WO2021173770A1

WO2021173770A1 - Polymeric stabilizing agents for implantable drug delivery devices

Info

Publication number: WO2021173770A1
Application number: PCT/US2021/019559
Authority: WO
Inventors: Ryan Olf; Lyle Gordon; Wouter Roorda
Original assignee: Nano Precision Medical, Inc.
Priority date: 2020-02-28
Filing date: 2021-02-25
Publication date: 2021-09-02

Abstract

The disclosure pertains to the field of treatment of patients with implantable delivery devices for long-term release of therapeutic agents. In particular, the disclosure provides devices and methods for the stabilization of the therapeutic agents inside the device for the duration of the implantation. The devices control the long-term release of the therapeutic agents by using a nanoporous membrane. The stabilization is achieved by using high-molecular weight stabilizers of a size that is larger than the diameter of the pores of the membrane, thereby preventing the release of the stabilizers.

Description

POLYMERIC STABILIZING AGENTS FOR IMPLANTABLE DRUG

DELIVERY DEVICES

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Patent Application No. 62/983,296, filed February 28, 2020, which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[0002] Many subjects, human as well as veterinary, are in need of long-term treatment with therapeutic agents. In order to improve adherence, many subjects would benefit from the compliance provided by an implantable device releasing a desired therapeutic agent at a desired rate and at a desired purity for an extended period of time. Since many therapeutic agents have limited stability under conditions of implantation, long-term stabilization of the therapeutic agents may be required.

[0003] WO 2008/061355 is drawn to an implantable hydrogel device for administration of GLP-1 or an analogue of GLP-1 for sustained release over extended periods of time as well as methods of manufacture.

[0004] WO 2009/158412 is drawn to implantable devices, formulations and methods of making implantable device for the release of a polypeptide from the implantable device. This reference uses a hydrogel for sustained release of the polypeptide.

[0005] In view of the above, there is a need for devices and formulations for long term release and stabilization of therapeutic agents, for methods of stabilization of the therapeutic agents, and for methods of preparation and use of such devices and formulations. The present disclosure satisfies these and other needs.

BRIEF SUMMARY

[0006] In some instances, an embodiment of the disclosure includes 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;

- the therapeutic agent disposed within the reservoir; and

- a polymeric stabilizing agent, disposed within the reservoir and comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups;

- wherein the nanoporous membrane provides a diffusion path for the therapeutic agent out of the reservoir; and wherein the polymeric stabilizing agent has dimensions larger than the pore size of the nanoporous membrane substantially preventing release of the polymeric stabilizing agent from the reservoir.

[0007] In some instances, the insoluble polymer is a cross-linked polymer.

[0008] In some instances, the therapeutic agent is a peptide or protein.

[0009] In some instances, the therapeutic agent is an incretin mimetic.

[0010] In some instances, the therapeutic agent is exenatide.

[0011] In some instances, the therapeutic agent and the stabilizing agent are present in a substantially dry solid form.

[0012] In some instances, the device further comprising a solvent for the therapeutic agent.

[0013] In some instances, the stabilizing agent includes one or both of acrylic acid residues and methacrylic residues.

[0014] In some instances, the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between about 3.5 and about 7.5.

[0015] In some instances, a fluid develops with a pH between about 5.0 and about 6.0.

[0016] In some instances, the stabilizing groups are neutralized between about 10% and about 75%, such as about 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, and/or 75%.

[0017] In some instances, the stabilizing groups are neutralized between about 30% and about 65%.

[0018] In some instances, the solvent has a pH between about 3.5 and about 7.5. [0019] In some instances, the solvent has a pH between about 5.0 and about 6.0.

[0020] In some instances, an embodiment of the disclosure includes a method for stabilizing a therapeutic agent, the method comprising:

- providing 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;

- disposing the therapeutic agent within the reservoir; and

- disposing a polymeric stabilizing agent within the reservoir, the polymeric stabilizing agent comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups;

[0021] In some instances, the insoluble polymer is a cross-linked polymer.

[0022] In some instances, the therapeutic agent is a peptide or protein.

[0023] In some instances, the therapeutic agent is an incretin mimetic.

[0024] In some instances, the therapeutic agent is exenatide.

[0025] In some instances, the therapeutic agent and the stabilizing agent are present in a substantially dry solid form.

[0026] In some instances, the device further comprising a solvent for the therapeutic agent.

[0027] In some instances, the stabilizing agent includes one or both of acrylic acid residues and methacrylic residues.

[0028] In some instances, the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between about 3.5 and about 7.5.

[0029] In some instances, a fluid develops with a pH between about 5.0 and about 6.0. [0030] In some instances, the stabilizing groups are neutralized between about 10% and about 75%.

[0031] In some instances, the stabilizing groups are neutralized between about 30% and about 65%.

[0032] In some instances, the solvent has a pH between about 3.5 and about 7.5.

[0033] In some instances, the solvent has a pH between about 5.0 and about 6.0.

[0034] In some instances, an embodiment of the disclosure includes a method of treating a disease in a subject in need thereof, the method comprising:

- administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 1 comprising a therapeutic agent and a polymer functionalized with a plurality of stabilizing, thereby treating the disease.

[0035] In some instances, an embodiment of the disclosure includes a therapeutic formulation, the formulation comprising:

- a therapeutic agent; and

- a polymeric stabilizing agent comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups, which is a member selected from the group consisting of a cross-linked poly-acrylic acid, a cross-linked poly-methacrylic acid, or mixtures thereof or copolymers of acrylic and methacrylic acid.

[0036] In some instances, the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between about 3.5 and about 7.5.

[0037] In some instances, the insoluble polymer is a cross-linked polymer.

[0038] In some instances, the therapeutic agent is a peptide or protein.

[0039] In some instances, the therapeutic agent is an incretin mimetic.

[0040] In some instances, the therapeutic agent is exenatide.

[0041] In some instances, the therapeutic agent and the stabilizing agent are present in a substantially dry solid form. [0042] In some instances, the formulation further comprises a solvent for the therapeutic agent.

[0043] In some instances, the stabilizing agent includes one or both of acrylic acid residues and methacrylic residues.

[0044] In some instances, the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between about 4.0 and about 7.0

[0045] In some instances, a fluid develops with a pH between about 5.0 and about 6.0.

[0046] In some instances, the stabilizing groups are neutralized between about 10% and about 75%.

[0047] In some instances, the stabilizing groups are neutralized between 30% and 65%.

[0048] In some instances, the solvent has a pH between about 3.5 and about 7.5.

[0049] In some instances, the solvent has a pH between about 5.0 and about 6.0.

[0050] These and other embodiments, aspects, and objects will become more apparent when read with the drawings which follow.

BRIEF DESCRIPTION OF THE DRAWINGS [0051] Fig 1 A represents an embodiment of a device with a single reservoir.

[0052] Fig. IB represents an embodiment of a device with 2 reservoirs.

[0053] Fig. 2 represents a pH vs. stability profile of a model peptide.

[0054] Fig. 3 A represents the effect of a stabilizing agent of the disclosure on the pH of a therapeutic agent of the disclosure.

[0055] Fig. 3B represents the effect of a stabilizing agent of the disclosure on the purity of a therapeutic agent of the disclosure.

[0056] Fig. 4A shows the presence of an ion exchange resin maintained a lower pH over at least 3 months (90 Days).

[0057] Fig. 4B shows the presence of an ion exchange resin maintained better purity of the exenatide over at least 3 months (90 Days). DETAILED DESCRIPTION

[0058] The disclosure pertains to the field of long-term treatment of subjects with implantable devices providing a sustained delivery of therapeutic agents.

[0059] Embodiments of the disclosure include devices, methods and formulations including one or more therapeutic agents together with one or more polymeric stabilizing agents.

[0060] Furthermore, embodiments of the disclosure include methods for the fabrication of the devices.

[0061] Additionally, embodiments of the disclosure include methods of treatment of a subject with devices and formulations of the disclosure.

Definitions

[0062] “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.

[0063] “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.

[0064] 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.

[0065] 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 Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser. (CAS Number: 141758-74-9).

[0066] “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. [0067] “Membrane” refers to a permeable structure allowing mass transport of molecules from one side of the structure to the other through the structure.

[0068] “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.

[0069] “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.

[0070] “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.

[0071] “Nanotube membrane” refers to a nanoporous membrane, wherein pores are formed by an array of nanotubes.

[0072] “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.

[0073] ‘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.

[0074] “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.

[0075] “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. [0076] “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.

[0077] “Fluid contact” refers to an entity being in contact with a fluid.

[0078] “Neutral pH” refers to a pH between 6.5 and 7.5.

Devices

[0079] As illustrated in Fig. 1A, devices of the disclosure include a capsule 101 suitable for implantation, wherein the capsule has a reservoir 102 suitable for holding a therapeutic agent and a stabilizing agent. In some embodiments, more than one reservoir is present. (Fig. IB). 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.

[0080] In some embodiments, the capsule is made of a single piece of material. In some embodiments, the capsule is made of multiple pieces of materials, for instance a capsule having a reservoir for holding a therapeutic agent and a stabilizing agent and having a cap holding a membrane as a pathway for release of the therapeutic agent, wherein the cap can be attached to the reservoir by any suitable means, such as welding, gluing, press fitting or using threaded means, or any combination of these.

[0081] The capsule may have any suitable size or shape. In some embodiments of the disclosure the capsule is cylindrical, facilitating implantation into the body by means of a tubular implantation device, such as a needle or trocar.

[0082] Devices of the disclosure have at least one membrane, as described in this disclosure, attached to the capsule and in fluid contact with the reservoir, wherein the membrane provides a pathway for mass transport of a therapeutic agent included within the reservoir out of that reservoir and into the body of a subject into which the capsule has been implanted. In this disclosure “attached to the capsule” refers to a component being fixed in place with respect to the capsule, and connected to the capsule directly or indirectly, by using any suitable means, including by welding, gluing, press-fitting and by using threaded means, or by any combination of these. [0083] In the case of membranes as described in US Patent No. 9814867, and as illustrated in Fig. 1 A, the nanotube membranes are part of an array of nanotubes 103, some of which are still attached to the titanium substrate 104 from which they were grown, and the substrate may be attached to the capsule. At least some of the nanotubes are open on both sides, 105 in Fig. 1 A, to allow for mass transport of a therapeutic agent out of the reservoir.

[0084] Fig. IB is a capsule 101b with two reservoirs 102b and two membranes 105b, which allow for mass transport of a therapeutic agent out of the reservoir. In this embodiment, the capsule 101b has at least two arrays of nanotubes 103b, some of which are still attached to the titanium substrate 104b. At least some of the nanotubes are open on both sides 105b in Fig. IB, to allow for mass transport of a therapeutic agent out of the reservoir.

[0085] In certain aspects, the filling capacity of the device may vary. The device may be from about 0.1 cm to about 15 cm in length (L) such as about 0.1 cm, 0.5 cm, 1 cm, 1.5 cm, 2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 5.5 cm, 6 cm, 6.5 cm, 7 cm, 7.5 cm, 8 cm, 8.5 cm, 9 cm, 9.5 cm, 10 cm, 10.5 cm, 11 cm, 11.5 cm, 12 cm, 12.5 cm, 13 cm, 13.5 cm, 14 cm, 14.5 cm, and/or 15 cm. The diameter can vary from 0.1 mm to about 10 mm, such as about 0.1 mm, 0.5 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, and/or 10 mm. The volume is equal to p r²xL, where r is the radius or ½ the diameter.

[0086] In some embodiments, more than one membrane is present. In some embodiments, more than one type of membrane is present. Membrane types may include dense and porous membranes, including nanoporous membranes and nanotube membranes.

[0087] In some embodiments, a titania nanotube membrane is present.

[0088] Some devices of the disclosure include at least one polymeric stabilizing agent, for instance stabilizing agents such as described in this disclosure. The stabilizing agent may be present in solid or fluid form. In some instances, the stabilizing agent may be present in mixed forms, such a suspension of a solid form such as a bead or particle of the stabilizing agent in a saturated solution of the stabilizing agent.

[0089] Some devices of the disclosure include 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.

[0090] Some devices of the disclosure include a polymeric plug, suitable for sealing one end of a capsule, for instance for sealing one end of a cylindrical capsule. In some embodiments, the plug may be inserted during the manufacturing of the device after a therapeutic agent and a stabilizing agent have been disposed into the reservoir. In some embodiments, the plug forms a septum suitable for piercing with a hollow needle, such as a hypodermic needle, and is attached to the capsule in a position to allow access to the reservoir of the capsule by piercing with the hollow needle. In some embodiments of the disclosure, the septum is used as an access port to the reservoir to facilitate filling the reservoir of the capsule with a fluid form of a therapeutic agent or of a stabilizing agent, or with components of a fluid form of a therapeutic agent or of a stabilizing agent. The septum may be made from any suitable biocompatible material, such as silicone, polyurethane, polyacrylate, polyolefin, polyester, polyamide and the like.

[0091] In some embodiments, the device has a capsule configured for implantation, a reservoir, and a nanoporous membrane with a plurality of pores, the membrane being attached to the capsule in fluid contact with the reservoir, wherein the membrane provides a pathway for mass transport of a therapeutic agent out of the reservoir. The membrane may be a nanotube membrane such as described in US Patent 9814867. The device includes an insoluble polymeric stabilizing agent, such as described in this disclosure, included within the reservoir and having dimensions larger than the pore size of the membrane, thereby substantially being prevented from being released out of the reservoir through the membrane. The device is configured for introducing into the reservoir a therapeutic agent at the discretion of an operator or medical personnel.

[0092] In some embodiments, the device has a capsule configured for implantation, a reservoir, and a nanoporous membrane with a plurality of pores, the membrane being attached to the capsule in fluid contact with the reservoir, wherein the membrane provides a pathway for mass transport of a therapeutic agent out of the reservoir. The membrane may be a nanotube membrane such as described in US Patent 9814867. The device includes an insoluble polymeric stabilizing agent, such as described in this disclosure, included within the reservoir and having dimensions larger than the pore size of the membrane, thereby substantially being prevented from being released out of the reservoir through the membrane. [0093] In some devices of the disclosure the stabilizing agent has a plurality of acidic groups. In some embodiments, the acidic groups are present on acrylic acid monomer residues or on methacrylic acid monomer residues, or on a combination of both types of residues.

[0094] The device further includes a therapeutic agent, such as described in this disclosure.

[0095] In some embodiments, the therapeutic agent is a polypeptide. In some embodiments, the polypeptide is an incretin mimetic. In some embodiments, the incretin mimetic is exenatide.

[0096] In some embodiments, the therapeutic agent and the stabilizing agent are present in a substantially dry solid form.

[0097] In some embodiments, a solvent for the therapeutic agent is present, creating a solution of at least part of the therapeutic agent. In some embodiments, a solid form of the therapeutic agent is present in a saturated solution of the therapeutic agent.

[0098] In an exemplary embodiment, the device has a cylindrical capsule configured for implantation and a reservoir capacity of about 50 microliters. In other instances, a reservoir capacity is about 1 pL to about 1 mL, such as about 1 pL, 25 pL, 50 pL, 75 pL, 100 pL, 125 pL, 150 pL, 175 pL, 200 pL, 225 pL, 250 pL, 275 pL, 300 pL, 325 pL, 350 pL, 375 pL, 400 pL, 425 pL, 450 pL, 475 pL, and/or 500 pL. In other instances, the capcity is about 1 pL- 500 pL; or 10 pL- 250 pL; or 10 pL-100 pL. The membrane is a titania nanotube membrane attached to one end of the cylindrical capsule.

[0099] The capsule further has a silicone septum attached to the opposite end of the capsule.

[0100] In one instance, the reservoir contains about 10 milligrams of a cross-linked form of methacrylic acid as the stabilizing agent and about 40 microliter of an aqueous solution of 25% (w/w) exenatide as the therapeutic agent, at a pH between 5.0 and 5.5 and with an NaCl concentration of about 154 millimolar.

[0101] Some embodiments of the disclosure include methods for preparation of devices of the disclosure. Generally, devices of the disclosure include a capsule having a reservoir for holding a therapeutic agent and for holding a stabilizing agent, and include a membrane providing a mass transport path out of the reservoir for the therapeutic agent, but not for the stabilizing agent. In some devices of the disclosure a pierceable septum is present to facilitate admitting fluid forms of the therapeutic agent and of the stabilizing agent into the reservoir. Device components and methods for their assembly are described in this disclosure.

[0102] Methods of preparation of membranes of the disclosure are described in US Patent Nos: 9814867 and 9770412.

[0103] Methods of preparation of capsules of the disclosure, such as cylindrical tubes made of metals such as stainless steel and titanium, or from polymers such as poly-urethanes and polycarbonate include many well-established machining processes.

[0104] Methods of preparation of septa of the disclosure include many polymer processing methods, such as casting from medical grade precursors like medical grade siloxanes.

[0105] Some devices of the disclosure include at least one therapeutic agent and at least one stabilizing agent, disposed within the reservoir. Therapeutic agents and stabilizing agents in this disclosure may be combined in any suitable combination in preparing devices of the disclosure, by any suitable means, and in any suitable state.

[0106] In some embodiments, a cylindrical capsule is closed at one end, and can be closed at the other end by attaching a membrane. Components of the final formulation are admitted to the reservoir before attaching the membrane, after which the capsule is closed by attaching the membrane. The membrane can be attached by any desirable means, such welding, gluing, press-fitting or using threaded means, or by any combination of these. In some embodiments, all components of the final formulation are admitted before attaching the membrane. In some embodiments, part of the components of the final formulation are added before attaching the membrane, such as dry formulation components, after which fluid formulation components are admitted through the membrane. In order to facilitate admitting fluid components, in some embodiments, the pressure inside the reservoir is reduced before admitting a fluid medium such as described in US Patent No. 10525248.

[0107] In some embodiments, admitting an aqueous fluid medium is facilitated by including a water-soluble gas in the reservoir, such as described in US Patent No. 9511212.

[0108] In some embodiments, a cylindrical capsule has a membrane attached to one end, and can be closed by attaching a septum to the other end. Components of the final formulation can be admitted to the reservoir before attaching the septum, after which the capsule can be closed by attaching the septum. The septum can be attached by any desirable means, such welding, gluing, press-fitting or using threaded means, or by any combination of these. In some embodiments, all components of the final formulation are admitted before attaching the septum. In some embodiments, part of the components of the final formulation are added before attaching the septum, such as dry formulation components, after which fluid formulation components are admitted through the septum by means of a hollow needle. In order to facilitate admitting fluid components, in some embodiments, the pressure inside the reservoir is reduced before admitting a fluid medium such as described in US Patent No. 10525248

[0109] In some embodiments, admitting an aqueous fluid medium is facilitated by including a water-soluble gas in the reservoir, such as described in US Patent No. 9511212.

[0110] Stabilizing agents in a fluid or solid state may be combined with therapeutic agents in a fluid or solid state.

[0111] Stabilizing agents and therapeutic agents may be combined in their solid states in a first step, and brought into a fluid state in a later step.

[0112] Stabilizing agents and therapeutic agents may be combined in fluid states in a first step, and brought into a solid state in a later step.

[0113] Combination of the therapeutic agent and the stabilizing agent may be performed by any suitable method, including dry powder mixing and preparing a fluid mixture of the therapeutic agent and the stabilizing agent.

[0114] These options may be combined in any suitable combination and permutation.

Membranes

[0115] 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.

[0116] A wide variety of membranes can be used in embodiments of the present disclosure.

[0117] Membranes of the disclosure include dense and porous membranes; porous membranes include nanoporous membranes and nanotube membranes.

[0118] 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. [0119] 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.

[0120] 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.

[0121] Some embodiments of the disclosure comprise a titania nanotube membrane, such as described in US Patent No. 9814867. The pore size of membranes of the disclosure can be controlled by processes such as described in US Patent No. 9770412.

[0122] Generally, average pore sizes of membranes of the disclosure may be between 1 and 1000 nanometers. In some embodiments, average pore sizes larger than 1000 nanometers may be present. In some embodiments the average pore size is from 1 to 5 nanometers. In some embodiments, the average pore size is from 5 to 10 nanometers. In some embodiments, the average pore size is from 10 to 50 nanometers. In some embodiments, the average pore size is from 50 to 100 nanometers. In some embodiments, the average pore size is from 15 to 40 nanometer. In some embodiments, the average pore size is from 1 to 50 nanometers, for example approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,

22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46

47, 48, 49, and/or 50. In some embodiments, the average pore size is from 100 to 1000 nanometers. In some embodiments, pore sizes of less than 1 nanometer may be present.

[0123] In some embodiments, the membrane pores have a diameter of the same order of magnitude as the hydrodynamic diameter of dissolved substances, such as a therapeutic agent in a formulation. In some embodiments, the pores have a diameter smaller than hydrodynamic diameter of dissolved substances in a formulation. Because of the finite size of the pores, such membranes may act as a size cut-off filter for dissolved substances in the formulations of the drug delivery systems.

[0124] In some embodiments, the membrane pores have diameters in a range of 1-5 times or 1, 2, 3, 4, or 5 times or even more times the size of the molecular diameter of the drug molecules diffusing through their aqueous phase. In some embodiments, the membrane pores have diameters, as described in US Patent Application No. 16/204890. It has been shown that under those conditions drug release rates may be achieved that are not controlled by a concentration gradient between the reservoir and the environment into which the drug is released as would be seen in typical Fickian diffusion, and that may approach a more constant release rate over time.

[0125] The membrane pores are in fluid contact with the therapeutic agent in the reservoir, such that molecules of the therapeutic agent are able to diffuse into and out of the pores and into an environment surrounding the device. The profile of the release rate over time may be any desired profile. In some embodiments, the profile is a declining profile, in accordance with regular Fickian diffusion out of the reservoir. In some embodiments, the release rate profile is non-Fickian, like a constant rate or near-constant rate profile. Constant rate profiles are sometimes referred to as zero-order release rate profiles. Some embodiments have a spike in drug release rate at early time points in the profile. Some embodiments have slow ramp up of release rates at early time points in the release rate profile.

[0126] The implantable drug delivery system of the present disclosure can have one or more membranes (See, Fig. IB). For example, the implantable drug delivery system can have 1, 2, 3, 4, or more membranes. Membrane types include nanoporous and non-porous membranes. Different nanoporous membranes can have the same or different pore diameters. When the implantable drug delivery system has more than one membrane each with the same pore diameter, each membrane can provide a diffusion pathway for the therapeutic agent. Alternatively, the membranes can each have different pore diameters such that one or more of the membranes does not provide a diffusion pathway for the therapeutic agent. In some embodiments, when two membranes are present in the implantable drug delivery system, only one membrane provides a diffusion pathway for the therapeutic agent.

Therapeutic agents

[0127] Some embodiments of the disclosure include low molecular weight therapeutic agents, sometimes referred to as “small molecule drugs.” Some embodiments of the disclosure include high molecular weight therapeutic agents, like peptides and proteins, carbohydrates and nucleic acids, and combinations thereof, like glycoproteins.

[0128] Some embodiments of the disclosure include more than one type of therapeutic agent. In one instance, a first therapeutic agent is in a first reservoir 102b of FIG. IB on the left and a second therapeutic agent in a second reservoir as in 102b on the right of Fig. IB.

[0129] Therapeutic agents of the disclosure may be present in any desired state, including fluid and solid forms. [0130] Some embodiments of the disclosure comprise a therapeutic agent in need of stabilization. In some embodiments, stabilization is provided by pH-controlling agents.

[0131] Stabilization mechanisms provided by embodiments of the disclosure include chemical or physical mechanisms, as well as combinations of both.

[0132] Many polypeptides include asparagine and/or glutamine residues, which are susceptible to degradation by deamidation reactions. The rate of these deamidation reactions is pH dependent, and typically starts to accelerate rapidly above pH levels around or about 6.0 to about 6.5. Likewise, other degradation reactions, such as isomerization and racemization may be pH dependent and may be controllable by embodiments of the disclosure.

[0133] Many polypeptides have a tendency to aggregate in a reversible or irreversible form, and frequently the propensity to aggregation reaches a maximum at the isoelectric point of the polypeptide. By maintaining pH levels away from the isoelectric point embodiments of the disclosure may reduce the tendency for polypeptide aggregation.

[0134] Any suitable therapeutic agent can be incorporated into embodiments of the disclosure. For example, the therapeutic agent can be a small molecule drug, such as one having a molecular weight of less than about 1000 g/mol, or less than about 750 g/mol, or less than about 500 g/mol. In some embodiments, the therapeutic agent can be tacrine, memantine, rivastigmine, galantamine, donepezil, levetiracetam, repaglinide, atorvastatin, alefacept, tadalafil, vardenafil, sildenafil, fosamprenavir, oseltamivir, valacyclovir and valganciclovir, abarelix, adefovir, alfuzosin, alosetron, amifostine, amiodarone, aminocaproic acid, aminohippurate sodium, aminoglutethimide, aminolevulinic acid, aminosalicylic acid, amlodipine, amsacrine, anagrelide, anastrozole, aprepitant, aripiprazole, asparaginase, atazanavir, atomoxetine, anthracyclines, bexarotene, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, cabergoline, capecitabine, carboplatin, carmustine, chlorambucin, cilastatin sodium, cisplatin, cladribine, clodronate, cyclophosphamide, cyproterone, cytarabine, camptothecins, 13-cis retinoic acid, all trans retinoic acid; dacarbazine, dactinomycin, daptomycin, daunorubicin, deferoxamine, dexamethasone, diclofenac, diethylstilbestrol, docetaxel, doxorubicin, dutasteride, eletriptan, emtricitabine, enfuvirtide, eplerenone, epirubicin, estramustine, ethinyl estradiol, etoposide, exemestane, ezetimibe, fentanyl, fexofenadine, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, fluticazone, fondaparinux, fulvestrant, gamma-hydroxybutyrate, gefitinib, gemcitabine, epinephrine, L-Dopa, hydroxyurea, icodextrin, idarubicin, ifosfamide, imatinib, irinotecan, itraconazole, goserelin, laronidase, lansoprazole, letrozole, leucovorin, levamisole, lisinopril, lovothyroxine sodium, lomustine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, memantine, mercaptopurine, mequinol, metaraminol bitartrate, methotrexate, metoclopramide, mexiletine, miglustat, mitomycin, mitotane, mitoxantrone, modafmil, naloxone, naproxen, nevirapine, nicotine, nilutamide, nitazoxanide, nitisinone, norethindrone, octreotide, oxaliplatin, palonosetron, pamidronate, pemetrexed, pergolide, pentostatin, pilcamycin, porfimer, prednisone, procarbazine, prochlorperazine, ondansetron, palonosetron, oxaliplatin, raltitrexed, rosuvastatin, sirolimus, streptozocin, pimecrolimus, sertaconazole, tacrolimus, tamoxifen, tegaserod, temozolomide, teniposide, testosterone, tetrahydrocannabinol, thalidomide, thioguanine, thiotepa, tiotropium, topiramate, topotecan, treprostinil, tretinoin, valdecoxib, celecoxib, rofecoxib, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, voriconazole, dolasetron, granisetron, formoterol, fluticasone, leuprolide, midazolam, alprazolam, amphotericin B, podophylotoxins, nucleoside antivirals, aroyl hydrazones, sumatriptan, eletriptan; macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, loratadine, desloratadine, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin; aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate; polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including penicllinase-sensitive agents like penicillin G, penicillin V; penicillinase-resistant agents like methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefmetazole, ceftazidime, loracarbef, and moxalactam, monobactams like aztreonam; and carbapenems such as imipenem, meropenem, and ertapenem, pentamidine isetionate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, salmeterol, ipratropium bromide, flunisolide, cromolyn sodium, and ergotamine tartrate; taxanes such as paclitaxel; SN-38, or tyrphostines. Therapeutic agents can also be aminohippurate sodium, amphotericin B, doxorubicin, aminocaproic acid, aminolevulinic acid, aminosalicylic acid, metaraminol bitartrate, pamidronate disodium, daunorubicin, levothyroxine sodium, lisinopril, cilastatin sodium, mexiletine, cephalexin, deferoxamine, or amifostine.

[0135] Other therapeutic agents useful in the present disclosure can include peptides, polypeptides, proteins, antibodies, etc. In some embodiments, the therapeutic agent can be erythropoietin, granulocyte colony stimulating factor (G-CSF), GM-CSF, interferon alpha, interferon beta, human growth hormone, imiglucerase, or RANK ligand. In other embodiments, the therapeutic agents can be Ab, agalsidase, alefacept, alkaline phosphatase, aspariginase, amdoxovir (DAPD), antide, becaplermin, botulinum toxin including types A and B and lower molecular weight compounds with botulinum toxin activity, calcitonins,

CD Id, cyanovirin, denileukin diftitox, erythropoietin (EPO), EPO agonists, dornase alpha, erythropoiesis stimulating protein (NESP), coagulation factors such as Factor V, Factor VII, Factor Vila, Factor VIII, B domain deleted Factor VIII, Factor IX, Factor X, Factor XII, Factor XIII, von Willebrand factor; ceredase, Fc gamma r2b, cerezyme, alpha-glucosidase, N-Acetylgalactosamine-6-sulfate sulfatase, collagen, cyclosporin, alpha defensins, beta defensins, desmopressin, GLP-1 analogs such as exendin-4 (EXENATIDE®), cytokines, cytokine receptors, granulocyte colony stimulating factor (G-CSF), thrombopoietin (TPO), alpha- 1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GM-CSF), fibrinogen, filgrastim, growth hormones human growth hormone (hGH), somatropin, growth hormone releasing hormone (GHRH), GRO-beta, GRO-beta antibody, bone morphogenic proteins such as bone morphogenic protein-2, bone morphogenic protein- 6, parathyroid hormone, parathyroid hormone related peptide, OP-1; acidic fibroblast growth factor, basic fibroblast growth factor, Fibroblast Growth Factor 21, CD40 ligand, ICOS, CD28, B7-1, B7-2, TLR and other innate immune receptors, heparin, human serum albumin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interferon omega, interferon tau, consensus interferon; interleukins and interleukin receptors such as interleukin- 1 receptor, interleukin-2, interleukin-2 fusion proteins, interleukin- 1 receptor antagonist, interleukin-3, interleukin-4, interleukin-4 receptor, interleukin-6, interleukin-8, interleukin- 12, interleukin- 17, interleukin-21, interleukin- 13 receptor, interleukin- 17 receptor; lactoferrin and lactoferrin fragments, luteinizing hormone releasing hormone (LHRH), insulin, pro-insulin, insulin analogues, amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), imiglucerase, influenza vaccine, insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), plasminogen activators such as alteplase, urokinase, reteplase, streptokinase, pamiteplase, lanoteplase, and teneteplase; nerve growth factor (NGF), trk A, trk B, osteoprotegerin, platelet-derived growth factor, tissue growth factors, transforming growth factor- 1, vascular endothelial growth factor, leukemia inhibiting factor, keratinocyte growth factor (KGF), glial growth factor (GGF), T Cell receptors, CD molecules/antigens, tumor necrosis factor (TNF) (e.g., TNF-a and TNF-b), TNF receptors (e.g., TNF-a receptor and TNF-b receptor), CTLA4, CTLA4 receptor, monocyte chemoattractant protein- 1, endothelial growth factors, parathyroid hormone (PTH), PTHrP, glucagon-like peptide, somatotropin, thymosin alpha 1, rasburicase, thymosin alpha 1 Ilb/IIIa inhibitor, thymosin beta 10, thymosin beta 9, thymosin beta 4, alpha- 1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 (very late antigen-4), VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal/permeability increasing protein (BPI), and anti-CMV antibody. Exemplary monoclonal antibodies include etanercept (a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kD TNF receptor linked to the Fc portion of IgGl), abciximab, adalimumab, afelimomab, alemtuzumab, antibody to B-lymphocyte, atlizumab, basiliximab, bevacizumab, biciromab, bertilimumab, CDP-484, CDP-571, CDP-791, CDP-860, CDP-870, cetuximab, clenoliximab, daclizumab, eculizumab, edrecolomab, efalizumab, epratuzumab, fontolizumab, gavilimomab, gemtuzumab ozogamicin, ibritumomab tiuxetan, infliximab, inolimomab, keliximab, labetuzumab, lerdelimumab, olizumab, radiolabeled lym-1, metelimumab, mepolizumab, mitumomab, muromonad-CD3, nebacumab, natalizumab, odulimomab, omalizumab, oregovomab, palivizumab, pemtumomab, pexelizumab, rhuMAb-VEGF, rituximab, satumomab pendetide, sevirumab, siplizumab, tositumomab, I^mtositumomab, trastuzumab, tuvirumab, visilizumab, or fragments or mimetics thereof.

[0136] In other embodiments, the therapeutic agent can be a fusion protein. For example, the therapeutic agent can be an immunoglobulin or portion of an immunoglobulin fused to one or more certain useful peptide sequences. The therapeutic agent can also contain an antibody Fc fragment.

[0137] In some embodiments, the therapeutic agent can be a human protein or human polypeptide, for example, a heterologously produced human protein or human polypeptide. Numerous proteins and polypeptides are disclosed herein for which there is a corresponding human form (i.e., the protein or peptide is normally produced in human cells in the human body). Examples of human proteins include, without limitation, human antibodies, human enzymes, human hormones and human cytokines such as granulocyte colony stimulation factor, granulocyte macrophage colony stimulation factor, interferons (e.g., alpha interferons and beta interferons), human growth hormone and erythropoietin.

[0138] Other examples of therapeutic agents include, without limitation, factor VIII, b- domain deleted factor VIII, factor Vila, factor IX, factor X, anticoagulants; hirudin, alteplase, tpa, reteplase, tpa, tpa-3 of 5 domains deleted, insulin, insulin lispro, insulin aspart, insulin glargine, long-acting insulin analogs, complement C5, hgh, glucagons, tsh, follitropin-beta, fsh, gm-csf, pdgh, ifin alpha2, ifn alpha2a, ifin alpha2b, inf-alphal, consensus ifin, ifn-beta, ifin- beta lb, ifn-beta la, ifn-gamma (e.g., 1 and 2), ifh-lambda, ifn-delta, it-2, il-11, hbsag, ospa, murine mab directed against t-lymphocyte antigen, murine mab directed against tag-72, tumor-associated glycoprotein, fab fragments derived from chimeric mab directed against platelet surface receptor gpII(b)/III(a), murine mab fragment directed against tumor- associated antigen cal25, lysyl oxidase, LOX2, murine mab fragment directed against human carcinoembryonic antigen, cea, murine mab fragment directed against human cardiac myosin, murine mab fragment directed against tumor surface antigen psma, murine mab fragments (fab/fab2 mix) directed against hmw-maa, murine mab fragment (fab) directed against carcinoma-associated antigen, mab fragments (fab) directed against nca 90, a surface granulocyte nonspecific cross reacting antigen, chimeric mab directed against cd20 antigen found on surface of b lymphocytes, humanized mab directed against the alpha chain of the il2 receptor, chimeric mab directed against the alpha chain of the il2 receptor, chimeric mab directed against tnf-alpha, humanized mab directed against an epitope on the surface of respiratory synctial virus, humanized mab directed against her 2, human epidermal growth factor receptor 2, human mab directed against cytokeratin tumor-associated antigen anti- ctla4, chimeric mab directed against cd 20 surface antigen of b lymphocytes dornase-alpha dnase, beta glucocerebrosidase, tnf-alpha, il-2-diptheria toxin fusion protein, tnfr-lgg fragment fusion protein laronidase, dnaases, alefacept, darbepoetin alpha (colony stimulating factor), tositumomab, murine mab, alemtuzumab, rasburicase, agalsidase beta, teriparatide, parathyroid hormone derivatives, adalimumab (lggl), anakinra, biological modifier, nesiritide, human b-type natriuretic peptide (hbnp), colony stimulating factors, pegvisomant, human growth hormone receptor antagonist, recombinant activated protein c, omalizumab, immunoglobulin e (lge) blocker, lbritumomab tiuxetan, ACTH, glucagon, somatostatin, somatotropin, thymosin, parathyroid hormone, pigmentary hormones, somatomedin, erythropoietin, luteinizing hormone, chorionic gonadotropin, hypothalmic releasing factors, etanercept, antidiuretic hormones, prolactin and thyroid stimulating hormone.

[0139] Further examples of therapeutic agents include, but are not limited, to HERCEPTIN™ (Trastuzumab) (Genentech, CA) which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO™ (abciximab) (Centocor) which is an anti-glycoprotein Ilb/IIIa receptor on the platelets for the prevention of clot formation; ZENAPAX™ (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection; PANOREX™ which is a murine anti-17- IA cell surface antigen IgG2a antibody (Glaxo Wellcome/Centocor); BEC2 which is a murine anti-idiotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225 which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™ which is a humanized anti-aVp3 integrin antibody (Applied Molecular Evolution/Medlmmune); Campath; Campath 1H/LDP- 03 which is a humanized anti CD52 IgGl antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN™ which is a chimeric anti-CD20 IgGl antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE™ which is a humanized anti-CD22 IgG antibody (Immunomedics); ICM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primate anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN™ is a radiolabelled murine anti-CD20 antibody (IDEC/Schering AG); IDEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC- 152 is a primatized anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti- CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (CS) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-a antibody (CATIBASF);

CDP870 is a humanized anti-TNF-a Fab fragment (Celltech); IDEC-151 is a primatized anti- CD4 IgGl antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CDP571 is a humanized anti-TNF-a IgG4 antibody (Celltech); LDP-02 is a humanized anti-a4p7 antibody (LeukoSite/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN™ is a humanized anti-VLA-4 IgG antibody (Elan); CAT-152, a human anti-TGF-Pi antibody (Cambridge Ab Tech); Cetuximab (BMS) is a monoclonal anti-EGF receptor (EGFr) antibody; Bevacizuma (Genentech) is an anti-VEGF human monoclonal antibody; Infliximab (Centocore, JJ) is a chimeric (mouse and human) monoclonal antibody used to treat autoimmune disorders; Gemtuzumab ozogamicin (Wyeth) is a monoclonal antibody used for chemotherapy; and Ranibizumab (Genentech) is a chimeric (mouse and human) monoclonal antibody used to treat macular degeneration.

[0140] Other antibodies, such as single domain antibodies are also useful in the present disclosure. A single domain antibody (sdAb, called Nanobody by Ablynx) is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, the sdAb is able to bind selectively to a specific antigen. With a molecular weight of only 12- 15 kDa, single domain antibodies are much smaller than common antibodies (150-160 kDa). A single domain antibody is a peptide chain of about 110 amino acids in length, comprising one variable domain (VH) of a heavy chain antibody, or of a common IgG.

[0141] In some embodiments, the therapeutic agent can be a peptide, polypeptide, or protein. In some embodiments, the therapeutic agent can be beta-glucocerobrosidase, interferon alpha, interferon beta, agasidase alpha, agasidase beta, exenatide, nutropin/somatropin, factor VIII, fondaparinux, aldesleukinand, risperidone, forigerimod, NP fusion proteins, IL-12, a melanocyte stimulating hormone, or bapineuzumab.

[0142] In certain instances, the amount therapeutic agent is between 0.1% to about 50% w/w of the formulation within the reservoir such as approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and/or 40% w/w. In certain instances, the amount of therapeutic agent is between 1% to about 30% w/w of the formulation. In certain instances, the amount of therapeutic agent is between 1% to about 20% w/w of the formulation. In certain instances, the amount of therapeutic agent is between 1% to about 10% w/w of the formulation.

[0143] In certain instances, the amount of therapeutic agent in a reservoir is about 1.0 mg to 1000 mg or even higher such as up to 10 grams. In certain instances, about 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, and/or 1000 mg. In certain instances, the amount of therapeutic agent is about 1.0 mg to 100 mg; or about 1.0 mg to 40 mg; or about 1.0 mg to 30 mg; or about 1.0 mg to 20 mg; or about 1.0 mg to 10 mg; or about 0.1 to about 10 mg such as approximately 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and/or 10 mg.

[0144] In some embodiments of the device and formulation, the therapeutic agent is an incretin mimetic.

[0145] Incretin mimetics of the disclosure include, but are not limited to, exenatide, liraglutide, semaglutide, cotadutide, dulaglutide, albiglutide, lixisenatide, sitagliptin, saxagliptin, alogliptin, and linagliptin. In some embodiments of the disclosure more than one incretin mimetic may be present. In some embodiments of the disclosure the incretin mimetic is exenatide.

[0146] In certain instances, the amount incretin mimetic is between 0.1% to about 50% w/w of the formulation such as approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,

27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and/or 40% w/w.

In certain instances, the amount of incretin mimetic is between 1% to about 30% w/w of the formulation. In certain instances, the amount of incretin mimetic is between 1% to about 20% w/w of the formulation. In certain instances, the amount of incretin mimetic is between 1% to about 10% w/w of the formulation.

[0147] In certain instances, the amount of exenatide is between 0.1% to about 40% w/w of the formulation such as approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%,

28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and/or 40% w/w. In certain instances, the amount of exenatide is between 1% to about 30% w/w of the formulation. In certain instances, the amount of exenatide is between 1% to about 20% w/w of the formulation. In certain instances, the amount of exenatide is between 1% to about 10% w/w of the formulation. [0148] In certain instances, the therapeutic agent is an incretin memetic such as exenatide. In certain instances, the amount of incretin memetic such as exenatide in a reservoir is about 1.0 mg to 1000 mg or even higher such as up to 10 grams. In certain instances, about 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg,

300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg,

825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, and/or 1000 mg. In certain instances, the amount of incretin memetic such as exenatide is about 1.0 mg to 100 mg; or about 1.0 mg to 40 mg; or about 1.0 mg to 30 mg; or about 1.0 mg to 20 mg; or about 1.0 mg to 10 mg; or about 0.1 to about 10 mg such as approximately 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, and/or 10 mg.

[0149] In some embodiments of the disclosure, control of the pH of the medium containing the therapeutic agent is required to maintain stability of the therapeutic agent for a desired period of time.

[0150] The desired pH of therapeutic agents of the disclosure can be set by titration of a solution of the therapeutic agent to a desired pH. In many instances, commercially available forms of a therapeutic agent are already formulated at an optimum pH for stability.

[0151] If a pH adjustment is required, the pH adjustment can be made inside reservoirs of the disclosure, by co-formulating the therapeutic agent with the appropriate additional ingredients. In other instances, it may be desirable to adjust the pH of the therapeutic agent before disposing it in the reservoir.

[0152] For the purpose of preparing full embodiments of the disclosure it may be advantageous to use a dry powder of the therapeutic agent that has been treated to produce the correct pH when hydrated. Such a dried powder may be prepared in any suitable preparation method, including drying or lyophilization of the therapeutic agent in solution. For the preparation of peptide and protein formulations lyophilization is often preferred.

Stabilizing agents

[0153] Some embodiments of the disclosure include stabilizing agents in the form of polymers having a plurality of stabilizing groups. In some embodiments of the disclosure the stabilizing groups include pH sensitive groups, such as acidic groups, basic groups, or a combination thereof.

[0154] In some embodiments, a single type of pH sensitive group is present on the polymer, in some embodiments a variety of pH sensitive groups is present. In some embodiments, the pH sensitive groups are weakly acidic groups. In some embodiments, the weakly acidic groups are present on acrylic acid monomer residues or on methacrylic acid monomer residues, or on a combination of both.

[0155] In some embodiments of the disclosure, the polymeric stabilizing agent is present in essentially insoluble form.

[0156] In some embodiments the essentially insoluble form is obtained by incorporating cross-linkers into the polymer.

[0157] Some cross-linked polymeric stabilizing agents may be referred to as cross-linked polyacids. Well-known cross-linked polyacids include weakly acidic materials, such as cross- linked poly acrylic acid and strongly acidic materials, such as cross-linked polystyrene sulfonic acids, as well as weakly basic materials, such as cross-linked polyacrylate backbones with tertiary amine groups, and strongly basic materials, such as cross-linked polystyrene backbones with quaternary ammonium groups. These materials are often used as ion exchange resins (IER), and commercially available ion exchange resins are potentially suitable for use as stabilizing agents in the present disclosure.

[0158] In some embodiments of the disclosure, weakly acidic or weakly basic ion exchange resins (IER) are present. Weakly acidic or weakly basic ion exchange resins may be used advantageously by employing their capability to form buffer systems. Buffer systems are essentially mixtures of weak acids or weak bases with their respective conjugated bases or acids (salts). For instance, a weakly acidic buffer might contain a certain amount of an organic acid, like a carboxylic acid R-COOH, together with its conjugated base, like the sodium salt R-COO Na⁺. Likewise, a weakly basic buffer might contain an amine R-NH2, together with its conjugated acid, like the HC1 salt R-NH3⁺ Cl .

[0159] The pH of a buffer system is determined by the pKa of the acid and the ratio of the concentrations of the conjugated acid and conjugated base, as described in the Henderson- Hasselbalch equation:

where [A ] is the concentration of the conjugated base, and [HA⁺] is the concentration of the conjugated acid. As a rule of thumb, the useable buffer range for a buffer system is between pH levels 2 units below the pKa of the acid in the formulation and 2 units above it. Preferred buffer ranges are between pH levels 1 unit below the pKa of the acid and 1 unit above it.

[0160] For example, a useable buffer range for acetic acid, with a pKa of about 4.7 is between about 2.7 and about 6 7 One buffer range is between about pH 3.7 and about 5 7

[0161] The use of buffering crosslinked polymeric stabilizing agents may be particularly advantageous in combination with therapeutic agents that require a limited pH range to remain stable.

[0162] Examples of acidic groups of the disclosure include, but are not limited to, carboxylic acids, carbonic acids, sulfonic acids, sulfmic acids, sulfenic acids, phosphonic acids and phosphenic acids.

[0163] Examples of basic groups of the disclosure include, but are not limited to, primary, secondary, tertiary amines and quaternary ammonium groups.

[0164] In some embodiments the stabilizing groups are based on the so-called “Good buffers”, developed by NE Good and his research team. These zwitterionic buffers meet most of the requirements that biological buffers have to fulfil.

[0165] Polymers of the disclosure may be present in variety of architectures, such as linear, branched, hyperbranched, star, dendritic, cross-linked, comb, etc.

[0166] Polymeric backbones of the disclosure include, but are not limited to, addition and condensation polymers.

[0167] Polymeric backbones may be homopolymers or copolymers. Copolymers include, but are not limited to, random copolymers and block copolymers.

[0168] Addition polymeric backbones include, but are not limited to polyolefines, polyvinyls, polyacrylates, polymethacrylates and polystyrenes. [0169] Condensation polymers include, but are not limited to, polyesters, polyethers, polyamides, polyurethanes, polycarbonates, polyureas, polysulfides and polysiloxanes

[0170] Crosslinking agents for addition polymers are well known in the art and include, but are not limited to a wide variety of di-functional olefins, such as divinyl benzene, ethylene glycol dimethacrylate and methylene bisacrylamide. Further lists of crosslinking agents are available in commonly accessible literature, such as commercial websites like the Sigma Aldrich website https://www.sigmaaldrich.com/content/dam/sigma- aldrich/docs/Aldrich/Technical_Ads/al_ms_adlO_crslking_agents.pdf

[0171] Crosslinking of condensation polymers is often achieved by including trifunctional or tetrafunctional monomeric analogs of the difunctional monomeric building blocks used for the linear polymer backbone.

[0172] In some embodiments of the disclosure, non-stabilizing monomers may be present in polymer chains of the polymeric stabilizing agents. For instance, in some embodiments of the disclosure acrylic monomers other than acidic or basic monomers may be present, such as methyl methacrylate or hydroxy ethylmethacrylate monomers.

[0173] In some embodiments, a single type of polymer is present, in some embodiments, multiple types of polymers are present.

[0174] The use of crosslinked polymeric stabilizing agents may be particularly useful in combination with sustained release drug delivery devices that are designed to release their payload of therapeutic agent over an extended period of time in the body of a subject being treated with the therapeutic agent releasing device. Many therapeutic agents, including many peptides and proteins have molecular sizes that are significantly larger than those of commonly used buffering agents, which are often relatively low molecular weight agents, such as acetate, fumarate, citrate and other low molecular weight species. Because of their small size, such buffer systems often have higher mobility and transport rates than larger molecules such as peptides and proteins, and they tend to be released from sustained release therapeutic agent delivery devices faster than the agents they are designed to protect. Some embodiments of the disclosure include macromolecular polymeric buffering agents, like polyacids such as polyacrylic and polymethacrylic acids or combinations thereof.

[0175] Based on their molecular size, these macromolecules may not be able to cross a nanoporous membrane through the nanopores. In some instances, these soluble macromolecules may have a significant effect on the viscosity of the solution, which in some instances may not be desirable.

[0176] Some forms of these polyacids, like cross-linked forms, are essentially non-soluble and are substantially prevented or retarded from being released through the membranes.

Some cross-linked polymeric stabilizing agents used in the present disclosure are essentially supramolecular structures with a macroscopic size that blocks their release from the sustained release drug delivery device.

[0177] Crosslinked polymers of the disclosure can be used in an any desired physical form.

[0178] In some embodiments, cross-linked polymers may be present in particulate form, ranging from finely divided powders to coarse beads. The average particle size range may be from about 1 micrometer to up to any size that will fit inside a reservoir of the disclosure. In some instances, average particle size ranges of less than 1 micrometer may be present.

[0179] In some embodiments, the diameter of the particles may be from 1 micrometer to several millimeters, for instance up to 5 millimeters. In some instances, particles of more than 5 millimeter may be present. The particle size range and distribution may be determined based on the needs or preferences of a particular application. In some instances, a fine powder may be preferred and a particle size distribution roughly between 10 and 100 micrometers may be suitable. In other instances, beads may be preferred and a particle size roughly between 50 and 250 micrometers may be suitable.

[0180] For instance, particle sizes of embodiments of the disclosure may be from 1 to 10 micrometer, or from 1 to 100 micrometer, or from 1 to 1000 micrometer, or from 1 to 5000 micrometer, or from 10 to 100 micrometer or from 10 to 1000 micrometer or from 10 to 5000 micrometer, or from 100 to 1000 micrometer, or from 100 to 5000 micrometer, or from 1000 to 5000 micrometer, or from any size range in between 1 and 5000 micrometer.

[0181] Particle size ranges may be between 10 micrometer and 1 millimeter, and more preferred particle size ranges may be between 100 micrometer and 1 millimeter.

[0182] The particle shape may be regular, or semi-regular, like spherical or near- spherical particles, such as those obtained from a suspension polymerization process. In other instances, the particles may be irregular in shape, such as those resulting from a grinding process. In some instances, the polymers may be present in specific shapes, like cylinders, cubes, spheres, oblongs, and the like. In some instances, the shapes may be specifically tailored to the delivery device, for instance a polymer shaped into a cylinder to match the inner diameter of the reservoir of the device.

[0183] In some instances, mixtures of different physical shapes may be used.

[0184] In some embodiments, the polymers may be used in a porous configuration, in order to facilitate transport of molecules and ions throughout the bulk of the polymer.

[0185] In some embodiments, the polymers may be used in a dense or low-porosity configuration.

[0186] In some instances, the polymers, in hydrated form, may be relatively rigid.

Typically, such polymers will have a high degree of cross-linking, like 5% (w/w) or more, to limit swelling during uptake of water. In some instances, the polymers, in hydrated form, may be soft and gel-like substances. Typically, such configurations will have low degrees of crosslinking, like 1% (w/w) or less. The exact desired degree of cross-linking may depend on several factors, including the hydrophilicity of the constituent monomers of the polymer, and may be determined experimentally.

[0187] Some embodiments, of the disclosure include polymeric stabilizing agents based on weakly acidic ion exchange resins (IER). Weakly acidic polymeric stabilizing agents may be particularly useful for the stabilization of therapeutic peptides and proteins. Many therapeutic peptides and proteins include asparagine residues which are particularly vulnerable to deamidation reactions converting the asparagine to aspartic acid. Glutamine residues have similar vulnerabilities albeit at lower reaction rates.

[0188] Deamidation reactions can be catalyzed by high or low pH, and in particular at pH levels above about 6.0 to about 6.5, depending on the specific peptide and protein, these reactions may proceed at rates that are unacceptable for the dosage form in which the therapeutic peptide or protein is formulated.

[0189] As can be seen in Fig. 2, there may be a saddle point in the pH-driven degradation rates of peptides and proteins susceptible to deamidation at pH levels between about 5.0 and 6.0. One therapeutic agent of the disclosure, exenatide, has a rapidly decreasing stability half- life above pH 6.5.

[0190] Cross-linked poly-acrylic acid and poly-methacrylic acid have pKa levels in the range of 5.5 to 6.0, which puts their useable buffer range in a pH range between about 3.5 and 8.0, and their typically preferred pH buffer range in a pH range between about 4.5 and 7.0, making them highly suitable stabilizing agents for many peptides and proteins of this disclosure.

[0191] In the specific context of this disclosure, a buffer range of embodiments of the disclosure may be as low as 2 units below the pKa of the buffering agent. Since upon implantation in the body of the subject the physiological pH of the medium surrounding the implant will be close to about pH 7.4, proton exchange between a formulation in the reservoir of an implanted device and this physiological environment will tend to drive the internal pH of the formulation up. Providing a formulation at the lower end of the pH range of an incorporated buffer may provide additional buffer capacity, if so desired.

[0192] Additionally, acrylic acid and methacrylic acid are relatively small monomers, and therefore polymers and copolymers of these monomers carry a high density of acidic groups on a weight by weight basis, making them highly effective as stabilizing agents. In some embodiments, the cross-linked polymeric stabilizing agents are cross-linked poly-acrylic acid or poly-methacrylic acid, or mixtures thereof or copolymers of acrylic and methacrylic acid.

[0193] Crosslinked poly-acrylic acid and poly-methacrylic acid are used commercially as ion exchange resins. In some embodiments of the disclosure ion exchange resins are used as stabilizing agents. Potentially suitable ion exchange resins are produced by Mitsubishi Chemical Corporation under the name “Diaion” and by Purolite Corporation under the name “Purolite”. In some instances, Diaion WK40L and Purolite 104plus and Purolite Cl 15 may be suitable stabilizing agents for the stabilization of peptide and protein formulations. Others include Diaion WKIO, Diaion WK11, Diaion WK100, and Diaion WTO IS.

[0194] In certain instances, the amount of polymeric stabilizing agent is about 0.1% to about 25% w/w or up to 50% w/w of the formulation containing the therapeutic agent. In certain instances, the amount of polymeric stabilizing agent is about 0.1% to about 15% w/w, or up to 20% w/w; or about 1% to about 12% w/w; or about 2% to about 10% w/w; or about 5% to about 15% w/w, or about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, and/or 15% w/w.

[0195] In certain instances, the amount of polymeric stabilizing agent in a reservoir is about 1.0 mg to 1000 mg, such as about 1 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, and/or 1000 mg. In certain instances, the amount of polymeric stabilizing agent is about 1.0 mg to 100 mg; or about 1.0 mg to 50 mg; or about 1.0 mg to 40 mg; or about 1.0 mg to 30 mg; or about 1.0 mg to 20 mg; or about 1.0 mg to 10 mg; or about 0.1 to about 15 mg such as approximately 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg,

5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg. In certain instances, 1-2 grams can be used.

[0196] In certain instances, the polymeric stabilizing agent is an insoluble polymer such as a solid that remains in the reservoir of the implantable device during operation. In certain instances, the polymeric stabilizing agent is an insoluble polymer that is not released during operation. In certain instances, the polymeric stabilizing agent is an insoluble polymer and forms a heterogeneous solid mixture with the therapeutic agent and the remaining formulation. In certain instances, the polymeric stabilizing agent does not form a hydrogel, xerogel or matrix for sustained release of the therapeutic agent. In certain instances, the polymeric stabilizing agent is a solid that remains in the reservoir of the implantable device.

[0197] In some embodiments of the disclosure, control of the pH of the stabilizing agent is required to maintain stability of the therapeutic agent for a desired period of time. The desired pH of polymeric stabilizing agents of the disclosure can be set by titration of a quantity of the stabilizing agents, in the case of a cross-linked polymeric acid by titration with a base, such as NaOH. Titration of polymeric acids is well-known in the art, and titration of stabilizing agents of the disclosure can be achieved by stirring a suspension of particulates of a cross- linked polymeric acid with an appropriate strength of a base like NaOH until equilibration at a desired pH level has been achieved. Background for experimental procedures with stabilizing agents in the form of ion exchange resins can be found in readily available literature, such as text books. E.g. Ion Exchange, F. Hellfferich, Dover Publications Inc. New York, 1995, P. 81 - 94). pH adjustments of Purolite PPC104 plus are shown in Table 1 in Example 3.

[0198] The pH adjustment can be made inside reservoirs of the disclosure by co formulating the stabilizing agents with the appropriate additional ingredients. In other instances, it may be desirable to adjust the pH of the stabilizing agent before disposing it in the reservoir.

[0199] In some embodiments, it may be preferred to use a dry powder or dry beads of a polymeric stabilizing agent that has been treated in advance to produce the correct pH when hydrated. Such dry powder or beads may be prepared by incubating a known amount of the powder or beads with an appropriate amount of base, and then filtering and drying the powder or beads.

[0200] Some embodiments include a step of partially neutralizing pH sensitive groups of the stabilizing agent to an extent that upon hydration of the cross-linked polymeric stabilizing agent and in the presence of the therapeutic agent in the reservoir with an aqueous solvent a formulation develops with a predetermined pH. In some embodiments, the pH is between about 3.5 and about 7, such as 3.5, 4.0, 4.5, 5.0, 6.0, 6.5, 7.0 or 7.5. In some embodiments, the aqueous solvent is interstitial fluid of a subject into which the device has been implanted.

[0201] All of the above examples of polymeric stabilizing agents and their compositional components may be used in embodiments of the disclosure, and those with ordinary skills in the art of polymer chemistry will be able to identify and select a suitable crosslinked polymeric stabilizing agent for the intended purpose of an embodiment of the disclosure.

Formulations

[0202] Some embodiments of the disclosure include formulations of therapeutic agents.

[0203] In one embodiment, the disclosure provides a therapeutic formulation, the formulation comprising: therapeutic agent; and a polymeric stabilizing agent comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups, which is a member selected from the group consisting of a cross-linked poly-acrylic acid, a cross-linked poly-methacrylic acid, or mixtures thereof or copolymers of acrylic and methacrylic acid.

[0204] In some instances, the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between 3.5 and 7.5. [0205] In some instances, the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between 3.5 and 7.5 such as about 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, and/or 7.5.

[0206] Some embodiments of the disclosure include formulations of therapeutic agents with polymeric stabilizing agents.

[0207] Any of the therapeutic agents in this disclosure may be combined with any of the stabilizing agents in this disclosure, as appropriate, and as can be determined by one of ordinary skills in the art of therapeutic agent stabilization.

[0208] In some embodiments of the disclosure, formulations of the therapeutic agent may be combined with devices of the disclosure, in which the devices include a capsule configured for implantation, a reservoir, and a nanoporous membrane with a plurality of pores. The membrane is attached to the capsule in fluid contact with the reservoir and provides a pathway for the therapeutic agent out of the reservoir.

[0209] Some formulations of the disclosure include a peptide or protein and a polyacid at a pH between about 5.0 and about 6.0. In some formulations, the peptide is an incretin mimetic. In some formulations the incretin mimetic is exenatide. In some embodiments, the polyacid is polyacrylic acid or polymethacrylic acid. In some embodiments, the polymeric stabilizing agent is Purolite 104+ or Purolite Cl 15, or Purlite C104Plus or an analog thereof.

[0210] Some formulations of the disclosure include a water soluble salt. Various salts include, but are not limited to, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, and sodium citrate. In some embodiments, the water soluble salt may be at a concentration of about 1 mM to 1M; or 10 mM to 500 mM; or about 70 mM to about 200 mM; or about 100 mM to about 170 mM; or about 140 mM to about 160 mM. In some instances, the water soluble salt may be sodium chloride at 154 mM. In some instances, a salt concentration is below 1 mM or above 1M may be present.

[0211] In certain instances, the reservoir contains about 5 to about 20 milligrams of a cross- linked form of methacrylic acid as the stabilizing agent and about 20 to about 60 microliter of an aqueous solution of between 10% -50% (w/w) exenatide as the therapeutic agent, at a pH between 4.0 and 7.0 and NaCl. [0212] In certain instances, the reservoir contains about 5 to about 20 milligrams of a cross- linked form of poly-acrylic acid as the stabilizing agent and about 20 to about 60 microliter of an aqueous solution of between 10%-50% (w/w) exenatide as the therapeutic agent, at a pH between 4.0 and 7.0 and NaCl.

[0213] In certain instances, the reservoir contains about 5 to about 20 milligrams of a cross- linked form of poly-acrylic acid and cross-linked poly-methacrylic acid as the stabilizing agent and about 20 to about 60 microliter of an aqueous solution of between 10% -50% (w/w) exenatide as the therapeutic agent, at a pH between 4.0 and 7.0 and NaCl.

[0214] In certain instances, the reservoir contains about 5 to about 20 milligrams of a cross- linked form of copolymers of acrylic acid and methacrylic acid as the stabilizing agent and about 20 to about 60 microliter of an aqueous solution of between 10% -50% (w/w) exenatide as the therapeutic agent, at a pH between 4.0 and 7.0 and NaCl.

[0215] Formulations of the disclosure may include the therapeutic agent in any desirable form, including solid forms, as well as fluid forms, such as solutions, suspensions, emulsions, colloids and dispersions. In some embodiments of the disclosure, therapeutic agents can be present in complexated form with polymeric stabilizers, for instance by complexation of a positively charged therapeutic agent with a negatively charged stabilizing agent.

[0216] Formulations of the disclosure may additionally include pharmaceutically acceptable inactive ingredients, such as buffering agents, solubility modifiers, surfactants, soluble high and low molecular weight stabilizers, anti-oxidants, antimicrobials and the like.

A list of potentially suitable inactive ingredients used in currently marketed pharmaceutical products in the US can be found on the website of the United States Food and Drug Administration (FDA).

[0217] Formulations of the disclosure may include any of the therapeutic agents in disclosure, and, if desired, any of the polymeric stabilizing agents in this disclosure.

[0218] Some embodiments of the disclosure provide methods for the preparation of formulations of one or more therapeutic agents. In some embodiments, the formulations include a polymeric stabilizing agent. Some embodiments of the disclosure include methods for the preparation of suitably pH adjusted formulations containing polymeric stabilizing agents and therapeutic agents. [0219] Polymeric stabilizing agents and therapeutic agents of the disclosure may be combined in any desired method into formulations of the disclosure. Resulting formulations may have any desired physical state, including dry powder formulations and suspensions of the polymeric stabilizing agent in a fluid formulation of the therapeutic agent. Suitable fluid formulations include solutions, suspensions, emulsion, colloids and dispersions.

[0220] The therapeutic agent and the polymeric stabilizing agent may be combined as dry powders, after which a liquid vehicle is added, or one or both components may be taken up in a liquid vehicle before combining them together.

[0221] For formulations intended for parenteral use, it is often desired to provide the formulation in a state resembling physiological conditions and in some embodiments adjustments of the sodium chloride concentration to physiological levels (154 mM) may be preferred.

Stabilization methods

[0222] Some methods of the disclosure provide stabilization of a therapeutic agent by combining the therapeutic agent with a stabilizing agent, in which the stabilizing agent is a polymeric agent having stabilizing groups. In some embodiments, the stabilizing agent is an insoluble polymeric agent. In some embodiments, the insoluble polymeric agent is a cross- linked polymeric agent. In some embodiments, the stabilizing groups are pH sensitive groups. In some embodiments, the pH sensitive groups are weakly acidic groups. In some embodiments, the weakly acidic groups are present on acrylic acid monomer residues or on methacrylic acid monomer residues, or on a combination of both.

[0223] In some embodiments of the disclosure the combined therapeutic agent and stabilizing agent are disposed within a reservoir of a capsule of a device for sustained release of the therapeutic agent, wherein the capsule is configured for implantation. The capsule has at least one nanoporous membrane, such as the titania nanotube membranes described in US Patent 9814867, providing a diffusion path for the therapeutic agent out of the reservoir. The dimensions of the stabilizing agent are larger than the pore size of the membrane, thereby substantially preventing release of the stabilizing agent from the reservoir.

[0224] In some embodiments of the disclosure the stabilizing agent is used as a buffer system, maintaining the pH of a fluid form of the therapeutic agent in the reservoir within a desired range. In some preferred embodiments, the pH range is between about 3.5 and about 7 5 In some embodiments, the pH range is between about 5.0 and about 6 0

[0225] Some methods of the disclosure include a partial pre-neutralization of the pH sensitive groups on the stabilizing agent and then drying the partially neutralized stabilizing agents, such that upon hydration of the stabilizing agent a fluid develops with a pH within a desired range. In some methods of the disclosure the hydrating fluid includes the therapeutic agent. In some methods of the disclosure the hydration is performed inside the reservoir of the capsule. In some methods of the disclosure the hydration is performed outside the capsule and filling of the capsule is performed with the fluid combining the therapeutic agent and the stabilizing agent.

[0226] Methods of the disclosure may be particularly useful for the stabilization of peptides and proteins. Many peptides and proteins have optimal stability in a pH range between about 3.5 and about 7 5 Some peptides and proteins have optimal stability in a pH range between about 5.0 and about 6 0

[0227] In some embodiments of the disclosure, the therapeutic agent is a peptide or protein. In some embodiments, the therapeutic agent is an incretin mimetic. In some embodiments, the incretin mimetic is exenatide.

[0228] Upon implantation of the device in the body of a subject mass transport of the therapeutic agent together with low molecular weight ionized species out of the reservoir occurs, resulting in a net transport of protons out of the reservoir. The resulting increase in pH is counteracted by increased levels of ionization of the stabilizing groups on the polymer, resulting in a reduction in the rate of pH increase.

Treatment methods

[0229] Some embodiments of the disclosure provide methods of treating a disease or condition in subjects using devices and formulations of the disclosure. Subjects include human and veterinary subjects. The methods include providing a device of the disclosure including a therapeutic agent and a stabilizing agent and implanting the device in the subject, thereby treating the disease or condition.

[0230] Any suitable therapeutic agent and polymer can be used in the method of the present disclosure, as described above. In some embodiments, the therapeutic agent can be exenatide. [0231] Any suitable type of diabetes can be treated using the method of the present disclosure. The term diabetes encompasses several different hyperglycemic indications.

These states include Type 1 (insulin-dependent diabetes mellitus or IDDM) and Type 2 (non insulin dependent diabetes mellitus or NIDDM) diabetes. The hyperglycemia present in individuals with Type 1 diabetes is associated with deficient, reduced, or nonexistent levels of insulin which are insufficient to maintain blood glucose levels within the physiological range. Methods of treatment of Type 1 diabetes involves administration of replacement doses of insulin, generally by a parenteral route.

[0232] The hyperglycemia present in individuals with Type 2 diabetes is initially associated with normal or elevated levels of insulin; however, these individuals are unable to maintain metabolic homeostasis due to a state of insulin resistance in peripheral tissues and liver and, as the disease advances, due to a progressive deterioration of the pancreatic b-cells which are responsible for the secretion of insulin. In some embodiments, the diabetes can be type 2 diabetes. In some embodiments, the diabetes can be type 1 diabetes. In some embodiments, the disease can be type 2 diabetes. In some embodiments, the disease can be type 1 diabetes.

[0233] In certain aspects, suitable daily dosage ranges for the therapeutics of the present disclosure include from about 0.1 pg to about 10,000 pg, or about 1 pg to about 1000 pg, or about 10 pg to about 750 pg, or about 25 pg to about 500 pg, or about 50 pg to about 250 pg. Suitable daily dosages for the compound of the present disclosure include about 1 pg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 pg.

[0234] In certain instances, the disclosure provides a method of treating diabetes (e.g., to a method lowering blood glucose levels, or to a method of improving glycemic control) by administering a GLP-1 analogue such as, for example, exenatide using an implantable device, the GLP-1 analogue is administered in an effective daily dose of about 1 pg to about 100 pg, or 10 pg to about 100 pg, or about 10 pg to about 50 pg (e.g., the implantable device provides release of the GLP-1 analogue at a range of about 10 pg to about 100 pg GLP-1 analogue each day, or about 10 pg to about 50 pg per day).

[0235] The doses suitable for the treatment of diabetes can provide any suitable mean steady-state plasma concentration of the therapeutic agent in the 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 for exenatide can be from 170 pg/ml to 600 pg/ml. In some embodiments, the mean steady state plasma concentration for exenatide can be from 170 pg/ml to 350 pg/ml. In some embodiments, the mean steady state plasma concentration for exenatide can be from 170 pg/ml to 290 pg/ml.

[0236] In certain embodiments, the exenatide concentration is sufficient to achieve an average or minimum circulating blood plasma level of exenatide of at least about 50 pg/ml for a period of at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 3 months, or at least about 6 months or even more such as 1 year.

[0237] The implantation can be performed by any means known to one of skill in the art, for instance through subcutaneous insertion of the device using a hollow needle or trocar.

Example 1

[0238] Therapeutic agent: Exenatide acetate (Bachem Holding AG, Switzerland).

[0239] Stabilizing agent: Diaion WK40L (Mitsubishi Chemical Corporation, Japan).

[0240] Membranes were developed based on the process as described in US Patent 9814867.

[0241] 50 microliter polycarbonate capsules and titanium screw caps to attach the membrane to the capsule were prepared by commonly available machining methods.

[0242] Silicone septa were prepared by in-place casting of the polymer.

[0243] Commercially available silicone O-rings were used for sealing the device at the appropriate connections.

[0244] In group 1, 15 mg of exenatide acetate was weighed out into reservoirs of the devices.

[0245] In group 2, 10 mg of exenatide and 10 mg of Diaion wk40L were weighed out into reservoirs of the devices.

[0246] The devices were sealed with the membranes in their titanium cap, and subsequently evacuated and packaged under vacuum.

[0247] The evacuated devices were sterilized by e-beam irradiation at 25 kGray at a temperature between - IOC and -20C. [0248] The devices were unpacked in a sterile biohood, and a vacuum was applied to the reservoir by evacuation through the membrane.

[0249] The devices were hydrated by inserting a hypodermic needle through the septum and injecting a sterile hydration buffer with 0.2M citrate buffer at pH 5.3 and 0.27% Polysorbate 20 (v/v) To aid in the hydration, vacuum was applied to the membrane side of the device during the hydration.

[0250] Devices were implanted dorsally in Sprague Dawley rats and retrieved at regular time intervals. The remaining inside solutions were collected for measurement of the pH and for determination of the exenatide purity by reverse phase HPLC.

[0251] As can be seen in Fig. 3, the pH remained significantly lower in the devices with the stabilizing agent, and the purity remained significantly higher.

Example 2

[0252] Therapeutic agent: Exenatide acetate (Bachem Holding AG, Switzerland). (Exenatide Acetate, CAS Number: 914454-01-6).

[0253] Stabilizing agent: Diaion WK40L (Mitsubishi Chemical Corporation, Japan).

[0254] Membranes were developed based on the process as described in CIS Patent No. 9814867.

[0255] 50 microliter polycarbonate capsules and titanium screw caps to attach the membrane to the capsule were prepared by commonly available machining methods.

[0256] Silicone septa were prepared by in-place casting of the polymer.

[0257] Commercially available silicone O-rings were used for sealing the device at the appropriate connections.

[0258] In group 1, 10 mg of exenatide and 10 mg of Diaion wk40L were weighed out into reservoirs of the devices.

[0259] In group 2, 15mg of exenatide acetate was weighed out into reservoirs of the devices.

[0260] The devices were sealed with the membranes in their titanium cap. [0261] The devices were hydrated by inserting a hypodermic needle through the septum and injecting sterile water for injection with 0.0011% Polysorbate 20 (v/v) into the reservoirs. To aid in the hydration, vacuum was applied to the membrane side of the device during the hydration.

[0262] The devices were submerged in 4 ml of sterile bis-tris buffer at pH 7.4 and 37C to establish the effectiveness of the ion exchange resin to maintain pH and exenatide purity under in vitro conditions mimicking the in-vivo implantation conditions. At regular intervals devices were removed from the incubation buffer. The remaining inside solutions were collected for measurement of the pH and for determination of the exenatide purity by reverse phase HPLC.

[0263] As can be seen in Fig. 4A and 4B, the presence of the ion exchange resin maintained a lower pH over at least 3 months, and significantly better purity of the exenatide.

Example 3

[0264] Table 1 below shows pH adjustment of an ion exchange resin (Purolite PPCKMplus) with NaOH and NaCl.

[0265] Purolite PPC104plus is a porous cross-linked polyacrylic acid in a spherical bead. The particle size ranges from 300-1600 pm.

[0266] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were 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 of ordinary skill in the art in light of the teachings of this disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A therapeutic formulation, the formulation comprising: a therapeutic agent; and a polymeric stabilizing agent comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups, which is a member selected from the group consisting of a cross-linked poly-acrylic acid, a cross-linked poly-methacrylic acid, or mixtures thereof or copolymers of acrylic and methacrylic acid.

2. The formulation of claim 1, wherein the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between 3.5 and 7 5

3. The formulation of claim 1 or 2, wherein the insoluble polymer is a cross-linked polymer.

4. The formulation of any one of claims 1-3, wherein the therapeutic agent is a peptide or protein.

5. The formulation of any one of claims 1-4, wherein the therapeutic agent is an incretin mimetic.

6. The formulation of any one of claims 1-5, wherein the therapeutic agent is exenatide.

7. The formulation of any one of claims 1-6, wherein the therapeutic agent and the stabilizing agent are present in a substantially dry solid form.

8. The formulation of any one of claims 1-7, wherein the formulation further comprises a solvent for the therapeutic agent.

9. The formulation of any one of claims 1-8, wherein the stabilizing agent includes one or both of acrylic acid residues and methacrylic residues.

10. The formulation of any one of claims 2-9, wherein the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH, a fluid develops with a pH between about 4.0 and about 7.0.

11. The formulation of claim 10, wherein a fluid develops with a pH between about 5.0 and about 6.0.

12. The formulation of claim 8, wherein the solvent has a pH between about 3.5 and about 7.0.

13. The formulation of claim 8, wherein the solvent has a pH between about 5.0 and about 6.0.

14. The formulation of any one of claims 1-13, wherein the stabilizing groups are neutralized between about 10% and about 75%.

15. The formulation of any one of claims 1-14, wherein the stabilizing groups are neutralized between about 30% and about 65%.

16. 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; the therapeutic agent disposed within the reservoir; and a polymeric stabilizing agent, disposed within the reservoir and comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent out of the reservoir; and wherein the polymeric stabilizing agent has dimensions larger than the pore size of the nanoporous membrane substantially preventing release of the polymeric stabilizing agent from the reservoir.

17. The device of claim 16, wherein the insoluble polymer is a cross- linked polymer.

18. The device of any one of claims 16-17, wherein the therapeutic agent is a peptide or protein.

19. The device of claim 18, wherein the therapeutic agent is an incretin mimetic.

20. The device of claim 19, wherein the therapeutic agent is exenatide.

21. The device of any one of claims 16-20, wherein the therapeutic agent and the stabilizing agent are present in a substantially dry solid form.

22. The device of any one of claims 16-20, the device further comprising a solvent for the therapeutic agent.

23. The device of any one of claims 16-22, wherein the stabilizing agent includes one or both of acrylic acid residues and methacrylic residues.

24. The device of any one of claims 16-23, wherein the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between 3.5 and 7.5.

25. The device of claim 24, wherein a fluid develops with a pH between

5.0 and 6.0.

26. The device of any one of claims 16-25, wherein the stabilizing groups are neutralized between 10% and 75%.

27. The device of any one of claims 16-26, wherein the stabilizing groups are neutralized between 30% and 65%.

28. The device of claim 22 or 23, wherein the solvent has a pH between

3.5 and 7.5.

29. The device of claim 28, wherein the solvent has a pH between 5.0 and

6 0

30. A method for stabilizing a therapeutic agent, the method comprising: providing 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; disposing the therapeutic agent within the reservoir; and disposing a polymeric stabilizing agent within the reservoir, the polymeric stabilizing agent comprising an insoluble polymer having a plurality of pH sensitive stabilizing groups; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent out of the reservoir; and wherein the polymeric stabilizing agent has dimensions larger than the pore size of the nanoporous membrane substantially preventing release of the polymeric stabilizing agent from the reservoir.

31. The method of claim 30, wherein the insoluble polymer is a cross- linked polymer.

32. The method of any one of claims 30-31, wherein the therapeutic agent is a peptide or protein.

33. The method of any one of claims 30-32, wherein the therapeutic agent is an incretin mimetic.

34. The method of any one of claims 30-33, wherein the therapeutic agent is exenatide.

35. The method of any one of claims 30-34, wherein the therapeutic agent and the stabilizing agent are present in a substantially dry solid form.

36. The method of any of claim 30-35, the device further comprising a solvent for the therapeutic agent.

37. The method of any one of claims 30-36, wherein the stabilizing agent includes one or both of acrylic acid residues and methacrylic residues.

38. The method of any one of claims 30-37, wherein the pH sensitive stabilizing groups are neutralized to an extent that upon hydration of the therapeutic agent and the stabilizing agent with an aqueous medium having a neutral pH a fluid develops with a pH between about 3.5 and about 7.5.

39. The method of claim 38, wherein a fluid develops with a pH between 5.0 and 6.0.

40. The method of any one of claims 30-38, wherein the stabilizing groups are neutralized between 10% and 75%.

41. The method of claim 40, wherein the stabilizing groups are neutralized b etween 30% and 65 % .

42. The method of claim 36 or 37, wherein the solvent has a pH between about 3.5 and about 7.5.

43. The method of claim 42, wherein the solvent has a pH between about 5.0 and about 6.0.

44. A method of treating a disease in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-15 comprising a therapeutic agent and a polymer functionalized with a plurality of stabilizing, thereby treating the disease.