Devices and methods for improving bioavailability of therapeutic agents

Abstract

The present disclosure provides a device for sustained release of a therapeutic agent, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a therapeutic agent disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent out of the reservoir; and the device further comprises an anti-inflammatory drug.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 348,754, filed on June 3, 2022, the contents of which are hereby incorporated by reference in their entirety for all purposes. Background Art

[0003] Many subjects, whether human or animal, require long-term treatment with a therapeutic agent. To improve compliance, many subjects would benefit from the compliance provided by an implantable device that releases the desired therapeutic agent at a desired rate for an extended period of time.

[0004] Despite many years of research, there remains a need to develop such devices, and in particular, a need to develop methods of controlling the rate at which therapeutic agents are released from such devices after implantation in a subject to be treated. The present disclosure satisfies this need and also provides other advantages. Summary of the invention

[0005] In one embodiment, the present disclosure provides a device for sustained release of a therapeutic agent, the device comprising:

[0006] a capsule configured for implantation and having a reservoir;

[0007] a nanoporous membrane having a plurality of pores;

[0008] a therapeutic agent within the reservoir; and

[0009] wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; and the device further comprises an anti-inflammatory drug.

[0010] A device as described above, wherein the anti-inflammatory drug is contained within a reservoir of the device.

[0011] The device as described above, wherein the anti-inflammatory drug is disposed on the outer surface of the capsule.

[0012] A device as described above, wherein the anti-inflammatory drug is a steroid and / or an NSAID.

[0013] A device as described above, wherein the anti-inflammatory agent is a biocompatible polymer.

[0014] A device as described above, wherein the anti-inflammatory drug is located at at least two different positions relative to the capsule.

[0015] In certain aspects, the polymer stabilizer is disposed within the reservoir and comprises an insoluble polymer having a plurality of pH sensitive stabilizing groups. Optionally, the size of the polymer stabilizer is larger than the pore size of the nanoporous membrane, thereby substantially preventing release of the polymer stabilizer from the reservoir.

[0016] In another embodiment, the present disclosure provides a method for improving the plasma level of a therapeutic agent released from a device for sustained release of the therapeutic agent, comprising:

[0017] The device is provided, comprising:

[0018] a capsule configured for implantation and having a reservoir;

[0019] a nanoporous membrane having a plurality of pores;

[0020] a therapeutic agent disposed within the reservoir;

[0021] wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; and the device further comprises an anti-inflammatory drug, wherein the anti-inflammatory drug improves plasma levels of the therapeutic agent after implantation of the device in a subject.

[0022] A method as described above, wherein the anti-inflammatory drug is contained within a reservoir of the device.

[0023] The method as described above, wherein the anti-inflammatory drug is disposed on the outer surface of the capsule.

[0024] A method as described above, wherein the anti-inflammatory drug is a steroid and / or an NSAID.

[0025] The method as described above, wherein the anti-inflammatory drug is a biocompatible polymer.

[0026] In certain aspects, the polymer stabilizer is disposed within the reservoir and comprises an insoluble polymer having a plurality of pH sensitive stabilizing groups. Optionally, the size of the polymer stabilizer is larger than the pore size of the nanoporous membrane, thereby substantially preventing release of the polymer stabilizer from the reservoir.

[0027] In yet another embodiment, the present disclosure provides a method of treating a subject with a therapeutic agent and an anti-inflammatory drug, comprising:

[0028] The device is provided, comprising:

[0029] a capsule configured for implantation and having a reservoir;

[0030] a nanoporous membrane having a plurality of pores;

[0031] a therapeutic agent disposed within the reservoir;

[0032] wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir;

[0033] The device further comprises an anti-inflammatory drug; and

[0034] The device is implanted in a subject.

[0035] A method as described above, wherein the anti-inflammatory drug is contained within a reservoir of the device.

[0036] The method as described above, wherein the anti-inflammatory drug is disposed on the outer surface of the capsule.

[0037] The method as described above, wherein the anti-inflammatory drug is a steroid and / or an NSAID.

[0038] The method as described above, wherein the anti-inflammatory drug is a biocompatible polymer.

[0039] In certain aspects, the polymer stabilizer is disposed within the reservoir and comprises an insoluble polymer having a plurality of pH sensitive stabilizing groups. Optionally, the size of the polymer stabilizer is larger than the pore size of the nanoporous membrane, thereby substantially preventing release of the polymer stabilizer from the reservoir.

[0040] In another embodiment, the present disclosure provides a method of improving the plasma level of a therapeutic agent released from a device for sustained release of the therapeutic agent, comprising:

[0041] The device is provided, comprising:

[0042] a capsule configured for implantation and having a reservoir;

[0043] a nanoporous membrane having a plurality of pores;

[0044] A therapeutic agent is disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; and

[0045] Co-administer anti-inflammatory drugs.

[0046] A method as described above, wherein the anti-inflammatory drug is co-administered topically.

[0047] A method as described above, wherein the anti-inflammatory drug is co-administered systemically.

[0048] A method as described above, wherein the anti-inflammatory drug is a steroid and / or an NSAID.

[0049] In certain aspects, the polymer stabilizer is disposed within the reservoir and comprises an insoluble polymer having a plurality of pH sensitive stabilizing groups. Optionally, the size of the polymer stabilizer is larger than the pore size of the nanoporous membrane, thereby substantially preventing release of the polymer stabilizer from the reservoir.

[0050] In yet another embodiment, the present disclosure provides a method of treating a subject with a therapeutic agent and an anti-inflammatory drug, comprising:

[0051] The device is provided, comprising:

[0052] a capsule configured for implantation and having a reservoir;

[0053] a nanoporous membrane having a plurality of pores;

[0054] a therapeutic agent disposed within the reservoir;

[0055] wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir;

[0056] implanting the device into a subject, and

[0057] Co-administer anti-inflammatory drugs.

[0058] A method as described above, wherein the anti-inflammatory drug is co-administered topically.

[0059] A method as described above, wherein the anti-inflammatory drug is co-administered systemically.

[0060] A method as described above, wherein the anti-inflammatory drug is a steroid and / or an NSAID.

[0061] In certain aspects, the polymer stabilizer is disposed within the reservoir and comprises an insoluble polymer having a plurality of pH sensitive stabilizing groups. Optionally, the size of the polymer stabilizer is larger than the pore size of the nanoporous membrane, thereby substantially preventing release of the polymer stabilizer from the reservoir.

[0062] In yet another embodiment, the present disclosure provides a method for improving the plasma level of a therapeutic agent released from a device for sustained release of the therapeutic agent, comprising:

[0063] The device is provided, comprising:

[0064] a capsule configured for implantation and having a reservoir;

[0065] a nanoporous membrane having a plurality of pores;

[0066] a therapeutic agent disposed within the reservoir;

[0067] wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir;

[0068] The device further comprises an anti-inflammatory drug, and wherein the anti-inflammatory drug improves the AUC of the therapeutic agent after implanting the device in the subject.

[0069] In certain aspects, the AUC is increased by at least 10%, or at least 25%, or at least 50%, or at least 75%, or the AUC is at least doubled.

[0070] A method as described above, wherein the anti-inflammatory drug is a steroid and / or an NSAID.

[0071] In certain aspects, the polymer stabilizer is disposed within the reservoir and comprises an insoluble polymer having a plurality of pH sensitive stabilizing groups. Optionally, the size of the polymer stabilizer is larger than the pore size of the nanoporous membrane, thereby substantially preventing release of the polymer stabilizer from the reservoir.

[0072] These and other aspects, objects and embodiments will become more apparent when read with reference to the ensuing detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] Figure 1 An apparatus of the present disclosure is shown.

[0074] Figure 2 One embodiment of the present disclosure is shown.

[0075] Figure 3 One embodiment of the present disclosure is shown, showing the release of dexamethasone.

[0076] Figure 4 One embodiment of the present disclosure is shown, showing the effect of dexamethasone in a rat model.

[0077] Figure 5 An alternative embodiment of the device is shown, showing the effect of dexamethasone in a cat model. DETAILED DESCRIPTION

[0078] The present disclosure relates to the field of long-term treatment of subjects with implantable devices that provide sustained delivery of a therapeutic agent at a controlled rate.

[0079] Embodiments of the present disclosure include devices, formulations, and methods of controlling the rate of release of therapeutic agents from such devices.

[0080] Additionally, embodiments of the present disclosure include methods of treating a subject with the devices and formulations of the present disclosure.

[0081] Implantable devices with nanoporous membranes for releasing therapeutic agents have been previously described, for example, in U.S. Pat. Nos. 9,814,867 and 9,770,412 and U.S. Patent Publication Nos. US2022 / 0008345, US2021 / 0246271, and US2017 / 0136224, each of which is incorporated herein by reference.

[0082] definition

[0083] "Polypeptide" refers to a molecule having a backbone of 2 or more amino acid residues. Some polypeptides may have additional associated groups, such as metal ions in metalloproteins, small organic molecules in hemoproteins, or carbohydrate groups such as in glycoproteins.

[0084] "Peptide" and "protein" refer to a subset of polypeptides. In the present disclosure, the definitions of peptides and proteins follow the conventions of the U.S. Food and Drug Administration (FDA), which defines peptides as polypeptides having no more than 40 amino acid residues and proteins as polypeptides having more than 40 amino acid residues.

[0085] Incretin mimetics refer to agents whose actions are similar to those of incretin hormones, such as glucagon-like peptide-1 (GLP-1). They bind to the GLP-1 receptor and stimulate glucose-dependent insulin release, thus exerting an anti-hyperglycemic effect.

[0086] Exenatide (natural, recombinant and synthetic, also known as exendin-4) refers to the amino acid sequence His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Ala Val ArgLeu Phe Ile Glu Trp Leu Lys Asn Gly Pro Ser Gly Ala Pro Ser.

[0087] "Formulation of a therapeutic agent" refers to the actual state of the therapeutic agent as it exists in a product or as an intermediate in the manufacture of a product, and includes the therapeutic agent plus optionally any additional therapeutic agents used, any formulation excipients used, and any formulation solvents used.

[0088] "Membrane" refers to a permeable structure that allows mass transfer of molecules through the structure from one side of the structure to the other side.

[0089] "Porous membrane" refers to a membrane characterized by the presence of a two-phase system, in which the membrane matrix material represents one phase, usually a continuous phase, which is permeated by open channels extending from one side of the membrane to the other and is filled with a second phase, usually a fluid phase, through which mass transport across the membrane can occur.

[0090] "Dense membrane" or "non-porous membrane" refers to a membrane without pores filled with fluid. In such membranes, mass transport can occur by a solution-diffusion mechanism, where the therapeutic agent permeates the membrane by dissolving in the membrane material itself and diffusing through the membrane.

[0091] "Nanoporous membrane" and "nanoporous membrane" are used interchangeably and refer to a porous membrane with a pore size of less than 1000 nanometers.

[0092] "Nanotube membrane" refers to a nanoporous membrane in which the pores are formed by an array of nanotubes.

[0093] "Titania nanotube film" refers to a titanium dioxide nanotube array on a titanium substrate, wherein at least a portion of the titanium dioxide nanotubes are open at both ends and can allow diffusion from one side of the film to the other side through the titanium dioxide nanotubes. In some cases, the titanium dioxide nanotube film has two faces or sides. The first face or first side has the titanium dioxide nanotube array and the second face or second side has the titanium substrate. In some aspects, the titanium dioxide nanotube array is grown on the titanium substrate by electrochemical anodization.

[0094] The "molecular diameter" of a polymer refers to the diameter of a sphere of rotation of the polymer, which is a physical measure of the size of a molecule and is defined as twice the mass-weighted average distance from the core of the molecule to the individual mass elements in the molecule.

[0095] "Stokes diameter" or "hydrodynamic diameter" refers to the size of a molecule plus its associated water molecules as it moves in aqueous solution and is defined as the radius of an equivalent hard sphere that diffuses at the same rate as the molecule being observed.

[0096] "Ion exchange resin" refers to an insoluble polymer containing acidic or basic groups or a combination thereof, rendered insoluble, for example, by cross-linking, and capable of exchanging anions or cations or a combination thereof with the surrounding medium.

[0097] "Fluid" and "fluid form" as used in this disclosure refer to the flowable state of matter and include, but are not limited to, gases, solutions, suspensions, emulsions, colloids, dispersions, and the like.

[0098] "Fluid contact" means that an entity is in contact with a fluid.

[0099] "Neutral pH" refers to a pH of 6 to 8, such as 6.5 to 7.5.

[0100] Implantable devices with nanoporous membranes for releasing therapeutic agents have been previously described, for example in U.S. Patents Nos. 9,814,867, 9,770,412 and 11,129,791 and WO2021 / 173770, each of which is incorporated herein by reference. It has been found that the release rate of therapeutic agents from these devices can be effectively controlled by the pH value of the therapeutic agent preparation. Some embodiments of the present disclosure include a device having a cylindrical capsule encapsulating a reservoir, a nanoporous membrane fixed at one end of the capsule, and a therapeutic agent preparation contained in the reservoir. The release of the therapeutic agent from the reservoir after the device is implanted in the subject is controlled by the nanoporous membrane. Some embodiments of the present disclosure utilize the pH value of the therapeutic agent preparation as another means of controlling the release rate. In addition, some embodiments use the orientation of the membrane relative to the reservoir to control the duration of the release of the therapeutic agent.

[0101] Device

[0102] like Figure 1 As shown, the device of the present disclosure includes a capsule 1000 suitable for implantation, wherein the capsule has a reservoir 1001 suitable for containing a therapeutic agent 1005, and optionally a pH control agent (e.g., an insoluble polymer having a plurality of pH-sensitive stabilizing groups) in the form of resin beads 1006. In some embodiments, there is more than one reservoir.

[0103] Capsule 1000 can be made of any suitable biocompatible material. In some embodiments, the capsule is made of medical grade metal (such as titanium or stainless steel) or medical grade polymer material (such as silicone, polyurethane, polyacrylate, polyolefin, polyester, polyamide, etc.). In some embodiments, the capsule is made of a variety of materials. In some embodiments of the present disclosure, the capsule is made of titanium.

[0104] The device of the present disclosure has at least one membrane 1004, as described herein, attached to the capsule and in contact with the reservoir fluid, wherein the membrane provides a passage for mass transfer of the therapeutic agent contained in the reservoir 1001 out of the reservoir and into the body of the subject in which the capsule has been implanted. In the present disclosure, "attached to the capsule" means that a component is fixed in place relative to the capsule and is directly or indirectly connected to the capsule using any suitable means, including by welding, gluing, press-fitting and by using threading means, or by any combination of these means.

[0105] In the case of a membrane such as that described in U.S. Pat. No. 9,814,867, Figure 1As shown, the nanotube film is part of an array of nanotubes 1003, some of which are still attached to the titanium substrate 1002 from which they grew, and the substrate can be attached to the capsule. At least some of the nanotubes are open on both sides to allow mass transfer of therapeutic agents from the reservoir. In one aspect, the membrane 1004 is a titanium dioxide nanotube membrane 1004 having two faces or sides. The first face or side has the titanium dioxide nanotube 1003 array and the second face or side has the titanium substrate 1002. Figure 1 The membrane is shown attached to the capsule with the titanium substrate 1002 facing the reservoir of the device. Some devices of the present disclosure also have a septum 1007 that can be pierced by a needle and is suitable as an access port to deposit the formulation 1005 into the reservoir 1001.

[0106] Further description of the apparatus of the present disclosure may be found in WO 2021 / 173770, which is incorporated herein by reference.

[0107] membrane

[0108] Embodiments of the present disclosure include at least one membrane that provides a pathway for mass transfer of a therapeutic agent out of a reservoir of a device of the present disclosure.

[0109] A wide variety of membranes may be used in embodiments of the present disclosure.

[0110] The membranes disclosed herein include dense membranes and porous membranes; the porous membranes include nanoporous membranes and nanotube membranes.

[0111] Materials suitable for use in the membranes of the present disclosure include organic and inorganic materials, polymers, ceramics, metals, metal oxides, and combinations thereof.Materials suitable for use in the membranes include silicon, silicon dioxide, titanium, and titanium dioxide.

[0112] 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 titanium dioxide nanotube membrane.

[0113] Embodiments of the present disclosure are particularly useful as sustained delivery devices for therapeutic agents, wherein the release of the agent is controlled by a nanoporous membrane.

[0114] The fabrication of the membranes of the present disclosure is described in US Pat. No. 9,814,867, and the control of the inner diameter of the nanopores is described in US Pat. No. 9,770,412, each of which is incorporated herein by reference.

[0115] Further description of the membranes of the present disclosure can be found in WO 2021 / 173770, which is incorporated herein by reference.

[0116] preparation

[0117] The device of the present disclosure includes a preparation having at least one therapeutic agent, such as a therapeutic agent such as described in the present disclosure. The therapeutic agent can be in solid or fluid form. In some cases, the therapeutic agent can be present in a mixed form, such as a suspension of a solid form therapeutic agent in a saturated solution of the therapeutic agent. In some cases, the preparation is in solid form, and in some cases, the preparation is in fluid form. The preparation in fluid form, for example, a preparation of a solution including at least a portion of the therapeutic agent in a reservoir, can have a certain pH value.

[0118] pH Control Agents

[0119] The material controlling pH can be the therapeutic agent itself, a low molecular weight stabilizer such as an acidic and basic compound, including weakly acidic and weakly basic compounds that can be used as a buffer, or a high molecular weight compound such as a polyacid or polybasic compound. Many such compounds are known in the literature, and one of ordinary skill in the art of pharmaceutical formulation development will be able to select suitable ingredients for the formulation without undue experimentation.

[0120] In some embodiments, the pH control material is an insoluble polymer stabilizer as described in WO 2021 / 173770, which is incorporated herein by reference. Other pH control agents suitable for use in the present disclosure can be found in U.S. Pat. Nos. 10,045,943 and 10,479,868, which are incorporated herein by reference. Ion exchange resins are examples of insoluble polymers having multiple pH sensitive stabilizing groups.

[0121] "Acid" means a compound that can donate a proton (H + ) or a compound that is an electron pair acceptor under the Lewis definition. Acids useful in the present disclosure are Bronsted-Lowry acids, including but not limited to alkanoic acids or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids, and mineral acids as defined herein. Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), halogen oxygen acids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid, and boric acid. Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.

[0122] A "base" is a compound that, under the Bronsted-Lowry definition, is capable of accepting a proton (H + ) or a compound that is an electron pair donor under the Lewis definition. Representative bases include, but are not limited to, hydroxyl, alkylhydroxyl, amine (-NRR), alkylamine, arylamine, amide (-C(O)NRR), sulfonamide (-S(O)2NRR), phosphonamide (-P(O)(-NRR)2), carboxylate (-C(O)O-), etc.

[0123] In some cases, the pH adjuster is a buffer. The buffer is selected from the group consisting of citrate / citric acid, acetate / acetic acid, phosphate / phosphoric acid, formate / formic acid, propionate / propionic acid, lactate / lactic acid, carbonate / carbonic acid, ammonium / ammonia, ethylenediaminetetraacetate / ethylenediaminetetraacetic acid, and combinations thereof.

[0124] Therapeutic agents

[0125] Therapeutic agents suitable for embodiments of the present disclosure have been described in WO2021 / 173770, which is incorporated herein by reference. In some embodiments, the therapeutic substance is a peptide or protein. In some embodiments, the peptide or protein is an incretin mimetic. In some embodiments, the incretin mimetic is exenatide.

[0126] manufacture

[0127] Methods of making devices and formulations are described in WO2021 / 173770, which is incorporated herein by reference.

[0128] Release rate control

[0129] The device of the present disclosure can release the therapeutic agent contained in the reservoir through the nanopores of the membrane at a controlled rate. In some cases, the release rate of the therapeutic agent is a non-Fickian release rate, that is, the release rate is not proportional to the concentration gradient driving the release (e.g., zero-order release). Examples of non-Fickian release rates by nanoporous membranes have been described in U.S. Patent No. 9,814,867, which is incorporated herein by reference.

[0130] The exact mechanism by which the nanopores of the membrane control the release rate is not fully understood. It is speculated that interactions between the diffusing molecules of the therapeutic agent and the inner wall of the nanotubes may play a role in this mechanism.

[0131] WO 2021 / 173770 (incorporated herein by reference) discloses the use of insoluble polymers with multiple pH-sensitive stabilizing groups that can be used to provide buffering capacity at a desired pH level, such as weakly acidic or weakly basic groups, thereby providing chemical stability for the therapeutic agent in the device of the present disclosure. These polymers stabilize the therapeutic agent by controlling the pH value of the preparation of the present disclosure. Incidentally, this chemical stabilizer can now also be used to control the release rate. Ion exchange resins are an example of insoluble polymers with multiple pH-sensitive stabilizing groups.

[0132] Cross-linked polyacrylic acid and polymethacrylic acid are used industrially as ion exchange resins. In some embodiments of the present disclosure, ion exchange resins are used as stabilizers. Possibly suitable ion exchange resins are produced by Mitsubishi Chemical Corporation under the name "Diaion" and by Purolite Corporation under the name "Purolite". In some cases, Diaion WK40L as well as Purolite 104plus and Purolite C115 may be suitable stabilizers for stabilizing peptide and protein formulations. Others include Diaion WK10, Diaion WK11, Diaion WK100 and Diaion WT01S.

[0133] Thus, embodiments of the present disclosure provide a method for controlling the release rate of a therapeutic agent through a nanoporous membrane by adjusting the pH of the therapeutic agent formulation.

[0134] Some embodiments of the present disclosure provide methods for controlling the rate at which a therapeutic agent is released from a reservoir through a nanotube membrane by controlling the pH of a formulation in the reservoir, wherein at least a portion of the (one or more) therapeutic agents are dissolved in the reservoir. In some embodiments, the release rate is controlled by controlling the pH using a polymer stabilizer such as described in WO 2021 / 173770, which is incorporated herein by reference.

[0135] In some embodiments, the release rate is controlled by controlling the pH with a soluble pH control stabilizer (such as a low molecular weight acid or base). In some cases, it is considered desirable that the rate of drug release from the implant gradually increases over time. For example, for Exenatide, a gradual increase in the daily delivered dose is associated with a reduction in the incidence of nausea. In some embodiments of the present disclosure, the initial internal pH of the device is set at a relatively low level, and as the internal pH slowly balances with the external environment of the device (i.e., interstitial fluid), it is allowed to rise over time. The gradual increase in pH is accompanied by a gradual increase in the release rate.

[0136] In some cases, a dry formulation of the therapeutic agent may be present in the device when implanted in a subject. In this case, a water absorption promoter, such as a water-soluble gas, may be present in the reservoir. After implantation, the water-soluble gas may promote the absorption of interstitial fluid into the reservoir through the membrane of the device. Embodiments of the present disclosure may include a dry formulation in the reservoir, which is composed of a liquid formulation having a pH value that provides a desired release rate of the therapeutic agent after absorbing interstitial fluid.

[0137] Anti-inflammatory drugs

[0138] In vitro, the rate of release of the therapeutic agent (eg, Exenatide) from the device of the present disclosure is maintained at a high level over a long period of time.

[0139] However, certain titanium-based devices of the present disclosure showed a significant decrease in in vivo plasma levels of the therapeutic agent over a similar period of time after implantation in laboratory animals. This effect was observed in both rat and cat models. In the rat model, a pH-stabilizing resin (Purolite PPC115PHDR, adjusted to pH 5.5 with NaOH) was included in the device, however, this resin was not included in the cat model.

[0140] Soon after the device is implanted in a subject, proteins and other biomolecules present in blood, plasma, and other biofluids rapidly adsorb to the surface of the implant's biomaterial.

[0141] Excessive inflammation and its expression of proteolytic and metabolic enzymes, as well as excessive formation of tissue capsules or other structural changes are known consequences of implanting non-biocompatible materials and may negatively affect plasma levels of therapeutic agents. However, titanium is considered the gold standard for implantable devices given its excellent biocompatibility.

[0142] Histology of tissue samples surrounding the implanted devices in rats showed no abnormal inflammation or abnormal structural changes and indicated the expected degree of biocompatibility. Mild to moderate inflammatory responses were observed in several cats. Therefore, while the anti-inflammatory effects of the added bioactive substances may be beneficial in some subjects, other factors that have not been identified to date may also play a role.

[0143] After the device was removed at the end of the in vivo implantation period, the device was opened and the remaining formulation was analyzed. In rats, exenatide is eliminated by renal clearance, and little or no enzymatic metabolic degradation is observed. Therefore, the degradation products found in the device in rats appear to be normal chemical degradation products, and no signs of enzymatic degradation were found.

[0144] In contrast, a specific fragment of exenatide was observed in cats, indicating enzymatic cleavage of the peptide backbone. The presence of this fragment correlated with decreased plasma levels of intact exenatide.

[0145] Therefore, the mechanisms underlying the suppression of plasma levels in rats and cats appear to be different, and only a partial correlation with inflammation was observed in cats but not in rats.

[0146] Despite the absence of signs of excessive inflammation or abnormal tissue remodeling, surprisingly, the addition of anti-inflammatory steroids (e.g., dexamethasone) did significantly improve plasma levels of therapeutic agents released from titanium devices in vivo. Therefore, it is believed that the significant increase in plasma levels of therapeutic agents with anti-inflammatory drugs represents a new mechanism for improving plasma levels of therapeutic agents released from implantable devices.

[0147] The concept of the area under the curve (AUC) is the basis for pharmacokinetic modeling of a subject's body exposure to an administered therapeutic. In short, samples are taken from the subject's body fluids at regular time intervals and the concentration of the therapeutic is determined. A curve is plotted that represents the concentration in the body fluid over time. The area under the curve is a measure of the body's exposure to the therapeutic.

[0148] from Figure 4 and Figure 5 As can be seen and as described in the Examples below, the AUC for implants releasing the therapeutic agent along with the anti-inflammatory drug is significantly greater than the AUC obtained for implants without the anti-inflammatory drug.

[0149] Embodiments of the present disclosure include devices, compositions, and methods for increasing the AUC of a therapeutic agent in a subject following implantation of an implantable device of the present disclosure. In some embodiments, the AUC is increased by about 10% to about 100%.

[0150] In some embodiments, the AUC is increased by at least 10% compared to plasma levels in the absence of the anti-inflammatory drug.

[0151] In some embodiments, the AUC is increased by at least 25% compared to plasma levels in the absence of the anti-inflammatory drug.

[0152] In some embodiments, the AUC is increased by at least 50% compared to plasma levels in the absence of the anti-inflammatory drug.

[0153] In some embodiments, the AUC is increased by at least 75% compared to plasma levels in the absence of the anti-inflammatory drug.

[0154] In some embodiments, the AUC is at least doubled compared to plasma levels in the absence of the anti-inflammatory drug.

[0155] Dexamethasone has been used to protect glucose sensors from reactive oxygen species (U.S. Pat. No. 9,931,068), and to protect cardiac pacemakers from tissue overgrowth (U.S. Pat. No. 7,164,948), and as a primary treatment for ophthalmic disease (U.S. Pat. No. 9,012,437), but has never been used before to improve the plasma levels and AUC achieved by delivering a different therapeutic agent as a primary treatment modality via an implantable device. Since inflammation does not appear to contribute to the occurrence of low plasma levels of the therapeutic agent delivered from the device of the embodiments, the mechanism of action of the anti-inflammatory drug is unclear.

[0156] Embodiments of the present disclosure may include any suitable type of anti-inflammatory drug. The anti-inflammatory drug of the present disclosure includes a binding agent, including certain anti-inflammatory coatings (such as suitable hydrogel coatings) and a release agent (such as an anti-inflammatory drug). The anti-inflammatory drug may include any type of anti-inflammatory drug, such as steroidal anti-inflammatory drugs ("steroids") and non-steroidal anti-inflammatory drugs ("NSAIDS") and combinations thereof.

[0157] Dexamethasone is a typical and representative member of the corticosteroid class of drugs, and is a subclass of steroid drugs. Any suitable type of steroid may be used, including but not limited to corticosteroids, such as cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, hydrocortisone, cortisone, Cortisol, flunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate, budesonide, mometasone furoate, ciclesonide, clobetasol and clobetasol.

[0158] Any suitable type of NSAID may be used, including non-selective COX inhibitors, selective COX 1 inhibitors and selective COX 2 inhibitors.

[0159] Suitable NSAIDS include, but are not limited to, diclofenac, indomethacin, sulindac, mefenamic acid, piroxicam, ibuprofen, ketoprofen, naproxen, phenylbutazone, aspirin, diflunisal, etodolac, fenoprofen, flurbiprofen, meclofenac, nabumetone, oxaprozin, tolmetin, meloxicam, nimesulide, celecoxib, etoricoxib, valdecoxib, celecoxib, rofecoxib, parecoxib, and acetaminophen.

[0160] In some cases, the anti-inflammatory drug is a biocompatible polymer. The biocompatible polymer can be a biodegradable or erodible polymer coating containing the anti-inflammatory drug. Other anti-inflammatory polymers include heparin, hyaluronic acid, α-melanocyte stimulating hormone (α-MSH), polyethylene glycol (PEG), cross-linked PEG, and polymers that inhibit proinflammatory cytokines.

[0161] The amount of anti-inflammatory drugs included in the embodiments of the present disclosure may vary depending on the desired intensity and duration of effect and the potency of the anti-inflammatory drug. For example, anti-inflammatory corticosteroids are available in a variety of strengths, with hydrocortisone being a low-strength agent, dexamethasone being a medium-strength agent, and clobetasol being one of the so-called extra-strength agents.

[0162] Experimental models, including animal models, can be used to test the effects of different dosage regimens of anti-inflammatory drugs, and one skilled in the art of drug development will be able to design experiments to determine the type of anti-inflammatory drug and dosage regimen that is needed.

[0163] Existing literature, prescribing information, and public regulatory filings may assist in such determinations. For example, but not limited to, the maximum prescribed oral dose of dexamethasone is 9 mg. The recommended dose of dexamethasone as a long-acting steroid injection in the facet joints is 0.8-1 mg. The tip of the permanently implanted pacemaker, the Medtronic Attain AbilityTM Model 4196Lead, is coated with a sustained-release coating containing 160 micrograms of dexamethasone.

[0164] In some embodiments, more than one anti-inflammatory drug may be present.

[0165] Embodiments of the present disclosure also include an implantable device for delivering a therapeutic agent to a subject, wherein in addition to the therapeutic agent, the device also includes an anti-inflammatory drug. In some cases, the anti-inflammatory drug improves the therapeutic effect of the therapeutic agent. The anti-inflammatory drug can be included in any suitable position on the device, including being present in a reservoir of the device, or being present on a coating outside the reservoir.

[0166] The amount of the anti-inflammatory drug is sufficient to co-diffuse with the therapeutic agent. If the device has sufficient sustained release active agent to diffuse for 1-52 weeks, 1-12 months, the same is true for the anti-inflammatory drug. In certain aspects, the concentration or amount of the anti-inflammatory drug depends on the amount or concentration of the active agent.

[0167] The preparation of therapeutic agent comprises therapeutic agent, anti-inflammatory agent and optional excipient and solvent.In some cases, the amount of therapeutic agent is about 5% to about 40% w / w of the preparation arranged together with implantable device.Preparation can be saline solution with pH adjusting agent (such as buffer).Therapeutic agent can be about 15% to about 35% w / w of preparation, or about 20% to about 30%, or about 25% to about 30% w / w or about 25% w / w.

[0168] The amount of therapeutic agent present in the device is sufficient to maintain extended release for about 1 month to about 12 months, for example, up to 1 month, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. The amount of anti-inflammatory drug in the device is sufficient to co-diffuse with the therapeutic agent. If the therapeutic agent delivers an extended release for 2 months, the anti-inflammatory drug will also co-diffuse for 2 months. The concentration amount of the anti-inflammatory drug can be greater or less than the amount of the therapeutic agent, as long as the amount of the anti-inflammatory drug is sufficient to co-diffuse within the same time frame.

[0169] In some aspects, the therapeutic agent has a first diffusion rate through the nanoporous membrane, and the anti-inflammatory drug has a second diffusion rate through the nanoporous membrane. The first diffusion rate can be less than, greater than, or equal to the second diffusion rate. As long as a certain amount of anti-inflammatory drug diffuses with the therapeutic agent, the amount of anti-inflammatory drug is sufficient.

[0170] In some aspects, it is generally assumed that the total potency scale covers a range of about 2000 times, so there is a wide choice in the number of anti-inflammatory drugs to be included. As a general guide, it seems that the local activity of the anti-inflammatory drug released is the reason for the beneficial effect, because a very low daily dose is required. For example, for dexamethasone, only about a quarter of a microgram (0.25 μg / day) is measured as a daily release. In some cases, 0.01 μg / day to about 5 μg / day can be released. Based on these considerations and the total expected duration of the implant device, the total load of therapeutic agent and anti-inflammatory drug can be determined.

[0171] Some embodiments of the present disclosure include kits, wherein there is an implantable device for delivering a therapeutic agent, and a dosage form of an anti-inflammatory drug. The dosage form can be any desired dosage form, such as encapsulated in microparticles or as a solid implant, or any other pharmaceutical preparation form with a desired dissolution profile, such as a reservoir of a long-acting corticosteroid.

[0172] Embodiments of the present disclosure also include methods for treating subjects with anti-inflammatory drugs and improving plasma levels of therapeutic agents delivered from the devices of the present disclosure. The methods of the present disclosure include applying any device or composition of the present disclosure to a subject in need of such application. The administration of the anti-inflammatory drug can be systemic or local. Systemic administration can include oral and parenteral administration, such as by injection, and trans-tissue administration, such as transdermal and transmucosal. Local administration can include including the agent in a reservoir of the device of the present disclosure, co-administered with a primary therapeutic agent, or administered from its own reservoir.

[0173] Alternatively or concurrently, the anti-inflammatory drug may be present on the device external to the reservoir, such as in a coating.

[0174] Furthermore, alternatively, the anti-inflammatory drug can be administered topically in its own delivery form, e.g., encapsulated in microparticles or in a solid implant, or in any other form of pharmaceutical formulation having the desired dissolution characteristics, such as a depot of a long-acting corticosteroid. Furthermore, alternatively, the anti-inflammatory drug can be administered systemically.

[0175] Embodiments of the present disclosure also include methods for improving the plasma levels of therapeutic agents released from implantable devices. The methods of the present disclosure include co-formulation, co-administration or otherwise providing simultaneous activity of therapeutic agents and anti-inflammatory drugs. The effect of anti-inflammatory drugs can inhibit the inflammatory response to the device implanted for sustained-release therapeutic agents, thereby reducing the degradation of therapeutic agents by proinflammatory agents (such as proteases produced by inflammatory cells).

[0176] Example

[0177] Dexamethasone release strips were made by mixing 1 part dexamethasone with 2 parts of the silicone precursor MED-4830 Binary Silicon until a visually homogeneous paste was obtained. The paste was drawn into a film of approximately 1 mm thickness on a glass plate and cured at 150°C for 180 minutes. The film was then cut into strips of approximately 1 x 1 x 7 mm.

[0178] In the following examples, the device used includes a titanium capsule having a length of about 25 mm and a diameter of about 2.25 mm. A titanium substrate having a titanium oxide nanoporous membrane is welded to one end of the device. The diameter of the nanoporous membrane is 0.3 mm and consists of about 6,000,000 nanopores. The average diameter of the nanopores at the substrate end is about 20 nm. About 10 mg of ion exchange resin Purolite PPC115PHDR (adjusted to a pH of 5.5 with NaOH) is filled into the reservoir as a pH control agent.

[0179] The group given the anti-inflammatory drug also additionally received one of the silicone strips loaded with dexamethasone as described above. A silicone septum was located at the other end of the device.

[0180] For the group not given dexamethasone strips, about 46 mg of 25% exenatide acetate (w / w), 0.25% Polysorbate 20, 154 mM Na + The preparation with a pH value of 5.5 was filled into the device. For the group given dexamethasone strips, about 40 mg of the drug preparation was loaded. In brief, the preparation was loaded into the filling device and the septum was pierced with a hollow needle. A vacuum was applied to the membrane of the device to reduce the pressure inside the reservoir, and the preparation was injected into the reservoir through the septum through the needle.

[0181] Example 1

[0182] For in vitro testing, devices without and with dexamethasone strips were prepared as described above and stored submerged in storage buffer containing 0.9% NaCl and 0.76% sodium acetate in water for injection (pH 5.5) at room temperature prior to initiating release rate testing.

[0183] In vitro release rate testing was performed by submerging the device in 3 ml of 26 mM bis-tris buffer, 154 mM NaCl on a shaker at 37°C and measuring the amount of exenatide and dexamethasone released at regular intervals by reverse phase HPLC.

[0184] exist Figure 2In the graph, the Y axis represents the release rate and the X axis represents the time (in days). It can be seen that the release rate of the device with the steroid strip is always slightly lower than the release rate of the device without the strip.

[0185] exist Figure 3 The release rate of dexamethasone from the device was plotted in a similar manner.

[0186] Example 2

[0187] For in vivo testing, devices without dexamethasone strips and devices with dexamethasone strips were prepared as described above and stored submerged in storage buffer containing 0.9% NaCl and 0.76% sodium acetate in water for injection (pH 5.5) at room temperature before initiating release rate testing.

[0188] In one study, the device was tested by implanting it in Sprague-Dawley rats and measuring the plasma concentration-time profile. Plasma samples were collected post-implantation and exenatide plasma levels were determined by LC / MS. After removal of several devices for interim analysis and removal of animals that showed evidence of exenatide antibody development, a total of three devices per group were implanted for the full 84 days.

[0189] exist Figure 4 In the , the Y-axis represents the plasma concentration in ng / mL and the X-axis represents time. It can be seen that the device containing the dexamethasone strip exhibits a significantly higher plasma level than the device without the dexamethasone strip.

[0190] The AUC after implantation of both devices was calculated using the trapezoidal method, a common method for estimating AUC. In short, each concentration point on the curve is connected to its corresponding time point with a line, thus forming a series of trapezoids. The surface area of ​​each trapezoid is calculated and added together to provide the total AUC. Following this method, the mean AUC for the device without anti-inflammatory drugs was 92 ng day / mL. The mean AUC for the device with anti-inflammatory drugs was 302 ng day / mL.

[0191] Example 3

[0192] In another study, the device was tested by implanting it in laboratory cats and measuring the plasma concentration-time profile. Plasma samples were collected after implantation and exenatide plasma levels were determined by LC / MS. A total of five animals were included in each group.

[0193] The devices implanted in these groups did not contain a pH-controlling resin.

[0194] exist Figure 5In the , the Y-axis represents the plasma concentration in ng / mL and the X-axis represents time. It can be seen that the device containing the dexamethasone strip exhibits a significantly higher plasma level than the device without the dexamethasone strip.

[0195] The AUC after implantation of the two devices was calculated using the trapezoidal method described above. According to this method, the mean AUC for the device without anti-inflammatory drugs was 112 ng day / mL. The mean AUC for the device with anti-inflammatory drugs was 214 ng day / mL.

[0196] The foregoing patents and patent publications are incorporated herein by reference.

Claims

1. A device for sustained release of a therapeutic agent, the device comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a therapeutic agent located within the reservoir; and wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; and the device further comprises an anti-inflammatory drug.

2. The device of claim 1, wherein the anti-inflammatory drug is contained within a reservoir of the device.

3. The device of claim 1, wherein the anti-inflammatory drug is disposed on an outer surface of the capsule.

4. The device according to any one of claims 1 to 3, wherein the anti-inflammatory drug is located at at least two different locations.

5. The device of claim 1, wherein the anti-inflammatory drug is a member selected from steroids, NSAIDs, and combinations thereof.

6. The device of claim 3, wherein the anti-inflammatory drug is a biocompatible polymer.

7. A method for improving the plasma level of a therapeutic agent released from a device for sustained release of the therapeutic agent, comprising: The device is provided, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a therapeutic agent disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; and the device further comprises an anti-inflammatory drug, wherein the anti-inflammatory drug improves plasma levels of the therapeutic agent after implantation of the device in a subject.

8. The method of claim 7, wherein the anti-inflammatory drug is contained within a reservoir of the device.

9. The method of claim 7, wherein the anti-inflammatory drug is disposed on an outer surface of the capsule.

10. The method of claim 7, wherein the anti-inflammatory drug is a member selected from steroids, NSAIDs, and combinations thereof.

11. The method of claim 9, wherein the anti-inflammatory drug is a biocompatible polymer.

12. A method of treating a subject with a therapeutic agent and an anti-inflammatory drug, comprising: The device is provided, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a therapeutic agent disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; The device further comprises an anti-inflammatory drug; and The device is implanted in a subject.

13. The method of claim 12, wherein the anti-inflammatory drug is contained within a reservoir of the device.

14. The method of claim 12, wherein the anti-inflammatory drug is disposed on an outer surface of the capsule.

15. The method of claim 12, wherein the anti-inflammatory drug is a member selected from steroids, NSAIDs, and combinations thereof.

16. The method of claim 14, wherein the anti-inflammatory drug is a biocompatible polymer.

17. A method for improving the plasma level of a therapeutic agent released from a device for sustained release of the therapeutic agent, comprising: The device is provided, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; A therapeutic agent is disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; and Co-administer anti-inflammatory drugs.

18. The method of claim 17, wherein the anti-inflammatory drug is co-administered topically.

19. The method of claim 17, wherein the anti-inflammatory drug is co-administered systemically.

20. The method of claim 17, wherein the anti-inflammatory drug is a member selected from steroids, NSAIDs, and combinations thereof.

21. A method of treating a subject with a therapeutic agent and an anti-inflammatory drug, comprising: The device is provided, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a therapeutic agent disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; implanting the device into a subject, and Co-administer anti-inflammatory drugs.

22. The method of claim 21, wherein the anti-inflammatory drug is co-administered topically.

23. The method of claim 21, wherein the anti-inflammatory drug is co-administered systemically.

24. The method of claim 21, wherein the anti-inflammatory drug is a member selected from steroids, NSAIDs, and combinations thereof.

25. A method for improving the plasma level of a therapeutic agent released from a device for sustained release of the therapeutic agent, comprising: The device is provided, comprising: a capsule configured for implantation and having a reservoir; a nanoporous membrane having a plurality of pores; a therapeutic agent disposed within the reservoir; wherein the nanoporous membrane provides a diffusion path for the therapeutic agent to exit the reservoir; The device further comprises an anti-inflammatory drug, and wherein the anti-inflammatory drug improves the AUC of the therapeutic agent after implanting the device in the subject.

26. The method of claim 25, wherein the AUC is increased by at least 10%.

27. The method of claim 25, wherein the AUC is increased by at least 25%.

28. The method of claim 25, wherein the AUC is increased by at least 50%.

29. The method of claim 25, wherein the AUC is increased by at least 75%.

30. The method of claim 25, wherein the AUC is at least doubled.

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