Multidrug formulations for biodegradable subcutaneous storage devices

Abstract

A reservoir device comprising an active agent formulation contained within a reservoir is described. The active agent formulation comprises more than one active agent. The reservoir is defined by a biodegradable, permeable polymer membrane. When placed subcutaneously within a subject, the membrane allows more than one active agent of the formulation to diffuse through it.

Description

[0001] Cross-reference to related applications

[0002] This application is an international application claiming priority to U.S. Provisional Application No. 63 / 006,163, filed April 7, 2020, the entire contents of which are incorporated herein by reference.

[0003] Federal Funding Explanation

[0004] This invention was made with the support of a cooperation agreement No. AID-OAA-A-17-00011 granted by the United States Agency for International Development. The government holds certain rights to this invention. Technical Field

[0005] This document describes a biodegradable subcutaneous reservoir device for the continuous delivery of an active agent over an extended period of time. The physical parameters of the device and the active agent formulation contained therein can be selected to provide efficient and continuous delivery of the active agent. In one embodiment, the reservoir device may contain an active agent formulation having more than one active agent. Background Technology

[0006] The need for effective biomedical interventions for preventative indications (such as pregnancy, infectious diseases) and therapeutic needs (such as diseases, opioid addiction) remains significant worldwide. End-users often struggle with suboptimal adherence to daily oral or on-demand interventions. Continuous, user-independent delivery of active pharmaceutical ingredients (APIs) or active agents allows users to avoid cumbersome time- or event-driven protocols and bypass many adherence challenges associated with user-dependent approaches. Furthermore, systemic administration combined with long-term delivery can significantly protect against and treat many disease indications without the first-pass effect of the liver (which reduces bioavailability).

[0007] One area where improvements in biomedical interventions have proven beneficial is the global HIV epidemic. HIV pre-exposure prophylaxis (PrEP) using antiretroviral (ARV) drugs is a promising biomedical strategy for addressing this global problem. Tenofovir-based PrEP has proven successful in terms of daily and on-demand dosing. Despite these advances, adherence to time- or event-driven regimens for PrEP remains a challenge. Long-acting (LA) delivery of ARV drugs simplifies traditional dosing regimens for PrEP by reducing the emotional and logistical burden of user-dependent approaches. For example, injectable LA formulations of the integrase inhibitor cabotegravir (CAB) are currently being investigated in a two-phase 2 / 3 HIV PrEP trial. See HPTN083 and HPTN084. While injectable formulations are accepted by many users and offer key advantages such as bi-monthly dosing and flexibility, drawbacks do exist. Injectable formulations cannot be removed in the event of drug-related adverse events, and there is a possibility of a long plasma "tail" at subtherapeutic drug levels.

[0008] A promising biomedical approach for LA-PrEP involves subcutaneous implants for sustained drug release, supporting longer-term adherence, enabling flexibility of use, reducing protocol burden, and maintaining reversibility throughout the treatment duration. Polymer implants can comprise different structures, each offering advantages in drug delivery. See Solorio, L. et al.; Yang, W.-W. et al.; and Langer, R. Reservoir implants involve a formulated drug core encapsulated by a rate-controlled polymeric barrier. Notable examples of implants with a core-sheath structure include the following collection of subcutaneous contraceptive implants: and For use in delivering levonorgestrel (LNG) using silicone-based polymer rods; and, and This implant is designed for delivery of etonogestrel (ENG) using ethylene-vinyl acetate (EVA)-based polymer rods. The low doses required for subcutaneous delivery of hormonal contraceptives allow these implants to last for many years. Furthermore, reservoir-type implants have shown practicality for ophthalmic indications.

[0009] Several implants for HIV PrEP are currently under development, each with a unique configuration and function. A subcutaneous silicone implant for delivering TAF from a polyvinyl alcohol (PVA)-coated orthogonal passageway showed 40 days of drug delivery in beagle dogs without observed adverse events. See Gunawardana, M. et al. A non-polymeric, refillable implant designed for delivering TAF and emtricitabine (FTC) from a single device showed sustained levels of tenofovir diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) for over 83 days in rhesus monkeys; however, only 28 days for FTC-TP due to the large required dosage and short plasma half-life. See Chua, CYX et al. A system called Medici Drug Delivery System... TM Titanium osmotic pump systems are being developed for use in PrEP and type 2 diabetes. See A New Collaboration for HIV Prevention, available online. Furthermore, matrix-type PrEP implants for delivering 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) have shown promising efficacy in HIV treatment and prevention, as demonstrated in animal models. See Barrett, SE, et al.

[0010] Currently, the need for long-acting, biodegradable drug delivery implants remains unmet. Such devices, exhibiting zero-order drug release kinetics, could provide a flat PK profile at steady state. Therefore, minimal tailing is expected when the active agent is depleted from the device, based on the drug's half-life. This technology could be used with a variety of therapeutic and preventative agents, including small molecules and biologics. Summary of the Invention

[0011] 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 μm. When subcutaneously placed within a subject, the membrane allows the more than one active agent of the formulation to diffuse through it.

[0012] The execution may include one or more of the following features: In the device, the permeable polymer membrane has a thickness of at least 45 μm. In the device, the surfactant formulation includes more than one surfactant and excipient.

[0013] In a second aspect of the invention, the reservoir device includes more than one active agent contained within the reservoir. The reservoir is defined by a biodegradable, permeable polymer membrane, wherein, when subcutaneously placed in a subject's body, the membrane allows the more than one active agent to diffuse through the membrane at zero-order release kinetics for at least 60 days.

[0014] The execution may include one or more of the following features. In the device, at least one of the more than one active agent includes tenofovir alafenamide fumarate (TAF), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), EFdA-alafenamide, levonorgestrel (LNG), etogestene (ENG), or a combination thereof. In the device, 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. In the device, the reservoir further contains an excipient. Attached Figure Description

[0015] The foregoing aspects and other features of this disclosure are explained in the following description in conjunction with the accompanying drawings, in which:

[0016] Figure 1A This is a schematic diagram of an exemplary drug delivery device according to aspects of the present invention. The left figure is a perspective view of the exemplary device. The right figure is a top view of the exemplary device.

[0017] Figure 1B yes Figure 4A A labeled version of the diagram.

[0018] Figure 1C This is a schematic diagram and a photograph of another exemplary device.

[0019] Figure 2A It is a line graph showing the daily EFdA release curve of a co-preparation unit containing EFdA and LNG formulations.

[0020] Figure 2B It is a line graph showing the daily EFdA release curve of a co-preparation device containing EFdA and ENG formulations.

[0021] Figure 3AIt is a line graph showing the daily LNG release curves of a multi-drug unit containing EFdA and LNG formulations.

[0022] Figure 3B It is a line graph showing the daily ENG release curve of a multidrug device containing EFdA and ENG formulations.

[0023] Figure 4A It is a line graph showing the daily TAF release curve of a co-preparation unit containing TAF and LNG formulations.

[0024] Figure 4B It is a line graph showing the daily TAF release curve of a co-preparation device containing TAF and ENG formulations.

[0025] Figure 5A It is a line graph showing the daily LNG release curves of a multi-drug unit containing TAF and LNG formulations.

[0026] Figure 5B It is a line graph showing the daily ENG release curve of a multidrug device containing TAF and ENG formulations.

[0027] Figure 6A It is a line graph showing the daily EFDA release curves of multidrug devices of different lengths containing EFdA and LNG formulations.

[0028] Figure 6B It is a line graph showing the daily EFDA release curves of multidrug devices with different wall thicknesses containing EFdA and LNG formulations.

[0029] Figure 7A It is a line graph showing the daily LNG release curves of multi-drug units of different lengths containing EFdA and LNG formulations.

[0030] Figure 7B It is a line graph showing the daily LNG release curves of multi-drug units with different wall thicknesses containing EFdA and LNG formulations.

[0031] Figure 8A It is a line graph showing the daily EFDA release curves of multidrug devices of different lengths containing EFDA and ENG formulations.

[0032] Figure 8B It is a line graph showing the daily EFDA release curves of multidrug devices with different wall thicknesses containing EFDA and ENG formulations.

[0033] Figure 9A It is a line graph showing the daily ENG release curves of multidrug devices of different lengths containing EFDA and ENG formulations.

[0034] Figure 9B It is a line graph showing the daily ENG release curves of multidrug devices with different wall thicknesses containing EFDA and ENG formulations.

[0035] Figure 10A It is a line graph showing the daily FTC and TAF release curves of a multidrug device containing FTC and TAF formulations (33% FTC, 33% TAF).

[0036] Figure 10B It is a line graph showing the daily FTC and TAF release curves of a multidrug device containing an FTC and TAF formulation (40% FTC, 40% TAF).

[0037] Figure 11A It is a line graph showing the daily BIC and EFdA release curves of a multidrug device containing BIC and EFdA formulations (8% EFdA, 39.5% BIC).

[0038] Figure 11B It is a line graph showing the daily BIC release curve of a multidrug device containing BIC and EFdA formulations.

[0039] Figure 11C It is a line graph showing the daily EFdA release curve of a multidrug device containing BIC and EFdA formulations. Detailed Implementation

[0040] To facilitate an understanding of the principles of this disclosure, reference will now be made to preferred embodiments, and these preferred embodiments will be described using specific language. Nevertheless, it should be understood that this is not intended to limit the scope of this disclosure, and such changes and further modifications to the disclosure as illustrated herein are contemplated by those skilled in the art to which this disclosure pertains.

[0041] The articles “a” and “a kind” are used in this document to refer to one or more (i.e., at least one) grammatical objects. For example, “storage device” means at least one storage device and may include more than one storage device.

[0042] 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 pertains.

[0043] A biodegradable medical device and accompanying formulation are described, capable of long-term, sustained delivery of more than one active pharmaceutical ingredient (API) in a single formulation. The device is capable of sustained release of more than one active agent with zero-order kinetics. In one embodiment, the medical device is in the form of a cylinder comprising a biodegradable polymer membrane, wherein the cylinder has a reservoir containing a formulation comprising at least two active agents and excipients. In some cases, the formulation can be used for the prevention or treatment of disease. The polymer is permeable to the drug after injection into the body. The drug release rate is controlled by the physicochemical properties of the formulation, API, and excipients within the reservoir, as well as the polymer thickness and the surface area of ​​the implant. The medical device may be preferably used for long-term prevention or treatment of disease, or for pregnancy prevention, or a combination of both.

[0044] This medical device is a biodegradable, level-zero implant capable of holding more than one drug within its reservoir. Formulating more than one active agent in a single formulation (also referred to herein as co-formulation or multidrug formulation) offers benefits and advantages. For example, including more than one drug in the implant reservoir facilitates simplification and scaling up of the implant fabrication and manufacturing process. Furthermore, formulations of multiple drugs can be tailored as needed to meet target release rates and target consumption profiles (i.e., multiple drugs are consumed from the implant simultaneously or at different times). Further, using a single implant with a multidrug formulation eliminates the need for inserting multiple implants (each with a unique drug). In implementation, the use of a multidrug formulation results in a preferred release profile for each drug compared to a single drug formulation. For example, ENG+TAF results in a faster release rate of both ENG and TAF from the implant compared to ENG or TAF alone.

[0045] The terms "active pharmaceutical ingredient" and "active agent" are used interchangeably throughout this specification. Similarly, the terms "co-formulation," "multi-active agent formulation," and "multi-drug formulation" are also used interchangeably throughout this specification. The term "multi-drug formulation" is understood to refer to a formulation containing more than one active agent. For example, a multi-drug formulation may contain two, three, four, five, or more active agents. Furthermore, a multi-drug formulation may also contain one or more excipients.

[0046] The medical device has a reservoir containing a multi-active agent formulation. The reservoir is defined by a biodegradable, permeable polymer membrane having a thickness of at least 45 μm. In a preferred embodiment, the polymer membrane has a thickness of at least 70 μm. When subcutaneously placed in the body of a subject, the membrane allows more than one active agent of the formulation to diffuse through the membrane.

[0047] The active agent formulation includes more than one active agent and excipients. One or more of the more than one active agent may be one or a combination of therapeutic agents, prophylactic agents, prophylactic drugs, and / or contraceptives. In some embodiments, at least one active agent includes an antibody, a small molecule, a protein, and / or a peptide. For example, in one embodiment, at least one active agent includes an antibody for preventing HIV infection. In other embodiments, at least one active agent includes a nucleotide reverse transcriptase inhibitor (NRTI) for preventing HIV infection. Exemplary active agents include tenofovir alafenamide fumarate (TAF), tenofovir (TFV), tenofovir disoproxil fumarate, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), or a prodrug of EFdA such as EFdA-alafenamide (or others), abacavir, bictegravir (BIC), raltegravir (RTG), dolutegravir (DTG), levonorgestrel (LNG), etogestene (ENG), emtricitabine (FTC), lamivudine (3TC), tamoxifen, tamoxifen citrate, naltrexone hydrochloride, naltrexone, naloxone, or combinations thereof. Not all active agents are suitable for use in the described device. An active agent with sufficient water solubility and stability, meeting dosage requirements and suitable for the device's size parameters, is suitable for the described device. Furthermore, in embodiments, the active agent maintains a high level of purity, ensuring safety and efficacy for the user throughout the intended dose duration, and is not susceptible to immediate degradation from environmental contents such as bodily fluids and physiological temperatures. In another embodiment, the solubility of the active agent in the potential excipient may range from 0.1 to 50 mg / mL. When selecting an active agent / excipient pair, consideration is given to whether the solubility of the active agent in the excipient allows for a sufficient drug release rate to meet therapeutic dose criteria. For example, elvitegravir (an integrase inhibitor used to treat HIV infection) was evaluated for use in the device, but was not selected for further development due to its relatively low solubility and poor potency. More specifically, the required subcutaneous dose of elvitegravir is estimated to be approximately 16 mg / day. In an exemplary device, one device (2.5 mm x 40 mm) has an active agent loading capacity of approximately 120 mg. Based on these values, the implants will run out within a week.

[0048] Other potential active pharmaceutical ingredients include active agents that can be used for a variety of indications, including but not limited to: hormones for thyroid diseases, autoimmune diseases, or adrenal insufficiency; androgen replacement therapy, sex hormone therapy, androgen blockade therapy; growth hormone deficiency; Cushing's syndrome; depression; as contraceptives; and diabetes; antibiotics; antiviral agents for HIV, influenza, rhinovirus, coronavirus, herpes, hepatitis B, and hepatitis C; opioid addiction; antidepressants; antipsychotics; attention deficit hyperactivity disorder (ADHD); hypertension; and breast cancer. Exemplary active pharmaceutical ingredients may include, but are not limited to, the following hormones: levothyroxine, thyroxine (T4), triiodothyronine (T3), cortisol, dexamethasone, testosterone, leuprorelin, goserelin, triptorelin, histrelin, buserelin, degarelix, cyproterone acetate, flutamide, nilutamide, bicalutamide, enzalutamide, growth hormone, somatotropin, recombinant growth hormone, anti-glucocorticoid compounds (mifepristone, metyrapone, ketoconazole), insulin, and contraceptives such as progestins: desogestrel, norethisterone, etynodiol. diacetat, levonorgestrel, ethinylestradiol, norgestrel, estrogen, ethinylestradiol, and mestranol.

[0049] Exemplary active pharmaceutical ingredients may include, but are not limited to, the following antibiotics: penicillins, cephalosporins, rifamycins, lipiarmycins, quinolones, sulfonamides, macrolides, lincosamides, and tetracyclines.

[0050] Exemplary active pharmaceutical ingredients may include, but are not limited to, the following HIV antiviral agents: integrase inhibitors, such as dolutegravir, erteiravir, and ralteiravir; nucleoside / 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 delavudine mesylate; proteases. Inhibitors, such as atazanavir, cobicistat, lopinavir, ritonavir, darunavir, fosamprenavir, tipranavir, nelfinavir, indinavir, saquinavir, and amprenavir; enterotropic inhibitors, such as enfuviride; CCR5 antagonists, such as maraviroc and vicriviroc; and P4503A inhibitors, such as cobicistat and ritonavir.Exemplary active pharmaceutical ingredients may further include, but are not limited to, the following influenza antiviral agents: amantadine, umifenovir, moroxydine, nitazoxanide, oseltamivir, peramivir, amantadine ethambutol, zanamivir; and the following herpes antiviral agents: acyclovir, edoxudine, famciclovir, foscarnet, inosine. The following antiviral agents are included: pranobex, idoxuridine, penciclovir, trifluridine, valacyclovir, and vidarabine; adefovir, entecavir, and pegylated interferon alpha-2a for hepatitis B; and so on, sofosbuvir, simeprevir, ledipasvir, daclatasvir, velpatasvir, telaprevir, and taribavirin. Exemplary active pharmaceutical ingredients may further include, but are not limited to, remdesivir, hydroxychloroquine, chloroquine, and azithromycin. Exemplary APIs may further include, but are not limited to, corticosteroids, including prednisone, prednisolone, methylprednisolone, beclometasone, betamethasone, dexamethasone, fluocortolone, halometasone, and mometasone.

[0051] Exemplary active pharmaceutical ingredients may include, but are not limited to, the following active agents used for opioid addiction: methadone, buprenorphine, naltrexone, naloxone, nalmefene, nalorphine, nalprofen dinicotinate, levallorphan, samidorphan, dezocine, nalbuphrine, pentazocine, phenazocine, and butophanol.Exemplary active pharmaceutical ingredients may include, but are not limited to, the following antidepressants and antipsychotics: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, venlafaxine, vilazodone, vortioxetine, trazodone, atomoxetine, reboxetine, teniloxazine, and viloxacin. xazine, bupropion, amitriptyline, oxyamitriptyline, clomipramine, desipramine, dibenzepin, dimetacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, opipramol, pipofezine, protriptyline, trimipramine, tetracyclic antidepressants Antidepressants, amoxapine, maprotiline, mianserin, mirtazapine, setiptiline, amisulpride, aripiprazole, brexpiprazole, lurasidone, olanzapine, quetiapine, risperidone, buspirone, lithium, and modafinil.Exemplary active pharmaceutical ingredients may include, but are not limited to, the following agents used for ADHD: Adderall XR, Concerta, Dexedrine, Evekeo, Focalin XR, Quillivant XR, Ritalin, Strattera, and Vyvanse. Exemplary active pharmaceutical ingredients may include, but are not limited to, the following agents used for hypertension: beta-blockers such as cebutolol, atenolol, betaxolol, bisoprolol, bisoprolol / hydrochlorothiazide, metoprolol tartrate, and metoprolol succinate. tartrate), 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 may include, but are not limited to, the following agents used for breast cancer: tamoxifen, anastrozole, exemestane, letrozole, fulvestrant, and toremifene.Exemplary active pharmaceutical ingredients may include, but are not limited to, the following agents: ritatolimod for chronic fatigue syndrome, cidofovir and fomivirsen for cytomegalovirus retinitis, metisazone for smallpox, pleconaril for picornavirus respiratory infections, ribavirin for hepatitis C or viral hemorrhagic fever, and valganciclovir for cytomegalovirus (CMV) infections.

[0052] The excipient can be mixed with more than one surfactant to form an surfactant formulation, and therefore, is also contained in 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, poloxamer PE / L (synperonic PE / L), or combinations thereof. Down-selection criteria for excipients include the stability (e.g., chemical purity) and compatibility (e.g., physical mixing properties) of the surfactant formulation and support for targeted release kinetics. As used herein, the stability of a component (active ingredient or excipient) means that the component retains its original chemical structure and biological activity after exposure to environmental conditions. For example, the chemical stability of a component may be greater than 90% as determined by HPLC-UVVIS analysis. For example, other potential excipients include polyethylene glycol 300 (PEG 300), PEG 400, PEG 600, PEG 40, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0053] The choice of excipients used in multi-drug formulations with active agents can affect the release rate and release profile of the active agent. For example, the solubility of a particular active agent in the excipient can affect the release rate and profile. In some embodiments, excipients with higher solubility in the active agent may exhibit a faster release rate. Moreover, the choice of excipient can have little to no effect on the release profile. For example, in formulations where a relatively small amount of excipient is used, the excipient may have almost no effect on the release profile.

[0054] Furthermore, the formulation or concentration ratio of one or more active agents to excipients can affect the release profile of the active agent. In embodiments, it is desirable to find the maximum or optimal ratio of active agent to excipient that maximizes the loading capacity of the active agent in the device while maintaining a zero-order release profile. When the ratio of active agent to excipient is higher than the maximum ratio, the release profile may not be a linear zero-order release profile. However, as the active agent is released from the device, the release profile can transition to a linear zero-order release profile over time. Devices with active agent formulations having an active agent ratio lower than the maximum ratio can provide a zero-order release profile. All other parameters being equal (e.g., excipient type, active agent, device size, and membrane thickness), a device with a lower ratio of drug to excipient has less active agent than a device with the maximum ratio, and therefore may have a shorter active agent release duration.

[0055] Furthermore, the properties and characteristics of a particular active agent or a particular excipient can determine the ideal formulation ratio for a specific application. Therefore, the formulation ratio of a single active agent may vary depending on the excipient used. Moreover, the formulation ratio of one active agent in a multi-pharmaceutical formulation may vary depending on the second (or subsequent) active agent in the multi-pharmaceutical formulation.

[0056] In the controlled release of one or more surfactants, two processes are involved: 1) dissolution of the surfactant (such as TAF) within the excipient, and 2) diffusion of the surfactant solution through the polymer membrane.

[0057] During the dissolution process, the surfactant particles continuously dissolve in the excipient solution. The Noyce-Whitney equation can be used to describe this dissolution process:

[0058]

[0059] 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, and D... s Where h is the diffusion coefficient within the excipient, and h is the thickness of the diffusion layer. s It is the saturation concentration of a substance in a solvent, and C b It is the mass concentration of a substance in the bulk solvent.

[0060] In this diffusion process, the surfactant (such as TAF) is first partitioned into the membrane and then diffuses to the other side of the membrane. Fick's first law of diffusion can be used to describe this diffusion process:

[0061]

[0062] In Fick's first law of diffusion, J is the diffusion rate, or the amount of drug released from the membrane per unit area per unit time, and Dm is the diffusion coefficient of the membrane. is the concentration, and x is the length. Figure 1 is a labeled schematic diagram of a drug delivery device.

[0063] According to Fick's first law of diffusion, when the reservoir is saturated, a constant concentration gradient is maintained in the membrane. Therefore, the drug flux rate J is constant and zero-order release is achieved. The constant release rate of the diffusion-controlled process can be calculated using the modified diffusion equation:

[0064]

[0065] In the modified equation, J is the amount of drug released from the membrane per unit area per unit time (mg / day / mm²). 2 Dm is the diffusion coefficient of the membrane, K is the partition coefficient, Cs is the saturation concentration of the substance in the excipient, and L is the thickness of the PCL membrane.

[0066] When the dissolution rate is greater than the diffusion rate, the release rate is controlled by the membrane, and the release curve is linear. Conversely, when the dissolution rate is less than the diffusion rate, the release rate is limited or controlled by the dissolution, and the release curve is non-linear.

[0067] Surfactant formulations may include other components. For example, antioxidant components (such as α-tocopherol, retinyl palmitate, selenium, vitamin A, vitamin C, cysteine, methionine, citric acid, sodium citrate, methylparaben, and propylparaben), buffers, and hydrophilic-lipophilic balance (HLB) modifiers may be included in the formulation. Exemplary buffers and HLB modifiers include, but are not limited to, sodium citrate, dipotassium hydrogen phosphate, sodium succinate, meglumine, glycine, tromethamine, Labrafac WL 1349 (HLB 1), Compritol 888 (HLB 1), Labrafil M2130 (HLB 9), and Gelot64 (HLB 10). Binders, including sugar alcohols (such as xylitol, sorbitol, mannitol), polysaccharides (such as starch, cellulose, hydroxypropyl cellulose), or disaccharides (such as sucrose, lactose), may also be used in the formulation. Those skilled in the art will understand that other suitable excipient components may be included as appropriate and / or as needed.

[0068] The biodegradable, permeable polymer membrane also affects the release kinetics of surfactants. For example, the membrane thickness affects the release rate of more than one surfactant. As the membrane thickness increases, the release rate of the surfactant decreases. In an exemplary embodiment, the membrane thickness can range from about 45 μm to about 500 μm. For example, the thickness of the membrane can be 45μm, 50μm, 60μm, 70μm, 80μm, 90μm, 100μm, 110μm, 120μm, 130μm, 140μm, 150μm, 160μm, 170μm, 180μm, 190μm, 200μm, 210μm, 220μm, 230μm, 240μm or 250μm, 260μm, 270μm, 280μm, 290μm, 300μm, 320μm, 340μm, 360μm, 380μm, 400μm, 420μm, 440μm, 460μm, 480μm or 500μm.

[0069] The polymer membrane may include homopolymers, blends of more than one homopolymer, block copolymers, or combinations thereof. The copolymer configuration may include random, linear block copolymers, and star-shaped block copolymers. A non-limiting example of a block copolymer is ABA, where A is a crystallizable block and B is an amorphous block. Non-limiting examples of star-shaped block copolymers include combinations of poly-ε-caprolactone and poly-valerol. Exemplary embodiments of the device may include one or more of the following polymers: poly-ε-caprolactone, poly(ε-caprolactone-copoly-ε-decanoic acid), polyglycolic acid, polylactic acid, poly(glycolic acid-copoly-lactic acid), polydioxane, polyvalerol, poly(3-hydroxyvalerate), poly(3-hydroxybutyrate), polypropionic acid, and poly(β-malonic acid).

[0070] The molecular weight of a polymer can affect the release rate of the active agent. For example, polymers with different starting molecular weights can be used to adjust the release rate of the active agent from the implant. Furthermore, polymer compositions comprising binary polymer blends offer the ability to further modulate biodegradation rates, API release rates, and mechanical properties. The membrane of the device may comprise a homopolymer. As used herein, "homogeneous polymer" means a polymer chain comprising a single monomer. Homopolymers can have varying molecular weights. Non-limiting examples of homopolymers include poly(ε-caprolactone) (PCL), poly(L-lactide), poly(D-lactide), poly(D,L-lactide), polyglycolic acid (PGA), polyacrylic acid, polydioxanone (PDO), poly(valerolactone), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate)(3-PHB), poly(4-hydroxybutyrate)(4-PHB), polyhydroxyvalerate (PHV), polytartronic acid, poly(D,L-methylethylglycolic acid), poly(dimethylglycolic acid), poly(D,L-ethylglycolic acid), and poly(β-malonic acid), or combinations thereof. In some embodiments, blends of two homopolymers are used.

[0071] In some embodiments, the membrane of the implant may comprise a copolymer. The copolymer may comprise various connectivity elements, including block copolymers, graft copolymers, random copolymers, alternating copolymers, star copolymers, and periodic copolymers. Non-limiting examples of copolymers include poly(L-lactide-copolymer-D,L-lactide), poly(L-lactide-copolymer-D-lactide), poly(L-lactide-copolymer-glycolic acid), poly(L-lactide-copolymer-ε-caprolactone), poly(D,L-lactide-copolymer-ε-caprolactone), poly(D,L-lactide-copolymer-glycolic acid), poly(glycolic acid-copolymer-ε-caprolactone), poly(ε-caprolactone-copolymer-D,L-ε-decanoic acid), polylactide-block-poly(ε-caprolactone-copolymer-ε-decanoic acid)-block-poly(lactide), poly(ethylene glycol-copolymer-ε-caprolactone), poly-ε-caprolactone-copolymer-polyethylene glycol, poly(3-hydroxybutyrate-copolymer-3-hydroxyvalerate), poly(ethylene glycol-copolymer-lactide), or combinations thereof.

[0072] For example, the membrane may comprise polycaprolactone (PCL) with a number-average molecular weight ranging from 15,000 to 140,000 Da. In some embodiments, higher molecular weight PCL (e.g., 80 kDa) results in a faster release rate of the active agent, while lower molecular weight PCL (e.g., 45 kDa) results in a slower release rate of the active agent. In embodiments, the implant may be made from PCL tubing having the following molecular weights (MW): approximately 50 kDa (PC08), 72 kDa (PC12), 106 kDa (PC17), 130 kDa (PC31), and >130 kDa (PC41).

[0073] In this embodiment, the implant is designed to biodegrade in vivo after the active agent is depleted. The biodegradable polymer (such as PCL) can be tailored to meet necessary biodegradation properties (i.e., optimizing the time between active agent depletion and complete polymer biodegradation). For example, biodegradation can be adjusted by selecting a target molecular weight of the homopolymer (such as PCL or blends of 45 kDa or 80 kDa) or by using copolymers as listed above. The polymer membrane has an initial molecular weight at implantation. In this embodiment, the polymer membrane is configured such that after the active agent is depleted from the device, the molecular weight of the membrane decreases to a range of 10 kDa to 2 kDa. For example, after the drug is depleted from the device, the molecular weight can decrease to a range of about 8 kDa to about 3 kDa. Without being theoretically constrained, it is believed that PCL biodegrades via bulk hydrolysis. For example, significant weight loss and polymer fragmentation can occur at about 5 kDa MW, while intracellular bioabsorption occurs at about 3 kDa MW. In embodiments, the polymer membrane may be configured such that it undergoes fragmentation over a period ranging from about 1 month to about 6 months after the surfactant has been depleted from the device. In this regard, exemplary embodiments with an 80 kDa MW PCL membrane have shown extended biodegradation rates, typically >24 months. Further description is provided through the examples below.

[0074] Polymer films may comprise blends of homopolymers having the same composition but different molecular weights (MW). For example, a polymer film may comprise blends of one or more of PC08, PC12, PC31, PC41, and PC17, wherein each homopolymer is PCL, but each has a different average molecular weight. Polymer films may comprise blends of homopolymers, wherein each homopolymer has a different composition and a different molecular weight. For example, a polymer film may comprise a blend of PCL and PLA. Polymer films may comprise copolymers, blends of copolymers, or blends of homopolymers and copolymers.

[0075] Furthermore, the composition, molecular weight, and thickness of the membrane affect the biodegradation rate of the device. The device, composed of a biodegradable polymer, is placed subcutaneously in the subject. It releases the active agent for the intended dose duration. The device is designed to lose its integrity due to biodegradation near the moment the active agent is available, but after the active agent is available. That is, the parameters of the polymer membrane can be selected so that the device can maintain its integrity for at least as long as the intended dose duration of the active agent within the device.

[0076] In this embodiment, the device structure remains intact over a period of approximately 3 months to approximately 2 years. For example, the device can be effectively used for active agent delivery lasting 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, or 24 months. In this embodiment, the device can be effectively used for active agent delivery lasting at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, at least 24 months, or up to 3 months, up to 6 months, up to 9 months, up to 12 months, up to 15 months, up to 18 months, up to 21 months, or up to 24 months.

[0077] This device is designed for subcutaneous implantation, which simplifies drug delivery but limits the size of the device and reservoir. In one embodiment, the device may have a cylindrical shape, for example, a cylinder with a length ranging from about 10 mm to about 50 mm and a width (or diameter) ranging from about 1 mm to about 3 mm. Furthermore, the device can be manufactured by extruding an FDA-approved biodegradable polymer to produce a fillable tube. This tube can then be ultrasonically welded or heat-sealed to seal the reservoir, thereby containing the active agent.

[0078] In one embodiment, the device has a cylindrical shape and includes a biodegradable polymer membrane containing a reservoir for an active agent formulation for the prevention or treatment of diseases.

[0079] When determining which form of device to use, various characteristics can be considered, including the desired release rate, drug loading capacity, geometry, size, and biodegradation rate. For example, the target release rate and loading capacity of the device may depend on the type and potency of the active agent. Wall thickness, surface area, and formulation can be adjusted to achieve the desired characteristics. The maximum amount of drug in the device reservoir (drug loading capacity) is a limiting factor considering the maximum daily dose of the reagent. In an exemplary embodiment, the polymer in the device may be designed to degrade in vivo after the active agent is depleted. The biodegradation timeframe of the polymer depends on the polymer's initial molecular weight (MW).

[0080] The release profile of the surfactant is influenced by the properties of the polymer used in the device, including surface area, thickness, and molecular weight (which affects crystallinity). These properties can be adjusted to provide the required dosage for surfactant delivery and the time range required for polymer bioabsorption.

[0081] Exemplary embodiments of implantable devices may include biodegradable subcutaneous implantable devices for multipurpose prophylaxis technology (MPT) for HIV and pregnancy prevention. The implants can be used to simultaneously deliver combinations of biologics (e.g., antibodies) and small molecules. Exemplary implantable devices utilize semi-crystalline aliphatic polyester PCL (first developed by Pitt et al. in the 1980s (G. Pitt et al.)) and have been largely neglected for the past 20 years (Woodruff, MA et al.). New demands for PCL have emerged due to the need for materials with long-term functionality, mechanical integrity, biocompatibility, and biodegradability and bioabsorption capabilities in biomedical applications, including tissue engineering and drug delivery. Currently, PCL is used in FDA-approved root canal fillings. and suture Among the products, and previously explored as a one-year contraceptive implant. In the case of HIV PrEP, PCL implants offer advantageous long-term delivery of ARV while also being bioresorbed at the end of the implant's lifespan. Biodegradable implants benefit healthcare systems by eliminating the need for clinical visits, thus requiring only minor surgical procedures for implant removal. The device is reversible and retrievable throughout the duration of treatment.

[0082] In embodiments of this device, the release rate of the active agent is controlled by various parameters, including but not limited to, the formulation within the reservoir, the physicochemical properties of the active agent and the polymer film, the surface area of ​​the device, and the thickness of the polymer film. In a preferred embodiment, the reservoir device can be used for relatively long-term disease prevention or treatment, or for pregnancy prevention, or a combination of both.

[0083] Advantageously, the biodegradable storage device has a zero-order release profile. Furthermore, the storage device possesses additional beneficial properties. For example, the device is subcutaneous; capable of releasing an active agent for varying durations (from approximately 3 months to approximately 2 years); removable within the drug delivery window; capable of providing zero-order release for multiple active agents; and adaptable based on various considerations, including, for example: (1) the active agent; (2) the composition and concentration of excipients (e.g., the excipient-to-active-agent ratio); (3) the thickness, molecular weight, composition, and crystallinity of the polymer film; and (4) the device surface area. The device can provide long-lasting zero-order release for more than one active agent. Moreover, the release kinetics are adjustable to meet different dosage requirements.

[0084] The reservoir device is designed for subcutaneous implantation, which simplifies drug delivery and facilitates access in resource-constrained settings. Furthermore, the biodegradable device reduces the need for additional clinical visits to remove the implant after the active agent has been depleted. However, because the active agent is delivered via the device rather than a gel or nanosuspension, the device can be removed or retrieved throughout its use. This feature can be beneficial in clinical situations requiring rapid removal, such as serious product-related adverse events. Additionally, the reservoir device can simultaneously deliver combinations of biologics (e.g., antibodies) and / or small molecules.

[0085] Storage devices can be designed for the controlled release of a wide range of therapeutic and prophylactic active pharmaceutical ingredients (also referred to herein as active agents). Unlike other sustained-release technologies, membrane-controlled devices can be functionally tuned to achieve zero-order release kinetics, resulting in a relatively flat drug release profile and a relatively tight concentration range over weeks, months, or possibly years.

[0086] Polymer properties and drug formulations affect the release rate of the active agent across the polymer membrane. Therefore, it is important to keep these properties in mind when designing the reservoir device to achieve zero-order release kinetics. This disclosure describes various reservoir devices, including those with different properties (e.g., different molecular weights, different active agents, different excipients, different formulation concentrations, and different membrane thicknesses), ultimately tuning the release kinetics according to the desired dose and duration.

[0087] exist Figure 1A and 1BA schematic diagram of an embodiment of the device is shown. As illustrated, a polymer membrane encapsulates a reservoir of a formulated active agent. A biofluid enters the implant, dissolving the active agent, which is then released controllably from the device. The release kinetics of the device are influenced by the properties of the polymer membrane. In this embodiment, the device is a flexible, permeable polymer membrane cylinder filled with an active agent and excipients.

[0088] like Figure 1A and 1B The device, as shown, comprises an active agent and excipients contained in a reservoir defined by a polymer membrane, which is sealed by heat sealing or ultrasonic welding. After implantation into a subject, the membrane is permeable to the active agent. When placed subcutaneously within the subject, the polymer membrane allows the active agent to diffuse through the membrane.

[0089] Figure 1C A schematic diagram of another exemplary device is provided. Figure 1C The device includes a formulated drug core (A) encapsulated by a rate-controlled PCL membrane (B). For cannula compatibility, the device is end-sealed using PCL material (C).

[0090] Figure 1C The device described is a reservoir-type PCL implant capable of delivering a co-formulated active agent with sustained zero-order release kinetics. Once inserted subcutaneously, biofluids from the surrounding environment are transported through the PCL membrane to the reservoir to dissolve the active agent, which is then passively transported through the PCL membrane and exits the implant. Unbound by theory, it is believed that, as an aliphatic polyester, PCL undergoes bulk hydrolysis via random chain scission as water permeates through the polymer. However, PCL biodegrades slowly and can require several years (e.g., 1-2 years) for complete bioabsorption, depending on the initial molecular weight (MW). Due to the slow bulk erosion of PCL, a faster drug delivery process is decoupled from biodegradation, enabling a zero-order release profile of the drug from the implant. Under this zero-order release profile, the daily drug delivery rate can be controlled by various parameters, including the device's surface area, the device's wall thickness, the properties of the polymer, and the drug formulation.

[0091] In some embodiments, the device can be manufactured by folding a polymer film to define a tubular cavity, depositing an active agent formulation into the cavity, and applying ultrasonic force or heat sealing to the film to create a seal that contains the active agent formulation within the tubular reservoir. When the device is placed subcutaneously in a subject's body, the film allows the active agent to diffuse through it.

[0092] In other embodiments, the implant is manufactured using the following steps: (1) Extruding a polymer tube comprising a hollow polymer cylinder. The wall thickness may vary and may be measured between 50 μm and 400 μm in some embodiments. An exemplary wall thickness of the tube is between 200 μm and 300 μm. An exemplary outer diameter (OD) is 2.5 mm. An exemplary length of the tube is 40 mm. The exemplary OD and length allow the implant to be used with commercially available cannulas. (2) Loading a formulation of at least two drugs into the hollow portion of the tube. The drug formulation is produced by combining at least two drugs with excipients. In a non-limiting example, the formulation is loaded into the tube via a syringe. Exemplary excipients include castor oil, sesame oil, PEG, glycerol, and ethyl oleate. (3) Then, sealing the end of the tube to ensure that the drug formulation is located within a reservoir. In a non-limiting example, sealing is performed by applying heat to the polymer to melt the polymer into a sealing end.

[0093] The ability to use more than one drug in a reservoir eliminates manufacturing complexity. For example, using multidrug formulations eliminates the need for segmented implants, where each segment contains a unique active agent formulation. Segmented devices have weak points at the segment interfaces, which are prone to mechanical failure and leakage. Using segmented devices also reduces the total available drug load in the implant, as the segment walls (i.e., the polymer portions forming the segments) occupy valuable space in the total length of a small implant (e.g., 40 mm). In another instance, using multidrug formulations eliminates the need to provide a patient with two separate implants, each containing a single API.

[0094] Simultaneous long-acting delivery of more than one drug is valuable for a variety of reasons. For example, it enables the simultaneous prevention of infectious diseases and pregnancy. Women's need for effective biomedical interventions for the prevention of infectious diseases and contraception is critical. The combination of systemic administration of drugs for the prevention of infectious diseases with long-acting delivery can significantly protect against a wider range of infection routes, including vaginal, rectal, and extra-gastrointestinal routes. Similarly, there is an unmet need for long-acting, biodegradable implants for contraception. Simple, acceptable, and readily available implants retain enormous potential to have a significant impact on public health. Women may cautiously accept dual protection even if, due to pressure from their sociocultural background (such as HIV stigma) or kinship, their stated intention is only to address one health need.

[0095] It is valuable to control the release rate of drugs from an implant while simultaneously delivering more than one drug over a longer period. In some embodiments, implants with a co-formulation of an ARV and a contraceptive hormone result in release rates different from those of implants containing a single active agent formulation. In one non-limiting example, an implant containing a co-formulation of ENG and TAF results in a higher release rate of both drugs compared to an implant with a single formulation having either ENG or TAF.

[0096] Furthermore, the implant described in this article enables the use of multiple antiretroviral drugs for HIV treatment. Highly active antiretroviral therapy (HAART) typically requires the administration of multiple antiretroviral drugs (ARVs) targeting different stages of the HIV life cycle. HAART regimens often require individuals to take multiple pills daily, which is cumbersome and prone to poor adherence. The ability to deliver multiple drugs from a single implant via a long-acting, continuous delivery of the implant will improve adherence and reduce the burden on HIV-positive individuals. The long-term reduction in viral load will also reduce the chance of HIV transmission (i.e., for prophylactic treatment).

[0097] The implants described herein enable the delivery of multiple medications to treat different types of infectious diseases. Individuals with comorbidities including multiple infectious diseases will benefit from a single implant that delivers multiple medications. Examples include co-infection with two or more of the following: HIV, hepatitis (A, B, or C), TB, gonorrhea, and malaria.

[0098] The implant described in this article enables the simultaneous treatment of substance use disorder and HIV. Individuals struggling with substance use disorder who are also HIV-positive (or at high risk of HIV infection) will benefit from the implant, which delivers ARV and medications for treating opioid addiction (including methadone, buprenorphine, naltrexone, naloxone, and combinations thereof).

[0099] This document provides, in its embodiments, a method for evaluating a device comprising a PCL membrane that meets the mechanical properties required for insertion and use of the device with a commercially available injection system. The size and geometry of the device have been adapted to accommodate an injection system (e.g., the cannula of a Jadelle contraceptive implant for hormone therapy).

[0100] Example

[0101] Example 1. Manufacturing of a biodegradable storage device with multiple drug formulations

[0102] Extruded polycaprolactone (PCL) tubes were cut into 40 mm lengths and heat-sealed at one end. A multidrug formulation was prepared by mixing a first drug, a second drug, and an excipient. The mixture was placed in a mortar and pestle and ground for 10 minutes. The multidrug formulation was loaded into a syringe, and the syringe was used to fill a PCL tube containing a single heat-sealed end. After filling the PCL tube with the multidrug formulation, the second end of the implant was heat-sealed.

[0103] Example 2. In vitro demonstration of zero-order kinetics of a multidrug formulation and the effect of the active agent to excipient ratio on the release of the active agent from the device.

[0104] Tests were conducted to evaluate multidrug formulations containing antiretroviral drugs and hormones for HIV prevention and contraception. Exemplary two-drug combinations included: 1) 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) mixed with levonorgestrel (LNG) in different ratios; 2) EFdA mixed with etogestrin (ENG) in different ratios; 3) tenofovir alafenamide (TAF) mixed with LNG in different ratios; and 4) TAF mixed with ENG in different ratios.

[0105] Table 1. Exemplary Multidrug Formulations

[0106]

[0107]

[0108] In this embodiment, the active agent combination is formulated with an excipient (such as castor oil or sesame oil). Exemplary excipients may include, but are not limited to, castor oil, sesame oil, oleic acid, polyethylene glycol, ethyl oleate, propylene glycol, glycerol, cottonseed oil, polysorbate 80, poloxamer PE / L, or combinations thereof.

[0109] In vitro testing of exemplary multidrug formulations containing EFdA-hormone-excipient

[0110] An exemplary multidrug formulation comprises EFdA, a hormone, and an excipient at concentrations of 50 / 35 / 25 wt% or 50 / 25 / 25 wt%. The formulation is contained in a 100 μm extrusion tube made of 93 kDa MW PCL (PC-17 polymer) derived from Corbion. The implant is 15 mm in length and 2.5 mm in outer diameter. The implant is incubated in 200 mL of 1X PBS (pH-7.4) at 37°C. The amount of drug released into the medium is measured three times weekly using an HPLC-UV instrument, during which time the implant is transferred to fresh buffer to maintain immersion conditions.

[0111] For devices containing EFdA formulated with hormones (LNG and ENG) and excipients (castor oil and sesame oil) at two different concentration ratios (50 / 35 / 15 wt% and 50 / 25 / 25 wt%), linear release curves were observed. Figure 2A and 2B It is a line graph showing the daily release curves of EFdA from the co-preparation device over 300 days.

[0112] Linear release profiles indicate a membrane-controlled release process in the co-formulated device containing EFDA and hormones. Although the EFdA / LNG / castor oil device demonstrated a higher initial release rate than the EFdA / LNG / sesame oil device, no significant difference in release rate was observed between implants after 350 days. Without being bound by theory, this observation is likely due to the relatively low concentration of excipients bound to the co-formulation and the low EFdA release rate.

[0113] The release rate of the device is normalized to the surface area of ​​a 10 mm long implant. Therefore, calculations can be performed to enable the use of implants with longer lengths to achieve the target release rate. Approximate release rates (based on normalized calculations) for the co-formulated EFdA device are shown in Table 2.

[0114] The average EFdA release rate of the multidrug formulation was approximately 16.9 ± 3.1 μg / day, which is comparable to the release rate (19.6 ± 5.0 μg / day) of an EFdA-only device using a PC17 extrusion tube with a 100 μm wall thickness. The results of this example suggest that formulation of EFdA with ENG or LNG does not appear to significantly affect the EFdA release rate.

[0115] Table 2. Approximate EFDA release rates of co-preparation devices containing EFdA, hormones (LNG or ENG), and excipients

[0116]

[0117] Figure 3A and 3B This is a line graph showing the daily hormone release curves (LNG or ENG) of a multidrug formulation containing EFDA and hormones (LNG or ENG). As shown, the co-formulated EFdA / hormone device exhibits a sustained zero-order release of both LNG and ENG. Similarly, the same constant release rate was observed for multidrug formulations with different drug-excipient ratios. This result demonstrates that a membrane-controlled release process for hormones has been achieved.

[0118] Furthermore, overlapping release curves were observed in devices formulated with castor oil or sesame oil. This result indicates that the excipients did not significantly affect the hormone release rate.

[0119] Table 3 shows the approximate hormone release rate of the EFdA / hormone / excipient implant (normalized to the surface area of ​​a 10 mm implant). It can be seen that ENG release is higher than LNG release rate. This result is consistent with historical ENG and LNG release rate data for single-active-agent devices. However, the co-formulated device releases ENG at a lower rate (15.2 ± 3.7 μg / day) than the device containing only ENG and excipients (51.5 ± 19.2 μg / day), while the LNG release rate of the multi-drug formulation (14.4 ± 3.15 μg / day) is similar to that of the device containing only LNG and excipients (approximately 22.7 ± 7.2 μg / day).

[0120] Table 3. Average hormone release rate of co-preparation devices containing EFDA and hormones (LNG or ENG)

[0121]

[0122]

[0123] In vitro testing of exemplary multidrug formulations containing TAF-hormone-excipient

[0124] For example implants, TAF is co-formulated with hormones (ENG or LNG) and excipients at different concentration ratios as follows: 33 / 33 / 33% by weight, 50 / 35 / 15% by weight, or 50 / 25 / 25% by weight.

[0125] To produce an exemplary implant, the mixture was ground in a mortar and pestle and loaded into a 100 μm PCL extrusion tube containing Corbion PC-17. The implant was incubated in 150 ml of 1X PBS (pH 7.4) at 37°C. The concentrations of TAF and hormone released into the medium over time were measured via UV-Vis and HPLC-UV, respectively. The device was transferred to fresh buffer three times weekly to maintain the immersion conditions.

[0126] Figure 4A and 4B This is a line graph showing the daily release curves of TAF from various TAF / hormone / excipient formulations. The implant is 40 mm in length and 2.5 mm in outer diameter. It can be seen that the co-formulated TAF / hormone / excipient device exhibits a linear release curve with a constant release rate over 120 days.

[0127] Approximate daily release rates of TAF formulated with different concentrations of hormones and excipients are shown in Table 4. The TAF release rate of the device was normalized to the surface area of ​​the implant over a length of 40 mm. Unlike EFdA, the release rate of TAF is affected by the presence of hormones. For example, the TAF / ENG / excipient device releases 0.25 ± 0.04 mg of TAF per day, which is lower than the daily release rate of the TAF / excipient formulation in a 100 μm PCL tube containing PC-17 (0.35 ± 0.09 mg / day). In contrast, the TAF / LNG / excipient device exhibits a higher release rate (i.e., 0.44 ± 0.04 mg / day) than the device containing only TAF as an active agent. Without being bound by theory, the higher release rate of TAF from the device containing TAF co-formulated with LNG (the TAF / LNG / excipient device) may be attributed to the faster release of LNG from the device, which results in a higher influent rate.

[0128] Table 4. Average TAF release rate from co-preparation devices containing TAF and hormones (LNG or ENG)

[0129]

[0130] The tests also showed that the hormone was continuously released at zero order from the co-formulated TAF / hormone / excipient device. Figure 5A and 5B It is a line graph showing the daily hormone release curve of a multidrug device containing TAF and hormones (LNG or ENG). Figure 5A and 5B The same constant hormone release rate was demonstrated for devices containing formulations with different concentrations of TAF / hormone / excipient. This result indicates that the hormone is released from the device via a diffusion-controlled process.

[0131] Table 5 provides approximate release rates of LNG or ENG from multidrug formulations. Release rates were normalized to the surface area of ​​a 10 mm implant. It can be seen that the release rate of ENG is significantly higher than that of LNG, consistent with historical data for single-active-agent formulations. The average release rate of LNG from multidrug formulations (17.4 ± 0.4 μg / day) is also similar to the average release rate from single-drug LNG formulations (approximately 22.7 ± 7.2 μg / day).

[0132] Implants containing TAF / ENG / excipient formulations exhibited an ENG release rate of 63.5 ± 4.2 μg / day, compared to 51.5 ± 19.2 μg / day for implants containing only ENG / excipient formulations. These results teach that the ENG release rate is influenced by the presence of TAF.

[0133] Table 5. Average hormone release rate of co-preparation devices containing TAF and hormones (LNG or ENG)

[0134]

[0135]

[0136] In summary, the multidrug formulations provide simultaneous and sustained release of ARV and hormones from a single drug reservoir over 300 days. When membrane-controlled release is achieved, formulations with different excipient ratios of ARV / hormone / excipient exhibit the same constant release rate. This data teaches that the release rates of EFdA and LNG are unaffected by co-formulations containing another active agent, while the release rates of TAF and ENG are altered by the presence of other active agents in the co-formulation. Furthermore, unlike previously tested EFdA / excipient-only formulations, the excipient does not appear to play a significant role in determining the release rate of the EFdA / hormone / excipient co-formulation. Without being bound by theory, this result can be attributed to the relatively low concentration of excipients in the co-formulation.

[0137] In vitro testing of exemplary multidrug formulations containing EFdA-LNG-sesame oil at different lengths and wall thicknesses

[0138] Exemplary lead multidrug formulations were downselected for further evaluation, comprising 50 / 25 / 25% by weight of EFdA, LNG, and sesame oil, and 50 / 35 / 15% by weight of EFdA, ENG, and sesame oil. To determine parameters influencing the release rate of the co-formulation device, the downselected formulations were contained in extrusion tubes of PC-17 polymer with varying wall thicknesses and implant lengths. The implants were incubated in 200 mL of 1X PBS (pH-7.4) at 37°C. The amount of drug released into the medium was measured twice weekly via HPLC-UV, during which time the implants were transferred to fresh buffer to maintain immersion conditions.

[0139] To evaluate the relationship between release rate and surface area of ​​the extruded PCL tube, the implants were manufactured with three different surface areas, achieved by varying the implant length (10, 30, and 50 mm). All devices contained: PC-17 with a wall thickness of 100 μm, and formulations of EFdA, LNG, and sesame oil at concentrations of 50 / 25 / 25% by weight. Figure 6A This is a line graph showing the linear release curves of EFdA from the co-formulated device over 90 days at implant lengths of 10, 30, and 50 mm. Similar to the single formulation, a higher surface area results in a higher release rate of EFdA from the implant. This demonstrates that the daily release rate of the co-formulated device is proportional to the surface area of ​​the implant, supporting a membrane-controlled release mechanism from these implants.

[0140] The wall thickness of the implant is another property that affects the release rate of EFdA. Figure 6B This is a line graph showing the linear release curves of EFdA from the co-formulated device over 90 days at wall thicknesses of 100, 150, 200, and 300 μm. Similar to the single formulation, the release rate of EFdA is negatively correlated with the PCL wall thickness. As the implant wall thickness increases from 100 μm to 300 μm, the release rate of EFdA decreases from 19.5 ± 1.8 μg / day to 2.3 ± 0.4 μg / day. Therefore, the release rate of the co-formulated implant can be modulated by the PCL wall thickness.

[0141] The approximate release rates of the co-formulated EFdA devices are shown in Table 6. Similarly, the average EFdA release rate of the multi-drug formulation is comparable to that of the EFdA-only device with a PC17 extrusion tube. The results of this example further confirm that EFdA formulation with LNG does not appear to significantly affect the EFdA release rate.

[0142] Table 6. Average EFdA release rate of co-preparation units containing EFdA and LNG

[0143]

[0144] The release of LNG from the EFdA / LNG / sesame oil co-formulation was also assessed. Figure 7A This is a line graph showing the daily LNG release curves of multidrug devices of different lengths containing the EFdA / LNG / sesame oil formulation. As shown, all co-formulated EFdA / LNG devices exhibited sustained zero-order LNG release over 50 days. Similarly, the LNG release rate was proportional to the implant surface area: higher release rates were achieved for devices with larger surface areas. This result also demonstrates that a membrane-controlled release process for the hormone has been achieved.

[0145] Figure 7B Daily release curves for multidrug devices containing EFdA / LNG / sesame oil formulations with different wall thicknesses are shown. Similarly, as the wall thickness increased from 100 μm to 300 μm, the LNG release rate decreased from 18.5 ± 4.0 μg / day to 5.3 ± 0.7 μg / day. This result demonstrates that the LNG release rate is also inversely proportional to the wall thickness of the PCL implant.

[0146] Table 7 shows the approximate hormone release rates of the EFdA / LNG / sesame oil implant. The LNG release rate of the multidrug formulation is comparable to that of devices containing only LNG and excipients, which is very consistent with previous data. This confirms the previous observation that co-formulating LNG with an ARV does not affect LNG release.

[0147] Table 7. Average LNG release rate of co-preparation units containing EFDA and hormones (LNG or ENG)

[0148]

[0149] For the exemplary implant, EFdA was also co-formulated with ENG and sesame oil at a concentration ratio of 50 / 35 / 15% by weight. Devices with different wall thicknesses and lengths were also manufactured to evaluate the effect of implant size on the implant release rate.

[0150] Figure 8A This is a line graph showing the daily release curves of EFdA from the EFdA / ENG / sesame oil formulation at different lengths ranging from 10 to 50 mm. It can be seen that the co-formulated EFdA / ENG / sesame oil device exhibits a linear release curve with a constant release rate over 90 days. The co-formulation device with a larger surface area results in a higher EFdA release rate.

[0151] Figure 8B This is a line graph showing the daily release curves of EFdA from the EFdA / ENG / sesame oil formulation at different wall thicknesses (100, 150, 200, and 300 μg). Similarly, the release rate of EFdA from the co-formulated EFdA / ENG / sesame oil device also decreases with increasing wall thickness. This demonstrates the effect of wall thickness on the release rate of the co-formulation device.

[0152] The approximate daily release rate of EFdA formulated with ENG and sesame oil is shown in Table 8. Similarly, the average EFdA release rate of the multidrug formulation is comparable to that of an EFdA-only device with a PC17 extrusion tube. The results of this example further demonstrate that formulating EFdA with ENG or LNG does not appear to significantly affect the EFdA release rate.

[0153] Table 8. Average EFdA release rate of co-preparation devices containing EFdA and ENG

[0154]

[0155]

[0156] The release of ENG from the co-formulation of EFdA / ENG / sesame oil was also evaluated. Figure 9A and 9B This is a line graph showing the daily ENG release curves of multidrug devices of different lengths containing the EFdA / ENG / sesame oil formulation over 50 days. Similar to previous data, the ENG release rate is proportional to the surface area of ​​the implant. Interestingly, unlike the EFdA release curve, the ENG release rate decreases over time. This may be attributed to the depletion of ENG within the device core, as the estimated release duration for the co-formulated EFdA / ENG device with a wall thickness of 100 μm is approximately 6 months, while the release duration for the EFdA component is >1 year.

[0157] In summary, we investigated the effects of wall thickness and surface area on the release of both ARV and hormone from the co-formulated device. As shown, similar to single formulations, the release rate of the co-formulated device was linearly related to the implant's surface area and negatively correlated with the wall thickness of the PCL device. These experiments demonstrate the ability to modulate the release rate of EFdA and hormone from reservoir-type co-formulated MPT implants using two parameters (surface area or wall thickness).

[0158] Table 9. Average ENG release rate of co-preparation devices containing EFdA and ENG

[0159]

[0160] In addition to evaluating ARV / hormone co-formulations, ARVs from the same drug class are co-formulated in the same implant. Figure 10A and 10B This is a line graph showing the daily release profiles of FTC and TAF from two different formulations of FTC / TAF / castor oil. The PC17 implant has a length of 40 mm, an outer diameter of 2.5 mm, and a wall thickness of 100 μm. As observed, the co-formulated ARV device exhibits a linear release profile with a constant release rate over 30 days. When the API:excipient ratio is significantly higher, the release profile exhibits a dissolution-controlled mechanism. As previously explained, 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.

[0161] Table 10 summarizes the overall FTC and TAF release rates from the implants. When the release rate is diffusion-controlled (i.e., 33% FTC formulation), the FTC release rate of the multidrug formulation is comparable to that of the implant containing only FTC and castor oil. Similarly, the TAF release rate from the multidrug implant is consistent with previous data where the implant contains only TAF and castor oil. Co-formulation of TAF and FTC does not affect the release rate of either drug.

[0162] Table 10. Average release rates of co-preparation devices containing FTC and TAF

[0163]

[0164] In addition, ARVs across different drug classes were co-formulated in the same PC17 implant with a wall thickness of 100 μm and a length of 40 mm. Figure 11A This is a compilation of line graphs showing the daily release profiles of EFdA and BIC from the same implant. Both drugs are formulated with a significantly low API:excipient ratio, which is inconsistent with previous data where each drug was formulated individually with excipients. However, both drugs exhibit linear release profiles up to 130 days.

[0165] Figure 11B Linear release profiles of BICs from a multi-drug PC17 implant with a wall thickness of 100 μm and a device length of 40 mm are shown up to 60 days. The release rate is consistent with that of BIC / sesame oil alone as the proportion of BICs in the co-formulation increases. The release rate is significantly lower when the BIC component in the formulation is ≤25%, which can be attributed to incomplete BIC coverage along the implant length (surface area affects the release rate). When a sufficient amount of BICs is present in the implant, its release rate appears to be unaffected by the presence of EFdA.

[0166] like Figure 11C The observed release rate of EFdA from multidrug formulations appears to increase with increasing EFdA content in the formulation. When the formulation contains 10–25% EFdA, the release rate is consistent with that of implants containing EFdA and sesame oil. Since the EFdA content is >25%, the presence of BIC appears to affect its release rate.

[0167] Table 11 summarizes the release rates of BIC and EFdA across these co-formulations. For both drugs, there appears to be a window where the release rate is unaffected by the presence of the other drug in the formulation. Once the amount of either drug falls outside these limits, the release rates of both BIC and EFdA vary depending on their ratio in the formulation.

[0168] Table 11. Average release rates of co-preparation devices containing BIC and EFdA

[0169]

[0170] Any patents or publications mentioned in this specification demonstrate the skill of a person skilled in the art to which this invention pertains. These patents and publications are incorporated herein by reference to such extent that it would be as if each individual publication were specifically and individually indicated to be incorporated by reference.

[0171] References

[0172] (HPTN),HPTNHPTN 083.A Phase 2b / 3Double Blind Safety and EfficacyStudy of Injectable Cabotegravir Compared to Daily Oral Tenofovir DisoproxilFumarate / Emtricitabine(TDF / FTC), for Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men, available online.

[0173] (HPTN),HPTNHPTN 084.A Phase 3Double Blind Safety and EfficacyStudy of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF / FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women, available online.

[0174] Solorio, L., Carlson, A., Zhou, H., Exner, A. A. Implantable Drug Delivery Systems. In Engineering Polymer Systems for Improved Drug Delivery, 1st Edition; Bader, R. A., Putnam, D. A. Eds., John Wiley & Sons, Inc.: 2014; doi: 10.1002 / 9781118747896.ch7.

[0175] Yang, W.-W.; Pierstorff, E. Reservoir-Based Polymer Drug Delivery Systems. Journal of Laboratory Automation 2012, 17, 50-58, doi: 10.1177 / 2211068211428189.

[0176] Langer, R. Implantable controlled release systems. Pharmacology & Therapeutics 1983, 21, 35-51, doi: https: / / doi.org / 10.1016 / 0163-7258(83)90066-9.

[0177] Gunawardana, M.; Remedios-Chan, M.; Miller, C. S.; Fanter, R.; Yang, F.; Marzinke, M. A.; Hendrix, C. W.; Beliveau, M.; Moss, J. A.; Smith, T. J. et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrobial agents and chemotherapy 2015, 59, 3913-3919, doi: 10.1128 / aac.00656-15.

[0178] Chua, C.Y.X.; Jain, P.; Ballerini, A.; Bruno, G.; Hood, R.L.; Gupte, M.; Gao, S.; Di Trani, N.; Susnjar, A.; Shelton, K. et al. Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis. Journal of Controlled Release 2018, 286, 315-325, doi: https: / / doi.org / 10.1016 / j.jconrel.2018.08.010.

[0179] A New Collaboration for HIV Prevention, available online.

[0180] Barrett, S.E.; Teller, R.S.; Forster, S.P.; Li, L.; Mackey, M.A.; Skomski, D.; Yang, Z.; Fillgrove, K.L.; Doto, G.J.; Wood, S.L. et al. Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention. Antimicrobial agents and chemotherapy 2018, 62, e01058-01018, doi: 10.1128 / aac.01058-18.

[0181] G.Pitt, C.; Chasalow, F.; Hibionada, Y.M.; M.Klimas, D.; J.Schindler, A. Aliphatic polyesters. I. The degradation of poly(ε-caprolactone) in vivo; 1981; Volume 26, pp. 3779-3787.

[0182] Woodruff,M.A.;Hutmacher,D.W.The return of a forgotten polymer—Polycaprolactone in the 21st century.Progress in Polymer Science2010,35,1217-1256,doi:https: / / doi.org / 10.1016 / j.progpolymsci.2010.04.002。

Claims

1. A reservoir device comprising an active agent formulation contained therein, wherein the active agent formulation comprises more than one active agent, and said more than one active agent is a co-formulation of ARV and hormone, wherein the reservoir is defined by a biodegradable, permeable polymer membrane that, when subcutaneously placed in a subject, allows more than one active agent of the formulation to diffuse through it. The ARV mentioned above is tenofovir alafenamide fumarate (TAF), bicretiravir (BIC), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), or a combination thereof. The hormone mentioned is a contraceptive hormone. The polymer film contains polycaprolactone (PCL) with a molecular weight range of 15,000-140,000 Da. The permeable polymer membrane has a thickness of 45µm to 300µm. The surfactant formulation further includes excipients, and The excipients include castor oil, sesame oil, oleic acid, polyethylene glycol 600, ethyl oleate, propylene glycol, glycerol, or combinations thereof.

2. The apparatus of claim 1, wherein the permeable polymer membrane has a thickness of 70 µm to 300 µm.

3. The apparatus of claim 1, wherein the ARV is 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

4. The apparatus of claim 1, wherein the hormone comprises etoposide (ENG).

5. The apparatus of any one of claims 1 and 2, wherein the more than one active agent is composed of EFdA and LNG.

6. The apparatus of any one of claims 1 and 2, wherein the more than one active agent is composed of EFdA and ENG.

7. The apparatus of any one of claims 1 and 2, wherein the more than one active agent is composed of LNG and TAF.

8. The apparatus of any one of claims 1 and 2, wherein the more than one active agent is composed of TAF and ENG.

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

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

11. The apparatus of claim 1, wherein the polymer film comprises one or more of homopolymers, random copolymers, alternating copolymers, block copolymers, graft copolymers, star-shaped homopolymers, and star-shaped copolymers.

12. The apparatus of claim 11, wherein the polymer film comprises a blend of homopolymers.

13. The apparatus of claim 12, wherein the blend of the homopolymer comprises one or more blends of PC08, PC12, PC31, PC41 and PC17.

14. The apparatus of claim 11, wherein the polymer film comprises a blend of homopolymer and copolymer.

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

16. A reservoir device comprising an active agent formulation contained therein, wherein the active agent formulation comprises more than one active agent, and said more than one active agent is a co-formulation of an ARV and a hormone, wherein the reservoir is defined by a biodegradable, permeable polymer membrane that, when subcutaneously placed in a subject, allows the more than one active agent to diffuse through the membrane at zero-order release kinetics for at least 60 days. The ARV mentioned above comprises tenofovir alafenamide fumarate (TAF), bicretiravir (BIC), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), or a combination thereof. The hormones mentioned include contraceptive hormones. The polymer film contains polycaprolactone (PCL) with a molecular weight range of 15,000-140,000 Da. The permeable polymer membrane has a thickness of 45µm to 300µm, and The storage device further includes excipients, and The excipients include castor oil, sesame oil, oleic acid, polyethylene glycol 600, ethyl oleate, propylene glycol, glycerol, or combinations thereof.

17. The apparatus of claim 16, wherein the polymer film comprises one or more of homopolymers, random copolymers, alternating copolymers, block copolymers, graft copolymers, star-shaped homopolymers, and star-shaped copolymers.

18. The apparatus of claim 17, wherein the polymer film comprises a blend of homopolymers.

19. The device of claim 16, wherein the device has a cylindrical shape with a length between 10 mm and 50 mm.

20. The device of claim 1 or 16, wherein the polymer membrane has an initial molecular weight upon implantation and wherein the membrane is configured such that after the more than one active agent is evacuated from the device, the molecular weight of the membrane decreases to a molecular weight in the range of 8 kDa to 3 kDa.

21. The apparatus of claim 1 or 16, wherein the polymer film is configured such that after the more than one surfactant is evacuated from the apparatus, the film undergoes fragmentation over a period ranging from 1 month to 6 months.

22. The apparatus of claim 1 or 16, wherein the biodegradable permeable polymer membrane is configured to degrade substantially or completely over a period of 3 months to 2 years.

23. The device of claim 1 or 16, wherein the device is movable within the drug delivery window.

24. The apparatus of claim 1 or 16, wherein the apparatus is configured for zero-order release of a variety of active agents.

25. The apparatus of claim 1 or 16, wherein the apparatus is configured to be adjusted based on various considerations, including: (1) Surfactant; (2) Composition and concentration of excipient; (3) Thickness, molecular weight, composition and crystallinity of polymer film; and (4) the surface area of ​​the device.

26. The apparatus of claim 25, wherein the various considerations include the ratio of excipient to surfactant.

27. The apparatus of claim 1 or 16, wherein the apparatus is configured to meet different dosage requirements.

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