WO2023235302A1

WO2023235302A1 - Devices, methods and formulations to control release of therapeutic agents from implantable devices

Info

Publication number: WO2023235302A1
Application number: PCT/US2023/023845
Authority: WO
Inventors: Lyle Gordon
Original assignee: Nano Precision Medical Inc
Current assignee: Nano Precision Medical Inc
Priority date: 2022-06-01
Filing date: 2023-05-30
Publication date: 2023-12-07
Anticipated expiration: 2024-12-01

Abstract

The disclosure provides devices and methods for sustained release of a therapeutic agent, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; a formulation of the therapeutic agent contained within the reservoir; the formulation including a surfactant; and wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use.

Description

DEVICES, METHODS AND FORMULATIONS TO CONTROL RELEASE OF THERAPEUTIC AGENTS FROM IMPLANTABLE DEVICES

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to US Application No. 63/347,724, filed June 1, 2022, the contents of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[0002] Many subjects, humans as well as animals, are in need of long-term treatment with therapeutic agents. In order to improve adherence, many subjects would benefit from the adherence provided by an implantable device releasing a desired therapeutic agent at a desired rate for an extended period of time.

[0003] Despite many years of research there is still a need for the development of such devices, and specifically for methods to control the rate of release of therapeutic agents from such devices upon implantation in a subject. The present disclosure satisfies this need and offers additional benefits as well.

BRIEF SUMMARY

[0004] In one embodiment, the present disclosure provides a device for sustained release of a therapeutic agent, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; a formulation of the therapeutic agent contained within the reservoir; the formulation including a surfactant; and wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use. [0005] In one aspect, the rate of release of the therapeutic agent is increased by at least 10% compared to a formulation without a surfactant.

[0006] In one aspect, the rate of release of the therapeutic agent is increased by at least 25% compared to a formulation without a surfactant.

[0007] In one aspect, the rate of release of the therapeutic agent is increased by at least 50% compared to a formulation without a surfactant.

[0008] In one aspect, the rate of release of the therapeutic agent is increased by at least 100% compared to a formulation without a surfactant.

[0009] In another embodiment, the present disclosure provides a method of treating a subject in need of treatment, the method comprising: providing a device with a therapeutic agent formulation disposed therein, the device as described herein; and implanting the device in the subject.

[0010] In one aspect, the therapeutic agent is exenatide.

[0011] In one aspect, the treatment results in plasma levels of an incretin mimetic e.g., exenatide between 50 pg/mL and 500 pg/mL.

[0012] In still another embodiment, the present disclosure provides a formulation of a therapeutic agent, the formulation comprising: the formulation being contained in a device for sustained release of the therapeutic agent, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; the formulation including a surfactant; and wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use.

[0013] In one aspect, the rate of release rate of the therapeutic agent is increased by at least 10% compared to a formulation without a surfactant.

[0014] In one aspect, the rate of release of the therapeutic agent is increased by at least 25% compared to a formulation without a surfactant. [0015] In one aspect, the rate of release of the therapeutic agent is increased by at least 50% compared to a formulation without a surfactant.

[0016] In one aspect, the rate of release of the therapeutic agent is increased by at least 100% compared to a formulation without a surfactant.

[0017] In one aspect, the rate of release of the therapeutic agent is at least tripled compared to a formulation without a surfactant.

[0018] In yet another embodiment, the present disclosure provides a method of treating a subject in need of treatment, the method comprising: providing a formulation as described herein contained within a device; and implanting the device in the subject.

[0019] In one aspect, the therapeutic agent is exenatide.

[0020] In one aspect, the treatment results in plasma levels of an incretin mimetic between 50 pg/mL and 500 pg/mL.

[0021] In another embodiment, the disclosure provides a method to increase the release rate of a therapeutic agent (e.g., an incretin mimetic e.g., exenatide) from a device, the method comprising: providing the device, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; a formulation of the therapeutic agent contained within the reservoir; the formulation including a surfactant; wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use; and placing the device into the environment of use.

[0022] In one aspect, the environment for use is the biological milieu of a subject wherein the device is implanted. A subject is a mammal such as a human.

[0023] In one aspect, the rate of release of the therapeutic agent is increased by at least 10% compared to a formulation without a surfactant. [0024] In one aspect, the rate of release of the therapeutic agent is increased by at least 25% compared to a formulation without a surfactant.

[0025] In one aspect, the rate of release of the therapeutic agent is increased by at least 50% compared to a formulation without a surfactant.

[0026] In one aspect, the rate of release of the therapeutic agent is increased by at least 100% compared to a formulation without a surfactant.

[0027] In one aspect, the rate of release of the therapeutic agent is at least tripled compared to a formulation without a surfactant.

[0028] These and other embodiments, aspects and objects will be more apparent when ready with the detailed description and drawings that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 illustrates an exemplary embodiment of an implantable device of the disclosure.

[0030] FIG. 2 shows the effect on release rate of addition of Tween 20 to a formulation of a therapeutic agent.

[0031] FIG. 3 shows the effect on release rate of addition of Tween 20 to a formulation of a therapeutic agent after prewarming of the device pre-release rate testing.

[0032] FIG. 4 shows the effect of surfactant formulations compared to an no-surfactant formulation.

DETAILED DESCRIPTION

[0033] The disclosure pertains to the field of long-term treatment of subjects with implantable devices providing a sustained delivery of therapeutic agents at a controlled rate. Embodiments of the disclosure include devices, formulations, and methods to control the rate of release of therapeutic agents from such devices.

Definitions

[0034] “Polypeptides” refers to molecules with a backbone chain of 2 or more amino acid residues. Some polypeptides may have additional associated groups, such as metal ions in metalloproteins, small organic molecules such as in heme proteins, or carbohydrate groups such as in glycoproteins.

[0035] “Peptides” and “Proteins” refers to subgroups of polypeptides. In this disclosure the definition of peptides and proteins follows the practice of the United States Food and Drug Administration, the FDA, which defines peptides as polypeptides with up to 40 amino acid residues, and proteins as polypeptides with more than 40 amino acid residues.

[0036] Incretin mimetics refers to agents that act like incretin hormones such as glucagon- like peptide- 1 (GLP-1). They bind to GLP-1 receptors and stimulate glucose dependent insulin release, therefore acting as antihyperglycemics. Drugs in the incretin mimetic class include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). Semaglutide, the generic name for Ozempic, is part of a class of medications known as incretin mimetics.

[0037] Exenatide (natural, recombinant and synthetic, also called exendin-4) refers to amino acid sequence His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Vai Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser.

[0038] “Formulation of a therapeutic agent” refers to the actual state in which a therapeutic agent is present in a product or in a product fabrication intermediate, and includes the therapeutic agent, plus, optionally, any used additional therapeutic agents, any used formulation excipients and any used formulation solvents.

[0039] “Membrane” refers to a permeable structure allowing mass transport of molecules from one side of the structure to the other through the structure.

[0040] “Porous membranes” refers to membranes characterized by the presence of a two- phase system, in which membrane matrix material represents one phase, typically a 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, through which mass transport through the membrane can take place.

[0041] “Dense” or “non-porous membranes” refers to membranes without fluid filled pores. In such membranes mass transport may take place by a dissolution-diffusion mechanism, in which therapeutic agents permeate the membrane by dissolving in the membrane material itself, and diffusing through it.

[0042] “Nanoporous membrane” and “nanopore membrane” are used interchangeably, and refer to porous membranes in which the pores have a smallest diameter of less than 1000 nanometer.

[0043] “Nanotube membrane” refers to a nanoporous membrane, wherein pores are formed by an array of nanotubes.

[0044] “ Titania nanotube membrane” refers to an array of titania nanotubes on a titanium substrate where at least a portion of the titania nanotubes are open at both ends and capable of allowing diffusion from one side of the membrane to the other through the titania nanotubes. In certain instances, the titania nanotube membrane has two faces or sides. A first face or side having an array of titania nanotubes and a second face or side of a titanium substrate. In certain aspects, the array of titania nanotubes are grown on the titanium substrate by electrochemical anodization.

[0045] “Molecular diameter” of a polymer refers to the diameter of the sphere of gyration of the polymer, which is a physical measure of the size of a molecule, and is defined as two times the mass weighted average distance from the core of a molecule to each mass element in the molecule.

[0046] “ Stokes diameter” or “hydrodynamic diameter” refers to the dimension of a molecule plus its associated water molecules as it moves through an aqueous solution, and is defined as the radius of an equivalent hard sphere diffusing at the same rate as the molecule under observation.

[0047] “Ion exchange resin” refers to a polymer comprising acidic or basic groups, or a combination thereof, made insoluble, for instance by cross-linking, and capable of exchanging anions or cations, or a combination thereof, with a medium surrounding it.

[0048] “Fluid” and “fluid form” as used in this disclosure refers to flowable states of matter and includes, but is not limited to gases, solutions, suspensions, emulsions, colloids, dispersions and the like.

[0049] “Fluid contact” refers to an entity being in contact with a fluid.

[0050] “Neutral pH” refers to a pH between 6 and 8 such as between 6.5 and 7.5. Devices

[0051] Implantable devices with nanoporous membranes for the release of therapeutic agents have been described previously, e.g. in US Patents Nos. 9,814,867 and 9,770,412 and US Patent Application Pub Nos. US 2022/0008345 and US 2021/0246271. Some embodiments of the disclosure include a device with a cylindrical capsule encapsulating a reservoir, a nanoporous membrane attached to one end of the capsule, and a formulation of a therapeutic agent contained within the reservoir. Release of the therapeutic agent from the reservoir after implantation of the device in a subject is controlled by the nanoporous membrane.

[0052] Some embodiments of the disclosure utilize the pH of the formulation of the therapeutic agent as a further means to control the release rate. Additionally, some embodiments control the duration of release of the therapeutic agent using the orientation of the membrane with respect to the reservoir.

[0053] As illustrated in FIG. 1, devices of the disclosure include a capsule 1000 suitable for implantation, wherein the capsule has a reservoir 1001 suitable for holding a formulation of a therapeutic agent 1005 and, optionally, a pH controlling agent, for instance in the form of resin beads 1006. In some embodiments more than one reservoir is present. The capsule may be made of any suitable biocompatible material. In some embodiments, the capsule is made of a medical grade metal, such as titanium or stainless steel, or of a medical grade polymeric material, such as silicone, polyurethane, polyacrylate, polyolefin, polyester, polyamide and the like. In some embodiments, the capsule is made of multiple materials. In some embodiments of the disclosure, the capsule is made of titanium.

[0054] Devices of the disclosure have at least one membrane 1004, attached to the capsule and in fluid contact with the reservoir, wherein the membrane provides a pathway for mass transport of a therapeutic agent included within the reservoir out of that reservoir and into the body of a subject into which the capsule has been implanted. In this disclosure “attached to the capsule” refers to a component being fixed in place with respect to the capsule, and connected to the capsule directly or indirectly, by using any suitable means, including by welding, gluing, press-fitting and by using threaded means, or by any combination of the foregoing. In the case of membranes as described in US Patent No. 9,814,867, and as illustrated in FIG. 1, the nanotube membranes are part of an array of nanotubes 1003, some of which are still attached to the titanium substrate 1002 from which they were grown, and the substrate may be attached to the capsule. At least some of the nanotubes are open on both sides, to allow for mass transport of a therapeutic agent out of the reservoir.

[0055] Some devices of the disclosure further have a septum 1007, pierceable with a needle, and suitable as an access port to deposit formulation 1005 into the reservoir 1001.

Membranes

[0056] Embodiments of the disclosure include at least one membrane providing a pathway for mass transport of a therapeutic agent out of a reservoir of a device of the disclosure.

[0057] A wide variety of membranes can be used in embodiments of the present disclosure.

[0058] Membranes of the disclosure include dense and porous membranes; porous membranes include nanoporous membranes and nanotube membranes. Suitable materials for membranes of the disclosure include organic and inorganic materials, polymers, ceramics, metals, metal oxides and combinations thereof. Suitable materials for the membrane include silicon, silica, titanium and titania.

[0059] 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.

[0060] Embodiments of the disclosure are particularly useful as sustained delivery devices for therapeutic agents, in which the release of the agents is controlled by a nanoporous membrane.

[0061] Fabrication of membranes of the disclosure is described in US Patent No. 9,814,867 and control of the internal diameter of the nanopores is described in US Patent No. 9,770,412.

[0062] Further description of membranes of the disclosure may be found in US patent application Nos. US 2022/0008345 and US 2021/0246271.

Formulations

[0063] Devices of the disclosure include a formulation having at least one therapeutic agent, for instance therapeutic agents such as described in this disclosure. The therapeutic agent may be in solid or fluid form. In some instances, the therapeutic agent may be present in mixed forms, such a suspension of a solid form of the therapeutic agent in a saturated solution of the therapeutic agent. In some instances, the formulation is in solid form, in some instances the formulation is in fluid form. Formulations in fluid form, for instance formulations including a solution of at least part of the therapeutic agent in the reservoir, may have a pH. pH controlling agents

[0064] Materials to control the pH may be the therapeutic agent itself, low molecular weight stabilizers, such as acidic and basic compounds, including weakly acidic and weakly basic compounds that can be used as buffering agent, or high molecular weight compounds like poly-acids or poly -bases. Many such compounds are known in the literature, and those with ordinary skills in the art of pharmaceutical formulation development will be able to select suitable ingredients for the formulation without undue experimentation.

[0065] In some embodiments the pH controlling materials are insoluble polymeric stabilizers as described in US patent application Pub Nos. US 2022/0008345 and US 2021/0246271. Other pH controlling agents suitable for the disclosure can be found in US Patents Nos. 10,045,943, and 10,479,868.

[0066] “Acid” refers to a compound that is capable of donating a proton (H+) under the Bronsted-Lowry definition, or is an electron pair acceptor under the Lewis definition. Acids useful in the present disclosure are Bronsted-Lowry acids that include, but are not limited to, alkanoic acids or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids and mineral acids, as defined herein. Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromice acid, etc.), halogen oxoacids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid and boric acid. Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, triflouromethanesulfonic acid, among others.

[0067] “Base” refers to a compound capable of accepting a proton (H+) under the Bronsted-Lowry definition, or is an electron pair donor under the Lewis definition. Representative bases include, but are not limited to, hydroxy, alkylhydroxy, amines ( — NRR), alkylamine, arylamine, amide ( — C(O)NRR), sulfonamide ( — S(O)2NRR), phosphonamide ( — P(O)( — NRR)2), carboxylate ( — C(O)O-), and others.

[0068] In certain instances, the pH adjusting agent is a buffer. The buffer is selected from the group consisting of citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, formate/formic acid, propionate/propionic acid, lactate/lactic acid, carbonate/carbonic acid, ammonium/ammonia, edentate/edetic acid, and combinations thereof. Therapeutic agents

[0069] Therapeutic agents suitable for embodiments of the disclosure have been described in US Patent Application Pub Nos. US 2022/0008345 and US 2021/0246271. In some embodiments the therapeutic substance is a peptide or protein. In some embodiments the peptide or protein is an incretin mimetic. In some embodiments the incretin mimetic is exenatide.

Manufacture

[0070] Methods of manufacture of devices and formulations are described in US Patent Application Pub Nos. US 2022/0008345 and US2021/0246271.

Release rate control

[0071] Devices of the disclosure have the capability to release therapeutic agents, contained in the reservoir, through the nanopores of the membrane at a controlled rate. In some instances, the rate of release of the therapeutic agent is a non-Fickian release rate, i.e. a release rate that is not proportional to the concentration gradient driving the release.

Examples of non-Fickian release rates through nanoporous membranes have been described in US Patent No. 9,814,867.

[0072] The exact mechanism by which the nanopores of the membranes control the release rate is not understood in detail. Hypothetically, interactions between the diffusing molecules of the therapeutic agent and the interior wall of the nanotubes could play a role in this mechanism.

[0073] US Patent Application Pub. Nos. US 2022/0008345 and US 2021/0246271 disclose the use of insoluble polymeric agents with a plurality of pH sensitive stabilizing groups that can be employed to provide buffering capacity at desirable pH levels, such as weakly acidic or weakly basic groups, to provide chemical stabilization for therapeutic agents in devices of the disclosure. These polymeric agents stabilize the therapeutic agents by controlling the pH of formulations of the disclosure. Serendipitously, such chemical stabilizers can now be used to control release rates as well.

[0074] Therefore, embodiments of the disclosure offer a method of controlling the release rate of a therapeutic agent through a nanoporous membrane by adjusting the pH of the formulation of the therapeutic agent. [0075] Some embodiments of the disclosure provide methods to control the rate of release of therapeutic agents from a reservoir through a nanotube membrane by controlling the pH of a formulation in the reservoir in which at least part of the therapeutic agent, or therapeutic agents, is dissolved. In some embodiments the release rate is controlled by controlling the pH with polymeric stabilizers such as described in US Patent Application pub Nos. US 2022/0008345 and US 2021/0246271. In some embodiments the release rate is controlled by controlling the pH with soluble pH controlling stabilizers, such as low molecular weight acids or bases. In some instances, a gradual rise of the release rate of a drug from an implant over time is considered desirable. For instance, with exenatide a gradual ramp-up of the delivered dose per day has been associated with a reduced incidence of nausea. In some embodiments of the disclosure the initial internal pH of a device is set at a relatively low level, and is allowed to rise over time as the internal pH slowly equilibrates with the external environment of the device, i.e. interstitial fluid. The gradual rise in pH is accompanied by a gradual increase in release rate.

[0076] In some instances, a dry formulation of a therapeutic agent may be present in a device at the time of implantation in a subject. In such instances a promotor of water uptake may be present in the reservoir, such as a water-soluble gas. After implantation the water- soluble gas may promote the uptake of interstitial fluid into the reservoir through the membrane of the device. Embodiments of the disclosure may include a dry formulation in the reservoir with a composition that, after uptake of the interstitial fluid, generates a liquid formulation with a pH that provides a desired release rate of the therapeutic agent.

Surfactants

[0077] The use of surfactants or wetting agents in formulations of therapeutic agents are typically used to improve the solubility and stability of the therapeutic agents, for instance by reducing a tendency for aggregation.

[0078] Surprisingly, it has now been found that addition of surfactants can significantly increase the rate of release of therapeutic agents into an environment of use from implantable devices of the disclosure. Any type of pharmaceutically acceptable surfactant may be used in embodiments of the disclosure, including, but not limited to, natural and synthetic surfactants, cationic surfactants, anionic surfactants, zwitterionic surfactants and non ionic surfactants.

[0079] Anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate sodium laureth sulfate, sodium myreth sulfate, dioctyl sodium sulfosuccinate, perfluorooctanesulfonate, perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl ether phosphates, carboxylates such as sodium stearate, sodium lauroyl sarcosinate, perfluorononanoate and perfluorooctanoate.

[0080] Cationic surfactants include, but are not limited to, primary, secondary, or tertiary amines, quaternary ammonium salts, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, dimethyldioctadecylammonium chloride, and di octadecyl dimethyl ammonium bromi de .

[0081] Zwitterionic surfactants include, but are not limited to, 3-[(3- cholamidopropyl)dimethylammonio]- 1 -propanesulfonate), cocamidopropyl hydroxysultaine, cocamidopropyl betaine, phosphatidyl serine, phosphatidylethanolamine, phosphatidylcholine, sphingomyelins, lauryldimethylamine oxide and myristamine oxide.

[0082] Non-ionic surfactants include fatty alcohol ethoxylates, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, alkylphenol ethoxylates, nonoxynols, Triton X-100, fatty acid ethoxylates, ethoxylated amines and/or fatty acid amides, polyethoxylated tallow amine, cocamide monoethanolamine, cocamide diethanolamine, terminally 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.

[0083] Some embodiments of the disclosure include more than 1 surfactant.

[0084] The mechanism of release rate acceleration by surfactants is not clear and may or may not be related to the critical micelle concentration (CMC) of the surfactants, or to the level to which they can lower surface tension.

[0085] However, those with ordinary skill in the art of pharmaceutical formulation development will be readily capable of experimentally testing the effect of the nature and concentration of surfactants on the release of therapeutic agents from implantable devices of the disclosure. Simple and well-understood methods to measure such release rates are available and are well known to those skilled in the art of pharmaceutical product development. See for instance US Pharmacopeia chapter 711, Dissolution Testing. [0086] Embodiments of the disclosure include implantable devices for the delivery of therapeutic agents to a subject, wherein the devices include surfactant in addition to the therapeutic agent. In some instances, the surfactant improves the therapeutic effect of the therapeutic agent.

[0087] A formulation of a therapeutic agent comprises a therapeutic agent and optionally excipients and solvents. No a priori limitations are known for the concentration of the therapeutic agent. In certain instances, the amount of therapeutic agent is from about 10% to about 50% w/w of the formulation disposed with the implantable device. The therapeutic agent can be about 15 % to about 40 % w/w, or about 20% to about 30% w/w or about 25% w/w of the formulation.

[0088] Suitable formulations include dry or a fluid formulation. Suitable fluid formulations include solutions as well as suspensions and emulsions. The formulation may include additional excipients, such as tonicity agents, ionic strength agents, solubilizing agents, pH control agents such as buffers, and excipients such as stabilizers for the therapeutic agent.

[0089] In some aspects, the amount of therapeutic agent e.g., exenatide can be from about 60 pg to about 50 mg, such as 100 pg, 200 pg, 300 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and/or 100 mg. In some instances lower or higher amounts of therapeutic agent may be present.

[0090] The surfactant content is typically less than 10 % w/w of the formulation, but in certain embodiments the concentration may be higher. In certain instances, the surfactant concentration is less than about 10%, or less than about 7.5%, or less than about 5%, or 3%, or 2%, or less than about 1% w/w of the formulation. In certain instances, the surfactant is less than 0.5%, 0.4%, 0.3%, 0.2% or less than about 0.1% w/w of the formulation.

[0091] In some aspects, the amount of surfactant can be from about 1 pg to about 100 pg, such as 5 pg, 10 pg, 20 pg, 30 pg, 40 pg, 50 pg, 60 pg, 70 pg, 80 pg, and/or 90 pg, 100 mg, 500 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, or 50 mg. In some instances, more than 50 mg of surfactant may be present.

[0092] In certain instances, the ratio of therapeutic agent to surfactant of the formulation is about 2:1 to about 500: 1, such as about 2: 1, 3: 1, 5:1, 10: 1, 20: 1, 30: 1, 40: 1, 50: 1, 60: 1, 70: 1, 80: 1, 90: 1, 100: 1, 110: 1, 120:1, 130: 1, 140: 1, 150: 1, 160: 1, 170: 1, 180: 1, 190: 1, 200: 1, 210: 1, 220: 1, 230: 1, 240: 1, or 250: 1, or about 500: 1. In some instances the ratio may be higher than 500: 1.

[0093] Embodiments of the disclosure further include methods for treating a subject with formulations including a surfactant and for improving the plasma levels of therapeutic agents delivered from devices of the disclosure. Methods of the disclosure include administration of any of the devices or compositions of the disclosure to subject in need of such administration.

[0094] Embodiments of the disclosure further include methods to improve the plasma levels of therapeutic agents released from implantable devices.

[0095] Embodiments of the disclosure include methods to treat subjects in need of treatment with therapeutic agents. In some methods the therapeutic agents are incretin mimetics. In some methods the incretin mimetic is exenatide.

[0096] In some embodiments the condition of the subject in need of treatment is Type 2 diabetes. In some embodiments the condition of the subject in need of treatment is obesity. In some embodiments the condition of the subject in need of treatment is non-alcoholic steatohepatitis (NASH). In some embodiments the condition of the subject in need of treatment is a neurodegenerative disease.

[0097] In some embodiments, the plasma levels of the subject after treatment (e.g., an incretin mimetic) with methods of the disclosure are between 50 pg/mL and 500 pg/mL. In some embodiments the plasma levels are between 500 pg/mL and 5 ng/mL. In some embodiments the plasma levels are between 5 ng/mL and 50 ng/mL. In some embodiments the plasma levels are between 50 ng/mL and 500 ng/mL.

[0098] Some embodiments of the disclosure include methods to treat subjects in need of treatment with exenatide, wherein the plasma levels of exenatide are between 50 ng/mL and 500 ng/mL.

[0099] In some embodiments of the disclosure the rate of release of a therapeutic agent with a surfactant from an implanted device is increased by at least 10% compared to a device or formulation without a surfactant.

[0100] In some embodiments of the disclosure the rate of release of a therapeutic agent with a surfactant from an implanted device is increased by at least 25% compared to a device or formulation without a surfactant. [0101] In some embodiments of the disclosure the rate of release of a therapeutic agent with a surfactant from an implanted device is increased by at least 50% compared to a device or formulation without a surfactant.

[0102] In some embodiments of the disclosure the rate of release of a therapeutic agent with a surfactant from an implanted device is increased by at least 100% compared to a device or formulation without a surfactant.

[0103] In some embodiments of the disclosure the rate of release of a therapeutic agent with a surfactant from an implanted device is at least tripled compared to a device or formulation without a surfactant.

Examples.

[0104] In the examples below the devices that were used included titanium capsules of approximately 25 mm length and 2.25 mm diameter. A titanium substrate with a titanium oxide nanoporous membrane was welded to one end of the device. The nanoporous membrane had a diameter of 0.3 mm and was composed of about 6,000,000 nanopores. The average diameter of the nanopores at the substrate end was approximately 20 nm. A silicone septum was inserted at the other end of the device. About 56 mg of a formulation containing 25% exenati de-acetate (w/w), 154 mM Na+ and a pH of 5.5 was filled into the device as per methods in PCT/US2021/019559. Briefly, the formulation was loaded into a filler apparatus with a hollow needle to pierce the septum. A vacuum was applied to the membrane of the device to reduce the pressure inside the reservoir, and the formulation was injected through the septum into the reservoir through the needle.

[0105] Release of the therapeutic agent into an environment of use was simulated by in vitro release rate testing by submerging the devices in 3 ml of a 26 mM bis-tris buffer, 154 mM NaCl on a shaker plate at 37°C and measuring the amounts released at regular intervals by reverse phase HPLC. Sodium azide was used in all experiments as an anti-microbial. The release rate profiles were plotted with release rates on the Y-axis, expressed as micrograms per day, and with time in days on the X-axis.

[0106] In US provisional patent application (Att. Docket No. 092795-1326250-003900US) the effects of prewarming on the release rate of therapeutic agents from implantable devices was disclosed. The examples below demonstrate that the effect of surfactants on release of the therapeutic agents is not significantly affected by prewarming steps. Example 1

[0107] 12 devices were prepared as described above. 6 devices received an additional amount of 0.25% (w/w) of polysorbate 20 (Tween 20). The devices were stored overnight submerged in a storage buffer containing 0.9% NaCl and 0.76% sodium acetate in water for injection at pH 5.5 at room temperature.

[0108] The effect of release rate is illustrated in FIG. 2. The release rates of the devices with Tween 20 were 2.5 times higher than those of the devices without Tween 20.

Example 2

[0109] 11 devices were prepared as described above. 5 devices received an additional amount of 0.25% (w/w) of polysorbate 20 (Tween 20). The devices were stored overnight submerged in a storage buffer containing 0.9% NaCl and 0.76% sodium acetate in water for injection at pH 5.5 at 45°C.

[0110] In this study the devices were prewarmed to 45°C for 1 hour. The effect of release rate is illustrated in FIG. 3. The release rates of the devices with Tween 20 was more than twice 3 times higher than those of the devices without Tween 20.

Example 3

[0111] Polycarbonate capsules with an internal reservoir volume of about 50 microliter were fitted with a silicone septum on one end, and with a titanium screw cap holding a titania nanotube membrane on the other end. The titania membrane on its titanium substrate was clamped between the polycarbonate capsule and the titanium screwcap using 2 O-rings. The nanoporous membrane had a diameter of 0.3 mm and was composed of about 6,000,000 nanopores. The average diameter of the nanopores at the substrate end was approximately 10 nm. A silicone septum was inserted at the other end of the device. About 50 mg of formulations containing 15% semaglutide (w/w), 154 mM Na+ and a pH of 7.4 was filled into the devices.

[0112] The devices were filled by pipetting the various formulation solutions into the open reservoirs of the capsule, and then carefully screwing on the titanium cap with the nanotube membrane.

[0113] Three formulations were tested. All three included 15% semaglutide (w/w) and NaCl for tonicity and were adjusted to pH 7.4 with NaOH. Three levels of Polysorbate 20 (Tween 20) were tested, 0%, 2.5% and 7.5% (w/w). [0114] Release of the therapeutic agent into an environment of use was simulated by in vitro release rate testing by submerging the devices in 3 ml of phosphate buffered saline and measuring the amounts released at regular intervals by reverse phase HPLC. Sodium azide was used in all experiments as an anti -microbial.

[0115] The release rate profiles were plotted with release rates on the Y-axis, expressed as micrograms per day, and with time in days on the X-axis.

[0116] As can be seen in Fig. 4, a significant increase in release rate was seen with both surfactant formulations compared to the no-surfactant formulation. Interestingly, the effect of 0.75% Polysorbate 20 (Tween 20) was greater than 7.5% Polysorbate 20 (Tween 20).

Prophetic Examples

[0117] In the examples below, the devices can include titanium capsules of approximately 25 mm length and 2.25 mm diameter. A titanium substrate with a titanium oxide nanoporous membrane is welded to one end of the device. The nanoporous membrane has a diameter of 0.3 mm and is composed of about 6,000,000 nanopores. A silicone septum is inserted at the other end of the device.

[0118] In order to achieve a desired release rate of any of the therapeutic agents below through the membrane, a series of membranes is prepared with variable pore diameters using the Atomic Layer Deposition process described in US Patent No. 9,770,412, and then welded to the test devices. By filling the devices with the formulations described below and measuring the resulting release rates as a function of pore diameter using the release rate method described above, the release rate of the therapeutic agents can be tuned to achieve the desired levels.

Example P-1

[0119] Interferon y 2 A is a recombinant form of a naturally occurring human protein with a molecular mass of about 19,000 Daltons.

[0120] Devices are filled with about 56 mg of a formulation containing 10% Interferon (w/w), 154mM Na+ and a pH of 5.5, as per methods in PCT/US2021/019559, and as described above. Using the release rate screening methods described below, a release rate of interferon of about 10 pg/day can be obtained.

[0121] In a comparative study of the effects of surfactants on release rates, 6 devices, having membranes providing a release rate of about 10 pg/day are filled with the formulation described above. 6 additional, identical devices are filled with the same formulation, but with addition of 0.25% Polysorbate 20 (Tween 20) (w/w) in the formulation.

[0122] A release rate experiment is performed as described above. The average daily release rate of the Interferon from devices with Polysorbate 20 is expected to be at least two times higher than the average release rate from the devices without the surfactant.

Example P-2

[0123] Goserelin Acetate is the acetate salt of a synthetic decapeptide analog of luteinizing horm one-releasing hormone with a molecular weight of 1269 Daltons.

[0124] Devices are filled with about 56 mg of a formulation containing 25% Goserelin (w/w), 154mM Na+ and a pH of 4.0, as per methods in PCT/US2021/019559, and as described above. Using the release rate screening methods described below, a release rate of goserelin of about 100 pg/day can be obtained.

[0125] In a comparative study of the effects of surfactants on release rates, 6 devices, having membranes providing a release rate of about 100 pg/day are filled with the formulation described above. 6 additional, identical devices are filled with the same formulation, but with addition of 0.25% Polysorbate 20 (Tween 20) (w/w) in the formulation.

[0126] A release rate experiment is performed as described above. The average daily release rate of the Goserelin from devices with Polysorbate 20 is expected to be at least two times higher than the average release rate from the devices without the surfactant.

Example P-3

[0127] Triton X-100 is a non-ionic surfactant of a different class than Polysorbate 20.

[0128] Devices are filled with about 56 mg of a formulation containing 25% exenatide (w/w), 154mM Na+ and a pH of 5.5, as per methods in PCT/US2021/019559, and as described above. Using the release rate screening methods described below, a release rate of exenatide of about 60 pg/day can be obtained.

[0129] In a comparative study of the effects of surfactants on release rates, 6 devices, having membranes providing a release rate of about 60 pg/day are filled with the formulation described above. 6 additional, identical devices are filled with the same formulation, but with addition of 0.25% Triton X 100 (w/w) in the formulation. [0130] A release rate experiment is performed as described above. The average daily release rate of the exenatide from devices with Triton X-100 is expected to be at least two times higher than the average release rate from the devices without the surfactant.

Example P-4

[0131] Sodium-dodecyl sulfate is a commonly used anionic surfactant

[0132] Devices are filled with about 56 mg of a formulation containing 25% exenatide (w/w), 154mM Na+ and a pH of 5.5, as per methods in PCT/US2021/019559, and as described above. Using the release rate screening methods described below, a release rate of exenatide of about 60 pg/day can be obtained.

[0133] In a comparative study of the effects of surfactants on release rates, 6 devices, having membranes providing a release rate of about 60 pg/day are filled with the formulation described above. 6 additional, identical devices are filled with the same formulation, but with addition of 0.25% sodium dodecyl sulfate (w/w) in the formulation.

[0134] A release rate experiment is performed as described above. The average daily release rate of the exenatide from devices with sodium dodecyl sulfate is expected to be at least two times higher than the average release rate from the devices without the surfactant.

[0135] This application references US Patent Application Nos. US 2022/0008345 and US 2021/0246271, and US Patent Nos. 9,814,867, 9,770,412, 10,045,943 and 10,479,868 which are both incorporated herein in their entirety by reference.

Claims

WHAT IS CLAIMED IS:

1 A device for sustained release of a therapeutic agent, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; a formulation of the therapeutic agent contained within the reservoir; the formulation including a surfactant; and wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use.

2. The device of claim 1, wherein the rate of release of the therapeutic agent is increased by at least 10% compared to a formulation without a surfactant.

3. The device of claim 1, wherein the rate of release of the therapeutic agent is increased by at least 25% compared to a formulation without a surfactant.

4. The device of claim 1, wherein the rate of release of the therapeutic agent is increased by at least 50% compared to a formulation without a surfactant.

5. The device of claim 1, wherein the rate of release of the therapeutic agent is increased by at least 100% compared to a formulation without a surfactant.

6. The device of claim 1, wherein the rate of release of the therapeutic agent is at least tripled compared to a formulation without a surfactant.

7. A method of treating a subject in need of treatment, the method comprising: providing a device according to any one of claims 1-6, and implanting the device in the subject.

8. The method of claim 7, wherein the therapeutic agent is exenatide.

9. The method of claim 8, wherein the treatment results in plasma levels between 50 pg/mL and 500 pg/mL.

10. A formulation of a therapeutic agent, the formulation contained in a device for sustained release of the therapeutic agent, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; the formulation including a surfactant; and wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use.

11. The formulation of claim 10, wherein the rate of release rate of the therapeutic agent is increased by at least 10% compared to a formulation without a surfactant.

12. The formulation of claim 10, wherein the rate of release of the therapeutic agent is increased by at least 25% compared to a formulation without a surfactant.

13. The formulation of claim 10, wherein the rate of release of the therapeutic agent is increased by at least 50% compared to a formulation without a surfactant.

14. The formulation of claim 10, wherein the rate of release of the therapeutic agent is increased by at least 100% compared to a formulation without a surfactant.

15. The formulation of claim 10, wherein the rate of release of the therapeutic agent is at least tripled compared to a formulation without a surfactant.

16. A method of treating a subject in need of treatment, the method comprising: providing a formulation contained within a device according to any one of claims 10-15, and implanting the device in the subject.

17. The method of claim 16, wherein the therapeutic agent is exenatide.

18. The method of claim 16, wherein the treatment results in plasma levels between 50 pg/mL and 500 pg/mL.

19. A method to increase the rate of release of a therapeutic agent from a device, the method comprising: providing the device, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane with a plurality of pores attached to the capsule and providing a diffusion path for release of the therapeutic agent out of the reservoir; a formulation of the therapeutic agent contained within the reservoir; the formulation including a surfactant, wherein the surfactant increases the rate of release of the therapeutic agent through the membrane into an environment of use; and placing the device into the environment of use.

20. The method of claim 19, wherein the rate of release of the therapeutic agent is increased by at least 10% compared to a formulation without a surfactant.

21. The method of claim 19, wherein the rate of release of the therapeutic agent is increased by at least 25% compared to a formulation without a surfactant.

22. The method of claim 19, wherein the rate of release of the therapeutic agent is increased by at least 50% compared to a formulation without a surfactant.

23. The method of claim 19, wherein the rate of release of the therapeutic agent is increased by at least 100% compared to a formulation without a surfactant.

24. The method of claim 19, wherein the rate of release of the therapeutic agent is at least tripled compared to a formulation without a surfactant.