is from about 6 to about 10.

32. 32. The method of any one of claims 29 to 31, wherein the method is substantially free of additional pharmaceutical excipients.

33. 33. The method of any one of claims 29 to 32, wherein a tonicity agent is present.

34. 34. The method of claim 33, wherein the tonicity agent is an isotonicity agent other than sodium chloride.

35. 34. The method of claim 33, wherein the tonicity agent is potassium chloride.

36. 36. The method of any one of claims 29 to 35, wherein the solvent is water.

37. 36. The method according to any one of claims 29 to 35, wherein the solvent is an organic solvent or an aqueous-organic solvent mixture.

38. 32. The method of any one of claims 29 to 31, wherein additional pharmaceutical excipients are present.

39. 39. The method of claim 38, wherein the additional pharmaceutical excipient is one or more selected from the group consisting of antimicrobial agents, surfactants, antioxidants, free radical scavengers, and peptide stabilizers.

40. 40. The method of claim 39, wherein the peptide stabilizer is one or more selected from the group consisting of cyclodextrins and amino acids.

41. 41. The method of claim 40, wherein the cyclodextrin is hydroxypropyl alpha cyclodextrin.

42. 41. The method of claim 40, wherein the amino acid is histidine.

43. 1. A device for the sustained release of a therapeutic agent, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a liquid formulation of a therapeutic agent having a solvent and disposed within the reservoir; Including, the device.

44. 44. The device of claim 43, wherein the therapeutic agent is an incretin mimetic selected from liraglutide, semaglutide, dulaglutide, liraglutide, tirzepatide, exenatide, albiglutide, lixisenatide, cotadutide, sitagliptin, saxagliptin, alogliptin, and linagliptin.

45. 1. A method for flattening the release rate profile of semaglutide from an implantable device, said method comprising: A device is provided, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a liquid formulation of semaglutide disposed within the reservoir; wherein the formulation comprises: solvent; Semaglutide at a concentration of at least 1%; cyclodextrin, providing a device comprising: introducing the device into an environment of use; A method comprising:

46. 46. ​​The method of claim 45, wherein the semaglutide concentration (w / w) 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% or about 35% w / w.

47. 46. ​​The method of claim 45, wherein the cyclodextrin concentration (w / w) is from 1% to about 15%.

48. 48. The method of any one of claims 45 to 47, wherein the cyclodextrin is hydroxypropyl alpha cyclodextrin.

49. 1. A method for flattening the release rate profile of a GLP-1 analogue from an implantable device, the method comprising: A device is provided, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; and a liquid formulation of a GLP-1 analog disposed within the reservoir; wherein the formulation comprises: solvent; a GLP-1 analogue at a concentration of at least 1%; cyclodextrin, providing a device comprising: introducing the device into an environment of use; A method comprising:

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