TECHNICAL FIELD

[0003] A subcutaneous biodegradable reservoir device for sustained delivery of an active agent over an extended period of time is described herein. Physical parameters of the device and active agent formulations contained therein can be selected to provide effective and sustained delivery of the active agent. In embodiments, the reservoir device may contain active agent formulations having more than one active agent.

BACKGROUND

[0004] The need for effective biomedical interventions for preventative indications (e.g., pregnancy, infectious disease) and therapeutic needs (e.g., disease, opioid addiction) remains important worldwide. In general, end-users have persistently struggled with suboptimal adherence to daily oral or on-demand interventions. Sustained, user-independent delivery of active pharmaceutical ingredients (APIs) or active pharmaceutical agents enables users to avoid burdensome time- or event-driven regimens and bypasses many adherence challenges of user-dependent methods. Also, systemic administration, combined with long-term delivery, may significantly protect and treat many disease indications without first pass effects through the liver, which can reduce the bioavailability.

[0005] An area where improvements in biomedical intervention could prove beneficial is the global HIV epidemic. HIV Pre-Exposure Prophylaxis (PrEP) with antiretroviral (ARV) drugs is a promising biomedical strategy to address the global problem. Tenofovir-based PrEP has demonstrated successes with daily and on-demand dosing. Despite these advancements, adherence to time- or event-driven regimens for PrEP remains a struggle. Long-acting (LA) delivery of ARV drugs simplifies traditional dosing regimens for PrEP by alleviating the emotional and logistical burden of user-dependent methods. For example, a LA-injectable formulation of the integrase inhibitor, cabotegravir (CAB), is currently under investigation in two phase 2/3 HIV PrEP trials. See, HPTN083 and HPTN084. Although injectable methods are acceptable to many users and offer key advantages, such as a bi-monthly dosing regimen and discretion, drawbacks do exist. Injectable formulations cannot be removed in the event of an adverse drug-related event and the potential exists for a long plasma “tail” of sub-therapeutic drug levels.

[0006] A promising biomedical approach for LA-PrEP involves implants that reside under the skin to continuously release drug, which supports adherence over longer time periods, enables discretion of use, lowers the burden of the regimen, and remains reversible during the therapeutic duration. Polymeric implants can comprise different architectures that each has advantages for drug delivery. See Solorio, L. et ak; Yang, W.-W. et ak; and Langer, R. Reservoir- style implants involve a formulated drug core encapsulated by a rate-controlling polymeric barrier. Notable examples of implants with a core-sheath configuration include the collection of subdermal contraceptive implants: Norplant® and Jadelle® for delivery of levonorgestrel (LNG) using a rod of silicone-based polymer and Implanon® and Nexplanon® for delivery of etonogestrel (ENG) using a rod of ethylene-vinyl acetate (EVA)-based polymer. The low dosages required for subcutaneous delivery of hormonal contraceptives enable these implants to last multiple years. Reservoir-style implants have also shown utility for indications in ophthalmology.

[0007] Several implants are currently under development for HIV PrEP, with each implant system holding unique configurations and features. A subdermal, silicone implant that delivers TAF from orthogonal channels coated with polyvinyl alcohol (PVA) showed 40-days of drug delivery in beagle dogs without observed adverse events. See Gunawardana, M. et al. A non-

polymeric, refillable implant designed to deliver TAF and emtricitabine (FTC) from separate devices showed sustained levels of tenofovir diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) over 83 days in rhesus macaques but only 28 days for FTC-triphosphate (FTC-TP) due to the large dosing required and short plasma half-life. See Chua, C.Y.X. et al. A titanium osmotic pump system, called the Medici Drug Delivery System™, is being developed for PrEP and for type-2 diabetes. See A New Collaboration for HIV Prevention Available online. Additionally, a matrix-style PrEP implant for delivery of 4’-ethylnyl-2-fluoro-2’-dexoyadenosine (EFdA) has shown promising efficacy for HIV treatment and prevention, as demonstrated in animal models. See Barrett, S.E. et al.

[0008] Currently, there is an unmet need for a long-acting, biodegradable drug delivery implant device. If such device had zero-order drug release kinetics, it could provide a flat PK profile at a steady state. As such, when active agent was depleted from the device, only a minimal tail would be expected according to the drug’s half-life. Such technology could be used for a wide variety of therapeutics and preventatives, including small molecules and biologies.

SUMMARY OF THE DISCLOSURE

[0009] In a first aspect of the invention, a reservoir device includes an active agent formulation contained within a reservoir. The active agent formulation comprises more than one active agent. For example, the formulation may comprise two or more active agents. The reservoir is defined by a biodegradable, permeable polymer membrane having a thickness of at least 45 pm. The membrane allows for diffusion of the more than one active agent of the formulation there through when positioned subcutaneously in a body of a subject.

[0010] Implementations may include one or more of the following features. The device where the permeable polymer membrane has a thickness of at least 45 pm. The device where the active agent formulation includes more than one active agent and an excipient.

[0011] In a second aspect of the invention, a reservoir device includes more than one active agent contained within a reservoir. The reservoir is defined by a biodegradable, permeable polymer membrane, wherein the membrane allows for diffusion of the more than one active agent there through with zero-order release kinetics for a time period of at least 60 days when positioned subcutaneously in a body of a subject.

[0012] Implementations may include one or more of the following features. The device where at least one of the more than one active agent includes tenofovir alafenamide fumarate (TAF), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), EFd A- alafenamide, levonorgestrel (LNG); etonogestrel (ENG) or combinations thereof. The device where at least one of the more than one active agent includes an antibody, a small molecule, a protein, a peptide, a hormone or a combination thereof. The device where the reservoir further contains an excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The foregoing aspects and other features of the disclosure are explained in the following description, taken in connection with the accompanying drawings, wherein:

[0014] FIG. 1A is a schematic representation of an exemplary drug delivery device in accordance with an aspect of the invention. The figure on the left is a perspective view of the exemplary device. The figure on the right is a top view of the exemplary device.

[0015] FIG. IB is a labelled version of the schematic representation of FIG. 4A.

[0016] FIG. 1C is a schematic representation of another exemplary device and a photograph of the exemplary device.

[0017] FIG. 2A is a line chart showing daily EFdA release profiles of co-formulated devices containing EFdA and LNG formulations.

[0018] FIG. 2B is a line chart showing daily EFdA release profiles of co-formulated devices containing EFdA and ENG formulations.

[0019] FIG. 3A is a line chart showing daily LNG release profiles of multi-drug devices containing EFdA and LNG formulations.

[0020] FIG. 3B is a line chart showing daily ENG release profiles of multi-drug devices containing EFdA and ENG formulations.

[0021] FIG. 4A is a line chart showing daily TAF release profiles of co-formulated devices containing TAF and LNG formulations.

[0022] FIG. 4B is a line chart showing daily TAF release profiles of co-formulated devices containing TAF and ENG formulations.

[0023] FIG. 5A is a line chart showing daily LNG release profiles of multi-drug devices containing TAF and LNG formulations.

[0024] FIG. 5B is a line chart showing daily ENG release profiles of multi-drug devices containing TAF and ENG formulations.

[0025] FIG. 6A is a line chart showing daily EFDA release profiles of multi-drug devices containing EFDA and LNG formulations at different lengths.

[0026] FIG. 6B is a line chart showing daily EFDA release profiles of multi-drug devices containing EFDA and LNG formulations at different wall thicknesses.

[0027] FIG. 7 A is a line chart showing daily LNG release profiles of multi-drug devices containing EFDA and LNG formulations at different lengths.

[0028] FIG. 7B is a line chart showing daily LNG release profiles of multi-drug devices containing EFDA and LNG formulations at different lengths wall thicknesses.

[0029] FIG. 8A is a line chart showing daily EFDA release profiles of multi-drug devices containing EFDA and ENG formulations at different lengths.

[0030] FIG. 8B is a line chart showing daily EFDA release profiles of multi-drug devices containing EFDA and ENG formulations at different wall thicknesses.

[0031] FIG. 9A is a line chart showing daily ENG release profiles of multi-drug devices containing EFDA and ENG formulations at different lengths.

[0032] FIG. 9B is a line chart showing daily ENG release profiles of multi-drug devices containing EFDA and ENG formulations at different wall thicknesses.

[0033] FIG. 10A is a line chart showing daily FTC and TAF release profiles of multi-drug devices containing FTC and TAF formulation (33% FTC, 33% TAF).

[0034] FIG. 10B is a line chart showing daily FTC and TAF release profiles of multi-drug devices containing FTC and TAF formulations (40% FTC, 40% TAF).

[0035] FIG. 11A is a line chart showing daily BIC and EFdA release profiles of multi-drug devices containing BIC and EFdA formulation (8% EFdA, 39.5% BIC).

[0036] FIG. 11B is a line chart showing daily BIC release profiles of multi-drug devices containing BIC and EFdA formulations.

[0037] FIG. llC is a line chart showing daily EFdA release profiles of multi-drug devices containing BIC and EFdA formulations.

DETAILED DESCRIPTION

[0038] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to preferred embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the disclosure is thereby intended, such alteration and further modifications of the disclosure as illustrated herein, being contemplated as would normally occur to one skilled in the art to which the disclosure relates.

[0039] Articles “a” and “an” are used herein to refer to one or to more than one (i.e. at least one) of the grammatical object of the article. By way of example, “a reservoir device” means at least one reservoir device and can include more than one reservoir device.

[0040] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0041] A biodegradable medical device and accompanying formulations that enable long-acting, sustained delivery of more than one active pharmaceutical ingredient (API) in a single formulation are described. The device can sustainably release more than one active agent at zero order kinetics. In embodiments, the medical device is in the form of a cylinder comprising a biodegradable polymer membrane, with the cylinder having a reservoir containing a formulation comprising at least two active agents and an excipient. The formulation can be used, in some situations, for prevention or treatment of disease. The polymer is permeable to the drug after injection into a body. The release rate of the drug is controlled by the formulation within the reservoir, the physicochemical properties of the API and excipient and the polymer thickness, the surface area of the implant. The medical device can be preferably used for long term prevention or treatment of disease or for prevention of pregnancy, or combinations of both.

[0042] The medical device is a biodegradable, zero-order implant that can accommodate more than one drug in the reservoir. Formulating more than one active agent in a single formulation (also referred to herein as co-formulating or multi-drug formulating) has benefits and advantages. For example, including more than one drug in the implant reservoir facilitates ease and scale-up during fabrication and manufacturing of the implant. Moreover, the formulation of multiple drugs can be tuned to meet targeted release rates and targeted depletion profiles (i.e., multiple drugs deplete simultaneously from the implant or at different times) as needed.

Further, using a single implant with a multi-drug formulation eliminates the need for insertion of multiple implants, each with a unique drug. In embodiments, the use of multi-drug formulations results in preferred release profiles of each drug, as compared to single drug formulations. For example, ENG + TAF results in faster release rates of ENG and TAF from the implant, as compared to ENG or TAF alone.

[0043] The terms “active pharmaceutical ingredient” and “active agent” are used interchangeably throughout the present description. Moreover, the terms “co-formulation,” “multi-active agent formulation” and “multi-drug formulation” are also used interchangeably throughout the present description. The term multi-drug formulation will be understood to mean a formulation comprising more than one active agent. For example, the multi-drug formulation may comprise two, three, four, five, or more active agents. Additionally, the multi drug formulation may also comprise one or more excipients.

[0044] The medical device has a reservoir that contains a multi-active agent formulation. The reservoir is defined by a biodegradable, permeable polymer membrane that has a thickness of at least 45 pm. In a preferred embodiment, the polymer membrane has a thickness of at least 70 pm. The membrane allows for diffusion of the more than one active agent of the formulation there through when positioned subcutaneously in a body of a subject.

[0045] The active agent formulation includes more than one active agent and an excipient. One or more of the more than one active agent can be one or a combination of a therapeutic, a preventative, a prophylactic and/or a contraceptive. In some embodiments, at least one of the active agents comprises an antibody, a small molecule, a protein, and/or a peptide. For example, in embodiments, at least one of the active agents comprises an antibody for the prevention of HIV infection. In other embodiments, at least one of the active agents comprises a nucleotide reverse transcriptase inhibitor (NRTI) for prevention of HIV infection. Exemplary active agents include Tenofovir Alafenamide Fumarate (TAF), Tenofovir (TFV), Tenofovir disoproxil fumarate, 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) or a pro drug of EFdA such as EFdA-alafenamide (or other), Abacavir, Bictegravir (BIC), Raltegravir (RTG), Dolutegravir (DTG), Levonorgestrel (LNG), Etonogestrel (ENG) Emtricitabine (FTC), Lamivudine (3TC), Tamoxifen, Tamoxifen citrate, Naltrexone hydrochloride, Naltrexone, Naloxone or combinations thereof. Not all active agents are amenable for use in the described device. Active agents having sufficient aqueous solubility and stability and dosing requirements and that are amenable to size parameters of the device are suitable for use in the described device. Moreover, in embodiments, the active agents retain a high level of purity that is both safe and efficacious to the user throughout the intended dosage duration and are not susceptible to immediate degradation caused by environmental contents (e.g., body fluids, physiological temperature). In additional embodiments, the solubility of active agents within potential excipients can range from 0.1-50 mg/mL. Whether the solubility of the active agents in the excipient enables a sufficient rate of drug release to meet therapeutic dose criteria is considered when selecting active agent/excipient pairings. For example, Elvitegravir, an integrase inhibitor used to treat HIV infection, was evaluated for use in the described device but was not selected for further development because of relatively low solubility and suboptimal potency of the drug. More particularly, the required subcutaneous dose for Elvitegravir is estimated to be ~16 mg/day. In an exemplary device, the active agent loading capacity of one device (2.5mm x 40mm) is about 120 mg. With these values, the implant would be depleted in a week.

[0046] Additional potential active pharmaceutical ingredients include active agents useful for various indications including, but not limited to, hormones for thyroid disorder, autoimmune disease or adrenal insufficiency, androgen replacement therapy, transgender hormone therapy, androgen deprivation therapy, growth hormone deficiency, Cushing’s syndrome, depression, use as contraceptive agents and diabetes; antibiotics; antivirals for HIV, Influenza, Rhinoviruses, Coronaviruses, Herpes, Hepatitis B, and Hepatitis C; Opioid addiction; antidepressants; antipsychotics; Attention-Deficit/Hyperactivity Disorder (ADHD); Hypertension; and Breast Cancer. Exemplary active pharmaceutical ingredients can include, without limitation, the following hormones: Levothyroxine, Thyroxine (T4), Triiodothyronine (T3), Cortisol, Dexamethasone, Testosterone, Leuprorelin, Goserelin, Triptoreline, Histrelin, Buserelin, Degarelix, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, Growth hormone, somatotropin, recombinant growth hormone, Antiglucocorticoid compounds (Mifepristone, metyrapone, ketoconazole), Insulin, Contraceptive agents such as Progestogens: desogestrel, norethisterone, etynodiol diacetate, levonorgestrel, lynestrenol, norgestrel, Estrogen, ethinylestradiol, and mestranol.

[0047] Exemplary active pharmaceutical ingredients can include, without limitation, the following antibiotics: penicillins, cephalosporins, rifamysins, lipiarmycins, quinolones, sulfonamides, macrolides, lincosamides, and tetracyclines.

[0048] Exemplary active pharmaceutical ingredients can include, without limitation, the following HIV antivirals: Integrase Inhibitors such as Dolutegravir, Elvitegravir, and Raltegravir; Nuceloside/Nucleotide reverse transcriptase inhibitors (NRTIs) such as abacavir, lamivudine, zidovudine, emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, EFdA, didanosine, stavudine, and zalcitabine; Non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as efavirenz, etravirine, nevirapine, rilpivirine, and delavidine mesylate; Protease inhibitors such as atazanavir, cobicistat, lopinavir, ritonavir, darunavir, fosamprenavir, tipranavir, nelfinavir, indinavir, saquinavir, and amprenavir; Entry Inhibitors such as enfuviride; CCR5 antagonists such as maraviroc, and vicriviroc; and P4503A inhibitors such as cobicistat and ritonavir. Exemplary active pharmaceutical ingredients can further include, without limitation, the following influenza antivirals: Amantadine, Umifenovir, Moroxydine, Nitazoxanide, oseltamivir, peramivir, rimantadine, zanamivir; the following Herpes antivirals: Acyclovir, edoxudine, famciclovir, foscamet, inosine pranobex, idoxuridine, penciclovir, trifluridine, valaciclovir, vidarabine; the following Hepatitis B antivirals: Adefovir, entecavir, pegylated interferon alfa-2a; and the following Hepatitis C antivirals: Sofosbuvir, simeprevir, ledipasvir, daclatasvir, velpatasvir, telaprevir, and taribavirin. Exemplary active pharmaceutical ingredients can further include, without limitation, remdesivir, hydroxychloroquine, chloroquine, and azithromycin. Exemplary APIs can further include, without limitation, corticosteroids, including prednisone, prednisolone, methylprednisolone, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone and mometasone.

[0049] Exemplary active pharmaceutical ingredients can include, without limitation, the following active agents for use with opioid addiction: Methadone, buprenorphine, naltrexone, naloxone, nalmefene, nalorphine, nalorphine dinicotinate, levallorphan, samidorphan, dezocine, nalbuphrine, pentazocine, phenazocine, and butophanol. Exemplary active pharmaceutical ingredients can include, without limitation, the following antidepressants and antipsychotics: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran, Venlafaxine, Vilazodone,

Vortioxetine, Trazodone,, Atomoxetine, Reboxetine, Teniloxazine, Viloxazine, Bipropion, Amitriptyline, Amitriptylinoxide, Clomipramine, Desipramine, Dibenzepin, Dimetacrine, Dosulepin, Doxepin, Imipramine, Lofepramine, Melitracen, Nitroxazepine, Nortriptyline, Noxiptiline, Opipramol, Pipofezine, Protriptyline, Trimipramine, Tetracyclic antidepressants, Amoxapine, Maprotiline, Mianserin, Mirtazapine, Setiptiline, Amisulpride, Aripiprazole, Brexpiprazole, Lurasidone, Olanzapine, Quetiapine, Risperidone, Buspirone, Lithium, and Modafinil. Exemplary active pharmaceutical ingredients can include, without limitation, the following agents for ADHD: Adderall XR, Concerta, Dexedrine, Evekeo, Focalin XR, Quillivant XR, Ritalin, Strattera, and Vyvanse. Exemplary active pharmaceutical ingredients can include, without limitation, the following agents for Hypertension: Beta-blockers such as cebutolol, atenolol, betaxolol, bisoprolol, bisoprolol/hydrochlorothiazide, metoprolol tartrate, metoprolol succinate, nadolol, pindolol, propranolol, solotol, timolol; Angiotensin converting enzyme inhibitors (ACE inhibitors) such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril; and Angiotensin-receptor blockers (ARBs) such as candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan. Exemplary active pharmaceutical ingredients can include, without limitation, the following agents for Breast Cancer: Tamoxifen, anastrozole, exemestane, letrozole, fulvestrant, toremifene. Exemplary active pharmaceutical ingredients can include, without limitation, the following agents: Rintatolimod for Chronic fatigue syndrome, Cidofovir, Fomivirsen for cytomegalovirus retinitis, Metisazone for smallpox, pleconaril for picornavirus respiratory infection, ribavirin for Hepatitis C or viral hemorrhagic fevers, and valganciclovir for cytomegalovirus CMV infection.

[0050] An excipient can be mixed with the more than one active agent to form the active agent formulation, and thus, is also contained within the reservoir. Exemplary excipients include, but are not limited to, castor oil, sesame oil, oleic acid, polyethylene glycol, ethyl oleate, propylene glycol, glycerol, cottonseed oil, polysorbate 80, synperonic PE/L or combinations thereof. Criteria for down- selection of the excipients include the stability (e.g., chemical purity) and compatibility (e.g., physical mixing properties) of the active agent formulation, and support of targeted release kinetics. As used herein, the stability of a component (active or excipient) means that the component retains its original chemical structure and biological activity after exposure to an environmental condition. For example, a component may have a chemical stability greater than 90%, as determined by HPLC-UVVIS analysis. Additional potential excipients include, for example, polyethylene glycol 300 (PEG 300), PEG 400, PEG 600, PEG40, a-cyclodextrin, b-cyclodextrin, and g-cyclodextrin.

[0051] The choice of excipient to use in a multi-drug formulation with active agents can affect the release rate and release profile of the active agents. For example, the solubility of the particular active agents in an excipient can affect the release rate and profile of the active agents. In some embodiments, an excipient with higher solubility for the active agents can show a faster release rate. Moreover, the choice of excipient may have little to no effect on the release profile. For example, in formulations wherein a relatively small amount of excipient is used, the excipient may have little to no effect on the release profile.

[0052] Additionally, the formulation or concentration ratio of active agent or agents to excipient can affect the release profile of the active agent. In embodiments, it is desirable to find a maximum ratio or optimal ratio of active agent(s) to excipient that maximizes loading capacity of active agents in the device while maintaining a zero-order release profile. When the ratio of active agents to excipient is above the maximum ratio, the release profile may not be a linear, zero-order release profile. However, the release profile may transition to a linear, zero-order release profile over time, as active agents are released from the device. A device having an active agent formulation with a ratio of active agents to excipient that is below the maximum ratio may provide a zero-order release profile. All other parameters being the same (for example, excipient type, active agent, device size, and membrane thickness), the device with the lower ratio of drugs to excipient has fewer active agents than a device having the maximum ratio and thus will likely have a shorter active agent release duration than the device with the maximum ratio.

[0053] Moreover, the properties and characteristics of a particular active agent or agents and a particular excipient can determine the formulation ratio that is ideal for a particular application. Accordingly, the formulation ratio for a single active agent may be different depending on the excipient that is used. Moreover, the formulation ratio for one active agent in a multi-agent formulation may be different depending on the second (or subsequent) active agent in the multi agent formulation.

[0054] Two processes are involved in the controlled release of an active agent or agents: 1) Dissolution of the active agent (e.g., TAF) within an excipient, and 2) Diffusion of the active agent solution through the polymer membrane.

[0055] With the dissolution process, particles of active agent are continuously being dissolved in the excipient solution. The Noyce- Whitney equation can be used to describe the dissolution process:

[0057] In the Noyce- Whitney equation, dm/dt is the dissolution rate, A is the surface area of the interface between the substance and the solvent, Ds is the diffusion coefficient within the excipient, h is the thickness of the diffusion layer, Cs is the saturation concentration of the substance within the solvent, and Ci, is the mass concentration of the substance in the bulk of the solvent.

[0058] With the diffusion process, the active agent (e.g., TAF) first partitions into the membrane and then diffuses to the other side of the membrane. Fick’s First Law of Diffusion can be used to describe the diffusion process:

[0060] In Fick’s first law of diffusion, J is diffusion rate or the amount of drug released from the membrane per unit area per unit time, Dm is diffusion coefficient through the membrane, f is concentration, and x is length. FIG. 1 is a labelled, schematic representation of a drug delivery device.

[0061] According to Fick’s first law of diffusion, when the reservoir is saturated, a constant concentration gradient dcpldx is maintained in the membrane, so the rate for drug flux J is constant and zero order release is achieved. The constant release rate for the diffusion-controlled process can be calculated according to the modified diffusion equation:

[0063] In the modified equation, J is the amount of drug released from the membrane per unit area per unit time (mg/day/mm2), Dm is diffusion coefficient through the membrane, K is partition coefficient, Cs is the saturation concentration of the substance within the excipient, L is thickness of the PCL membrane.

[0064] When the dissolution rate is greater than the diffusion rate, the release rate is membrane controlled and the release profile is linear. In contrast, when the dissolution rate is less than the diffusion rate, the release rate is dissolution limited or controlled and the release profile is non linear.

[0065] The active agent formulation can include additional components. For example, antioxidant components (e.g., a-tocopherol, retinyl palmitate, selenium, Vitamin A, Vitamin C, cysteine, methionine, citric acid, sodium citrate, methyl paraben, and propyl paraben), buffering agents and hydrophile lipophile balance (HLB) modifiers can be included in the formulation. Exemplary buffering agents and HLB modifier include, but are not limited to, sodium citrate, dibasic potassium phosphate, sodium succinate, meglumine, glycine, tromethamine, Labrafac WL 1349 (HLB 1), Compritol 888 (HLB 1), Labrafil M2130 (HLB 9) and Gelot 64 (HLB 10). Binders can also be used in the formulation including sugar alcohols (e.g., xylitol, sorbitol, mannitol), polysaccharides (e.g., starches, cellulose, hydroxypropyl cellulose), or disaccharides (e.g., sucrose, lactose). One of ordinary skill in the art will understand that additional suitable excipient components may be included as appropriate and/or as needed.

[0066] The biodegradable, permeable polymer membrane also affects the release kinetics of the active agent. For example, the thickness of the membrane affects the release rate of the more than one active agent. As the thickness of the membrane increases, the release rate of the active agents decreases. In exemplary embodiments, the membrane can have a thickness ranging from about 45 pm to about 500 pm. For example, the membrane may have a thickness of 45 pm, 50 pm, 60 pm, 70 pm, 80 pm, 90 pm, 100 pm, 110 pm, 120 pm, 130 pm, 140 pm, 150 pm, 160 pm, 170 pm, 180 pm, 190 pm, 200 pm, 210 pm, 220 pm, 230 pm, 240 pm or 250 pm, 260 pm, 270 pm, 280 pm, 290 pm, 300 pm, 320 pm, 340 pm, 360 pm, 380 pm, 400 pm, 420 pm, 440 pm, 460 pm, 480 pm, or 500 pm.

[0067] The polymer membrane can comprise homopolymers, blends of more than one homopolymer, block co-polymers, or combinations thereof. Configurations of the co-polymers can include random, linear block co-polymers, and star-shaped block co-polymers. A non limiting example of a block co-polymer is ABA, where A is a crystallizable block and B is an amorphous block. A non-limiting example of a star-shaped block co-polymer includes the

combination of Poly-s-caprolactone and Poly-valerolactone. Exemplary embodiments of the device may include one or more of the following polymers: Poly-a-caprolactone, Poly(a-caprolactone-co-c-decalactone), Polyglycolic acid, Polylactic acid, Poly(glycolic-co-lactic) acid, Polydioxanone, Polyvalerolactone, Poly(3-hydroxyvalerate), Poly(3-hydroxylbutyrate), Polytartronic acid, and Poly( -malonic acid).

[0068] The molecular weight of the polymer can affect the release rate of the active agents. For example, release rates of active agents from the implant can be tuned using polymers of different starting molecular weights. Moreover, polymer compositions that include binary polymer blends offer the ability to further tailor biodegradation rates, API release rates, and mechanical properties. The membrane of the device may comprise homopolymers. As used herein, “homopolymer” means a polymer chain comprising a single monomer. Homopolymers can be different molecular weights. Non-limiting examples of homopolymers include poly-e-caprolactone (PCL), poly(L-lactide), poly(D-lactide), poly(D,L-lactide), polyglycolide (PGA), polyacrylic acid, polydioxanone (PDO), poly(valerolactone), poly(3-hydroxyvalerate), poly(3-hydroxylbutyrate) (3-PHB), poly(4-hydroxylbutyrate) (4-PHB), polyhydroxyvalerate (PHV), polytartronic acid, poly(D,L-methylethylglycolic acid), poly(dimethylglycolic acid), poly (D,L-ethylglycolic acid), and poly( -malonic acid) or combinations thereof. In certain embodiments, blends of two homopolymers are used.

[0069] In certain embodiments, the membrane of the implant may comprise co-polymers. Co polymers can comprise different connectivity including block co-polymers, graft co-polymers, random co-polymers, alternating co-polymers, star co-polymers, and periodic co-polymers. Nonlimiting examples of co-polymers include poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-D-lactide), poly(L-lactide-co-glycolide), poly(F-lactide-co-a-caprolactone), poly(D,L-lactide-co-a-caprolactone), poly(D,L-lactide-co-glycolide), poly(glycolide-co-a-caprolactone), poly(8-caprolactone-co-D,L-8-decalactone), polylactide-block-poly(a-caprolactone-co-a-decalactone)-block-poly(lactide), poly(ethylene g 1 ycol -co- e-capro 1 ac to ne) , poly-e-caprolactone-co-polyethylene glycol, poly(3-hydroxylbutyrate-co-3-hydroxylvalerate), poly(ethylene glycol-co-lactide), or combinations thereof.

[0070] For example, the membranes may comprise polycaprolactone (PCF) at a number average molecular weight ranging from 15,000 to 140,000 Da. In some embodiments, a

higher molecular weight PCL (e.g., 80 kDa) results in a faster release rate of active agent, whereas a lower molecular weight PCL (e.g., 45 kDa) results in a slower release rate of active agent. In embodiments, implants can be fabricated from PCL tubes with MW of approximately 50 kDa (PC08), 72kDa (PC12), 106kDa (PC17), 130 kDa (PC31), and >130kDa (PC41).

[0071] In embodiments, the implant is designed to biodegrade within the body after the active agents are depleted. The biodegradable polymer (e.g., PCL) can be tuned to meet the requisite biodegradation properties (that is, to optimize the time between depletion of active agents and complete polymer biodegradation). For example, biodegradation can be tuned by selecting targeted molecular weights of a homopolymer (e.g., PCL of 45 kDa or 80kdA or blends) or by using co-polymers, as listed above. The polymer membrane has an initial molecular weight at implantation. In embodiments, the polymer membrane is configured such that the molecular weight of the membrane is reduced to a molecular weight ranging from 10 kDa to 2 kDa after the active agents are depleted from the device. For example, the molecular weight may be reduced to a molecular weight ranging from about 8 kDa to about 3 kDa after the drugs are depleted from the device. Without being bound by theory, it is believed that PCL undergoes biodegradation via bulk mode hydrolysis. For example, substantial loss of weight and fragmentation of polymer can occur at about 5 kDa MW, with intracellular bioresorption taking place at about 3 kDa MW. In embodiments, the polymer membrane can be configured such that it undergoes fragmentation at a time ranging from about 1 month to about 6 months after the active agents are depleted from the device. In this regard, exemplary embodiments having 80 kDa MW PCL films have shown an extended rate of biodegradation, typically on the order of >24 months. Further description is provided by the examples below.

WE CLAIMS:

The invention claimed is:

1. A reservoir device comprising an active agent formulation contained within a reservoir, wherein the active agent formulation comprises more than one active agent, and wherein the reservoir is defined by a biodegradable, permeable polymer membrane, the membrane allowing for diffusion of the more than one active agent of the formulation there through when positioned subcutaneously in a body of a subject.

2. The device of claim 1, wherein the permeable polymer membrane has a thickness of about 45 pm to about 300 pm, preferably about 70 pm to about 300 pm.

3. The device of claim 1, wherein the active agent formulation comprises the more than one active agent and an excipient.

4. The device of claim 3, wherein at least one of the more than one active agent comprises Tenofovir Alafenamide Fumarate (TAF), 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), Abacavir, Levonorgestrel (LNG); Etonogestrel (ENG), emtricitabine (FTC), Tenofovir (TFV), Tenofovir disoproxil fumarate (TDF), EFdA-alafenamide, bictegravir, raltegravir, dolutegravir, lamivudine (3TC), tamoxifen citrate, naltrexone or combinations thereof.

5. The device of any one of claims 1-4, wherein the more than one active agent comprises EFdA and LNG.

6. The device of any one of claims 1-4, wherein the more than one active agent comprises EFdA and ENG.

7. The device of any one of claims 1-4, wherein the more than one active agent comprises LNG and TAF.

8. The device of any one of claims 1-4, wherein the more than one active agent comprises TAF and ENG.

9. The device of claim 1, wherein the active agent formulation comprises TAF and ENG, the polymer membrane has a defined thickness, and TAF diffuses from the device at a TAF release rate, wherein the TAF release rate from the device is greater than a release rate of TAF from a second device having the same physical characteristics as the device of claim 1 except that the second device only has TAF as active agent in the active agent formulation.

10. The device of claim 1, wherein the active agent formulation comprises TAF and ENG, the polymer membrane has a defined thickness, and ENG diffuses from the device at an ENG release rate, wherein the ENG release rate from the device is greater than a release rate of ENG from a second device having the same physical characteristics as the device of claim 1 except that the second device only has ENG as active agent in the active agent formulation.

11. The device of claim 3, wherein at least one of the more than one active agent comprises an antibody, a small molecule, a protein, a peptide, or a combination thereof.

12. The device of claim 3, wherein the excipient comprises castor oil, sesame oil, oleic acid, polyethylene glycol 600, ethyl oleate, propylene glycol, glycerol, cottonseed oil, polyethylene glycol 40, polyethylene glycol 300, polyethylene glycol 400, Polysorbate 80, Synperonic PE/L 44, a-cyclodextrin, b-cyclodextrin, g-cyclodextrin or combinations thereof.

13. The device of claim 3, wherein the more than one active agent includes a first active agent and a second active agent, which is different from the first active agent.

14. The device of claim 13, wherein the first active agent comprises EFdA or TAF and the second active agent comprises LNG or ENG.

15. The device of claim 1, wherein the polymer membrane comprises polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA) or a blend thereof.

16. The device of claim 1, wherein the polymer membrane comprises polycaprolactone (PCL) at a molecular weight ranging from 15,000-140,000 Da.

17. The device of claim 1, wherein the polymer membrane comprises one or more of a homopolymer, a random co-polymer, an alternating co-polymer, a block co-polymer, a graft co-polymer, a star homopolymer, a star co-polymer.

18. The device of claim 17, wherein the polymer membrane comprises a blend of homopolymers.

19. The device of claim 18, wherein the blend of homopolymers comprises a blend of one or more of PC08, PC 12, PC31, PC41, and PC 17.

20. The device of claim 17, wherein the polymer membrane comprises a blend of a

homopolymer and a co-polymer.

21. The device of claim 1 , wherein the device has a cylindrical shape with a length between about 10 mm and 50 mm.

22. A reservoir device comprising an active agent formulation contained within a reservoir, wherein the active agent formulation comprises more than one active agent, and wherein the reservoir is defined by a biodegradable, permeable polymer membrane, the membrane allowing for diffusion of the more than one active agent there through with zero-order release kinetics for a time period of at least 60 days when positioned subcutaneously in a body of a subject.

23. The device of claim 22, wherein at least one of the more than one active agent comprises Tenofovir Alafenamide Fumarate (TAF), 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), Abacavir, Levonorgestrel (LNG); Etonogestrel (ENG), emtricitabine (FTC), Tenofovir (TFV), Tenofovir disoproxil fumarate (TDF), EFdA-alafenamide, bictegravir, raltegravir, dolutegravir, lamivudine (3TC), tamoxifen citrate, naltrexone or combinations thereof.

24. The device of claim 22, wherein at least one of the more than one active agent comprises an antibody, a small molecule, a protein, a peptide, or a combination thereof.

25. The device of claim 22, wherein the reservoir further contains an excipient.

26. The device of claim 25, wherein the excipient comprises castor oil, sesame oil, oleic acid, polyethylene glycol 600, ethyl oleate, propylene glycol, glycerol or combinations thereof.

27. The device of claim 22, wherein the polymer membrane comprises one or more of a homopolymer, a random co-polymer, an alternating co-polymer, a block co-polymer, a graft co-polymer, a star homopolymer, a star co-polymer.

28. The device of claim 27, wherein the polymer membrane comprises a blend of homopolymers.

29. The device of claim 22, wherein the polymer membrane comprises polycaprolactone (PCL), poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA) or a blend thereof.

30. The device of claim 22, wherein the polymer membrane comprises polycaprolactone (PCL) at a molecular weight ranging from 15,000-140,000 Da.

31. The device of claim 22, wherein the thickness of the permeable polymer membrane is between about 45 pm and about 300 pm.

32. The device of claim 22, wherein the device has a cylindrical shape with a length between about 10 mm and 50 mm.

33. The device of claim 1 or claim 22, wherein the polymer membrane has an initial molecular weight at implantation and wherein the membrane is configured such that the molecular weight of the membrane is reduced to a molecular weight ranging from 8kDa to 3 kDa after the more than one active agent is depleted from the device.

34. The device of claim 1 or claim 22, wherein the polymer membrane is configured such that the membrane undergoes fragmentation at a time ranging from about 1 month to about 6 months after the more than one active agent is depleted from the device.

35. The device of claim 1 or claim 22, wherein the biodegradable, permeable polymer membrane is configured to substantially or fully degrade within a time period of about 3 months to about 2 years.

36. The device of claim 1 or claim 22, wherein the device is removable within the window of drug delivery.

37. The device of claim 1 or claim 22, wherein the device is configured for zero-order release of multiple active agents

38. The device of claim 1 or claim 22, wherein the device is configured to be tuned based on various considerations, including, for example: (1) active agents; (2) excipient composition and concentration (e.g., ratio of excipient to active agent); (3) polymer membrane thickness, molecular weight, composition and crystallinity; and (4) device surface area.

39. The device of claim 1 or claim 22, wherein the device is configured to meet different dosing requirements.

40. A method of preventing or aiding in preventing HIV comprising, implanting the device of claim 1 or claim 22 into a subject in need thereof.

41. A method of contraception comprising implanting the device of claim 1 or claim 22 into subject in need thereof.

42. A combinatorial method of preventing or aiding in preventing HIV and contraception comprising implanting the device of claim 1 or claim 22 into a subject in need thereof.