Subdermal implants for sustained drug delivery

Abstract

The present disclosure relates to the use of long-acting implantable or injectable devices for the delivery of biologically active compounds, for example antiviral compounds, such as peptide conjugates of antiviral drugs disclosed herein, at a controlled rate over an extended period of time, and methods of making the same. The devices are biocompatible and biostable, and are useful as implants and / or injectables within patients (human and animal) for the delivery of suitable bioactive agents to tissues or organs.

Description

[Technical field]

[0001] Statement of Government Interest This invention was made with government support under grants AI120748, R01HD101344, U19AI113048, and R01AI154561 awarded by the National Institutes of Health (NIH). The Government has certain rights in this invention.

[0002] The present disclosure relates generally to the field of implantable sustained release drug delivery devices.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS Priority is claimed to U.S. patent application Ser. No. 63 / 297,191, filed Jan. 6, 2022, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0004] Drug delivery is an important area of ​​medicine. The efficacy of many drugs is directly related to their method of administration. Current drug delivery modes, such as topical application, oral delivery, and intramuscular, intravenous, and subcutaneous injections, can result in high and low blood concentrations and / or short half-lives in the blood. In some cases, achieving therapeutic efficacy with these standard administrations requires large amounts of the drug, which can result in toxic side effects. Technologies related to controlled drug release attempt to avoid some of the pitfalls of traditional therapies. Their goal is to provide the drug in a continuous and sustained manner. Additionally, local controlled drug release applications can be site or organ specific (e.g., controlled intravaginal delivery) and minimize systemic exposure to the drug.

[0005] Traditional routes of administration are problematic in that they require strict patient compliance, i.e., when drugs such as antibiotics, hormones, and vitamins are administered orally, or when the route of administration is by injection, requiring repeated doctor visits. These methods of administration are particularly problematic when the patient is a child, elderly, or when the drug must be administered chronically, i.e., weekly allergy injections. Adherence to taking a drug is problematic for many adults because they forget to take it. Furthermore, weekly injections deter many people from receiving necessary treatment because weekly injections at the clinic interfere with their activities or schedules. In other words, adherence to frequent dosing is a burden for users and has emerged as an important factor in explaining the heterogeneous efficacy results of many therapeutic and prophylactic regimens. Extended release or "long-acting" drug formulations hold great promise as a means of reducing dosing frequency, thereby increasing the efficacy of the regimen.

[0006] Implantable microdevices, reservoir delivery systems, overcome the above-mentioned adherence concerns because they do not require user intervention. In recent years, the development of microdevices for local drug delivery has been one of the areas in which steady progress has been made. Activation of drug release can be passively or actively controlled. They are theoretically capable of delivering drugs at a controlled rate for months, even years, and are often composed of polymeric materials. Polymeric implants as drug delivery systems have been known for some time. Implantable delivery systems of polymeric materials are known for the delivery of contraceptives, for example, as either subcutaneous implants or intravaginal rings. Prior art implants do not adequately control drug release. Various devices have been proposed to solve this problem. However, none have been completely satisfactory. Such problems result in drug delivery devices that administer drugs in unpredictable patterns, thereby resulting in insufficient or reduced therapeutic effects.

[0007] Injectable long-acting delivery systems are also known in the art to be beneficial. These include particle suspensions injected subcutaneously, intramuscularly, or into other anatomical compartments, formulations that solidify into solid or semi-solid implants after injection into anatomical compartments such as the subcutaneous space, and microarray (microneedle) patches consisting of microscopic projections applied to the outermost layer of the skin to deliver their cargo to the epidermal / dermal layer.

[0008] For example, a representative drug delivery device is a drug-eluting stent. A stent is a mesh-like steel or plastic tube used to open coronary arteries clogged with arteriosclerosis or narrowed blood vessels. Drugs can be attached to or impregnated into the stent, which is thought to prevent re-blocking or restenosis of the blood vessel. However, the initial release of the drug can be very rapid, releasing 20-40% of the total drug load in one day. Such high concentrations of drugs have been reported to result in cytotoxicity at the target site. As a result of these issues, there is a need for a drug delivery device that can be optimized to deliver any therapeutic, diagnostic, or preventative agent for up to several years while maintaining a controlled desired rate.

[0009] Microdevices implanted at various anatomical sites can be broadly divided into two categories: resorbable polymer-based devices and non-resorbable devices. Polymeric devices can be biodegradable, thus avoiding the need for removal after implantation.

[0010] Non-biodegradable drug delivery systems include, for example, Vitrasert® (Bausch & Lomb, Inc.), a surgical implant that delivers ganciclovir into the eye, Duros® (Alza Corp.), a surgically implanted osmotic pump that delivers leuprolide acetate to treat advanced prostate cancer, and Implanon™ (Merck & Co., Inc.), a type of subdermal contraceptive implant. Additionally, there are commercially available implantable devices for use within the vagina, such as NuvaRing® (Merck & Co., Inc.), an intravaginal ring that delivers etonogestrel and ethinyl estradiol for contraception.

[0011] Biodegradable implants include, for example, Lupron Depot® (leuprolide acetate, TAP Pharm. Prods., Inc.), a sustained-release microsphere suspension injection of luteinizing hormone-releasing hormone (LH-RH) analogue for the treatment of prostate cancer, and Posurdex® dexamethasone anterior segment drug delivery system (Allergan, Inc.).

[0012] Both systemic and local parenteral long-acting drug delivery systems are feasible depending on good drug pharmacological properties. The dosing frequency of a long-acting drug candidate is determined, among other things, by the drug's water solubility, potency, and systemic clearance kinetics. These criteria severely limit the number of drugs suitable for development. The field of HIV-1 prevention and treatment illustrates this predicament and is discussed below as a non-limiting illustrative example.

[0013] An injectable, long-acting formulation of the integrase strand transfer inhibitor (ISTI) cabotegravir (CAB) has been demonstrated to be superior to daily oral tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC) in preventing HIV-1(1,2). Accordingly, a sustained-release CAB nanosuspension administered as an IM injection (600 mg in 3 mL) once every two months was approved by the US FDA for HIV-1PrEP (December 21, 2021). The non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV, 300 mg mL -1 ) injectable nanoparticle suspension of CAB (200 mg mL -1 ) became the first LA regimen for the treatment of HIV to receive US FDA approval (January 21, 2021). The product is administered once monthly as two separate intramuscular continuous injections (2 mL of formulation each) in each buttock site. While these attempts are promising, they do not leverage the full portfolio of currently available antiretroviral (ARV) agents, particularly drugs from the well-established backbone NRTI mechanistic class.

[0014] As in HIV-1 treatment, many in the field believe that multiple drugs will be required for effective, long-term HIV-1 PrEP (e.g., oral TDF-FTC and TAF-FTC), further complicating the development of viable long-acting candidates. Oral formulations of DTG, a second-generation ISTI with a high barrier to resistance, combined with the established NRTI lamivudine (3TC) constitute the first FDA-approved two-drug cART regimen for the treatment of HIV. Both drugs have excellent and established safety profiles, including in adolescent and pediatric populations, and are recommended for use during pregnancy by the NIH's Office of AIDS Research.

[0015] There have been no reports of 3TC or DTG subdermal implants. In situ forming implants are a well-established drug delivery technology with a 30-year history and have produced several FDA-approved products. The most common approach ("Atrigel") relies on subcutaneous injection of a biodegradable polymer (usually PLGA or PLA) dissolved in an organic solvent (usually NMP or DMSO) and an active pharmaceutical ingredient (API). The Atrigel system has been used to deliver DTG to mice and macaques (3). This platform has significant drawbacks, including an initial burst drug release, toxicity of the organic solvent, and local inflammation caused by low molecular weight oligomers and acids formed as the polymer degrades.

[0016] DTG is potent against HIV-1 in vitro, with an IC in peripheral blood mononuclear cells (PBMCs) of 0.51 nM. 50 , 0.15 μM (64 ng mL -1 ) protein regulation IC 90 (PA-IC 90 ) (4) and a long systemic half-life (12-15 hours) (4, 5). 50 PA-IC has a broad range of potency (0.003-15 μM) (6), and its elimination half-life in humans ranges from 5 to 7 hours (7). 90 Implants that maintain steady-state DTG plasma concentrations above 100 mg / kg for 6 months are theoretically feasible, but would require multiple devices. The potency and PK of 3TC make long-acting delivery via implant or injection impractical.

[0017] Enhancement of the potency of DTG and 3TC for subcutaneous implant delivery is a highly promising HIV-1 PrEP strategy. Prodrugs can increase the potency of the parent drug, extend its in vivo half-life, and provide tunability in key formulation parameters such as solubility. This design flexibility has been exploited for several small molecule prodrugs in commercially available sustained release injectable formulations, as described in (8), which is incorporated herein in its entirety. Established ARV agents have been converted to prodrugs for injectable long-acting drug delivery, which primarily involves conjugation with fatty acids to dramatically reduce drug solubility, facilitating nanoparticle formulations. These approaches do not necessarily improve efficacy. Sillman et al. conjugated DTG with myristoyl chloride to give the corresponding ester prodrug, MDTG (9). MDTG was 8.7-fold less water soluble than DTG, a key attribute for nanoparticle formulations, but the IC of both agents against HIV-1 was 1.2-fold lower. 50 were not statistically different.

[0018] The enhanced efficacy prodrug strategy disclosed herein uses libraries of peptides as drug conjugation moieties for cell targeting and increased cell penetration. This approach is designed to enable, for example, long-acting parenteral drug delivery and extends to other indications beyond HIV-1 prevention and treatment.

[0019] There remains a need for more economical, practical, and efficient production and manufacturing methods of drug delivery systems that can be used locally or systemically in solid or semi-solid formulations.The present disclosure is generally in the field of long-acting drug delivery devices, and more specifically in the field of devices for the controlled release of drugs from implantable or injectable devices in body cavities or lumen, or subcutaneously, transdermally, or vaginally implantable devices. Summary of the Invention

[0020] Provided herein is a drug delivery device comprising one or more peptide-drug conjugates, the drug delivery device comprising: (a) one or more kernels comprising the peptide-drug conjugates; and (b) one or more skins comprising a continuous membrane, the one or more kernels and / or the one or more skins comprising defined pores that are not mechanically generated, the peptide-drug conjugates comprising a cell penetrating or cell targeting peptide covalently bonded to one or more drugs via one or more linkers. In some embodiments, the drug delivery device comprises: (a) one or more drug-peptide conjugates or prodrugs; (b) one or more kernels comprising the one or more drug-peptide conjugates and optionally one or more additional pharma- ceutical active agents; and (c) one or more skins comprising a continuous membrane, the one or more kernels and / or skins comprising defined pores that are not mechanically generated. In some embodiments, the reservoir kernel comprises a paste comprising one or more APIs. In some embodiments, the kernel comprises a fiber-based carrier. In some embodiments, the kernel comprises a porous sponge. In some embodiments, the drug-peptide conjugate is injected as a long-acting formulation, hi other embodiments, the drug-peptide conjugate is administered as a microarray patch, also known in the art as a microneedle patch.

[0021] Also provided is a drug delivery device for implantation or injection into a patient's body. In some embodiments, the device further comprises a shape adapted to be disposed within a patient's body. In some embodiments, the device is in the shape of a capsule. In some embodiments, the device is in the shape of a torus. In some embodiments, the device comprises one or more cylindrical core elements disposed within a first skin, the core element comprising a kernel and, optionally, a second skin.

[0022] Also provided is a method of delivering one or more APIs to a patient in need thereof, comprising implanting a device disclosed herein within the patient's body. In some embodiments, the present disclosure further provides methods of providing sustained and long-term release of an API to a patient using the materials and methods described herein. [Brief description of the drawings]

[0023] [Figure 1] Figure 1 shows a synthetic strategy for preparing peptide prodrugs using orthogonal coupling, where R is the resin backbone, L1 and L2 are linkers, P is the peptide, and D is the drug. [Diagram 2] Figure 1 shows a synthetic strategy for preparing peptide prodrugs using N-terminal direct coupling, where R is the resin backbone, L1 and L2 are linkers, P is peptide, and D is drug. [Diagram 3] A non-limiting general example of a D-L2-P construct containing a labile ester bond at D and an amide bond at P (1≦n≦20) is shown. [Figure 4] A non-limiting example is shown where the linker L2 is derived from succinic anhydride. [Diagram 5] Shown is a pegylated linker L2 conjugated to a peptide P via an ester bond and to a drug D via a carbamate bond. [Figure 6] Figure 1 shows a synthetic strategy for preparing peptide prodrugs using orthogonal coupling after cleavage from the resin. L2 is a linker, P is a peptide, D is a drug. X = H, NH2, Na, K, NH4 + or other pharma- ceutically acceptable salt, Y = H, Ac, Pyr, or other pharma- ceutically acceptable salt. [Figure 7] Figure 1 shows a synthetic strategy for preparing peptide prodrugs using N-terminal direct coupling after cleavage from the resin. L2 is a linker, P is a peptide, and D is a drug. X = H, NH2, Na, K, NH4 +, or other pharma- ceutically acceptable salt. [Figure 8]1 shows a synthetic strategy for preparing peptide prodrugs using C-terminal direct coupling after cleavage from the resin. L2 is a linker, P is a peptide, and D is a drug. X=H, NH2, Na, K, NH4 +; Y=H, Ac, Pyr. Y=H, Ac, Pyr, or other pharma- ceutically acceptable salts. [Figure 9] N-terminal thiol-maleimide conjugation is shown. [Figure 10AB] A general peptide antiretroviral (ARV) prodrug synthesis strategy, Rink amide resin backbone, aspartic acid linker, peptide conjugate, R group indicates ARV drug fragment. (i) Orthogonal O-allyl deprotection with catalytic Pd(PPh3)4, phenylsilane, DCM, (ii) esterification with R-OH using N,N'-diisopropylcarbodiimide, 4-dimethylaminopyridine, DMF, (iii) N-terminal deprotection with piperidine in DMF followed by cleavage from the resin using TFA-triisopropylsilane-water. Both inset boxes indicate the ARV drug backbone corresponding to the R group. The primary amino group on 3TC is 4,4'-dimethoxytrityl- (DMTr) protected as N-DMTr-3TC, and this group is removed along with all orthogonal amino acid protecting groups during cleavage. In Figure 10A, the aspartic acid linker is located at the C-terminus. In Figure 10B, the aspartic acid linker is located at the N-terminus. Although the scheme is described in the context of antiretroviral drugs, the process is applicable to other types of drugs. [Figure 11] Screening decision tree for the selection of lead candidates for ARV prodrugs. [Prodrug]tox, onset of cytotoxicity (>10%). [Figure 12] 1 illustrates an exemplary embodiment of a subcutaneous or intramuscular implant design. [Figure 13A-D] 1 shows an exemplary embodiment of a single membrane capsule shaped implant design. [Fig. 14A-G] 13 shows an alternative exemplary embodiment of a single membrane capsule shaped implant design. [Figure 15A-E] 1 illustrates an exemplary embodiment of a double membrane capsule shaped implant design. [Fig. 16AB] 1 shows an exemplary embodiment of an alternative disk design to the capsule-shaped implant design. [Figure 17] 1 illustrates an exemplary embodiment of an intravaginal ring design. [Figure 18A-D] 13 shows an alternative exemplary embodiment of an intravaginal ring design with a cylindrical kernel / skin within a perforated carrier scaffold. [Figure 19A-D] 1 shows an alternative exemplary embodiment of an intravaginal ring design with separate compartments for peptide-drug conjugates and / or APIs. [Fig. 20A-E] 13 shows an alternative exemplary embodiment of an intravaginal ring design with separate compartments for peptide-drug conjugates and / or non-toroidal shaped APIs. [Fig. 21A-E] 13 shows an alternative exemplary embodiment of a non-circular cross-section intravaginal ring design with separate compartments for peptide-drug conjugates and / or API and a separate skin. [Figure 22] 1 shows an exemplary embodiment of a pessary ring design. [Diagram 23] 1 illustrates an exemplary embodiment of an intrauterine device (IUD) design. [Figure 24] 1 illustrates an exemplary embodiment of a matrix implant design. [Diagram 25] 1 illustrates an exemplary embodiment of a multi-kernel matrix implant design. [Figure 26] 1 illustrates an exemplary embodiment of a reservoir implant design. [Figure 27] 1 illustrates an exemplary embodiment of a reservoir implant design. [Figure 28] 1 illustrates an exemplary embodiment of an implant design with various exterior skins. [Figure 29] 1 illustrates an exemplary embodiment of an implant design with various exterior skins. [Diagram 30] 1 illustrates an exemplary embodiment of an implant design with various exterior skins. [Diagram 31]1 illustrates an exemplary embodiment of an implant design with various kernels and outer skins. [Diagram 32] 1 illustrates an exemplary embodiment of an implant design with various kernels and outer skins. [Diagram 33] 1 illustrates an exemplary embodiment of an implant plug. [Fig. 34AB] 35A-35B show drawings of patterned silicon skins formed by microlithography. The skins are shown with square (1.5×1.5 mm) in FIG. 35A and hexagonal (1.15 mm sides) in FIG. 35B grid support structures. The support grid walls are 500 μm wide and 250 μm high. The skin thickness exposed for drug diffusion (between the grid walls) is 100 μm. [Fig. 35AB] XRD spectra of monoolein-water semi-solid gels are shown. Figure 35A contains 20% w / w water and gives a main peak at 1.96° corresponding to a channel with a diameter of 4.50 nm. Figure 35B contains 30% w / w water and gives a main peak at 1.8° corresponding to a channel with a diameter of 4.8 nm. [Diagram 36] Preliminary implant prototype solid model and specifications are shown. OD is outer diameter, L is outer length, H is outer height, W is outer width, and V is volume. [Figure 37A-C] We show how ePTFE membranes provide linear and controlled drug release. Figure 37A, an AFM image of ePTFE membrane, shows micro / nanoporous structure based on nodes (n) and fibrils (arrows). Scale bar, 5 μm. Figures 37B and 37C, In vitro release studies into 1×PBS comparing ePTFE membrane types, API, and excipients. Figure 37B, BSA release from 33% w / v BSA depots in monoolein is affected by ePTFE membrane treatments, non-sintered, 0.24 mm ePTFE (0.75 mg d-1), 0.17 mm, sintered ePFTE (0.24 mg d-1). FIG. 37C: hIgG release is controlled by excipients (castor oil monoolein, 4:1 (4.1 mg d-1), monoolein-lecithin-medium chain triglyceride, 5:1.8:3.2 (0.87 mg d-1)) without modifying the ePTFE membrane. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Provided herein is a drug delivery device comprising one or more peptide-drug conjugates, the drug delivery device comprising: (a) one or more kernels comprising the peptide-drug conjugates; and (b) one or more skins comprising a continuous membrane, wherein the one or more kernels and / or skins comprise defined pores that are not mechanically generated, and the peptide-drug conjugates comprise cell-penetrating or cell-targeting peptides covalently attached to one or more drugs via one or more linkers.

[0025] All references cited herein are incorporated by reference in their entirety as if fully set forth. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Allen et al., Remington: The Science and Practice of Pharmacy 22 nd ed., Pharmaceutical Press (September 15, 2012); Hornyak et al., Introduction to Nanoscience and Nanotechnology, CRC Press (Boca Raton, FL, 2008); Oxford Textbook of Medicine, Oxford Univ.Press(Oxford,England,UK,May 2010,with 2018 update);Harrison's Principles of Internal Medicine,Vol.1and 2,20 th ed., McGraw-Hill (New York, NY, 2018); Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 3 rded.,revised ed.,J.Wiley&Sons(New York,NY,2006);Smith,March's Advanced Organic Chemistry Reactions,Mechanisms and Structure 7 th ed., J. Wiley & Sons (New York, NY, 2013); and Singleton, Dictionary of DNA and Genome Technology, 3 rd ed., Wiley-Blackwell (Hoboken, NJ, 2012), will provide those of skill in the art with a general guide to many of the terms used herein.

[0026] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of this disclosure. Indeed, this disclosure is in no way limited to the methods and materials described. For purposes of this disclosure, certain terms are defined below.

[0027] "Treatment" and "prevention" and related terms include, but are not limited to, treating a medical condition, preventing a medical condition, reducing the likelihood of having a medical condition, reducing the severity of a medical condition, and / or slowing the progression of a medical condition in a subject, hereinafter referred to as an "application." Such conditions or applications can be remedied by the use of one or more agents administered through a sustained release agent delivery device.

[0028] These conditions, or applications, are further described under "Device Uses and Applications" and may include, but are not limited to, infectious diseases (e.g., human immunodeficiency virus (HIV) infection, acquired immune deficiency syndrome (AIDS), herpes simplex virus (HSV) infection, hepatitis virus infection, respiratory viral infections (including, but not limited to, influenza viruses and coronaviruses, e.g., SARS-CoV-2), tuberculosis, other bacterial infections, and malaria), diabetes, cardiovascular disorders, cancer, autoimmune diseases, central nervous system (CNS) conditions, and similar conditions in non-human mammals.

[0029] Additionally, the present disclosure provides for administration of biologics such as proteins and peptides for the treatment or prevention of various disorders such as conditions treatable with leuprolide (e.g., anemia due to bleeding from uterine leiomyomas, intrauterine fibroid tumors, prostate cancer, and central premature puberty), exenatide for the treatment of diabetes, histrelin acetate for the treatment of central premature puberty, etc. A more detailed list of illustrative examples of potential applications of the present disclosure is provided under "Device Uses and Applications."

[0030] As used herein, the term "HIV" includes HIV-1 and HIV-2.

[0031] As used herein, the term "drug" includes, but is not limited to, any drug or prodrug.

[0032] As used herein, the terms "drug," "pharmaceutical agent," and "therapeutic agent" are used interchangeably.

[0033] As used herein, the term "API" refers to an active pharmaceutical ingredient, including drugs as described herein. The term "API" includes drugs, as well as peptide-drug conjugates and peptide prodrugs.

[0034] As used herein, the terms "peptide-drug conjugate" and "peptide prodrug" are used interchangeably and refer to a drug covalently attached to a peptide for the purpose of, e.g., enhancing the pharmacological properties of the drug.

[0035] The terms "drug delivery device" and "implant" and / or "injectable" are used interchangeably herein unless otherwise indicated and include, for example, devices for use intravaginally, subcutaneously, intramuscularly, intraocularly, in the ear, brain, oral cavity, nasal cavity, or any other body compartment.

[0036] As used herein, the term "IVR" refers to an intravaginal ring, including the embodiments described herein.

[0037] As used herein, the terms "microarray patch" and "microneedle patch" are used interchangeably and are composed of multiple micrometer-sized projections that can painlessly pierce the skin and access the epidermis / dermal layer to deliver peptide-drug conjugates.

[0038] A "kernel" is defined as one or more compartments that contain one or more peptide-drug conjugates, optionally in combination with one or more APIs, and that make up the majority of the device volume.

[0039] A "matrix system" is a specific type of kernel defined as a system in which one or more peptide-drug conjugates are uniformly distributed in a matrix material and have no other release barriers other than diffusion from the matrix material.

[0040] A "reservoir system" is a specific type of kernel defined as a system in which one or more peptide-drug conjugates are formulated in a central compartment along with excipients.

[0041] A "skin" is defined as a low volume element of a drug delivery system that covers some or all of the kernel. In some cases, the skin refers to the outer portion of the drug delivery system that contacts the external environment. The terms "skin," "membrane," and "layer" are used interchangeably herein.

[0042] A "rate-limiting skin" is a particular embodiment of a skin defined by a portion of the system that includes a polymer with a relatively low permeability for the therapeutic agent.

[0043] The terms "patient" and "subject" are used interchangeably herein and refer to a human or non-human mammal.

[0044] "Permeability" refers to the measurement of the ability of a therapeutic agent to pass through a thermoplastic polymer.

[0045] As used herein, "mammal" refers to any member of the class Mammalia, including, but not limited to, humans and non-human primates such as chimpanzees and other ape and monkey species, farm animals such as cows, sheep, pigs, goats and horses, domesticated mammals such as dogs and cats, laboratory animals including rodents such as mice, rats and guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn mammals, whether male or female, are intended to be included within the scope of this term.

[0046] In various embodiments, the present disclosure teaches devices, systems and methods for treating a medical condition, preventing a medical condition, reducing the likelihood of having a medical condition, reducing the severity of a medical condition, and / or slowing the progression of a medical condition in a subject.

[0047] Peptide-drug conjugates The present disclosure provides peptide prodrugs, also referred to as peptide-drug conjugates, to enhance the pharmacological properties of the parent drug. Exemplary embodiments are described below.

[0048] The pharmacological properties that peptide-drug conjugates enhance compared to parent drugs may include, but are not limited to, increased efficacy for target indications, increased in vivo half-life, increased accumulation in target physiological compartments, and reduced toxicity.The primary delivery mode contemplated for peptide-drug conjugates is parenteral.For amino acid, dipeptide, or tripeptide drug conjugates that target human peptide transporter 1 (PEPT1) in the small intestinal lumen and PEPT2 renal proximal tubule, targeting molecular transporter proteins for increased oral bioavailability, as is well known in the art (e.g., valacyclovir), is not contemplated herein.

[0049] The peptide component of the peptide-drug conjugate (peptide prodrug) can be synthesized using techniques and reagents known in the art. In one embodiment, automated, 9-fluorenylmethoxycarbonyl (Fmoc), Rink amide resin, solid-phase synthesis techniques are used. In another embodiment, tert-butyloxycarbonyl (Boc) solid-phase synthesis techniques are used. The methods (e.g., automated microwave-assisted peptide synthesis) and reagents (i.e., resins, coupling agents, cleavage chemistries) are well known in the art.

[0050] Peptides - General Characteristics The peptide forming the basis of the peptide-drug conjugate comprises a linear peptide or a cyclic peptide. In some cases, the peptide is a linear peptide. In some cases, the peptide is a cyclic peptide. The peptide comprises an amino acid sequence of 3 to 30 amino acids, preferably 4 to 20 amino acids. In one embodiment, the amino acid belongs to the 20 natural amino acids known in the art and is an I-isomer. In another embodiment, the amino acid belongs to the 20 natural amino acids known in the art and is a D-isomer. In another embodiment, one or more amino acids in the peptide sequence are unnatural amino acids known in the art, including, but not limited to, protected N-methyl amino acids, I-indoline-2-carboxylic acid, I-2-cyclohexylglycine. Representative unnatural amino acid building blocks for peptide synthesis are standard catalog items from commercial vendors (e.g., Chem-Impex International, Inc., Wood Dale, IL, USA).

[0051] The peptides used to form drug conjugates with enhanced pharmacological properties are from two main classes: (1) cell penetrating peptides and (2) cell targeting peptides, as described in more detail below. In some cases, the peptide comprises a cell penetrating peptide. In some cases, the peptide comprises a cell targeting peptide. In some cases, the peptide is an immune enhancing peptide.

[0052] Non-limiting examples of suitable peptides include those listed in Table A below. [Table 1] [Table 2] [Table 3]

[0053] The peptide-drug conjugates of the present disclosure utilize native functional groups in the drug, peptide, and / or optional linker that can be derivatized. Conjugation strategies are further described in the art (e.g., in references 10-13, which are incorporated herein in their entirety). Exemplary non-limiting functional groups suitable for derivatization include esters, carbonates, phosphates, and phosphonates (e.g., phosphonooxymethyl ethers, phosphoramidates, CycloSal, HepDirect, ProTide), acylsulfonamides, amides, carbamates, N-Mannich adducts, N-acyloxyalkylamines, azoconjugates, imines, hydrazones, sulfenamides, amidines, and guanidines.

[0054] In some embodiments, the drug of the peptide-drug conjugate of the present disclosure comprises two or more conjugable functional groups, which can be the same or different. In some cases, the conjugate comprises two or more peptides conjugated to the drug, which can be the same or different. As a non-limiting example, the hydroxy group in 3TC can be conjugated to a first peptide, while the amino group can be conjugated to a second peptide via a carbamate, or vice versa.

[0055] synthesis One general, non-limiting synthetic strategy for preparing peptide prodrugs described herein involves direct coupling of the peptide with the drug, as shown generally in Figures 1-2.

[0056] In the strategy shown in Figures 1 and 2, the linker L1 anchors the peptide P to a solid-phase resin, and R and L2 directly link the drug D to P via an in vivo chemically labile bond (e.g., ester, carbamate, carbonate). In one embodiment, L1 forms part of the resin. There are numerous examples in the art of such L1-R systems, as exemplified by standard catalog items from commercial vendors (e.g., Chem-Impex International, IL, USA). For example, Rink amide resin results in an amidated C-terminus, and the amide amino group is transferred from the resin to the peptide. In another example, a sulfonamide resin such as 4-sulfamylbutyryl AM resin is used, and once synthesis is complete, the peptide-resin conjugate is activated using iodoacetonitrile (ICH2CN), followed by cleavage with ethyl mercaptoacetate (HSCH2CH2CO2Et, H-SR) and acidolytic deprotection to yield the fully deprotected peptide α-thioester. The C-terminal thioester functionality (SR) is transferred to the peptide during workup.

[0057] The term "linker", as used herein, refers to a moiety that includes two reactive groups linked by one or more carbon or heteroatoms. In some cases, one or more linkers are covalently attached to a terminal residue of a peptide. In some cases, the terminal residue is an N-terminal residue. In some cases, the terminal residue is a C-terminal residue. In some cases, one or more linkers are covalently attached to a non-terminal residue of a peptide. In some cases, one or more linkers are covalently attached to a side chain of a non-terminal residue. In some cases, the non-terminal residue is a lysine, cysteine, aspartic acid, or glutamic acid residue.

[0058] In some cases, one or more of the linkers is selected from the group consisting of (C1-C8) alkyl, (C1-C8) alkenyl, (C1-C8) alkynyl, (C3-C 10 )Cycloalkyl, (C6-C 10 )aryl, (C2-C9)heteroalkyl, or (C2-C9)heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl is (C1-C6)alkyl, 1-4 halogen, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, hydroxy, amino, (C1-C4)alkylamino, (C1-C4)dialkylamino, (C3-C 10 )cycloalkyl, (C1-C6)alkylcarbonyloxy, (C1-C6)alkylcarbonylamido, (C1-C4)alkylamidocarbonyl, (C1-C4)dialkylamidocarbonyl, nitro, cyano, (C1-C4)alkylamino, mercapto, or (C1-C4)alkylmercapto.

[0059] In some cases, one or more of the linkers has the structure: -C(O)-JC(O)-KC(O)-, In the formula, K is -C 10 Alkylene-, -(CH2), A-(CH2) t -, -, and Q, and -C(O)-J- is absent, an amino acid residue, or a peptide of 2 to 10 amino acid residues; -C(O)- is derived from the carboxy terminus of an amino acid or peptide; A is -O-, -S-, -NR1-, -N + (R1)2-, -SS-, -[OCH2CH2] r -O-, -L-, or -OYO-; Q is L or -Z=N-NH-S(O) v -L-, L is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Z is -(CH2) w -C(CH3)=, -(CH2) wCH=cycloalkyl or heterocycloalkyl; R1 is hydrogen or C1-C4 alkyl; s and t are independently integers selected from 1 and 2; r is an integer selected from 1, 2, and 3; v is an integer selected from 0, 1, and 2; w is an integer selected from 1, 2, 3, and 4.

[0060] In some cases, the one or more linkers comprise two or more amino acids, peptides, polyethers such as polyethylene glycol (i.e., PEG), and / or combinations thereof. In some cases, the one or more linkers comprise two or more amino acids. In some cases, the one or more linkers are peptides. In some cases, the one or more linkers comprise polyethers. In some cases, the one or more linkers comprise polyethylene glycol (i.e., PEG), and / or combinations thereof. Common linkers include Gly-Ser-Gly ("GSG") or multiples thereof (GSG). n In some cases, one or more of the linkers comprises Gly-Ser-Gly ("GSG"). In applications where it is important to have a long distance between the drug D and the peptide P, polyethylene glycol ("PEG") chains of various lengths [i.e., (PEG) n ) is inserted between these two parts.

[0061] In the embodiment shown in Figures 1-2, drug D is directly coupled to the peptide during solid phase synthesis, i.e., the peptide is resin anchored. Coupling is accomplished using a suitable reactive chemical functionality on one of the orthogonal amino acid side chains (Figure 1) with a suitable reactive chemical functionality in the drug. In one non-limiting embodiment, the orthogonal carboxylic acid in aspartic acid (β-carboxyl group) and glutamic acid (γ-carboxyl group) can be coupled with an alcohol functionality in the drug to give an ester. In one non-limiting embodiment, the orthogonal amino group in lysine (ε-amino group) can be coupled with an alcohol functionality in the drug to give a carbamate or with a carboxylate functionality in the drug to give an amide. In another non-limiting embodiment, the orthogonal hydroxyl group in serine (β-hydroxyl group) can be coupled with an alcohol functionality in the drug to give a carbonate, a carboxylate functionality in the drug can give an ester, or an amino functionality in the drug can give a carbamate. Coupling is accomplished using synthetic methods and reagents well known in the art, such as carbodiimides in the presence of activators (e.g., N-hydroxybenzotriazole) and / or catalysts (e.g., 4-dimethylaminopyridine) or 1,1'-carbonyldiimidazole. In an embodiment in which drug D is directly attached to an orthogonal reactive group in the peptide, selective deprotection of the reactive group is accomplished using methods and reagents well known in the art to avoid deprotection of other reactive groups in the peptide side chain. In a non-limiting embodiment, the aspartic acid β-carboxyl group is protected as an O-allyl ester and deprotected with catalytic tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] and phenylsilane in dichloromethane. In some cases, one or more linkers are conjugated to the peptide and / or drug via an ester, carbonate, carbamate moiety, succinimidyl thioether, or triazole moiety. In some cases, one or more linkers are conjugated to the peptide and / or drug via an ester, carbonate, or carbamate moiety.In some cases, one or more linkers are conjugated to the peptide and / or drug via an ester moiety. In some cases, one or more linkers are conjugated to the peptide and / or drug via a carbonate moiety. In some cases, one or more linkers are conjugated to the peptide and / or drug via a carbamate moiety. In some cases, one or more linkers are conjugated to the peptide and / or drug via a succinimidyl thioether or triazole moiety. In some cases, one or more linkers are conjugated to the peptide and / or drug via a succinimidyl thioether moiety. In some cases, one or more linkers are conjugated to the peptide and / or drug via a triazole moiety.

[0062] A non-limiting example of a general peptide-ARV prodrug synthesis approach is shown in Figures 10A and 10B. An aspartic acid linker (shown at the C-terminus in Figure 10A and at the N-terminus in Figure 10B) is added to all sequences shown in Table A for orthogonal conjugation to give the corresponding ester prodrug. This innovative synthetic design allows peptide assembly followed by drug conjugation to be performed using automated solid-phase synthesis, which holds advantages in simplicity and efficiency compared to carrying out the prodrug reaction steps separately using traditional flask chemistry (i.e., additional protection / deprotection or intermediate purification steps). In this non-limiting example, peptide ARV drug conjugates are synthesized using automated standard 9-fluorenylmethoxycarbonyl (Fmoc), Rink amide resin, solid-phase synthesis techniques.

[0063] In another non-limiting embodiment, direct drug-peptide conjugation occurs at the resin-supported peptide N-terminus (Figure 2).

[0064] In another non-limiting embodiment involving on-resin coupling of a drug D to a peptide P via a linker, e.g., L2 (Figures 1-2), the linker consists of a molecular linker attached via a covalent bond to both D and the linker, e.g., L. In one embodiment, the bond between the linker, e.g., L2, and D is readily cleaved by enzymatic and / or chemical conversion in vivo to release the active parent drug D (Figure 3).

[0065] Non-limiting examples of such bonds are ester, carbonate, and carbamate bonds. In some embodiments, the bond between the linker, e.g., L2, and P, may be easily cleaved by enzymatic and / or chemical conversion in vivo or may be stable to in vivo cleavage, such as some amides and triazoles. For example, a drug D containing a hydroxyl group can be reacted with succinic anhydride to give a monoester of 1,4-butanedioic acid (succinic acid). The free carboxylic acid can then be condensed with an amino group (side chain or N-terminus) in the peptide P to give the corresponding amide (Figure 4).

[0066] In another non-limiting embodiment, the linker, e.g., L2, contains a labile bond to the peptide P and a less stable bond to the drug, D. Under this embodiment, the peptide is first hydrolyzed to release the drug, which is still chemically bound to the linker, and the linker is later cleaved from the drug. In another embodiment, the peptide P enhances the delivery of the drug D to one or more pharmacological compartments before cleaving P from the linker, e.g., L2. The drug linker, e.g., D-L2 conjugate, then has superior pharmacological properties compared to D alone. For example, the drug D contains a hydroxyl group that is conjugated to a pegylated linker, e.g., L2, via a carbamate group. A free carboxylic acid group (e.g., aspartic acid or glutamic acid) on the peptide P side chain or N-terminus is also conjugated to a linker, e.g., L2, via an ester bond. The ester bond is first cleaved in vivo, releasing the pegylated drug carbamate.

[0067] In another embodiment, a synthetic strategy for preparing peptide prodrugs described herein involves drug-peptide conjugation after the peptide is cleaved from the resin, as shown in Figures 6-8.

[0068] In these embodiments, peptide-linker-drug coupling is achieved using chemoselective synthesis strategies known in the art to avoid side reactions with unprotected orthogonal reactive groups in peptide P. In one non-limiting embodiment, coupling is achieved using so-called "click chemistry". Click chemistry applicable to the disclosed peptide-drug conjugates involves a functional group on peptide P that reacts with another complementary functional group on drug D to give a product linked via a linker, e.g., L2. Non-limiting examples of such click chemistry tools include the following:

[0069] These include the copper catalyzed reaction of azides with alkynes to give the corresponding triazoles, sterically strained trans cycloalkenes with azides, tetrazines, and tetrazoles, or the reaction of thiols (e.g., cysteine) with maleimides to give the corresponding succinimidyl thioethers. Non-limiting examples are shown in FIG.

[0070] Peptide Classes and Sequences In various aspects, the drug is conjugated or linked to a moiety that enhances the delivery and / or penetration of the drug into a target cell. In this regard, the present disclosure provides, for example, the use of cell membrane penetrating peptides to enhance the uptake of a drug in a target cell. Cell penetrating peptides (CPPs), also known as protein transduction domains, are a class of amino acid sequences, generally 3-30 residues in length, that can cross biological membranes and deliver a wide variety of payloads to cells. A common (but not required) attribute of CPPs is a series of cationic amino acids combined with a sequence that forms an alpha helix at low pH. See, for example, (14). Many CPPs have an amino acid composition that is rich in basic amino acids (e.g., lysine or arginine). Simply for illustration, a CPP can include any combination of at least two arginines and at least two hydrophobic amino acids, for example, a combination of two to three arginines and at least two hydrophobic amino acids, but this is not required.

[0071] In various aspects, the peptide of the peptide-drug conjugate is a cationic CPP, an amphipathic CPP, a hydrophobic CPP, or a cyclic CPP. Exemplary peptides suitable for use as CPPs include, but are not limited to, protamine, nucleolin, spermine or spermidine, polylysine-containing peptides (e.g., peptides containing 3, 4, 5, 6, 7, 8, 9, 10 or more lysines), polyarginine-containing peptides (e.g., peptides containing 3, 4, 5, 6, 7, 8, 9, 10 or more arginines), polyproline-containing peptides (e.g., peptides containing 3, 4, 5, 6, 7, 8, 9, 10 or more prolines), Transportan, or MPG peptides, HIV-binding peptides, transcriptional transactivator (TAT)-derived peptides (residues 47-57 of HIV-1 TAT, including a cysteine-free version of a TAT-derived peptide), members of the penetratin family (e.g., penetratin), antennapedia-derived peptides (e.g., a peptide derived from Drosophila antennapedia), antibacterial-derived CPPs, SynB, PVEC, hCT-derived peptides, SAP, PPTG, VP22-derived peptides, and the like. In various embodiments, the CPP is a cationic CPP, an amphipathic CPP, a hydrophobic CPP, and / or a cyclic CPP. Examples of CPPs are provided in Table A.

[0072] Optionally, the peptide of the peptide-drug conjugation is a cell-targeting peptide (CTP). "Cell-targeting peptide" refers to a peptide that recognizes and preferentially binds to specific cells and tissues. In one embodiment, the cell-targeting peptide targets surface features of immune cells and is referred to as an immune enhancing peptide. Like CPPs, CTPs are generally short peptides (e.g., 3-30 residues in length) and are often derived from motifs that allow the peptide to target biological markers on the cell surface. In some examples, CPPs can also function as CTPs. In various aspects, CTPs target, for example, cancer cells, endothelial cells, adipocytes, cells of the blood-brain barrier, immune cells, etc. Examples of CTPs are provided in Table A herein. It will be understood that common motifs are shared by various CTPs that target cell or tissue types. For example, a CTP that binds to breast cancer cells may contain the motif AEGEF (SEQ ID NO: 69), QEXSP (SEQ ID NO: 66), where X is Y, or F, or MX1RX2X3X4, where X1 contains a polar uncharged amino acid such as S, T, N, or Q, or a hydrophobic non-aliphatic amino acid such as A, V, I, or M, X2 is T, S, N, Q, M, A, V, I, L, K, E, or D, X3 is T, S, N, Q, M, A, V, I, L, K, E, or D, and X4 is T, S, N, Q, M, A, V, I, L, K, E, or D. CTPs that target prostate, pancreatic duct, breast cancer, bone, brain, or cervical cancer cells may, but need not, have the consensus motifs of arginine, glycine, and aspartic acid.CTP is a kinase inhibitor that regulates the function of a disintegrin and metalloproteinase (ADAM, e.g., ADAM15), CXC chemokine receptors (e.g., CXCR4), epinephrine-A, epinephrine-A receptor (e.g., EphA4), ephrin-B3, ErbB-2, selectins (e.g., E-selectin), Gal β 1→3GalNAc Any cell surface molecule of interest may be targeted, including, but not limited to, alpha disaccharides, galectin-3, HER2 (human epidermal growth factor receptor 2), integrins (e.g., alpha-5beta-3 or alpha-5beta-5 or alpha-5beta-1), aminopeptidase N (CD13) and integrin alpha-5beta-3 (CD51 / CD61), membrane type 1 matrix metalloproteinase (MT1-MMP), neuropilin 1 (NRP-1), nucleolin, podoplanin, prospero homeobox protein 1 (Prox-1), lymphactin endothelial factor endothelial anan receptor 1-1 (LYVE-1), vascular endothelial growth factor receptors (e.g., VEGFR-10 or VEGFR-11), proterican, LDR1, low density lipoprotein receptor (LDLR), bombesin, or gastrin releasing peptide.

[0073] The CPP or CTP can be a linear or cyclic peptide. The peptide can include about 3-30 amino acids or about 4-20 amino acids, such as about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, and about 19 amino acids, including all ranges and subranges therebetween. Optionally, the amino acids of the CPP or CTP belong to the 20 naturally occurring amino acids and are l-isomers. In another embodiment, one or more amino acids belong to the 20 naturally occurring amino acids and are d-isomers. Alternatively, or in addition, one or more amino acids in the peptide sequence are unnatural amino acids, including, but not limited to, protected N-methyl amino acids, 1-indoline-2-carboxylic acid, 1-2-cyclohexylglycine. Representative unnatural amino acid building blocks for peptide synthesis are available from commercial vendors (eg, Chem-Impex International, Inc., Wood Dale, IL, USA).

[0074] The present disclosure contemplates CPPs or CTPs having at least about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence disclosed herein, e.g., an amino acid sequence disclosed in Table A. The present disclosure also contemplates CPPs or CTPs having one, two, three, or four amino acid substitutions (e.g., conservative substitutions). Desirably, the CPP or CTP retains the structural and functional characteristics of the parent CPP or CTP. Such polypeptide variants can be prepared by substituting (eg, using conservative substitutions), deleting or adding amino acid residues from the original sequence.

[0075] CPPs and CTPs are further described, for example, in U.S. Patent Publication Nos. 20140227344 and 20220378946, U.S. Patent No. 11510991, and (15), (16), and (17), each of which is incorporated by reference in its entirety, particularly with respect to disclosure of CPP and CPP sequence characteristics. CPPs are also further described, for example, at crdd.osdd.net / raghava / cppsite / .

[0076] Implantable API Delivery Devices The implantable devices disclosed herein for local or systemic API delivery include the following elements:

[0077] One or more partitions that contain one or more APIs and make up a significant portion of the device's volume, also known as the "kernel."

[0078] One or more skin layers that are API-transparent covering one or more kernels and meet one or more of the following requirements: a) It acts as a diffusion-limiting barrier that controls the release of the API from the central compartment. b) Protecting the central compartment from one or more components of the external environment. c) Provide structural support for the device.

[0079] A skin comprises a continuous membrane that covers all or a portion of a device and is not perforated with orifices or channels (e.g., mechanical punches, laser drilling) created during fabrication of the device.

[0080] Defined microscopic pore structure. The pore structure is optionally incorporated into one or both of the above elements. In other words, one or more kernels and / or one or more skins have a microscopic pore structure. A "microscopic pore" structure, as known by those skilled in the art (18), is defined as follows:

[0081] Microporous, with defined pores having diameters less than 2 nm.

[0082] Mesoporous, with defined pores with diameters between 2 and 50 nm.

[0083] Macroporous, with defined pores having diameters larger than 50 nm and typically smaller than 250 μm.

[0084] Provided herein is a drug delivery device comprising: (a) one or more kernels that contain one or more APIs; and (b) one or more skins that comprise a continuous membrane, wherein the one or more kernels and / or skins comprise defined pores, and the pores are not mechanically generated.

[0085] In some cases, the device comprises one kernel. In some cases, the device comprises multiple kernels.

[0086] In some cases, the kernel(s) comprise a defined microscopic or nanoscopic pore structure. In some cases, the kernel is a reservoir kernel.

[0087] In some cases, the reservoir kernel comprises a powder comprising one or more APIs. In some cases, the reservoir kernel comprises a powder comprising one API. In some cases, the reservoir kernel comprises a powder comprising two or more APIs. In some cases, the powder comprises a microscale API carrier or a nanoscale API carrier. In some cases, the powder comprises a microscale API carrier. In some cases, the powder comprises a nanoscale API carrier. In some cases, the API carrier is a bead, a capsule, a microgel, nanocellulose, a dendrimer, or a diatom.

[0088] Devices embodying these elements contain a hierarchical structure based on three levels of organization.

[0089] Primary Structure: Based on the physicochemical properties of the components and materials that make up the implant kernel and skin, including but not limited to factors such as polymeric or elastomeric composition, molecular weight, degree of crosslinking, hydrophobicity / hydrophilicity, and rheological properties, API physicochemical properties such as solubility, log P, and strength.

[0090] Secondary Structure: The complex microstructure of the kernel and / or skin. This can include, but is not limited to, properties such as the size, shape, and structure of the API particles (e.g., core-shell architecture), the fibrous structure of the API or excipients in the kernel, the pore characteristics of sponge-based kernel materials or porous skins (pore density, pore size, pore shape, etc.).

[0091] Tertiary Structure: The macroscopic geometry and architecture of an implantable device. This includes, but is not limited to, factors such as the size and shape of the implant, the kernel and skin dimensions (thickness, diameter, etc.), the layers of the kernel and / or skin, and their relative orientation.

[0092] The incorporation of these elements into an implantable or injectable API delivery device determines the characteristics of the controlled, sustained delivery of one or more APIs at a given location in the body (ie, the implantation / injection site).

[0093] In one embodiment, the device is implanted or injected into a sterile anatomical compartment, including but not limited to the subcutaneous space, intramuscular space, eye, ear, and brain, hi another embodiment, the device is implanted into a non-sterile anatomical compartment, including but not limited to the vagina, rectum, oral cavity, and nasal cavity.

[0094] The devices described herein are intended to be left in place for periods ranging from one day to a year or more and provide one or more APIs during this period of use. In certain exemplary, non-limiting embodiments, the devices are implanted or injected subcutaneously or intramuscularly and deliver one or more APIs for 3-12 months. In certain exemplary, non-limiting embodiments, the devices are used intravaginally as an IVR and deliver one or more APIs for 1-3 months.

[0095] Additional details of exemplary embodiments are provided below.

[0096] Implant Geometry The implant geometry is based on a number of shapes. In one exemplary, non-limiting embodiment, the shape of the device is based on a cylinder, and in some cases the ends of the cylinder are joined to provide a toroid. These geometries are well known in the art.

[0097] Devices for subcutaneous implantation are typically of regular cylindrical geometry. Regular geometry can simplify implant manufacturing. In one embodiment, the implant has a cylindrical or rod-like geometry with a diameter smaller than its length (100). Preferred lengths of rod-like implants are, for example, 5-50 mm, 5-10 mm, 10-20 mm, 20-30 mm, 30-40 mm, 40-50 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm. Preferred rod diameters are, for example, 1-6 mm, 1-2 mm, 2-3 mm, 3-4 mm, 4-5 mm, 5-6 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 5 mm, or 6 mm. In an alternative embodiment, the geometry can be a rectangular prism (102). The cylindrical or rectangular prism geometry can be flat or can have a curved shape (103).

[0098] In some embodiments, the implant is optionally shaped like a capsule with a diameter of about 3 to about 50 mm and a height of up to about 5 mm. In some embodiments, for example 600 illustrated in Figures 13A-13D, the implant comprises or consists of a reservoir 602 and an impermeable disk-shaped cover 601 that seals the reservoir. In some embodiments, the reservoir comprises an outer sealing ring 603 that forms a seal with the cover, one or more skin regions 604 that are permeable to bodily fluids and API and serve as zones of API release, and one or more rib structures 605 that support the skin membrane and define a compartment that includes the single skin region. The reservoir may be fabricated as a single piece from one material, or may be assembled from a first part including the outer sealing ring and any rib structures, and a second part including a separate skin membrane attached to the first part using an adhesive or another assembly method disclosed herein. In any of the embodiments described herein, a kernel as described herein can be included in these compartments formed between the internal reservoir surface and the cover. In any of the embodiments described herein, all compartments defined by the rib structure may be filled with kernel material including API and suitable excipients, or some compartments may be filled and some remain unfilled. In any of the embodiments described herein, all compartments contain the same kernel material. In any of the embodiments described herein, different compartments may contain different kernel materials. In any of the embodiments described herein, the multiple compartments contain a total of two kernel materials. In another preferred embodiment, the multiple compartments contain a total of three or more kernel materials. Those skilled in the art will recognize from the disclosure provided herein that the compartments in the reservoir may contain any of several possible combinations of kernel materials, all possible combinations being included herein.

[0099] In some embodiments, for example those illustrated in Figures 14A-14G, the capsule-shaped implant comprises a skin-containing disk 610 inserted into an API-impermeable housing 611. In some embodiments, the housing comprises a sealing ring 612 encapsulated on one side by an impermeable backing to form a reservoir. In some embodiments, the disk (bottom view, 614, and top view, 615) comprises an outer lip 616 that forms a seal that fits inside the sealing ring of the housing, one or more skin regions 617 that are permeable to bodily fluids and the API and serve as zones of API release, and one or more rib structures 618 that support the skin membrane and define a compartment that includes the single skin region. In some embodiments, the disk may be fabricated as a single piece from one material, or may be assembled (630) from a first portion 631 including the outer sealing ring and any rib structures, and a second portion 632 including a separate skin membrane attached to the first portion using an adhesive or another assembly method disclosed herein. In some embodiments, the API is released from one or more compartments formed between the skin membrane and the housing backing, surrounded by the housing sealing ring.

[0100] In some embodiments, for example those illustrated in Figures 15A-15E, a capsule-shaped implant 620 comprises two skin-containing disks 621 inserted into an API-impermeable sealing ring 622. In some embodiments, the disks comprise an outer lip 623 that forms a seal that fits inside the sealing ring, one or more skin regions 624 that are permeable to bodily fluids and API and serve as zones of API release, and one or more rib structures 625 that support the skin membranes and define compartments that include a single skin region. In some embodiments, each disk can be fabricated as a single piece from one material, or assembled (630) from a first portion 631 that includes the outer sealing ring and any rib structures, and a second portion 632 that includes a separate skin membrane attached to the first portion using an adhesive or another assembly method disclosed herein. In some embodiments, the API is released from one or more compartments formed between the two disk structures and encapsulated by the sealing ring and any rib structures.

[0101] In some embodiments, the implant is disc-shaped with a diameter greater than or equal to its length, from about 3 to about 50 mm, and up to about 5 mm.

[0102] In one non-limiting embodiment, a device for vaginal use such as an IVR is toroidal in geometry with an outer diameter of 40-70 mm and a cross-sectional diameter of 2-10 mm (104). A preferred IVR outer diameter is 50-60 mm, or 54-56 mm, with a cross-sectional diameter of 3-8 mm, or 4-6 mm. The cross-sectional shape of the IVR can be other than circular, such as square, rectangular, triangular, or other shapes (105). The IVR can include separate compartments containing the API and other components of the API delivery function, which are connected by a section of elastomeric material that serves to hold the compartments in a ring-like orientation and allow retention of the IVR in the vagina (106). In another embodiment, the central compartment can include an API delivery device with an outer ring that functions only to retain the device in the vaginal cavity (107). The API delivery functionality may be contained in a module that is inserted into the central compartment through opening 107a, with multiple large openings allowing the API to exit the central compartment but playing no role in controlling the release rate of the API. In an alternative embodiment, both the ring compartment and the central compartment may contain an API delivery component.

[0103] A pessary is a device inserted into the vaginal cavity to reduce protrusion of pelvic structures and to support and reduce stress on the bladder and other pelvic organs. Vaginal implants for API delivery have a geometry similar to that of a pessary, combining vaginal API delivery with structural support. In various embodiments, the vaginal API delivery device has the geometry of a ring pessary 110, a ring pessary supporting a central structure 111, or a Gelhorn pessary 112. The API release function can be contained in the ring, flat support, or knob portion of the pessary.

[0104] In one non-limiting embodiment, a device for vaginal use such as an IVR is toroidal in geometry with an outer diameter of 40-70 mm and a cross-sectional diameter of 2-10 mm (104). A preferred IVR outer diameter is 50-60 mm, or 54-56 mm, with a cross-sectional diameter of 3-8 mm, or 4-6 mm. The cross-sectional shape of the IVR can be other than circular, such as square, rectangular, triangular, or other shapes (105). The IVR can include separate compartments containing the API and other components of the API delivery function, which are connected by a section of elastomeric material that serves to hold the compartments in a ring-like orientation and allow retention of the IVR in the vagina (106). In another embodiment, the central compartment can include an API delivery device with an outer ring that functions only to retain the device in the vaginal cavity (107). The API delivery functionality may be contained in a module that is inserted into the central compartment through opening 107a, with multiple large openings allowing the API to exit the central compartment but playing no role in controlling the release rate of the API. In an alternative embodiment, both the ring compartment and the central compartment may contain an API delivery component.

[0105] In one embodiment, e.g., 700 illustrated in Figs. 18A-18D, the vaginal implant includes one or more cylindrical core elements 701, consisting of kernels 703, with or without skins 702, held within a perforated carrier. In some cases, the skins include a non-medicated elastomer. The core elements are inserted into the carrier through the perforations (705). Additional perforations 706 in the carrier allow the kernels to interact with vaginal fluids, but the perforations do not play a role in controlling the release rate of the API. An alternative embodiment, e.g., 710 illustrated in Figs. 19A-19D, includes a molded substructure 712 with one or more separate compartments comprising one or more kernels 713. The bottom of each compartment is a drug-permeable membrane, functioning as a skin to regulate API release from the kernel. A superstructure 711 is bonded to the carrier 712 to seal the compartments and form a ring structure. Matching protruding and recessed structures may be located around the inner and outer periphery of the top and bottom of the IVR to facilitate assembly and sealing of the device during manufacture. Alternatively, both the top and bottom structures may include skins to allow API release from the top and bottom of the IVR. In an alternative embodiment, such as 720 illustrated in Figures 20A-20E, the compartments are contained in lobes that project inwardly from the circular outer rim of the IVR. The bottom portion 721 includes a kernel 725 within one or more compartments 723, the bottom surface of which is API permeable and acts as a skin. The top portion 722 may include matching recessed structures 724 bonded to the bottom structure to facilitate sealing of the top and bottom compartment portions. Alternatively, the recessed area of ​​the top portion may act as an additional API permeable membrane to allow API release from both the top and bottom surfaces of the IVR. Another embodiment, such as 730 illustrated in Figures 21A-21E, includes a substructure that includes one or more compartments 731 to contain one or more kernels. The compartments are surrounded by a discrete membrane material 732 that is sealed to the carrier body and acts as a release rate controlling skin. An additional protective mesh 733 may be present on top of the skin to protect against punctures. A sealing ring or other structure 734 may be used to hold the skin and mesh in place on top of the kernel compartments.The compartment may contain ribs 735 to further subdivide the compartment covered by one skin structure and to provide support to the skin and mesh.

[0106] In some cases, the device is in the shape of a torus. In some cases, the device comprises one or more cylindrical core elements disposed within a first skin, the core element comprising a kernel and, optionally, a second skin.

[0107] In some cases, the device comprises a molded lower structure including one or more compartments containing one or more kernels, and an upper structure coupled to the lower carrier to seal the multiple compartments. In some cases, a skin covers the lower carrier. In some cases, a skin covers the lower structure and the upper structure.

[0108] In some cases, the device comprises one or more lobes projecting inwardly from the outer edge of the torus. In some cases, the device comprises two lobes projecting inwardly from the outer edge of the torus. In some cases, one or more compartments are disposed in the lobes. In some cases, the device comprises one or more recessed structures in one portion and matching protruding structures in another portion to facilitate sealing of the device. In some cases, one or more compartments comprise ribs. In some cases, the device further comprises a protective mesh disposed on a surface of the device.

[0109] Intrauterine devices (IUDs) are an established method of contraception consisting of a T-shaped implant placed in the uterus. Approved IUDs contain copper wire coils that deliver progestin hormones to inhibit follicular development and prevent ovulation, or cause a toxic inflammatory response to sperm and eggs (ova), preventing pregnancy. Progestin IUDs 120 have a central segment 120a that contains progestin, and copper IUDs 121 have one or more copper wire coils 121a wound around the T-structure. In one embodiment, the drug delivery device is in the shape of an IUD and contains one or more copper wire coils to provide contraception in addition to delivering progestin hormones or delivering APIs for indications other than contraception.

[0110] Implant Kernel The implant kernel is the main device component that contains the API. Several exemplary, non-limiting systems are disclosed below.

[0111] Matrix series In one embodiment, the implant kernel comprises a matrix type design (200). In a matrix design, the API material is distributed throughout the kernel as a solution in an elastomer (201). In another embodiment, the API material is distributed throughout the kernel in solid form as a suspension. As used herein, "solid" can include crystalline or amorphous forms. In one embodiment, the size distribution of the solid particles is polydisperse (202). In one embodiment, the size distribution of the solid particles is monodisperse (203). In one embodiment, the solid particles comprise nanoparticles (average diameter <100 nm). In one embodiment, the average diameter of the particles is 100-500 nm. Suitable average particle sizes can be in the range of 0.5-50 μm, 0.5-5 μm, 5-50 μm, 1-10 μm, 10-20 μm, 20-30 μm, 30-40 μm, and 40-50 μm. Other suitable average particle sizes may be in the range of 50-500 μm, 50-100 μm, 100-200 μm, 200-300 μm, 300-400 μm, and 400-500 μm. Suitable particle shapes include, for example, spheres, needles, diamonds, cubes, and irregular shapes.

[0112] In one embodiment, the implant core comprises or comprises multiple modular kernels assembled into a single device, each module being a matrix-type component containing one or more API substances. In one embodiment, the modules can be directly joined to each other (e.g., ultrasonically welded) (204) or separated by an impermeable barrier to prevent API diffusion between the segments (205).

[0113] At least a portion of the matrix-type devices disclosed herein are covered with one or more skins, as described more fully under "implant skins."

[0114] Reservoir System In one embodiment, the implant includes a reservoir type design (206). In a reservoir implant, one or more kernels 206a are loaded with the API material. The kernels can span the entire length of the device, or a partial length. The kernels are partially or completely surrounded by a skin 206b (described in more detail under "Implant Skin"), which in some embodiments forms a barrier to API diffusion, i.e., slows down the rate of API release from the device. Thus, release of the API material from such implants depends on permeation (i.e., molecular dissolution and subsequent diffusion) of the kernel-loaded API material through the outer sheath, or skin. The API release rate can be modified by changing the thickness of the rate-controlling skin, and the composition of the skin. API release kinetics from reservoir type implants is zero- to first-order, depending on the properties of the kernel and the skin.

[0115] There are many embodiments that describe the physical and chemical properties of the reservoir kernel. In one embodiment, the kernel comprises a powder comprised of the API with or without excipients.

[0116] In another embodiment, the powder that makes up the reservoir kernel comprises a microscale (1-1,000 μm cross section) or nanoscale (1-1,000 nm cross section) API carrier. An API carrier is a particulate material that contains the API, either internally or on its surface. Non-limiting examples of such carriers that are known in the art are beads, capsules, microgels including but not limited to chitosan microgels (19), nanocellulose (20, 21), dendrimers, and diatoms (22, 23) and are incorporated herein by reference. The carrier is saturated or coated with the API using impregnation or other methods known in the art (e.g., freeze drying, rotary solvent evaporation, spray drying).

[0117] In another embodiment, the kernel comprises one or more pellets or microtablets. (207)(24). In these embodiments, it may be desirable to maximize API loading and minimize the use of excipients. However, the use of excipients may lead to beneficial physical properties such as lubrication and binding during tableting.

[0118] Provided herein are devices comprising a kernel comprising a pellet, a tablet, or a micro-tablet. In some cases, the kernel comprises a pellet. In some cases, the kernel comprises a tablet. In some cases, the kernel comprises a micro-tablet.

[0119] Semi-solid preparations (pastes) In one non-limiting embodiment of the present disclosure, the kernel comprises solid API particles blended or mixed with one or more liquid or gel excipients to form a semi-solid preparation or paste. This embodiment retains the advantage of making the formulation easily dispensable into the implant shell, providing manufacturing benefits. The nature of the excipients can also affect the API release kinetics from the preparation. The paste is contained in a shell or structure, such as a tube or cassette. The paste can be separated from the external environment by one or more skins, as described herein. In certain embodiments, the structure can function as a skin. Non-limiting examples of structures that surround and contain the kernel paste include, but are not limited to, a tube or cartridge. In certain embodiments, the structure is composed of a solid / continuous (non-porous) elastomer, i.e., both non-resorbable as described herein - e.g., silicone, ethylene vinyl acetate (EVA), and poly(urethane), i.e., resorbable as described herein - e.g., poly(caprolactone) (PCL). In certain embodiments, the structures are composed of porous materials, such as expanded poly(tetrafluoroethylene) (ePTFE) and porous metal as described herein.

[0120] In one embodiment, the liquid excipient comprises an oil with a history of pharmaceutical use, including subcutaneous or intramuscular use. Non-limiting examples of such oils known in the art include triethyl citrate (TEC), polyethylene glycols (PEGs, e.g., PEG-300 and PEG-400), and vegetable oils (e.g., sunflower oil, helianthus annuus oil, sesame oil, etc.). The paste may comprise API particles and a single liquid, or may be a mixture of two or more liquids and API particles. In some embodiments, one or more additional excipients may be added to the paste to modify selected paste properties, including physical properties (e.g., viscosity, adhesion, lubricity) and chemical properties (e.g., pH, ionic strength). In some cases, the use of excipients can affect the solubility of the API material from the kernel and thus the implant release rate. Certain excipients can be used to increase the solubility of the API in water, while others can decrease the solubility. In some cases, the excipients can provide API stabilization. Exemplary excipients are described in more detail below (see "API Formulations"). In another embodiment, such pastes may contain a blend of two or more APIs for the purpose of delivering two or more API substances from a single kernel.

[0121] In another embodiment, the excipient comprises a so-called "ionic liquid" (25-27), which are incorporated by reference in their entirety. Broadly defined, ionic liquids are well known in the art as salts that melt below 100°C and consist entirely of ions. The choice of cation strongly influences the properties of the ionic liquid and often defines its stability. The chemistry and functionality of the ionic liquid is generally controlled by the choice of anion. In one embodiment, the concentration of API substance particles in the paste is 5-99% w / w, with preferred concentration ranges being 5-10% w / w, 10-25% w / w, 25-35% w / w, 35-50% w / w, 50-60% w / w, 60-70% w / w, 70-80% w / w, 80-90% w / w, and 90-99% w / w. FIG. 37C shows results illustrating in vitro how different excipients that make up the paste can affect the release kinetics of, for example, the biomolecule hIgG through an ePTFE tube.

[0122] In one non-limiting set of embodiments, the paste comprises a phase inversion system, where the semi-solid API paste undergoes phase inversion upon contact with physiological fluids, such as subcutaneous, cervicovaginal, and oral fluids. The phase inversion results in hardening of the kernel, generating a solid or semi-solid structure in situ. In one non-limiting embodiment, the phase inversion system comprises a resorbable polymer (e.g., poly(lactic acid), poly(glycolic acid), (lactic acid-glycolic acid) copolymers, poly(caprolactone), and mixtures thereof) and a pharma-ceutically acceptable water-miscible solvent (e.g., N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, benzyl alcohol, benzyl benzoate, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, and the like). Such formulations are suitable for subcutaneous injection, sometimes referred to as "in situ forming implants." See, for example, Dunn et al. (28-31), which are incorporated by reference in their entirety. In one embodiment, the concentration of the API substance particles in the paste is 5-99% w / w, with suitable concentration ranges being 5-10% w / w, 10-25% w / w, 25-35% w / w, 35-50% w / w, 50-60% w / w, 60-70% w / w, 70-80% w / w, 80-90% w / w, and 90-99% w / w.

[0123] Phase inversion systems based solely on phospholipids or in combination with medium chain triglycerides and pharma- ceutically acceptable water-miscible solvents (see above) are also known in the art to form solid or semi-solid depots when in contact with physiological fluids and are used in the disclosed invention to constitute the kernel. In some embodiments, the phase inversion system comprises one or more phospholipids. In some cases, the phase inversion system comprises a combination of one or more phospholipids and one or more medium chain triglycerides (MCTs). Illustrative examples, which are incorporated by reference in their entirety, include (32-36). In non-limiting embodiments, the phospholipids are animal-based (e.g., derived from eggs), plant-based (e.g., derived from soybeans), or synthetic. Commercial suppliers of phospholipids include, but are not limited to, Creative Enzymes, Lipoid, and Avanti. In one non-limiting embodiment, the phospholipid is lecithin. In some embodiments, the MCTs comprise triglycerides from a range of carboxylic acids, such as, but not limited to, those supplied by ABITEC Corporation. In one embodiment, the concentration of API substance particles in the paste is, for example, 5-99% w / w, with suitable concentration ranges being 5-10% w / w, 10-25% w / w, 25-35% w / w, 35-50% w / w, 50-60% w / w, 60-70% w / w, 70-80% w / w, 80-90% w / w, and 90-99% w / w.

[0124] In some embodiments, the phase inversion system comprises one or more lyotropic liquid crystals. In another non-limiting set of embodiments, the excipient formulation that constitutes the kernel paste-API suspension results in lyotropic liquid crystals when in contact with physiological fluids. Certain lipid-based systems, such as monoglycerides, including but not limited to compounds 1-5 below, form lyotropic liquid crystals in the presence of water (37). These systems self-assemble into an ordered mesophase that contains nanoscale water channels, while the remaining three-dimensional structure is hydrophobic. Figure 36 shows an exemplary XRD spectrum of monoolein (MYVEROL 18-92K, a food emulsifier) ​​mixed with 20% and 30% w / w water, which self-assembles into a network of ordered channels approximately 5 nm wide. [ka]

[0125] In one embodiment, the lyotropic lipid-based system can be used to form a paste formulation suspension with API substance particles. In one embodiment, the concentration of API substance particles in the paste is, for example, 5-99% w / w, with suitable concentration ranges being 5-10% w / w, 10-25% w / w, 25-35% w / w, 35-50% w / w, 50-60% w / w, 60-70% w / w, 70-80% w / w, 80-90% w / w, and 90-99% w / w.

[0126] In another non-limiting embodiment, the paste comprises a shape-memory self-healing gel, as known to those skilled in the art. Illustrative examples, which are incorporated by reference in their entirety, include (38-40). Shapes holding injectable hydrogels based on polysaccharide backbones (e.g., alginate, chitosan, HPMC, hyaluronic acid), and in some cases non-covalently linked to nanoparticles (non-medicinal or medicinal), form part of this embodiment for semi-solid preparations, including (41-43), which are incorporated by reference in their entirety. In one embodiment, the physically crosslinked nanoparticles comprise or consist of API nanoparticles. In one embodiment, the concentration of the API substance particles in the paste is 5-99% w / w, with suitable concentration ranges being 5-10% w / w, 10-25% w / w, 25-35% w / w, 35-50% w / w, 50-60% w / w, 60-70% w / w, 70-80% w / w, 80-90% w / w, and 90-99% w / w.

[0127] In one embodiment of the present disclosure, the paste comprises stimuli-responsive gels as described in (44, 45), which are incorporated by reference in their entirety. Such gels change their physical properties (e.g., from liquid to viscous gel or solid) in response to external or internal stimuli, including, but not limited to, temperature (46), pH, mechanical (i.e., thixotropic), electrical, electrochemical, magnetic, electromagnetic (i.e., light), and ionic strength. One non-limiting embodiment of a thermosensitive polymer suitable for kernel formulation consists of amphiphilic triblock copolymers of poly(ethylene oxide) and poly(propylene oxide) (PEO-PPO-PEO), including linear (e.g., poloxamer or Pluronic®) or X-shaped (e.g., poloxamine or Tetronic®). This group of polymers is suitable for API delivery, see, for example, (47), which is incorporated by reference in its entirety. In one embodiment, the concentration of the API substance particles in the paste is 5-99% w / w, with suitable concentration ranges being 5-10% w / w, 10-25% w / w, 25-35% w / w, 35-50% w / w, 50-60% w / w, 60-70% w / w, 70-80% w / w, 80-90% w / w, and 90-99% w / w.

[0128] Provided herein are devices comprising a paste comprising one or more APIs. In some cases, the device comprises one or more reservoir kernels comprising a paste comprising one or more APIs. In some cases, the paste comprises an oil vehicle, an ionic liquid, a phase inversion system, or a gel. In some cases, the paste comprises an oil vehicle. In some cases, the paste comprises an ionic liquid. In some cases, the paste comprises a phase inversion system. In some cases, the paste comprises a gel.

[0129] In some cases, the phase inversion system includes a biodegradable polymer, a combination of phospholipids and medium chain triglycerides, or a lyotropic liquid crystal. In some cases, the phase inversion system includes a biodegradable polymer. In some cases, the phase inversion system includes a combination of phospholipids and medium chain triglycerides. In some cases, the phase inversion system includes a lyotropic liquid crystal.

[0130] In some cases, the gel is a stimulus-responsive gel or a self-healing gel. In some cases, the gel is a stimulus-responsive gel. In some cases, the gel is a self-healing gel.

[0131] In some embodiments, multiple reservoir modules (208a, 208b) are combined (208) to form a single implant. In some embodiments (209), the segments are separated by an impermeable barrier 209a to prevent API diffusion between the segments.

[0132] Fiber-Based Systems In another embodiment, the API kernel can comprise or consist of an API dispersion in a high surface area fiber-based carrier suitable for tissue engineering, chemotherapy delivery, and wound management devices, as described in (48), which is incorporated herein by reference in its entirety. In one embodiment, the high surface area carrier comprises fibers produced by electrospraying. In one embodiment, the high surface area carrier comprises electrospun fibers, including but not limited to electrospun nanofibers. Electrospun fibers are further described, for example, in (49-56), which are incorporated by reference in their entireties.

[0133] Electrospun fibers, API-containing fibers, can have a number of configurations. For example, in one embodiment, the API is embedded in the fiber, which is a miniaturized version of the matrix system described above (57). In another exemplary embodiment, an API fiber system is produced by coaxial electrospinning to give a core-shell structure, which is a miniaturized version of the reservoir system described above (58, 59). Core-shell fibers by coaxial electrospinning produce encapsulation of water-soluble agents such as biomolecules, including but not limited to proteins, peptides, etc. (60). In yet another exemplary embodiment, Janus nanofibers can be prepared, and exemplary suitable methods are described in (61). Janus fibers contain two or more distinct surfaces with distinct physical or chemical properties, and in the simplest case are two fibers coaxially connected along an edge. In some embodiments, it may be advantageous to modify the fibers by surface functionalization, for example, as described in (62, 63), which are incorporated herein by reference in their entirety.

[0134] At least a portion of the fiber-based devices disclosed herein are covered with one or more skins, as described more fully under "implant skins."

[0135] The electrospun fibers can be used to form the kernel of a reservoir implant. In one embodiment, the reservoir implant is formed by packing the API-containing fibers into a tubular implant skin and sealing the tube ends as described in the subsequent section. The fibers formed by electrospinning can be collected on a plate or other flat surface and cut, ground, or otherwise reduced in size by methods known in the art to a size that can be effectively packed into an implant to form a packed powder kernel. The resulting reduced size electrospun fiber material can also be formulated into a kernel using any of the methods described herein for the API powder or API exposure agent powder mixture. In an alternative embodiment, the electrospun fibers can be collected on a fixed or stationary collector surface (e.g., a plate or drum) in the form of a mat. The mat can then be cut (e.g., cut into strips or sheets) to the appropriate size and geometry and arranged into a tubular skin structure to form a reservoir implant. In another embodiment, the electrospun, API-containing mat can be rolled into a multi-layered cylindrical shape to form the kernel of a tubular reservoir implant. In yet another embodiment, the kernel is formed from electrospun fiber yarn fabrication, suitable methods are described, for example, in (64-68), which are incorporated herein by reference in their entirety. In another embodiment, a fiber kernel of cylindrical geometry can be prepared by collecting the fibers directly during the spinning process on a rotating wire, fiber, or small diameter mandrel.

[0136] Electrospinning can also be used to create skins. In one embodiment, a film or mat of electrospun fibers collected on a rotating plate or drum can be used as a skin. The skin thus formed can be wrapped around a preformed kernel to form a reservoir implant, or can be rolled into a tubular shape and filled with kernel material and sealed. Alternatively, a tubular skin can be formed directly by collecting the electrospun fibers on a rotating mandrel during the spinning process.

[0137] An alternative embodiment utilizes an electrospinning process to fabricate both the kernel and the skin, using the methods described herein for each. In yet another embodiment, electrospinning may be used to form the skin layer, the kernel layer, or both of the layered implant embodiments described in subsequent sections.

[0138] While the above paragraphs describe embodiments incorporating fibers produced by electrospinning, additional non-limiting embodiments use the same approach incorporating fibers formed by alternative spinning methods. In one embodiment, rotary jet spinning, a rapidly rotating perforated reservoir propels a jet of liquid material outward from the reservoir orifice toward a stationary cylindrical collector surface. The fiber material can be thermally liquefied by melting, resulting in a process similar to that used in cotton candy machines, or dissolved in a solvent to allow fiber generation at low temperatures (i.e., without melting the material). Prior to impaction, the jet stretches, dries, and eventually solidifies to form nanoscale fibers in a mat or bundle on the collector surface. The fiber material can be comprised of medicamentarily acceptable excipients, such as glucose or sucrose, or polymeric materials, such as resorbable or non-resorbable polymers described herein. In another embodiment, the solid API and excipients or polymers are premixed as solids and formed into a fiber mat by spinning. Rotary jet spinning processes are known in the art, e.g., (69-72), which are incorporated by reference in their entireties.

[0139] In another embodiment, fibers may be produced by wet spinning (73) or dry jet wet spinning (74, 75) methods. In wet spinning, fibers are formed by extruding a polymer solution through a small needle spinneret into a stationary or rotating coagulation bath consisting of a solvent with low polymer solubility but miscibility with the polymer solution solvent. Dry jet wet spinning is a similar process that involves initial fiber formation in air before collection in the coagulation bath.

[0140] Provided herein are devices in which the kernel comprises a fiber-based carrier. In some cases, the fiber-based carrier comprises an electrospun microfiber or an electrospun nanofiber. In some cases, the fiber-based carrier comprises an electrospun microfiber. In some cases, the fiber-based carrier comprises an electrospun nanofiber. In some cases, the electrospun nanofiber is a Janus microfiber or a Janus nanofiber. In some cases, the electrospun nanofiber is a Janus microfiber. In some cases, the electrospun nanofiber is a Janus nanofiber.

[0141] In some cases, the fiber-based carrier comprises random or oriented fibers. In some cases, the fiber-based carrier comprises random fibers. In some cases, the fiber-based carrier comprises oriented fibers.

[0142] In some cases, the fiber-based carrier comprises a bundle of fibers, a thread, a woven mat, or a nonwoven mat. In some cases, the fiber-based carrier comprises a bundle of fibers, a thread, a woven mat, or a nonwoven mat. In some cases, the fiber-based carrier comprises a bundle of fibers. In some cases, the fiber-based carrier comprises a thread of fibers. In some cases, the fiber-based carrier comprises a woven mat of fibers. In some cases, the fiber-based carrier comprises a nonwoven mat of fibers.

[0143] In some cases, the fiber-based carrier comprises rotary jet spun fibers, wet spun fibers, or dry jet spun fibers. In some cases, the fiber-based carrier comprises rotary jet spun fibers. In some cases, the fiber-based carrier comprises wet spun fibers. In some cases, the fiber-based carrier comprises dry jet spun fibers.

[0144] In some cases, the fibers include glucose, sucrose, or a polymeric material. In some cases, the fibers include glucose. In some cases, the fibers include sucrose. In some cases, the fibers include a polymeric material. In some cases, the polymeric material includes a resorbable or non-resorbable polymeric material described herein, such as poly(dimethylsiloxane), silicone, poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, poly(siloxane), copolymers thereof, or combinations thereof. In some cases, the polymer includes expanded poly(tetrafluoroethylene) (ePTFE) or ethylene vinyl acetate (EVA). In some cases, the polymer includes expanded poly(tetrafluoroethylene) (ePTFE). In some cases, the polymer is ethylene vinyl acetate (EVA). In some cases, the polymer comprises a poly(amide), poly(ester), poly(ester amide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sebacate), poly(lactic acid), poly(glycolic acid), (lactic acid-glycolic acid) copolymer, poly(caprolactone) (PCL), PCL derivatives, amino alcohol-based poly(ester amide) (PEA), poly(octane-diol citrate) (POC), copolymers thereof, or mixtures thereof.

[0145] Porous sponge type In some embodiments, the implant kernel comprises a porous support structure containing the API. The support has a porous microstructure (pore size 1-1,000 μm). In some embodiments, the support has a porous nanostructure (pore size 1-1,000 nm). In still other embodiments, the support has both a porous microstructure and a porous nanostructure. Examples of these microscopic pores include, but are not limited to, silica sol-gel materials (76), xerogels (77), mesoporous silica (78), polymeric microsponges (79) including polymethylsiloxane (PMDS) sponges (80, 81) and polyurethane foams (82), nanosponges including cross-linked cyclodextrins (83), as well as electrospun nanofiber sponges (84) and aerogels (85), all of which are incorporated herein by reference. In some embodiments, the porous sponge comprises silicon, a silica sol-gel material, a xerogel, a mesoporous silica, a polymeric microsponge, a polyurethane foam, a nanosponge, or an aerogel. In some embodiments, the porous sponge comprises silicon. In some embodiments, the porous sponge comprises a silica sol-gel material, a xerogel, a mesoporous silica, a polymeric microsponge, a polyurethane foam, a nanosponge, or an aerogel.

[0146] In other embodiments, the implant kernel comprises a porous metal structure. Porous metal materials, including but not limited to titanium and nickel-titanium (NiTi or Nitinol) alloys in structural forms including foams, tubes, and rods, can be applied as both kernel and skin materials. Such materials have been used in other applications including bone substitute materials (86-88), filtration media (89, 90), and structural components in aviation and aeronautics (91). These materials have desirable properties for API delivery devices, including corrosion resistance, low weight, and relatively high mechanical strength. Importantly, these properties can be controlled by modifying the pore structure and morphology. The pore architecture can be uniform, bimodal, gradient, or honeycomb, and the pores can be open or closed. NiTi alloys additionally possess shape memory properties (the ability to recover the original shape from significant and seemingly plastic deformation when a certain stimulus such as heat is applied), and superelastic properties (the alloy deforms reversibly by the formation of stress-induced phases under infilling that become unstable, and recovers the original phase and shape when the infilling is removed). In the case of NiTi alloys, these properties result from the transformation between the low-temperature monoclinic allotrope (martensite phase) and the high-temperature cubic (austenite phase). Porous NiTi materials maintain shape memory and / or superelastic properties (92). Both mechanical properties and corrosion resistance are determined by the chemical composition of the titanium alloy. Surface treatments, including chemical treatments, plasma etching, and heat treatments, can be employed to increase or decrease the bioactivity of Ti and Ti-alloy porous materials. Porous Ti metals with porosity of 40% and pore sizes of 300-500 μm were penetrated with deeper newly grown bone following NaOH and heat treatments (93).

[0147] There are few examples of API-loaded nanoporous coatings on implants or implantable devices that have been used to deliver drugs in a sustained manner, such as (94), which is fully incorporated herein by reference. In a rare example, an antibiotic-loaded layered double hydroxide coating on a porous titanium metal substrate has been shown to limit infection over a period of one week. (95) In these cases, API release occurs directly from a thin coating (similar to an API-releasing stent) rather than from a bulk implant material (porous or solid), and these systems typically exhibit first-order dissolution kinetics.

[0148] In one embodiment, the implant kernel comprises a sponge structure known in the art, an illustrative example is provided above, and the API is incorporated by impregnation using methods known in the art. In one non-limiting example, the API is introduced into the internal sponge microarchitecture using a liquid medium that has an affinity for the sponge material. For example, polydimethylsiloxane (PDMS) is a material commonly used in the art and is highly hydrophobic. Thus, the PDMS sponge can be easily impregnated with a non-polar solvent solution of the API and subsequently dried. Multiple impregnation cycles allow for API accumulation in the device. In another non-limiting embodiment, the solvent serves as a vehicle to load the sponge with the API particle suspension. In a related embodiment, biomolecules (e.g., peptides or proteins) are suspended in n-hexane and impregnated into the PDMS sponge, followed by drying at room temperature in a vacuum oven. Multiple impregnation-drying cycles are used to increase API loading. In a non-limiting example, a suspension of VRC01, a broadly neutralizing antibody against HIV, in n-hexane is impregnated into the PDMS sponge. In another non-limiting example, a suspension of tenofovir alafenamide in n-hexane is impregnated into a PDMS sponge. The above examples are illustrative of API impregnation of a PDMS sponge, including with a peptide-drug conjugate.

[0149] In some embodiments, the sponge is magnetic, for example to allow for remotely triggered API release, see, e.g., (96), incorporated herein by reference.

[0150] In one embodiment, the sponge pores are created in situ during use using templated excipients. Numerous porogens are known in the art and have been used to generate porous structures as described in (97), which is incorporated herein by reference in its entirety. Methods for creating pores during use (i.e., in vivo) include, but are not limited to, the inclusion of excipient particles in the implant kernel that dissolve upon exposure to bodily fluids, such as subcutaneous fluid and cervicovaginal fluid. As used herein, solid particles can include crystalline or amorphous forms. In one embodiment, the size distribution of the solid particles is polydisperse. In one embodiment, the size distribution of the solid particles is monodisperse. In one embodiment, the solid particles comprise or consist of nanoparticles (mean diameter <100 nm). In one embodiment, the mean diameter of the particles can range from 1 to 10 nm, 10 to 25 nm, 25 to 100 nm, and 100 to 500 nm. Suitable average microparticle diameters can range from 0.5-50 μm, 0.5-5 μm, 5-50 μm, 1-10 μm, 10-20 μm, 20-30 μm, 30-40 μm, and 40-50 μm. Other suitable average particle sizes can range from 50-500 μm, 50-100 μm, 100-200 μm, 200-300 μm, 300-400 μm, 400-500 μm, and 0.5-5 mm. Suitable particle shapes include spheres, needles, diamonds, cubes, and irregular shapes. The templated particles can be comprised of salts (e.g., sodium chloride), sugars (e.g., glucose), or other water-soluble excipients known in the art. One skilled in the art will know how to prepare such particles of well-defined shapes and sizes. The mass ratio of pore-forming particles to API in the kernel ranges from 100 to 0.01. More specifically, the ratio can range from 100 to 20, 20 to 5, or 5 to 1. In other embodiments, the ratio can range from 1 to 0.2, 0.2 to 0.05, or 0.05 to 0.01.

[0151] In one non-limiting embodiment, the porogen comprises a fiber mat, as described above. In another embodiment, the porogen comprises a microfiber mat. In another embodiment, the porogen comprises a nanofiber mat. The fiber mat is fabricated by any suitable method, such as those known in the art. In one embodiment, the fibers are produced by electrospinning. In another embodiment, the fibers are produced by rotary jet spinning. In yet another embodiment, the fibers are produced by wet jet spinning or dry jet wet spinning. The fiber material can include or consist of one or more biocompatible polymers (resorbable and non-resorbable) as listed herein. The fiber material can also include or consist of pharma- ceutically acceptable excipients, such as glucose (i.e., cotton candy).

[0152] In one non-limiting embodiment, the porogen particles are fused by exposure to a suitable solvent vapor. Particle fusion may be required to result in the potentially desirable open-cell sponge architecture. A non-limiting example of porogen particle fusion is provided in Example 11. The fusion solvent can be a polar solvent such as water, or an organic solvent with a polarity ranging from polar (e.g., methanol) to non-polar (e.g., hexane), depending on the solubility of the templating agent. The solvent vapor is generated by any suitable method, such as heating, using a suitable container, such as a screen, mesh, or perforated plate, with or without a filter, or a Buchner funnel, to contact and suspend a column of porogen particles with the vapor. The exposure time can be determined experimentally to achieve the desired degree of particle fusion.

[0153] In some embodiments, the pores are formed during manufacture (ie, prior to use) by immersing the device in a suitable fluid (eg, water or an organic solvent) to dissolve the porogen.

[0154] In some embodiments, pores may form as a result of mechanical, temperature, or pH changes following implantation / use.

[0155] In one non-limiting embodiment, the one or more APIs constitute a sponge templating agent. As the drug is released from the device, the sponge is formed. In one embodiment, the API templating agent comprises a mat of microneedles. In a non-limiting example, the API templating agent comprises a mat of tenofovir alafenamide microneedle crystals as described in Example 4.

[0156] In one non-limiting embodiment, the sponge is composed of PDMS and the hydrophobic microscopic channels are modified using methods known in the art, such as chemical and plasma treatment. In another embodiment, a linking agent is used between the internal PDMS microchannels and a surface modifier to modify the internal surface properties of the sponge. Surface modification chemistries are well known in the art. In one non-limiting embodiment, 3-aminopropyl)triethoxysilane is used as a coupling agent and proteins are attached to the PDMS surface as described by Priyadarshani et al. (98), which is incorporated herein by reference in its entirety.

[0157] Provided herein are devices where the kernel comprises a porous sponge. In some cases, the porous sponge comprises silicon, a silica sol-gel material, a xerogel, a mesoporous silica, a polymeric microsponge, a polyurethane foam, a nanosponge, or an aerogel. In some cases, the porous sponge comprises silicon. In some cases, the porous sponge comprises a silica sol-gel material. In some cases, the porous sponge comprises a xerogel. In some cases, the porous sponge comprises a mesoporous silica. In some cases, the porous sponge comprises a polymeric microsponge. In some cases, the porous sponge comprises a polyurethane foam. In some cases, the porous sponge comprises a nanosponge. In some cases, the porous sponge comprises an aerogel.

[0158] In some cases, the porous sponge comprises a porogen. In some cases, the porogen comprises a fiber mat. In some cases, the fiber mat comprises glucose. In some cases, the porogen comprises an API. In some cases, the porous sponge is impregnated with an API. In some cases, the porous sponge comprises a sponge material that has an affinity for a solvent capable of dissolving the API. In some cases, the porous sponge comprises polydimethylsiloxane (PDMS).

[0159] At least a portion of the porous devices disclosed herein are covered with one or more skins, as described more fully under "implant skins."

[0160] Implant Skin It is advantageous to have a skin as part of the disclosed device, which can cover the kernel partially or entirely.

[0161] The in vitro and in vivo API release profiles of the matrix implants disclosed herein are generally nonlinear, with an initial burst of API release followed by a lower sustained release phase. In certain indications, it may be desirable to linearize the API release profile of the implant. In an advantageous embodiment of such an implant 300, the exterior surface of the device 301 is covered by a rate-controlling skin 302. In one embodiment, the skin is composed of a biocompatible elastomer, as described herein. The composition and thickness of the skin determine the degree of linearization of drug release as well as the rate of API release. The skin thickness may range, for example, from 5 to 700 μm. Suitable thicknesses of the skin may range from 5 to 700 μm, 10 to 500 μm, 15 to 450 μm, 20 to 450 μm, 30 to 400 μm, 35 to 350 μm, and 40 to 300 μm. In certain embodiments, the skin thickness is 10 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, and 300 μm. In some embodiments, the skin thickness is 30 μm, 50 μm, or 80 μm. These skin characteristics also apply to reservoir type designs.

[0162] In one set of embodiments, a single external skin encapsulates the API-containing compartment. In another embodiment (303), multiple external skins encapsulate the API-containing compartment. In some embodiments, 2-20 separate (303b,c) layered skins encapsulate the API-containing compartment 303a. In some embodiments, the skins comprise or consist of the same material with the same or different thicknesses. In some embodiments, the skins comprise or consist of one or more different materials with the same or different thicknesses.

[0163] In another set of embodiments, multiple skins are distributed throughout the device, isolating different regions of the main component volume from each other. In one embodiment, these interspersed skins can be envisioned by analogy with rings in a tree trunk (304). In such an embodiment, the skins (304b, 304d) can be made of one or more different materials with the same or different thicknesses. The volumes separated by the skins (kernels - 304a, 304c) can all contain the same API at the same concentration, or different APIs at different concentrations. Some of the volumes can be non-medicinal. The excipients in or comprising the volumes can be the same or different across the compartments separated by the skins.

[0164] In certain embodiments described herein, the implant kernel may be a single compartment. In other embodiments, the kernel of the drug delivery device described herein may include two compartments in a split arrangement as in 208, or may be arranged in two layers (401, 402) as in 400. In other embodiments, the kernel of the drug delivery device described herein may include three or more compartments or layers. Each kernel layer may contain one or more therapeutic agents or may not contain a therapeutic agent. For example, in certain embodiments of the implant drug delivery device described herein, the kernel includes a first layer 401 and a second layer 402, where the second layer is adjacent to a skin 403, and the first layer is adjacent to the second layer. A second skin layer 404 may optionally be present adjacent to the first skin layer. In certain embodiments, one or more skin layers may contain a therapeutic agent as described above for embodiments 300, 303, and 304. In one embodiment, the first kernel layer 401 is completely surrounded by the second kernel layer 402. Only the second kernel layer is in contact with the first skin layer. In an alternative embodiment, the first kernel layer 405 is concentric with the second kernel layer 406, but a portion of the first kernel layer contacts the first skin layer 409 at the end of the implant. The first skin layer may be continuous around the entire implant or may be comprised of a second material in the form of an end cap 409 that contacts the first kernel layer. In a further embodiment, the first kernel layer 410 is separated from the second kernel layer 412 by a barrier layer 411 that does not contain a therapeutic agent. An optional first skin layer 413 and a second skin layer 414 may be adjacent to the second kernel layer.

[0165] In certain embodiments, the first, second, and third layers of the kernel are made from the same polymer. However, it can be envisioned that different polymers can be used for the first, second, and third layers of the kernel, so long as the first therapeutic agent in the kernel experiences reduced permeation resistance as it is released through the skin and meets the release criteria necessary to achieve the desired therapeutic effect.

[0166] In yet another set of embodiments, one or more skins can be medicated with one or more APIs. In certain embodiments, the first therapeutic agent is in a dissolved form in the kernel and the second therapeutic agent is in a solid form in the skin. As used herein, "solid" can include crystalline or amorphous forms. In certain embodiments, the first therapeutic agent is in a solid form in the kernel and the second therapeutic agent is in a solid form in the skin. In certain embodiments, the first therapeutic agent is in a solid form in the kernel and the second therapeutic agent is in a dissolved form in the skin. In certain embodiments, the first therapeutic agent is in the kernel of the reservoir type system and the second therapeutic agent is in a solid form in the skin. As used herein, solid can include crystalline or amorphous forms. In certain embodiments, the first therapeutic agent is in the kernel of the reservoir type system and the second therapeutic agent is in a dissolved form in the skin.

[0167] In one embodiment, the skin is non-resorbable. It may be formed from medical grade silicone, as known to those skilled in the art. Other examples of suitable non-resorbable materials include synthetic polymers selected from poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), including but not limited to (ethylene-vinyl acetate) copolymers, or ethylene vinyl acetate (EVA), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene), and other fluorinated polymers, poly(siloxane), copolymers thereof, and combinations thereof. The implant skin may also be made of biocompatible metals, such as titanium, nickel-titanium alloys, stainless steel, and others known in the art. To facilitate and control API release from the kernel, the metal skin may include the porous metal materials described above for kernel applications.

[0168] In one embodiment, one or more of the skins are made of the non-resorbable polymer expanded poly(tetrafluoroethylene) (ePTFE), also known in the art as Gore-Tex (99).

[0169] In another embodiment, the implant shell is resorbable. In one embodiment of the resorbable device, the sheath is formed from a biodegradable or bioerodible polymer. Examples of suitable resorbable materials include synthetic polymers selected from poly(amides), poly(esters), poly(ester amides), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo-poly(amino acids), poly(glycerol-sebacate), copolymers thereof, and mixtures thereof. In a preferred embodiment, the resorbable synthetic polymer is selected from poly(lactic acid), poly(glycolic acid), (lactic acid-glycolic acid) copolymers, poly(caprolactone) (PCL), and mixtures thereof. Other curable bioresorbable elastomers include PCL derivatives, amino alcohol-based poly(ester amides) (PEA), and poly(octanediol citrate) (POC). PCL-based polymers may require additional crosslinkers such as lysine diisocyanate or 2,2-bis(-caprolactone-4-yl)propane to achieve elastomeric properties.

[0170] In one embodiment, the skins used to modulate or control the rate of API release from the kernel as well as the release kinetics (e.g., zero order vs. first or second order) are microfabricated using methods known in the art and described herein, such as additive manufacturing. In some embodiments, the skins comprise a poly(caprolactone) / (lactic acid-glycolic acid) copolymer scaffold blended with tricalcium phosphate constructed using solid freeform fabrication (SFF) techniques (100), which are incorporated by reference in their entirety. In another embodiment, the skins comprise or consist of nanostructured elastomeric thin films formed by casting and etching of sacrificial templating agents (e.g., zinc oxide nanowires) as described in the art (101), which are incorporated by reference in their entirety. In another embodiment, the skins comprise or consist of one or more elastomeric thin films generated via highly reproducible, controllable, and scalable microfabrication methods, see, for example, (102), which are incorporated by reference in their entirety. These include microelectromechanical systems (MEMS), nanoelectromechanical systems (NEMS), as well as microfluidic and nanofluidic systems known in the art. One embodiment, known in the art as soft lithography, involves the fabrication of a master with patterned features that can be reproduced in an elastomeric material by replica molding. Briefly, a substrate (typically a silicon wafer) is coated with photoresist (e.g., a photoactive polymer commonly used in photolithography such as SU-8) and exposed to UV radiation through a photomask to generate the desired pattern in the photoresist. The resist is then developed and the substrate is etched such that the desired pattern is reproduced on the substrate in the negative (i.e., channels and recesses in the areas exposed to UV and not protected by the photoresist). A skin is fabricated by replica molding using the patterned master. An elastomeric resin is poured onto the SU-8 patterned silicon master and the material is cured against the master to obtain the desired pattern.Suitable elastomers include, but are not limited to, polydimethylsiloxane (PDMS, silicone), thermosetting polyester (TPE), photocurable perfluoropolyether (PFPE). In another embodiment, the patterned skin is fabricated using an embossing technique. A patterned master (stamp) is generated by methods known in the art, including soft lithography (see above), micromachining, laser machining, electrode discharge machining (EDM), electroplating, or electroforming. An elastomer in the form of a thin sheet is pressed against the master in a heated hydraulic press to replicate the master pattern in the elastomer. Elastomers suitable for embossing include, but are not limited to, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), ethylene-co-vinyl acetate (EVA), high consistency rubber (HCR) silicone, polymethacrylate (PMMA), polycarbonate (PC), cyclic olefin copolymer (COC), polystyrene (PS), polyvinyl chloride (PVC), and polyethylene glycol (PETG).

[0171] Figures 35A and 35B show exemplary drawings of skins created by microlithography. The grid-like pattern, similar to an egg carton or waffle, contains an array of dimples of well-defined shape (e.g., circle, square, hexagon, etc.), size (e.g., height and width), and draft (i.e., non-parallel walls) protruding from a thin film of defined thickness. Varying the density and physical properties of the surface features along with the film properties and composition can be used to control the API release kinetics (sequence and rate) from the kernel over a wide range.

[0172] Provided herein are devices comprising one skin or multiple skins. In some cases, the device comprises one skin. In some cases, the device comprises multiple skins.

[0173] In some cases, the skin covers a portion of the device or the entire device. In some cases, the skin covers a portion of the device. In some cases, the skin covers the entire device. In some cases, the skin includes a rate-limiting skin.

[0174] In some cases, the skin is non-resorbable. In some cases, the skin comprises a biocompatible elastomer. In some cases, the skin comprises poly(dimethylsiloxane), silicone, one or more synthetic polymers, and / or metal. In some cases, the synthetic polymer is poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, poly(siloxane), copolymers thereof, or combinations thereof. In some cases, the polymer is expanded poly(tetrafluoroethylene) (ePTFE) or ethylene vinyl acetate (EVA). In some cases, the polymer is expanded poly(tetrafluoroethylene) (ePTFE). In some cases, the polymer is ethylene vinyl acetate (EVA).

[0175] In some cases, the metal is titanium, a nickel-titanium (nitinol) alloy, or stainless steel. In some cases, the metal is titanium or stainless steel. In some cases, the metal is titanium. In some cases, the metal is stainless steel.

[0176] In some cases, the skin is resorbable. In some cases, the skin comprises a biocompatible elastomer. In some cases, the skin comprises a poly(amide), poly(ester), poly(ester amide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo poly(amino acid), poly(glycerol-sebacate), poly(lactic acid), poly(glycolic acid), (lactic acid-glycolic acid) copolymer, poly(caprolactone) (PCL), PCL derivatives, amino alcohol-based poly(ester amide) (PEA), poly(octane-diol citrate) (POC), copolymers thereof, or mixtures thereof. In some cases, the polymer is crosslinked PCL. In some cases, the crosslinked PCL comprises lysine diisocyanate or 2,2-bis(-caprolactone-4-yl)propane. In some cases, the polymer comprises poly(caprolactone) / (lactic acid-glycolic acid) copolymer and tricalcium phosphate.

[0177] In some cases, the skins are fabricated via casting and etching, soft lithography, or microlithography. In some cases, the skins are fabricated via casting and etching. In some cases, the skins are fabricated via soft lithography. In some cases, the skins are fabricated via microlithography.

[0178] In some cases, the skin includes a defined surface morphology. In some cases, the defined surface morphology includes a grid pattern.

[0179] In some cases, the defined pores are microscopic pores or nanoscopic pores. In some cases, the defined pores are microscopic pores. In some cases, the defined pores are nanoscopic pores.

[0180] In some cases, the defined pore has a diameter of less than 2 nm. In some cases, the defined pore has a diameter of 0.1 nm, 0.5 nm, 1 nm, 1.5 nm, or 2 nm. In some cases, the defined pore has a diameter of 2 nm to 50 nm. In some cases, the defined pore has a diameter of 2 nm, 5 nm, 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, 40 nm, 45 nm, or 50 nm. In some cases, the defined pore has a diameter of more than 50 nm.

[0181] Resorbable and biodegradable devices Some applications of the present disclosure benefit from resorbable and biodegradable devices. For purposes of this disclosure, "resorbable" is intended to mean a device that is degraded and assimilated in vivo (e.g., resorbable sutures) and "biodegradable" is intended to mean a device that is capable of being broken down by bacteria or other living organisms after use. Non-limiting exemplary embodiments of both device types are provided below.

[0182] Resorbable Devices The main advantage of resorbable devices is that, in certain cases, their API cargo does not need to be removed once delivered. The resorbable implants described herein are composed, at least in part, of materials that degrade in vivo during the period of use. In some embodiments, the entire device is resorbable over the period of use. In some embodiments, the in vivo degradation of the device occurs primarily after the majority of all API cargo has been released. In certain embodiments, one or more of the device components described above (e.g., skin and / or kernel) comprise or include a resorbable elastomer (see "Implant Skin" and "Implant Material" for exemplary elastomers).

[0183] Biodegradable Devices The impetus for biodegradable implants stems primarily from the desire to minimize harmful environmental impacts after use, i.e., waste minimization. For example, IVRs delivering the antiretroviral drug dapivirine are currently being evaluated for HIV prevention in large-scale clinical trials (103, 104). These 28-day devices are made almost exclusively of silicone, and once approved, regular use of the product by millions of women in sub-Saharan Africa could lead to a significant waste burden. Over one million women worldwide use the contraceptive IVR NuvaRing®, made primarily of EVA, another non-biodegradable elastomer creating further disposal concerns.

[0184] In comparison to bioresorbable implants, which are designed to degrade in the body to avoid the need for removal at the end of their use period, biodegradable implants are designed to maintain their integrity while inserted into the body and begin the degradation process once removed (i.e., after use). One approach uses poly(lactic acid) polymers that are degraded by carboxylesterase enzymes produced by bacteria, similar to those used in biodegradable, disposable plastic items such as shopping bags and food containers. An alternative approach is to utilize polymers that degrade in the presence of ultraviolet (UV) irradiation (i.e., sunlight). An important consideration is that the degradation process (and degradation kinetics) be separated in time from the use period, such that the delivery of the API is not affected by the degradation process during the implant use period.

[0185] Other Design Considerations Considerations for biomolecule delivery Due to their large molecular weight, hydrophilicity, and chemical / physical instability, biomolecules (e.g., peptides, peptide-drug conjugates, proteins, (ribo)nucleic acid oligomers) can be difficult to deliver in a controlled manner from long-acting drug delivery devices. Many embodiments of the present disclosure overcome these limiting obstacles by immobilizing biomolecules in a porous kernel or water-soluble scaffold (e.g., PVA nanofibers) encapsulated in a rate-limiting skin such as ePTFE.

[0186] In addition to biomolecules that have been approved by regulatory agencies to prevent or treat disease, the present disclosure also serves as a platform for delivering agents for new applications. For example, in one non-limiting embodiment, messenger ribonucleic acid (mRNA) (synthetic or natural) is delivered to stimulate the in vivo expression of one or more proteins (105), such as antibodies (106) and vaccine adjuvants (107). This approach has the advantage of utilizing the biochemical capabilities of the host by stimulating it to synthesize the targeted agent in vivo, rather than delivering it directly from the implant. This can overcome the high production costs of some biomolecules and their instability (e.g., cold chain avoidance).

[0187] In some embodiments, certain excipients can improve control of the release rate of biomolecules from the implant (see "API Formulations"). For example, silk fibroin can be used to modulate the release rate of proteins as described by Zhang et al. (108), which is incorporated herein by reference in its entirety.

[0188] In other embodiments, certain excipients can stabilize biomolecules against degradation or loss of biological activity using approaches known to those skilled in the art (109). Certain excipients stabilize biomolecules by creating a "water-like" environment in the dry state through hydrogen bonding interactions (e.g., sugars (110) and amino acids (111)). Other excipients create a glassy matrix that provides hydrogen bonding to immobilize biomolecules and prevent aggregation that leads to loss of biological activity (e.g., trehalose, inulin). Still other excipients can stabilize the pH in the implant formulation (e.g., buffer salts). Finally, surfactants can reduce the concentration of biomolecules at the air-water interface during the drying process of the formulation, reducing shear stress and insoluble aggregate formation, allowing the aforementioned stabilization mechanisms to occur throughout the drying process.

[0189] In vivo localization of implants In various embodiments, one or more radiopaque materials (e.g., barium sulfate) are incorporated into the elastomeric implant shell (i.e., API-opaque polymer) or by fabricating it into the end plugs used to seal the shell (24, 112), which are incorporated herein by reference. The radiopaque material can be integrated in the form of one or more bands or other shapes, or can be dispersed throughout the API-opaque polymer. In various embodiments, the elastomeric material that constitutes part of the implant is coated with a metal (e.g., titanium) to make it radiopaque, using any suitable process, such as those known in the art.

[0190] In certain embodiments, ultrasound is used to identify the location of the implant, in these embodiments, polymers or polymer additives known in the art to be opaque to ultrasound examination (e.g., calcium) are employed to aid in visualizing the device in vivo.

[0191] The device may include at least one magnetic element to facilitate removal of the device (e.g., after API delivery is completed) (113), which is incorporated herein by reference. In certain embodiments, the magnetic element may be located at the first end, the second end, or both the first and second ends of the cylindrical device. A soft polymer coating may be provided over the magnetic element.

[0192] To aid in insertion and / or removal of the implant, a hole may be punched, molded, or otherwise formed in one end of the implant. The hole may be used to grasp the implant with a nail or another suitable tool. A loop made of suture material, wire, or other suitable material may be tied or otherwise attached to the hole to help grasp the implant for insertion and / or removal.

[0193] Foreign body reaction For example, silicone implants are cheap and easy to handle, but they induce foreign body reactions and tend to migrate. ePTFE implants are more biocompatible and allow for ingrowth, but are expensive. Silicone-ePTFE composites have a silicone core and an ePTFE liner and are used in surgical applications such as rhinoplasty (114, 115) and buccolabial fold rejuvenation (116), which are incorporated herein by reference. In one embodiment, an elastomeric implant sheath is bonded to an outer ePTFE sleeve to form a composite (i.e., the ePTFE sleeve only mitigates foreign body reactions and does not control or affect API release from the device). In other embodiments, the ePTFE skin serves to control the API release rate from the device.

[0194] It is known in the art that the host foreign body response can affect the safety of the implanted device, especially for subcutaneous implants (117), or other types of devices implanted in body compartments. This response includes protein adsorption on the implant surface, inflammatory cell infiltration, macrophage fusion to foreign body giant cells, fibroblast activation, and ultimately fibrotic encapsulation. This sequence of events can affect the function of the subdermal implant, including inhibition of API diffusion from long-acting API delivery depots and failure of the medical device. To date, combination approaches such as hydrophilic coatings to reduce protein adsorption combined with delivery of dexamethasone have been most effective.

[0195] In certain embodiments, the implantable drug delivery device releases one or more agents to alleviate or reduce the foreign body response in addition to the primary API. These agents are mixed with the API and optional excipients and formulated into API kernels (see "API Formulations" below). The agents are released from the implant along with the API. In one embodiment, the agent included to reduce the foreign body response is a steroid. In one embodiment, the steroid is dexamethasone or a dexamethasone derivative, such as dexamethasone 21-acetate or dexamethasone 21-phosphate disodium salt.

[0196] Hydrogels, especially zwitterionic hydrogels, can significantly reduce the foreign body response to subdermal implants. For further discussion, see, e.g., (118), which is incorporated by reference in its entirety.

[0197] Implant materials In one embodiment, the implant drug delivery device disclosed herein comprises one or more suitable thermoplastic polymers, elastomeric materials, or metals suitable for pharmaceutical use. Examples of such materials are known in the art and described in the literature (119, 120), which are incorporated by reference in their entireties.

[0198] In one embodiment, the elastomeric material of the implant is non-resorbable. It may include medical grade poly(dimethylsiloxane) or silicone, as known to those skilled in the art. Exemplary silicones include, but are not limited to, fluorosilicones, i.e., polymers with a siloxane backbone and fluorocarbon pendant groups, such as poly(3,3,3-trifluoropropylmethylsiloxane). Other examples of suitable non-resorbable materials include poly(ethers), poly(acrylates), poly(methacrylates), poly(vinylpyrrolidone), poly(vinyl acetate), including but not limited to EVA, poly(urethanes), cellulose, cellulose acetate, poly(siloxanes), poly(ethylene), poly(tetrafluoroethylene), and other fluorinated polymers, including ePTFE, poly(siloxanes), copolymers thereof, and combinations thereof. The implant may also include or consist of biocompatible metals, such as titanium, nickel-titanium alloys (NiTi or Nitinol), stainless steel, and / or others known in the art.

[0199] In another embodiment, the elastomeric material of the implant is resorbable. In one embodiment of the resorbable device, the skin is formed from a biodegradable or bioerodible polymer. Examples of suitable resorbable materials include synthetic polymers selected from poly(amides), poly(esters), poly(ester amides), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudopoly(amino acids), poly(glycerol-sebacates), copolymers thereof, and mixtures thereof. In one embodiment, the resorbable synthetic polymer is selected from poly(lactic acid), poly(glycolic acid), (lactic acid-glycolic acid) copolymers, PCL, and mixtures thereof. Other curable bioresorbable elastomers include PCL derivatives, amino alcohol-based PEA, and POC. PCL-based polymers may require additional crosslinkers, such as lysine diisocyanate or 2,2-bis(-caprolactone-4-yl)propane, to obtain elastomeric properties.

[0200] In one embodiment of the implanted drug delivery device described herein, the elastomeric material comprises a suitable thermoplastic or elastomeric material, which in principle can be any thermoplastic or elastomeric material suitable for pharmaceutical use, such as silicone, low density polyethylene, EVA, polyurethane, and styrene-butadiene-styrene copolymer.

[0201] In certain embodiments, EVA is used in the kernel and skins due to its excellent mechanical and physical properties. The EVA material used for the kernel as well as the skins can be any commercially available EVA, such as products available under the trade names Elvax, Evatane, Lupolen, Movriton, Ultrathene, and Vestypar.

[0202] Small to medium sized API molecules (M≦600 g mol -1 The permeability of EVA copolymers for VA skins is determined primarily by the ratio of vinyl acetate to ethylene. Low VA content EVA copolymers are substantially less permeable than high VA content skins and are therefore the rate limiting property when used as skins. EVA copolymers with a VA content of 19% w / w or less (≦19% w / w) are substantially less permeable than polymers having a VA content of 25% w / w or more (>25% w / w).

[0203] In some embodiments, the first thermoplastic polymer is EVA and has a vinyl acetate content of 28% or more. In other embodiments, the first thermoplastic polymer has a vinyl acetate content greater than 28%. In yet other embodiments, the first thermoplastic polymer has a vinyl acetate content of 28-40%. In yet other embodiments, the first thermoplastic polymer has a vinyl acetate content of 28-33%. In one embodiment, the first thermoplastic polymer has a vinyl acetate content of 28%. In one embodiment, the first thermoplastic polymer has a vinyl acetate content of 33%. In some embodiments, the second thermoplastic polymer is an ethylene-vinyl acetate copolymer and has a vinyl acetate content of 28% or more. In other embodiments, the second thermoplastic polymer has a vinyl acetate content greater than 28%. In yet other embodiments, the second thermoplastic polymer has a vinyl acetate content of 28-40%. In yet other embodiments, the second thermoplastic polymer has a vinyl acetate content of 28-33%. In one embodiment, the second thermoplastic polymer has a vinyl acetate content of 28%. In one embodiment, the second thermoplastic polymer has a vinyl acetate content of 33%.

[0204] In some embodiments, the second thermoplastic polymer is EVA and has a vinyl acetate content of 28% or less. In other embodiments, the second thermoplastic polymer has a vinyl acetate content less than 28%. In yet other embodiments, the second thermoplastic polymer has a vinyl acetate content of 9-28%. In yet other embodiments, the second thermoplastic polymer has a vinyl acetate content of 9-18%. In one embodiment, the second thermoplastic polymer has a vinyl acetate content of 15%. In one embodiment, the second thermoplastic polymer has a vinyl acetate content of 18%.

[0205] It should be noted that when a particular vinyl acetate content, e.g., 15%, is mentioned, it refers to the manufacturer's target content and the actual vinyl acetate content may vary from the target content by plus or minus 1% or 2%. One skilled in the art will appreciate that suppliers may use internal analytical methods for determining vinyl acetate content and therefore there may be offsets between methods.

[0206] Other Long-Acting API Delivery Platforms Delivery of peptide-drug conjugates, in certain cases in combination with other APIs, from other long-acting systems may be beneficial for preventing, treating, and / or managing disease of medical disorders. In one non-limiting embodiment, the formulation is injected into a body cavity (e.g., subcutaneously, intramuscularly, intratumorally) as a particle suspension. As used herein, solid particles can include crystalline or amorphous forms. In one non-limiting embodiment, the particles consist of the pure API or the API mixed with one or more excipients. In another non-limiting embodiment, the particles consist of the API suspended in a polymer matrix, similar to the various systems described for implants above. In another non-limiting example, the particles are coated with one or more polymer skins. In another non-limiting embodiment, the API is injected as a solution or suspension into a system that hardens in vivo to form an implant in situ (e.g., Atrigel system), as described above.

[0207] In one embodiment, the size distribution of the solid particles is polydisperse. In one embodiment, the size distribution of the solid particles is monodisperse. In one embodiment, the solid particles comprise or consist of nanoparticles (mean diameter <100 nm). In one embodiment, the mean diameter of the particles may range from 1-10 nm, 10-25 nm, 25-100 nm, and 100-500 nm. Suitable mean microparticle diameters may range from 0.5-50 μm, 0.5-5 μm, 5-50 μm, 1-10 μm, 10-20 μm, 20-30 μm, 30-40 μm, and 40-50 μm. Other suitable mean particle sizes may range from 50-500 μm, 50-100 μm, 100-200 μm, 200-300 μm, 300-400 μm, 400-500 μm, and 0.5-5 mm. Suitable particle shapes include spheres, needles, diamonds, cubes, and irregular shapes.

[0208] In another non-limiting embodiment, the API is delivered from a microarray (microneedle) patch. This delivery platform is well known in the art, as described in (121, 122), which are incorporated herein by reference in their entireties. The microarray patch can be formulated with one or more APIs in solution or suspension using resorbable or non-resorbable polymers. In one embodiment, one or more APIs are delivered intradermally via the microarray patch. In another non-limiting embodiment, the microarray patch is used to achieve intraocular delivery of one or more APIs, as described in (123, 124), which are incorporated herein by reference in their entireties.

[0209] Formulation Considerations The API formulation can include essentially any therapeutic, prophylactic, or diagnostic agent that would be useful for localized delivery to a body cavity.

[0210] Targeted in vivo API release kinetics and profile The API formulation may provide a time-controlled release profile or a more continuous or consistent release profile. Pulsed release may be achieved from multiple kernels, which may be implanted simultaneously or in a time-staggered manner. For example, different degradable skins may be used to time-stagger the release of one or more agents from each of several kernels.

[0211] Choice of drug The API formulation can essentially include any therapeutic, prophylactic, or diagnostic agent that would be useful to deliver to an anatomical compartment. The drug delivery device disclosed herein includes at least one pharmacoactive agent, including but not limited to agents used in the art for the applications described in "Device Use and Applications," as well as combinations thereof. In one embodiment, the drug delivery device includes two or more pharmacoactive agents. In this case, the pharmacoactive agents can have the same hydrophilicity or hydrophobicity, or different hydrophilicity or hydrophobicity. At least one of the APIs delivered from the long-acting device consists of a peptide-drug conjugate. Non-limiting examples of drugs are provided below.

[0212] Non-limiting examples of hydrophobic pharmacoactive agents include cabotegravir, dapivirine, fluticasone propionate, chlordiazepoxide, haloperidol, indomethacin, prednisone, and ethinyl estradiol.Non-limiting examples of hydrophilic pharmacoactive agents include acyclovir, tenofovir, atenolol, aminoglycosides, exenatide acetate, leuprolide acetate, acetylsalicylic acid (aspirin), and levodopa.

[0213] In some cases, the pharma- ceutically active agent is chloroquine or hydroxychloroquine, a pharma- ceutically acceptable salt thereof, or a combination thereof. In some cases, the pharma- ceutically acceptable salt is a phosphate, such as a diphosphate, or a chloride, such as a dichloride, or a combination thereof.

[0214] In some cases, the pharma- ceutical active agent is an antibacterial agent. In some cases, the antibacterial agent is a broad-spectrum antibacterial agent. A non-limiting example of an antibacterial agent includes azithromycin.

[0215] In some cases, the medicamentously active agent is an antiviral agent. Non-limiting examples of antiviral agents include remdesivir (Gilead Sciences), acyclovir, ganciclovir, and ribavirin, and combinations thereof. In some cases, the medicamentously active agent is an antiretroviral agent. In some cases, the antiretroviral agent is used to treat HIV / AIDS. Non-limiting examples of antiretroviral agents include protease inhibitors. In some cases, the antiretroviral agent is one or more antiretroviral agents used in pre-exposure prophylaxis (PrEP). In some cases, the antiretroviral agent is GSK2838232 (8232), islatravir (ISL), rilpivaline (RPV), cabotegravir (CAB), emtricitabine (FTC), tenofovir (TFV), dolutegravir (DTG), lamivudine (3TC), or combinations thereof. In some cases, the antiviral agent is a prodrug of an antiretroviral drug. In some cases, the antiviral agent is a prodrug of emtricitabine, tenofovir, dolutegravir (DTG), lamivudine (3TC), or a combination thereof. In some cases, the antiviral agent is cabotegravir, tenofovir disoproxil fumarate (TDF), tenofovir diphosphate (TFV-DP), tenofovir alafenamide (TAF), emtricitabine, or a combination thereof. In some cases, the antiviral agent is dolutegravir (DTG), lamivudine (3TC), or a combination thereof.

[0216] In some cases, the pharma- ceutical active agent is an agent that affects immune and fibrotic processes. Non-limiting examples of agents that affect immune and fibrotic processes include inhibitors of Rho-associated coiled-coil kinase 2 (ROCK2), such as KD025 (Kadmon).

[0217] In some cases, the pharma- ceutical active agent is a sirtuin (SIRT1-7) inhibitor. In some cases, the sirtuin inhibitor is EV-100, EV-200, EV-300, or EV-400 (Evrys Bio). In some cases, administration of the sirtuin inhibitor restores cellular metabolism and immunity in a human host.

[0218] The pharmacoactive substances described herein can be administered alone or in combination. The combination of pharmacoactive substances can be administered using one implant or multiple implants. In some cases, the drug delivery device described herein comprises one pharmacoactive substance. In some cases, the drug delivery device described herein comprises two or more pharmacoactive substances. In some cases, the drug delivery device described herein comprises a combination of pharmacoactive substances. In some cases, the combination of pharmacoactive substances is chloroquine and azithromycin, hydroxychloroquine and azithromycin, lopinavir and ritonavir, KD025 and ribavirin, KD025 and remdesivir, EV-100 and ribavirin, or EV-100 and remdesivir.

[0219] In one embodiment, HIV and HBV can be treated and / or prevented using one or more implants delivering potent antiviral agents, including, but not limited to, the potent pro-drug combination of tenofovir alafenamide, lamivudine (3TC), and dolutegravir (DTG).

[0220] In one embodiment, IVR delivering two or more APIs against HIV may be advantageous. Non-limiting examples include tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) combined with a third anti-HIV compound from a different mechanistic class, such as DTG, elvitegravir, antiviral peptide C5A, and broadly neutralizing antibodies against HIV, such as VRC01. In some embodiments, TDF is used without FTC in these combinations. In other embodiments, FTC is used without TDF in these combinations.

[0221] The suitability of any given pharma- ceutical active agent is not limited or predicted by any given medical application, but rather is a function of the following non-limiting parameters:

[0222] Potency: the potency of an API determines whether it can be formulated into a long-acting delivery system (e.g., one or more drug delivery devices) and maintains pharmacologically relevant concentrations in key anatomical compartments over the target period of use (see Example 1). In some cases, it may be possible to use only one implant at a time, depending on the anatomical compartment (e.g., IVR).

[0223] Implant payload; the amount of API that can be formulated into a long-acting delivery system, the number of feasible devices to be implanted, or the size of a single injection (volume of the injected area of ​​a patch), along with the potency of the API, are the major limiting factors in selecting an API for a given application (see Examples 1 and 2).

[0224] Solubility: the water solubility of the API must be such that delivery via the implant can be achieved at the target rate. The solubility, and therefore the release rate, of the API can also be adjusted (increased or decreased) through the formulation strategies described above, using suitable excipients, by preparing pharma- ceutically acceptable salts, as well as through conjugation to pro-drugs, as is well known in the art.

[0225] Targeted delivery; implant API delivery as disclosed herein can be targeted to the systemic circulatory system (e.g., subcutaneous or intramuscular implants) or to a local compartment (e.g., vaginal or ocular devices).

[0226] Local toxicity; the systemic toxicity profile of many of the APIs contemplated in the disclosed application has been determined prior to formulation into an implant, especially when using FDA approved agents. Thus, local toxicity at the implant site is the greatest safety concern in these cases and may limit the rate of delivery of the API. In some cases, drugs may have a low therapeutic index (TI) and the rate of drug release from the implant may not be controllable to provide a safe and effective concentration in the target pharmacological compartment.

[0227] Cost; API cost and / or manufacturing cost may be limiting in certain cases.

[0228] The development of in silico predictions of implant specifications and target product profiles for any given API and medical application is very challenging as known in the art for other sustained release drug delivery technologies and usually requires pre-clinical studies followed by clinical validation of the pharmacology in terms of pharmacokinetics (PK) and pharmacodynamics (PD, safety and efficacy).

[0229] API Formulation The API formulation may consist of only the drug or may contain one or more other agents and / or one or more pharma- ceutically acceptable excipients, which are known in the art and may include viscosity modifiers, bulking agents, surfactants, dispersing agents, disintegrants, osmotic agents, diluents, binders, anti-adherents, lubricants, glidants, pH modifiers, antioxidants and preservatives, as well as other inactive ingredients of the formulation intended to facilitate handling of the API and / or affect the release kinetics of the API.

[0230] In some embodiments, the binder and / or disintegrant may include, but is not limited to, starch, gelatin, carboxymethylcellulose, croscarmellose sodium, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, sodium starch glycolate, lactose, sucrose, glucose, glycogen, propylene glycol, glycerol, sorbitol, polysorbate, and colloidal silicon dioxide. In certain embodiments, the anti-adhesive or lubricant may also include, but is not limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium behenate. In some embodiments, the glidant may include, but is not limited to, fumed silica, talc, and magnesium carbonate. In some embodiments, the pH adjuster may include, but is not limited to, citric acid, lactic acid, and gluconic acid. In some embodiments, antioxidants and preservatives can include, but are not limited to, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), cysteine, methionine, vitamin A, vitamin E, sodium benzoate, and parabens.

[0231] Effect of excipients on API release The devices disclosed herein can include excipients to facilitate and / or control the release of the API from the device. Non-limiting examples of these excipients include PEG and TEC. It is envisioned that the release kinetics of the API can be adjusted by incorporating different excipients into the devices disclosed herein. That is, the release kinetics of the API can be adjusted over a wide range by changing the nature and / or amount of the excipients contained therein. In some cases, the device contains a low concentration of the excipient, for example, about 0% to about 30% by weight of the excipient. In some cases, the excipient is a polyether or ester. In some cases, the excipient is PEG or TEC. In some cases, the device includes PEG to achieve a less sustained release of the API. In some cases, the device includes TEC to achieve a more immediate and larger dose of the API.

[0232] Targeted Implant Specifications The amount of pharma- ceutical active incorporated into the implant device can also be calculated as a pharma- ceutical effective amount, and the present implant device contains one or more pharma- ceutical actives in a pharma- ceutical effective amount. By "pharma- ceutical effective" is meant an amount sufficient to produce a desired physiological or pharmacological change in a subject. This amount will vary depending on factors such as the potency of the particular pharma- ceutical active, the density of the pharma- ceutical active, the shape of the implant, the desired physiological or pharmacological effect, and the duration of the intended treatment.

[0233] In some embodiments, the pharma- ceutical active is present in an amount ranging from about 1 mg to about 25,000 mg of pharma- ceutical active per implanted device, including embodiments in which the amount ranges from about 2 mg to about 25 mg, about 25 mg to about 250 mg, about 250 mg to about 2,500 mg, and about 2,500 to about 25,000 mg of pharma- ceutical active per implanted device.

[0234] The size of the API depot determines the maximum amount of pharmacologic active substance in the implant. For example, subdermal implants traditionally consist of cylindrical devices with a diameter of 2-5 mm and a length of 40 mm. The maximum amount of pharmacologic active substance per implanted device of this nature is less than 1,000 mg. A typical IVR weighs less than 10 g, which means that the maximum amount of pharmacologic active substance per implanted device of this nature is less than 10 g.

[0235] In certain embodiments of the implanted drug delivery devices described herein, the first therapeutic agent is present in the kernel at about 0.1%-99% w / w, in other embodiments, the first therapeutic agent is present in the kernel at about 0.1-1% w / w, about 1-5% w / w, about 5-25% w / w, about 25-45% w / w, about 45-65% w / w, about 65-100% w / w, about 65-75% w / w, or about 75-85% w / w, or about 85-99% w / w.

[0236] In certain embodiments, the implanted drug delivery devices described herein are capable of releasing a therapeutic agent contained therein over a period of 1, 2, 3, 4, 5, or 6 weeks. In certain embodiments, the implanted drug delivery devices described herein are capable of releasing a therapeutic agent contained therein over a period of 8, 10, 12, or 14 weeks. In certain embodiments, the implanted drug delivery devices described herein are capable of releasing a therapeutic agent contained therein over a period of 1, 2, 3, or 6 months. In certain embodiments, the implanted drug delivery devices described herein are capable of releasing a therapeutic agent contained therein over a period of 1, 2, 3, or 4 years.

[0237] In one embodiment, the subdermal implant drug delivery device described herein delivers 0.05 to 3 mg / d over a period of 3, 4, 6, or 6 weeks, or 8, 10, 12, or 14 weeks, or 1, 2, 3, 6, or 12 months. -1In certain embodiments, the subdermal implants described herein are capable of releasing a peptide conjugate of tenofovir alafenamide (TAF), or a pharma- ceutically acceptable salt thereof, at an average rate of 0.1 to 2 mg / d. -1 In certain embodiments, the subdermal implants described herein are capable of releasing the peptide conjugate of TAF, or a pharma- ceutically acceptable salt thereof, at an average rate of 0.1 to 1 mg / d -1 In certain embodiments, the subdermal implants described herein are capable of releasing a peptide conjugate of TAF, or a pharma- ceutically acceptable salt thereof, at a rate of 0.25 mg / d over a period of 3, 6, or 12 months. -1 In certain embodiments, the subdermal implants described herein are capable of releasing the peptide conjugate of TAF, or a pharma- ceutical acceptable salt thereof, at an average rate of 0.5 mg / d -1 In certain embodiments, the subdermal implants described herein are capable of releasing the peptide conjugate of TAF, or a pharma- ceutical acceptable salt thereof, at an average rate of 1 mg / d -1 Upon stimulation with the peptide conjugate of TAF, or a pharma- ceutically acceptable salt thereof, can be released.

[0238] In certain embodiments of the implanted drug delivery devices described herein, the second therapeutic agent is present in the skin at about 5-50% w / w, hi other embodiments, the second therapeutic agent is present in the skin at about 10-50% w / w, about 20-50% w / w, about 10%, 30% or 50% w / w of the skin.

[0239] In certain embodiments, the implant drug delivery device described herein is stable at room temperature. As used herein, "room temperature" is anywhere between about 18°C ​​and about 30°C. As used herein, a physical implant drug delivery device is a device that can be stored at about 18-30°C for at least about one month.

[0240] Implant Fabrication Also described herein is a method of making an implantable drug delivery device.

[0241] Fabrication of implants containing API and / or excipients in polymer dispersions Implants in which the API and / or excipients are dissolved or suspended in solid form in an elastomer (e.g., matrix-type implant devices) are fabricated using methods known in the art. For example, an extrusion process can be used. Elastomer pellets frozen into a powder are blended with the API material powder. Alternatively, the API material can be combined directly with the elastomer pellets prior to introduction into the extruder, or mixing of the API material and elastomer pellets can be a continuous process that controls the mass flow rate of the API material and elastomer into the extruder screw to achieve the desired API:polymer ratio. A wide range of API material concentrations from 0.1 to 99% w / w can be used with this approach. The API and polymer blend is hot melt molded to produce the implant drug product.

[0242] Also described herein are methods of making implants in which the API and / or excipients are dissolved or suspended in solid form in the elastomers described herein (e.g., matrix-type implant devices), including:

[0243] Producing a homogenous polymer kernel granule containing a first therapeutic agent and a loaded skin layer granule containing a second therapeutic agent, or simply a non-medicated skin;

[0244] Co-extruding kernel granules containing a first therapeutic agent with skin layer granules containing a second therapeutic agent (or non-medicinal) to form a bilayer drug delivery device, or co-extruding kernel granules containing a first therapeutic agent with an additional kernel layer and / or skin granules containing a second therapeutic agent (or non-medicinal) to form a multi-layer drug delivery device.

[0245] Also described herein is the following method of producing drug-loaded kernel or skin granules. a) grinding the polymer; b) dry powder mixing the ground polymer with the respective active compound; c) blending and extruding the powder mixture obtained in step (b); d) cutting the resulting filled polymer strands into granules, thereby obtaining kernel granules and / or skin layer granules; e) If necessary, lubricate the granules prior to coextrusion.

[0246] Reservoir implant fabrication Also described herein is a method of manufacturing the reservoir design implant drug delivery device.

[0247] In one embodiment of a reservoir type implant, the API, and any other solid agents or excipients, can be filled into the implant shell as a powder or slurry using filling methods known in the art. In another embodiment, the solid active agent and carrier can be compressed into a microtablet / tablet form to maximize loading of the active agent (24, 112) using means common in the art.

[0248] In one example, the drug formulation is in the form of a solid drug rod. Drug rod embodiments and methods for making such drug rods have been described in the art, such as (125), which is incorporated by reference in its entirety. Drug rods may be formed by adapting other extrusion or molding techniques known in the art. For example, a drug rod containing an API may be formed by filling a tube with an aqueous solution of the API and then allowing the solution to evaporate. In another example, a drug rod containing an API may be formed by extrusion, as known in the art. In many embodiments, the drug formulation desirably contains no or minimal amounts of excipients for the same reasons of volume / size minimization.

[0249] The open end of the implant can be plugged with a pre-fabricated end plug to ensure a smooth end and a tight seal (500). The plug can be sealed to the implant end using frictional forces (e.g., a rim and groove that lock together to form a seal), adhesives, induction or laser welding, or another form of heat sealing that melts the plug and implant end together. In another embodiment, the end is sealed without the use of a solid plug (501) by one of several methods known to those skilled in the art, including but not limited to heat sealing, induction welding, laser welding, or sealing with an adhesive.

[0250] Fabrication of porous implant components The porous material(s) can be used in the implant fabrication for either the kernel or the skin, as described in detail above. In one embodiment, the API-permeable portion of the implant device is formed from a porous membrane of polyurethane, silicone, or other suitable elastomeric material. Open-cell foams and their manufacture are known to those skilled in the art (126). Open-cell foams can be produced through the formation of closed pores in the polymer using blowing agents, typically carbon dioxide or hydrogen gas, or low-boiling liquids present during the manufacturing process, followed by a cell opening step that breaks the seal between the cells and forms an interconnected porous structure through which diffusion can occur. An alternative embodiment employs the pneumocystrophic method to create ordered porous polymeric membranes for API release (127). In this method, hexagonal micropore arrays are obtained by water droplet condensation during fast solvent evaporation under wet flow. Porous membranes can also be fabricated using the porogen leaching method (128), whereby the polymer is mixed with salts or other soluble particles of controlled size before casting, spin-coating, extruding, or other processing into the desired shape. The polymer composite is then immersed in a suitable solvent known in the art, and the porogen particles are leached out, leaving a structure with a porosity controlled by the number and size of the leached porogen particles. A preferred approach is to use water-soluble particles and water as the solvent for porogen leaching and removal. Highly porous scaffolds with porosity values ​​up to 93% and average pore sizes up to 500 μm can be formed using this technique. A variation of this method is melt molding, which involves filling a mold with polymer powder and porogen and heating the mold above the glass transition temperature of the polymer to form the scaffold. After removal from the mold, the porogen is leached out to form a porous structure with independent control of morphology (from the porogen) and shape (from the mold).

[0251] Phase separation processes can also be used to form porous membranes (128). A second solvent is added to the polymer solution (quenching) and the mixture undergoes phase separation to form a polymer-rich and polymer-poor phase. The polymer-rich phase solidifies and the polymer-poor phase is removed, leaving a highly porous polymer network with micro- and macrostructures controlled by parameters such as polymer concentration, temperature, and quenching rate. A similar approach is freeze-drying, where a polymer solution is cooled to a frozen state, the solvent forms ice crystals, and the polymer aggregates in the interstitial spaces. The solvent is removed by sublimation, resulting in an interconnected porous polymer structure (128). A final method to form porous polymer membranes is to use a stretching process to create an open-cell network (129).

[0252] Porous metal materials can be fabricated by traditional sintering processes (130, 131). Loose powder or gravity sintering creates pores from voids in the packed powder as the particles bond by diffusion bonding processes. Pore size and density are determined primarily by the morphology of the starting metal powder material and are difficult to control. Porogens can be used to create open-cell interconnected metal foams with pore sizes of 100-600 μm and porosities of about 35-80%, in a manner similar to that described herein for polymer foams. Porogens can include salts (e.g., NaCl, NaF, and NH4HCO3), organic materials [e.g., tapioca starch (132), urea (133-135)], or other metals (e.g., magnesium). The porogens are removed to form pores thermally during sintering or post-sintering processes, or by dissolving in a solvent. The high melting point of Nitinol (1310°C) limits the preparation of the porous material to powder metallurgy techniques (136). The material can be prepared by sintering Ni and Ti powders in a predetermined ratio to form a NiTi alloy during the sintering process. Alternatively, pre-alloyed NiTi powder can be sintered with or without additional porogen to form a porous structure with a controlled Ni-Ti ratio.

[0253] Additive Manufacturing of Implant Components Additive manufacturing, commonly referred to in the art as 3D printing technology, is one of the fastest growing applications for the fabrication of plastics. The components that make up the implants can be fabricated by additive techniques that allow complex and asymmetric three-dimensional structures to be obtained using 3D printing devices and methods such as those known to those skilled in the art (137, 138), which are incorporated herein by reference. Currently, there are three main methods for additive manufacturing: stereolithography (SLA), selective laser sintering (SLS), and fused modeling (FDM).

[0254] The SLA process requires a liquid plastic resin, a photopolymer, which is then cured by an ultraviolet (UV) laser. SLA machines require an excess amount of photopolymer to complete the print, and a common g-code format can be used to convert the CAD model into assembly instructions for the printer. SLA machines typically store the excess photopolymer in a tank below the print bed, and as the printing process continues, the bed is lowered into the tank, curing successive layers along the way. Due to the small cross-sectional area of ​​the laser, SLA is considered one of the slower additive manufacturing methods, as small parts can take hours or days to complete. Additionally, material costs are relatively high due to the proprietary nature and limited availability of the photopolymer. In one embodiment, one or more components of the implant are fabricated by the SLA process.

[0255] The SLS process is similar to SLA, building parts layer by layer through the use of a high-energy pulsed laser. In SLS, however, the process starts with a tank full of bulk material in powder form. As printing continues, the bed lowers itself with each new layer, advantageously supporting the overhang of the upper layer with excess bulk powder that is not used in forming the lower layer. To facilitate processing, the bulk material is typically heated to just below its transition temperature to allow for faster particle fusion and printing transfer, as described in the art (139). In one embodiment, one or more components of the implant are fabricated by the SLS process.

[0256] Porous metal materials formed by traditional sintering can suffer from inherent brittleness of the final product, as well as limited control of pore shape and distribution. Additive manufacturing techniques can overcome some of these limitations, improving control of various pore parameters and mechanical properties and allowing fabrication of parts with complex shapes and geometries. These include techniques using powder beds such as SLS (140), selective laser melting (SLM) (86, 141). Aluminum and titanium composites can be produced by SLS with control of porosity characteristics and mechanical properties by varying the laser power at low powers (25-40 W), materials exhibiting higher porosity and lower mechanical strength at higher laser powers (60-100 W), and dense parts formed with macroporosity generated from implant structural designs (142). Advanced manufacturing processes can be based on layered manufacturing to additively manufacture parts. CAD / CAM-based layered manufacturing techniques have found applications in near-net-shape fabrication of porous parts with controlled porosity. Electron beam melting (EBM) and direct metal laser sintering (DMLS) processes allow for the direct digital-enabled fabrication of porous custom titanium implants with controlled porosity characteristics and desired external and internal properties (143, 144). Typically, these rapid manufacturing techniques are utilized for aerospace applications, but the systems can be easily expanded for use in the fabrication of medical implants. EBM is a direct-to-metal CAD prototyping process that can produce dense, porous metal parts by directional solidification of metal powder into a predetermined 3D structure by melting the metal powder layers layer by layer with an electron beam. SLS and SLM processes are similar but use a laser to melt the powder, typically producing denser structures. Direct 3D deposition and sintering of Ti alloy fibers can produce scaffolds with controlled porosity (100–700 μm) and total porosity (up to 90%) (145–147).An alternative is the Laser Engineered Net Shape (LENS) process, an additive manufacturing technique developed to fabricate metal parts directly from computer-aided design (CAD) solid models by using metal powder injected into a molten pool generated by a focused high-power laser beam (140, 148).

[0257] Rather than using a laser to form polymer or sintered particles together, FDM works by extruding and laying down successive layers of material at high temperature from a polymer melt, allowing adjacent layers to cool and bond together before the next layer is deposited. In the most common FDM approach, condensed fiber fabrication (FFF), polymer in the form of a filament is continuously fed to a heated printhead print, whereby the polymer melts and is deposited onto the print surface. The printhead moves on a horizontal plane to deposit the polymer in one layer, and the printhead or printing platform moves along a vertical axis to start a new layer. A second FDM approach uses a printhead design based on a traditional single-screw extruder to melt polymer particles (powder, flakes, or pellets) and force the polymer melt through a nozzle, whereby it is deposited onto the print surface, similar to FFF. This approach allows the use of standard polymer materials in their granulated form, without the need to first fabricate a filament through a separate extrusion step. In one embodiment, one or more components of the implant are fabricated by FDM and / or FFF processes.

[0258] In another embodiment, Arburg Plastic Freeforming (APF) (149) is an additive manufacturing technique used in implant fabrication. In this embodiment, a plasticizing cylinder with a single screw is used to generate a homogenous polymer melt, similar to the process of thermoplastic injection molding. The polymer melt is fed under pressure from the screw cylinder to a piezoelectrically actuated deposition nozzle. The nozzle ejects individual polymer droplets of controlled size at precalculated locations, building each layer of the three-dimensional polymer print from the fused droplets. The screw and nozzle assembly is fixed in place, and the build platform holding the printed part is moved along three axes to control the droplet deposition location. The droplets bonded together on cooling to form a solid part. The technique can operate at high temperatures (around 300 °C) and pressures (around 400 bar). One advantage of the APF method is that it is directly compatible with many processes used for injection molding and extrusion (e.g., granulated polymer feedstock, no organic solvents).

[0259] In another embodiment, Droplet Deposition Modeling (DDM) is used as an additive manufacturing technique by generating discrete streams of material during deposition, as is well known in the art for inkjet systems.

[0260] A preferred method of additive manufacturing that avoids successive layer deposition to form three-dimensional structures is to use continuous liquid interface manufacturing (CLIP), a technique recently developed by Carbon3D. In CLIP, three-dimensional objects are built from a high-velocity, continuous flow of liquid resin that is successively polymerized using UV under controlled oxygen conditions to form monolithic structures with desired geometries. The CLIP process is capable of producing solid parts that are pulled from the resin at speeds of hundreds of mm per hour. Implant scaffolds containing complex geometries can be formed using CLIP from a variety of materials, including polyurethane and silicone.

[0261] In one embodiment, the implant is manufactured under completely aseptic conditions, hi another embodiment, the implant is terminally sterilized using methods known in the art, such as gamma sterilization, steam sterilization, dry heat sterilization, UV irradiation, ethylene oxide sterilization, etc.

[0262] Methods for implanting and removing devices - Patents.com Methods for the insertion and removal of IVRs or other vaginal devices such as IUDs, pessaries, etc. are known in the art. Similar methods can be used for embodiments in which the implantable device is a vaginal drug delivery device.

[0263] Implantation embodiments are described herein that describe subcutaneous or intramuscular drug delivery devices. In some cases, the drug delivery device is a subcutaneous or intramuscular implant, an intravaginal ring, or a microarray patch. In some cases, the drug delivery device is a subcutaneous implant. In some cases, the drug delivery device is an intramuscular implant. In some cases, the drug delivery device is an intravaginal ring. In some cases, the drug delivery device is a microarray patch. In some embodiments, one or more devices are implanted together. In one embodiment, insertion and removal are performed by a medical professional.

[0264] The devices of the present disclosure can be implanted in a subject / patient according to standard procedures by a trained professional. The term "subject / patient" includes all mammals (e.g., humans, valuable livestock, sport or farm animals, laboratory animals). In one embodiment, insertion can alternatively be facilitated by the use of a trocar to facilitate access. Insertion and removal of such devices (150, 151) have been described in the art, for example for subcutaneous implants, and are fully incorporated herein by reference (152, 153).

[0265] Dissolvable / resorbable implants are not expected to require removal under normal conditions.

[0266] Identification of implants targeted for extraction is based on tracking markers that will be incorporated into the implant manufacture and through the use of imaging techniques (ultrasound, magnetic detection, infrared, x-ray, or similar methods).

[0267] Once identified, a local anesthetic is applied / injected locally to the distal end of the implant where a small incision is made (usually about 2-6 mm) to allow for visual identification of the implant and / or retraction of the indication (hole) using standard blunt end forceps or similar to grasp / hook the distal end. Mosquito forceps or similar forceps are then inserted to grasp the end.

[0268] Based on the implant components as well as individual response, most can be directly grasped and extracted without complication. Many can be "pushed out" with hand / instrument pressure applied to the posterior / proximal end of the implant.

[0269] Implant sheath ePTFE has been used in the art as a sheath material lining the pocket in which saline or silicone gel breast implants are surgically placed (see above). The ePTFE liner allows the implant to integrate with the body by growing tissue without the formation of a capsule (scar tissue) and also prevents the pocket from closing on itself, thus keeping the pocket open. A typical ePTFE liner is 0.35 mm thick and has a microporosity of about 40 μm. This allows the body to grow into the pores without forming a fibrous scar around the material. The material is permanent and does not degrade in the body. It can be removed if necessary. In some embodiments, the ePTFE liner is placed in the subcutaneous pocket in which the implant is located to reduce foreign body reaction and facilitate implant exchange for sequential therapy. In some embodiments, the ePTFE liner is placed in the intramuscular pocket in which the implant is located to reduce foreign body reaction and facilitate implant exchange for sequential therapy.

[0270] Provided herein are devices for implantation within a patient's body. In some cases, implantation within the body includes implantation within a sterile anatomical compartment. In some cases, the sterile anatomical compartment is selected from the subcutaneous space, the intramuscular space, the eye, the ear, and the brain. In some cases, the sterile anatomical compartment is the subcutaneous space. In some cases, the sterile anatomical compartment is the intramuscular space. In some cases, the sterile anatomical compartment is the eye. In some cases, the sterile anatomical compartment is the ear. In some cases, the sterile anatomical compartment is the brain.

[0271] In some cases, implantation within the body includes implantation into a non-sterile anatomical compartment. In some cases, the non-sterile anatomical compartment is selected from the vagina, the rectum, and the nasal cavity. In some cases, the non-sterile anatomical compartment is the vagina. In some cases, the non-sterile anatomical compartment is the rectum. In some cases, the non-sterile anatomical compartment is the nasal cavity.

[0272] Provided herein are devices with a shape adapted to be placed within a patient's body. In some cases, the devices are capsule-shaped.

[0273] Device Use and Intended Use Provided herein is a method of delivering one or more APIs to a subject in need thereof, the method comprising providing to the subject a drug delivery device described herein. In some cases, providing the drug delivery device comprises implanting the drug delivery device in the subject's body. Also provided is a method of treating or preventing a disease or disorder in a subject, the method comprising providing to the subject a drug delivery device described herein. In some cases, the disease or disorder is an infectious disease, transplant rejection, a condition indicative of hormonal therapy, a physiological or pathophysiological application, diabetes, an allergy or hypersensitivity, an autoimmune disorder, cancer, a hematological disease, a musculoskeletal disorder, a psychological or neurological disorder, a genetic disease, or a veterinary condition. In some cases, the disease or disorder is an infectious disease. In some cases, the infectious disease is HIV.

[0274] One purpose of the drug delivery device described herein is to deliver one or more APIs to a body compartment for the purpose of treating a medical condition, preventing a medical condition, reducing the likelihood of having a medical condition, reducing the severity of a medical condition, and / or slowing the progression of a medical condition in a subject, hereinafter referred to as "application". In some cases, the anatomical compartment is the vagina. In other cases, the targeted body compartment is the systemic circulation. The purpose is augmented by the associated intention of improving patient compliance by reducing problems in adhering to treatments and preventions associated with more frequent dosing regimens. Thus, the present disclosure relates to multiple applications. Illustrative, non-limiting examples of such applications are provided below in summary form. Based on these examples, one skilled in the art can adapt the disclosed technology to other applications. One skilled in the art will recognize whether such applications include local API delivery (e.g., certain vaginal implant devices such as IVR, microarray patches for transdermal or ocular delivery) or systemic API delivery (e.g., subcutaneous or intramuscular implant devices, subcutaneous or intramuscular injection of particle suspensions).

[0275] Infectious diseases, including multiple overlapping infections: In some cases, a patient in need of treatment for a disease or disorder disclosed herein, such as an infectious disease, is symptomatic for the disease or disorder. In some cases, a patient in need of treatment for a disease or disorder disclosed herein, such as an infectious disease, is asymptomatic for the disease or disorder. A patient in need of treatment for a disease or disorder disclosed herein, such as an infectious disease, can be identified by a skilled practitioner, such as, but not limited to, a doctor or nurse.

[0276] HIV prevention using one or more suitable peptide conjugates with antiretroviral agents (including biologics) delivered from a drug delivery device and / or one or more vaccines and / or adjuvants (i.e., implantable or injectable formulations as described herein), and treatment using one or more suitable peptide conjugates with antiretroviral agents (including biologics) delivered from a drug delivery device.

[0277] Sexually Transmitted Infections (STIs), including but not limited to, prevention or treatment of both active and chronically active infections, by peptide conjugates with one or more suitable antimicrobial agents delivered from a drug delivery device. Illustrative examples of STIs include, but are not limited to, gonorrhea, chlamydia, lymphogranuloma venereum, syphilis, including multi-drug resistant (MDR) organisms, hepatitis C virus, and herpes simplex virus.

[0278]

[0033] Bacterial vaginosis (BV) and other microbial vaginal disorder conditions, including but not limited to, prevention or treatment of both active and chronically active forms, with one or more suitable APIs delivered from a drug delivery device.

[0279] Prevention or treatment of both active and chronic forms of Hepatitis B Virus (HBV) with one or more suitable APIs delivered from a drug delivery device.

[0280] Prevention or treatment of herpes simplex virus (HSV) and varicella zoster virus (shingles) / shingles, both active and chronic, by one or more suitable APIs delivered from a drug delivery device.

[0281] Prevention or treatment of both active and chronic cytomegalovirus (CMV) and congenital CMV infections with one or more suitable APIs delivered from a drug delivery device.

[0282] Prevention or treatment of both active and chronic forms of malaria with one or more suitable APIs delivered from a drug delivery device.

[0283] Prevention or treatment of tuberculosis, including multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis, both active and chronic, by one or more suitable APIs delivered from a drug delivery device.

[0284] Treatment or management of acne with one or more suitable APIs delivered from a drug delivery device.

[0285] Prophylaxis or treatment of respiratory viral infections, including but not limited to influenza viruses and coronaviruses, e.g., SARS-CoV-2.

[0286] Influenza spreads worldwide in seasonal epidemics, with hundreds of thousands of deaths annually during pandemic years. For example, three influenza pandemics occurred in the 20th century, resulting in tens of millions of casualties, but each of these pandemics was caused by the emergence of a new strain of the virus in humans. Often, these new strains result from the spread of existing influenza viruses from other animal species to humans. Influenza viruses are RNA viruses in the family Orthomyxoviridae, which includes five genera: influenza A virus, influenza B virus, influenza C virus, isavirus, and thogotovirus. Influenza A viruses can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes identified in humans, in order of the number of known human pandemic deaths, are as follows: H1N1 (caused the Spanish flu in 1918), H2N2 (caused the Asian flu in 1957), H3N2 (caused the Hong Kong flu in 1968), H5N1 (a pandemic threat in the 2007-08 flu season), H7N7 (with unusual zoonotic potential), H1N2 (endemic to humans and pigs), H9N2, H7N2, H7N3 and H10N7. Influenza type B causes seasonal influenza, while influenza type C causes localized epidemics, and both influenza types B and C are less common than influenza type A.

[0287] Coronaviruses are a common family of viruses that cause a variety of illnesses in humans, ranging from the common cold to severe acute respiratory syndrome (SARS). Coronaviruses can also cause many illnesses in animals. Coronaviruses are enveloped, positive-stranded RNA viruses that get their name from their characteristic crown-like appearance in electron micrographs. Coronaviruses are classified as a family within the order Nidovirales, which are viruses that replicate using a nested set of mRNAs. The Coronavirinae subfamily is further divided into four genera: Alphacoronaviruses, Betacoronaviruses, Gammacoronaviruses, and Deltacoronaviruses. Human coronaviruses (HCoVs) are two of these genera: Alphacoronaviruses (which include HCoV-229E and HCoV-NL63) and Betacoronaviruses (which include HCoV-HKU1, HCoV-OC43, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), and SARS-CoV-2).

[0288] Transplantation - Graft Rejection: Chronic immunosuppressive therapy post-transplant with one or more suitable APIs delivered from a drug delivery device.

[0289] Hormone therapy: Contraception comprising estrogen and progestin with one or more suitable APIs delivered from a drug delivery device.

[0290] Hormone replacement with one or more suitable APIs delivered from a drug delivery device.

[0291] Testosterone replacement with one or more suitable APIs delivered from a drug delivery device.

[0292] Thyroid replacement / blocker with one or more suitable APIs delivered from a drug delivery device.

[0293] Hormonal therapy for regulating triglycerides (TG) using one or more suitable APIs delivered from a drug delivery device.

[0294] Chronic pharmacological support for all transgender individuals (all stages from cis to trans) using one or more suitable APIs delivered from a drug delivery device.

[0295] Physiology and Pathophysiology: Gastrointestinal (GI) applications with one or more suitable agents delivered from the implant, including, but not limited to, treatment / management of diarrhea, pancreatic insufficiency, liver cirrhosis, fibrosis in all organs; GI-related parasitic diseases, gastroesophageal reflux disease (GERD).

[0296] Cardiovascular applications with one or more suitable APIs delivered from the drug delivery device, including, but not limited to, treatment / management of hypertension (HTN) using, for example, statins or equivalent drugs, cerebral / peripheral vascular disease, stroke / embolism / arrhythmia / deep vein thrombosis (DVT), for example, using anticoagulants and anti-atherosclerotic cardiovascular disease (ASCVD) drugs, and congestive heart failure (CHF), for example, using beta-blockers, ACE inhibitors, and angiotensin receptor blockers.

[0297] Pulmonary applications with one or more suitable APIs delivered from a drug delivery device, including but not limited to treatment / management of sleep apnea, asthma, long term pulmonary therapy, pulmonary HTN, fibrosis, and pneumonia.

[0298] Bone applications with one or more suitable APIs delivered from a drug delivery device, including but not limited to, chronic pain (joints and bones including the sternum), osteomyelitis, osteopenia, cancer, idiopathic chronic pain, and treatment / management of gout.

[0299] Urology applications with one or more suitable APIs delivered from the drug delivery device, e.g., treatment / management of benign prostatic hyperplasia (BPH), bladder cancer, chronic infections (throughout the urinary system), chronic cystitis, prostatitis.

[0300] Ophthalmic applications including, but not limited to, glaucoma, treatment / management of eye infections with one or more suitable APIs delivered from a drug delivery device.

[0301] Cholesterol management by one or more suitable APIs delivered from a drug delivery device.

[0302] Metabolic applications with one or more suitable APIs delivered from the drug delivery device, including but not limited to weight gain, weight loss, obesity, malnutrition (replenishment), osteopenia, vitamin deficiencies (B vitamins / D), folic acid, and treatment / management of smoking / drug reduction / cessation.

[0303] Diabetes: Treatment and management of diabetes (type 1 and type 2) with one or more suitable APIs delivered from a drug delivery device.

[0304] Allergies and hypersensitivities, often with "desensitization" requiring repeated exposure to low doses: Type: Type I (IgE-mediated reactions), Type II (antibody-mediated cytotoxic reactions), Type III (immune complex-mediated reactions), and Type IV delayed-type hypersensitivity (154), depending on one or more suitable APIs delivered from a drug delivery device.

[0305] Hypersensitivity reactions (HSRs) due to one or more of the suitable APIs delivered from the drug delivery device.

[0306] With one or more suitable APIs delivered from the drug delivery device, antibiotics, biologics (drugs and antibody moieties), chemotherapy (e.g., platins), progesterone, and other treatments known in the art and described in (154).

[0307] Food allergies (e.g., nuts, shellfish) with one or more suitable APIs delivered from the drug delivery device.

[0308] Dosing of allergy medication with one or more suitable APIs delivered from a drug delivery device as an alternative to allergy shots, recommended for individuals with severe allergy symptoms that do not respond to regular medications, individuals who experience significant side effects from medications, individuals whose lives are disrupted by allergies / insect bites, or individuals whose allergies may be life-threatening.

[0309] Autoimmune disorders, often classified as chronic inflammatory disorders: Treatment and management of Crohn's disease and ulcerative colitis with one or more suitable APIs delivered from a drug delivery device.

[0310] Treatment and management of rheumatoid arthritis (RA) with one or more suitable APIs delivered from a drug delivery device.

[0311] Treatment and management of multiple sclerosis (MS) with one or more suitable APIs delivered from a drug delivery device.

[0312] Treatment and management of psoriasis with one or more suitable APIs delivered from a drug delivery device.

[0313] Treatment and management of lupus with one or more suitable APIs delivered from a drug delivery device.

[0314] Treatment and management of autoimmune thyroiditis with one or more suitable APIs delivered from a drug delivery device.

[0315] Oncology: Chronic or sub-chronic cancer management of chemotherapy and targeted therapy (e.g., Ig) with one or more suitable APIs delivered from a drug delivery device.

[0316] Hematologic disorders: Treatment / management of hemophilia A with one or more suitable APIs (e.g., Factor VIII orthologues) delivered from a drug delivery device.

[0317] Administration of anticoagulant and / or antiplatelet therapy by one or more suitable APIs delivered from a drug delivery device.

[0318] Treatment / management of leukemia / lymphoma and bone marrow transplant (MBT) therapy with one or more suitable APIs delivered from a drug delivery device.

[0319] Iron replacement therapy with one or more suitable APIs delivered from a drug delivery device.

[0320] Musculoskeletal Applications: One or more anti-inflammatory APIs (e.g., NSAIDS) delivered from the drug delivery device.

[0321] Opioid addiction / pain management with one or more suitable APIs delivered from a drug delivery device.

[0322] Hypertrophic fibrosis / scar tissue.

[0323] Psychological and neurological disorders: Treatment and management of depression with one or more suitable APIs delivered from a drug delivery device.

[0324] Treatment and management of schizophrenia and related disorders with one or more suitable APIs delivered from a drug delivery device.

[0325] Treatment and management of bipolar disorder with one or more suitable APIs delivered from a drug delivery device.

[0326] Treatment and management of thymic disorders with one or more suitable APIs delivered from a drug delivery device.

[0327] Treatment and management of seizure control with one or more suitable APIs delivered from a drug delivery device.

[0328] Treatment and management of ADD / ADHD and hyperactivity disorder with one or more suitable APIs delivered from a drug delivery device.

[0329] Behavioral / emotional secondary treatment and management of early onset (child / adolescent), substance use, physical, sexual, emotional abuse, PTSD, and anxiety with one or more suitable APIs delivered from a drug delivery device.

[0330] Treatment and management of seizures, including but not limited to epilepsy and traumatic brain injury, with one or more suitable APIs delivered from an adrug delivery device.

[0331] Treatment and management of Parkinson's disease with one or more suitable APIs delivered from a drug delivery device.

[0332] Treatment and management of Alzheimer's disease with one or more suitable APIs delivered from a drug delivery device.

[0333] Genetic disorders: Treatment of congenital genetic deficiencies, including genetic excess diseases, with one or more suitable APIs delivered from a drug delivery device.

[0334] Treatment of primary immunodeficiencies (e.g., agamaglobulinemia, secretory IgA deficiency, sIgA deficiency) with one or more suitable APIs delivered from a drug delivery device.

[0335] Severe Combined Immune Deficiency (SCID) - Treatment of SCID with one or more suitable APIs delivered from a drug delivery device, including, but not limited to, enzyme replacement therapy (ERT) with pegylated bovine ADA (PEG-ADA).

[0336] Muscular dystrophies treated and managed by one or more suitable APIs delivered from a drug delivery device.

[0337] Treatment or management of Duchenne's disease with one or more suitable APIs (e.g., eteplirsen) delivered from a drug delivery device.

[0338] Treatment or management of Pompe disease with one or more suitable APIs delivered from a drug delivery device, including ERT, such as intravenous administration of recombinant human acid alpha-glucosidase.

[0339] Treatment or management of Gaucher's disease with one or more suitable APIs delivered from a drug delivery device.

[0340] Veterinary uses including all mammals, including but not limited to dogs, cats, horses, pigs, sheep, goats, and cattle.

[0341] In one embodiment, the delivery of API from the drug delivery device serves multiple purposes, targeting two or more applications simultaneously. Examples of such multi-purpose API delivery devices include prevention of HIV infection by delivery of one or more antiretroviral agents, including peptide-drug conjugates, and contraception by delivery of one or more contraceptive agents. In another embodiment, the multi-purpose API delivery device protects against multiple diseases using a single agent. Intravaginal delivery of peptides against encapsulated viruses, taken from the group described by Cheng et al. (155), which is incorporated by reference in its entirety, is used to prevent HIV and HSV infection, among other encapsulated viruses. Peptides can also be combined with other agents (e.g., contraceptives and / or antivirals, and their conjugates) in IVR as a multi-purpose prevention technique.

[0342] The present disclosure also provides a method of delivering an API to a subject via a device of the present disclosure, comprising a kernel comprising an excipient and an API (such as a TAF) that is implanted in the subject. In some cases, the API is delivered with a consistent sustained release profile. In some cases, the excipient is PEG or TEC.

[0343] Provided herein are methods of delivering one or more APIs to a patient in need thereof, comprising implanting a device disclosed herein into the patient's body. In some cases, the device delivers one or more APIs for 1-12 months. In some cases, the device delivers one or more APIs for 1-3 months. In some cases, the device delivers one or more APIs for 3-12 months. In some cases, the device delivers one or more APIs for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the device delivers one API for 1-12 months. In some cases, the device delivers one API for 1-3 months. In some cases, the device delivers one API for 3-12 months. In some cases, the device delivers one API for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the device delivers two or more APIs for 1-12 months. In some cases, the device delivers two or more APIs for 1-3 months. In some cases, the device delivers two or more APIs for 3-12 months. In some cases, the device provides two or more APIs for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0344] In some cases, the API comprises a hydrophobic drug or a hydrophilic drug. In some cases, the API comprises a hydrophobic drug. In some cases, one or more drugs are hydrophobic. In some cases, the API comprises a hydrophilic drug. In some cases, one or more drugs are hydrophilic. In some cases, the API is tenofovir alafenamide, ivermectin, or a ROCK2 inhibitor. In some cases, the API is tenofovir alafenamide. In some cases, the API is ivermectin or a ROCK2 inhibitor. In some cases, the ROCK2 inhibitor is KD025 (Kadmon). In some cases, the one or more drugs are an antiretroviral agent, an antibacterial agent, an antibacterial agent, an antiviral agent, a hormone agent, a statin, a beta blocker, an ACE inhibitor, an angiotensin receptor blocker, a vitamin agent, a steroid, a biologic, an anticancer agent, an allergy agent, an anticoagulant, an antiplatelet therapy, a nonsteroidal anti-inflammatory drug, a vaccine, or a combination thereof. In some cases, the one or more drugs is an antiretroviral. In some cases, the one or more drugs include zidovudine, cabotegravir, dapivirine, fluticasone propionate, chlordiazepoxide, haloperidol, indomethacin, prednisone, ethinyl estradiol, acyclovir, tenofovir, atenolol, aminoglycosides, exenatide acetate, leuprolide acetate, acetylsalicylic acid (aspirin), levodopa, remdesivir, acyclovir, ganciclovir, ribavirin, lamivudine, dolutegravir, chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir, EV-100, EV-200, EV-300, EV-400, KD025, tenofovir, emtricitabine, elvitegravir, lenacapavir, islatravir, C5A, VRC01, or a combination thereof. In some cases, the one or more drugs include tenofovir. In some cases, the one or more drugs include tenofovir alafenamide or tenofovir disoproxil fumarate. In some cases, the one or more drugs include tenofovir alafenamide. In some cases, the one or more drugs include tenofovir disoproxil fumarate.

[0345] Equivalent The disclosure should not be limited with respect to the specific embodiments described in this application, which are intended as examples of various aspects. Many modifications and variations can be made without departing from the spirit and scope of the disclosure, as will be apparent to those skilled in the art. In addition to those enumerated herein, functionally equivalent methods, systems, and devices within the scope of the disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be within the scope of the appended claims. The disclosure is limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that the disclosure is not limited to specific methods, reagents, compounds compositions, or biological systems, which can, of course, vary. It is also to be understood that the terms used herein are merely for the purpose of describing specific embodiments, and are not intended to be limiting. As will be understood by those skilled in the art, for any and all purposes, such as providing a written description, all ranges disclosed herein also encompass any and all possible subranges, and combinations of those subranges.

[0346] Those skilled in the art will readily recognize that many modifications can be made to the preferred embodiments without departing from the scope thereof. It is intended that all material contained herein be considered as illustrative of the disclosure and not in a limiting sense.

[0347] Various aspects and embodiments have been disclosed herein, and other aspects and embodiments will be apparent to those of skill in the art. All references cited herein are incorporated by reference in their entirety. EXAMPLES

[0348] Example 1 - Tenofovir Alafenamide and Exemplary Subdermal Implant Specifications for HIV Prevention The disclosed implant technology for sustained and controlled delivery of APIs to the systemic circulation is a platform technology and is not targeted to any particular API or application. Restrictions on the selection of APIs and applications are outlined under "API Selection". Illustrative, non-limiting examples of the interaction of API physical, chemical, and biological properties with implant properties are provided herein.

[0349] Tenofovir alafenamide (TAF) is a nucleoside reverse transcriptase inhibitor (NRTI) and a potent antiretroviral drug against HIV. Preclinical and clinical studies suggest that TAF can be delivered systemically to safely prevent HIV infection in uninfected individuals. Many in the art believe that the steady-state concentration of tenofovir diphosphate (TFV-DP), the active metabolite of TAF, in peripheral blood mononuclear cells (PBMCs) is predictive of efficacy in preventing sexual transmission of HIV. Furthermore, many in the art believe that a TFV-DP concentration in PBMCs of 50 fmol per million cells is a good target concentration for effective HIV prevention. Simulations using physiologically based PK (PB-PK) modeling have shown that TAF is effective at preventing HIV infection at a dose of 0.5 mg d -1 We estimate that a linear subcutaneous release of TAF at a rate of 0.01 mg / day would lead to protective TFV-DP PBMC concentrations as described above (165). Another study estimated that the rate was approximately 0.3 mg / day. -1 It was speculated that a lower TAF release rate of 166 may be protective. Two subcutaneous implants of design 206 shown in Figure 26 (dimensions, diameter 2.5 mm, length 40 mm, volume 196 mm) were used. 3 , TAF content 75% w / v), each containing TAF-peptide conjugate equivalent to 130 mg of TAF and 0.25 mg d -1 Each is delivered in 100 mg / dose, has zero-order kinetics, and can prevent HIV infection for up to one year.

[0350] Example 2 - Exemplary Subdermal Implant Specifications for Cabotegravir and HIV Prevention The disclosed implant technology for sustained and controlled delivery of APIs to the systemic circulation is a platform technology and is not targeted to any particular API or application. Restrictions on the selection of APIs and applications are outlined under "API Selection". Illustrative, non-limiting examples of the interaction of API physical, chemical, and biological properties with implant properties are provided herein.

[0351] Cabotegravir (CAB) is a potent strand transfer integrase inhibitor being developed for the treatment and prevention of HIV. Steady-state plasma concentrations of CAB are believed by many in the art to be predictive of efficacy in preventing sexual transmission of HIV. Steady-state plasma CAB concentrations of 0.66 μg mL -1 or protein adjusted IC from non-human primate efficacy studies 90 (PA-IC 90 ) concentrations is further considered by many skilled in the art to be a good target for effective HIV prevention (167, 168). The target was subsequently adjusted based on human clinical PK data (169). A Phase 2a study evaluating an injectable intramuscular long-acting CAB formulation showed that male and female participants receiving 600 mg every 8 weeks achieved trough concentrations of 4× and 1× PA-IC, respectively. 90 It has been suggested that the 80% and 95% goals were achieved in over 100 participants (170). Due to the tail (i.e., non-steady state) PK profile of the injectable CAB formulation (169, 170), lower doses or longer duration should be achievable from CAB-peptide implants with linear in vivo drug release profiles. Two subcutaneous or intramuscular implants of design 202 shown in FIG. 24 (dimensions 3.5 mm × 2.5 mm × 35 mm, volume 306 mm) with geometry 102 shown in FIG. 12 were used. 3 , with a CAB content of 85% w / v), each containing CAB-peptide conjugate equivalent to 250 mg of CAB, yielded 2.2 mg d -1 It is estimated that delivery of each of these vaccines can prevent HIV infection for up to three months.

[0352] Example 3 - Exemplary Drug Delivery Implant Specification Calculator A non-limiting example of an algorithm for calculating implant specifications for any application is given below.

number

[0353] The value of RR is determined in part by how efficiently the API distributes to the target compartment to achieve consistency in efficacy and pharmacological effectiveness. In many cases, RR is determined in preclinical studies and must be confirmed clinically.

[0354] Example 4 - TAF Microneedles as Porogens in PDMS Tenofovir alafenamide free base (TAF, 5.00 g) was added to toluene (200 mL) at 90 °C in a conical flask. To the cloudy solution, more toluene (25 mL) was added with magnetic stirring. When the cloudy suspension reached thermal equilibrium, it was filtered at high temperature to give a clear solution. The hot TAF solution was cooled to room temperature overnight, followed by additional cooling at 4 °C, resulting in the deposition of a large amount of needles at the bottom of the flask. The solids were collected by filtration in vacuum to obtain colorless TAF microneedles (4.35 g, 87%), typically 10-25 μm wide x 250-450 μm long, followed by washing with cold n-hexane and drying under high vacuum.

[0355] Example 5 - BSA release kinetics from ePTFE implants The implant consisted of an ePTFE tube skin (approximately 20 mm long, 2.0 mm inner diameter, 0.18 mm wall thickness, ρ = 0.84 g cm -3 ) and filled with bovine serum albumin (BSA) as a powder at 100% (i.e., in the absence of excipients) or at 50% w / w blended with D-(+)-trehalose (45% w / w) and L-histidine hydrochloride (5% w / w). In another group, BSA (30% w / w) was blended with monoolein (Myverol 18-93K, 70% w / w) and added to the hollow tube as a paste. The implants contained 10-20 mg of BSA depending on the formulation. The ends of the tubes were sealed before performing the in vitro release test in 20 mL of release medium (1x PBS containing 0.1% Solutol HS 15 and 0.01% sodium azide) at 37 °C in an orbital shaking incubator at 30 RPM. Analysis of BSA in the release medium was performed using Bradford reagent (λ max595 nm). Implants containing BSA formulated with D-(+)-trehalose and L-histidine hydrochloride released the BSA payload within 2 days, while 100% BSA powder was not significantly released from the implant over 28 days. However, when co-formulated with monoolein as a paste, BSA was released linearly from the implant over 8 days. Data were analyzed using a simple linear regression fit model (solid line) to reveal a linear release of 1.7 mg d -1 (R 2 =0.9800). It was unexpected and unpredictable that these three formulations would result in such dramatically different release profiles of the biological model, BSA. The fact that the release of BSA, a highly water-soluble compound, from a monoolein paste through an ePTFE skin was linear and controllable over a one week period is novel and unknown to those skilled in the art.

[0356] Example 6 - Cell-penetrating peptide conjugates of lamivudine The disclosed technology for sustained and controlled delivery of APIs is not targeted to any particular API or application. Limitations on the selection of APIs and applications are outlined under "Selection of APIs". Illustrative and non-limiting examples are provided herein.

[0357] The antiviral agent lamivudine (3TC) is used to treat viral infections including HIV and HBV, but is not potent enough to be delivered efficiently using most systemic long-acting formulation approaches.

[0358] In this example, 3TC is reacted with succinic anhydride to give the corresponding succinate ester. The carboxylic acid group is linked to the N-terminus of a side-chain protected octaarginine on the resin. Cleavage and purification of the resulting deprotected peptide-drug conjugate by HPLC affords the target compound. [ka]

[0359] Example 7 - Cell-targeting peptide conjugates of dolutegravir The disclosed technology for sustained and controlled delivery of APIs is not targeted to any particular API or application. Limitations on the selection of APIs and applications are outlined under "Selection of APIs". Illustrative and non-limiting examples are provided herein.

[0360] The antiretroviral agent dolutegravir (DTG) is used to treat HIV infection, but is highly protein bound and therefore not potent enough to be delivered efficiently using most systemic, long-acting formulation approaches.

[0361] In this example, the N-terminus of side-chain protected tuftin (TKPR) on resin is reacted with chloromethyl chloroformate to give the corresponding N-[(chloro-methyl)oxy]carbonyl derivative, which is reacted with DTG under phase transfer catalysis to give the target peptide conjugate after resin cleavage and purification by HPLC. [ka]

[0362] Example 8 - Cell-targeting peptide conjugates of lamivudine In this example, 3TC was reacted with succinic anhydride to give the corresponding succinate ester. The carboxylic acid group was coupled to the N-terminus of side-chain protected HIV-1 gp120 V3-A (RKSIHIGPGRAFYTTG) on resin. Cleavage of the resulting deprotected peptide-drug conjugate afforded the target compound with a purity of 69% by HPLC prior to purification. HRMS (ES-TOF) (m / z): C 91 H 139 N 29 O 25 S, 1036.0190[M+2H] 2+ , 691.0151[M+3H] 3+ , and 518.5132[M+4H] 4+The calculated and measured values ​​are 1036.0178 (-1.16 ppm), 691.0137 (-2.03 ppm), and 518.5126 (-1.16 ppm). [ka]

[0363] Example 9 - Screening Algorithm When multiple drug-peptide conjugates are being screened during discovery, it may be beneficial to use a decision tree to select candidates for further testing. A non-limiting example of a decision tree is shown in FIG. 11. Decision trees are used to score, rank, and down-select candidates based on clearly defined quantitative rules informed by results from the evaluation pipeline, with the goal of selection being to select lead candidates for formulation. In one non-limiting example of a decision tree shown in FIG. 11, approximately 28 compounds per ARV drug are used for in vitro screening testing. As shown in FIG. 11, potency is measured as a molar amount, while the dose-capped cargo mass fraction taken up by the ARV drug compared to the prodrug is determined by their relative molecular weight. The larger the peptide molecular weight, the more diluted the drug implant content. This important consideration is factored into the selection process by also considering potency in mass concentration units. Recognize that the decision tree (FIG. 11) is a "living algorithm" and evolves as screening progresses.

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Claims

1. 1. A drug delivery device comprising one or more peptide-drug conjugates, said device comprising: (a) one or more kernels comprising said peptide-drug conjugate; (b) one or more skins comprising a continuous membrane; the one or more kernels and / or the skins comprise defined pores that are not mechanically generated; A drug delivery device, wherein the peptide-drug conjugate comprises a cell penetrating or cell targeting peptide covalently attached to one or more drugs via one or more linkers.

2. The drug delivery device of claim 1 , wherein the peptide comprises a cell-penetrating peptide.

3. The drug delivery device of claim 1 , wherein the peptide comprises a cell targeting peptide.

4. The drug delivery device of claim 3 , wherein the peptide is an immune enhancing peptide.

5. The drug delivery device of any one of claims 1 to 4, wherein the peptide is linear.

6. The drug delivery device of any one of claims 1 to 4, wherein the peptide is cyclic.

7. The drug delivery device of any one of claims 1 to 6, wherein the peptide is selected from the peptides of Table A.

8. The drug delivery device of any one of claims 1 to 7, wherein the one or more linkers are covalently attached to a terminal residue of the peptide.

9. The drug delivery device of claim 8 , wherein the terminal residue is an N-terminal residue.

10. The drug delivery device of claim 8 , wherein the terminal residue is a C-terminal residue.

11. The drug delivery device of any one of claims 1 to 7, wherein the one or more linkers are covalently attached to a non-terminal residue of the peptide.

12. The drug delivery device of claim 11 , wherein the one or more linkers are covalently attached to a side chain of the non-terminal residue.

13. The drug delivery device of claim 11 or 12, wherein the non-terminal residue is a lysine, cysteine, aspartic acid, or glutamic acid residue.

14. The one or more linkers are １ -C ８ ) alkyl, (C ２ -C ８ ) alkenyl, (C ２ -C ８ ) alkynyl, (C ３ -C １０ ) cycloalkyl, (C ６ -C １０ ) aryl, (C ２ -C ９ ) heteroalkyl, or (C ２ -C ９ ) heteroaryl moiety, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl is 1 to 3 (C １ -C ６ ) alkyl, 1 to 4 halogen, (C １ -C ４ ) alkoxy, (C １ -C ４ ) alkoxycarbonyl, hydroxy, amino, (C １ -C ４ ) alkylamino, (C １ -C ４ ) dialkylamino, (C ３ -C １０ ) cycloalkyl, (C １ -C ６ ) alkylcarbonyloxy, (C １ -C ６ ) alkylcarbonylamide, (C １ -C ４ ) alkylamidocarbonyl, (C １ -C ４ ) Dialkylamidocarbonyl, nitro, cyano, (C １ -C ４ ) alkylimino, mercapto, or (C １ -C ４ 14. The drug delivery device of claim 1, wherein said compound is optionally substituted with an alkyl mercapto moiety.

15. The one or more linkers have the structure: -C(O)-J-C(O)-K-C(O)-, In the formula, K is -C １ -C １０ Alkylene-, -(CH ２ ), A-(CH ２ ) ｔ -, -, and Q, -C(O)-J- is absent, an amino acid residue, or a peptide of 2 to 10 amino acid residues; the -C(O)- is derived from the carboxy terminus of the amino acid or peptide; A is -O-, -S-, -NR １ -, -N ＋ (R １ ) ２ -, -S-S-, -[OCH ２ CH ２ ] ｒ -O-, -L-, or -O-Y-O-, Q is L or -Z=N-NH-S(O) ｖ -L-, L is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Z is -(CH ２ ) ｗ -C(CH ３ ) =, -(CH ２ ) ｗ CH=, cycloalkyl, or heterocycloalkyl; R １ is hydrogen or C １ -C ４ is alkyl, s and t are independently integers selected from 1 and 2; r is an integer selected from 1, 2, and 3; v is an integer selected from 0, 1, and 2; The drug delivery device according to any one of claims 1 to 13, wherein w is an integer selected from 1, 2, 3 and 4.

16. The drug delivery device of any one of claims 1 to 13, wherein the one or more linkers comprise two or more amino acids.

17. The drug delivery device of claim 16 , wherein one or more linkers is a peptide.

18. The drug delivery device of claim 17 , wherein the one or more linkers comprises Gly-Ser-Gly ("GSG").

19. The drug delivery device of any one of claims 1 to 13, wherein one or more linkers comprises a polyether.

20. 20. The drug delivery device of claim 19, wherein the one or more linkers comprise polyethylene glycol.

21. The drug delivery device of any one of claims 1 to 20, wherein the one or more linkers are conjugated to the peptide and / or the drug via an ester, carbonate, or carbamate moiety.

22. The drug delivery device of any one of claims 1 to 21, wherein the one or more linkers comprise a succinimidyl thioether or triazole moiety.

23. The drug delivery device of any one of claims 1 to 22, wherein the one or more drugs are hydrophobic.

24. 24. The drug delivery device of any one of claims 1 to 23, wherein the one or more drugs are antiretroviral agents, antibacterial agents, antibacterial agents, antiviral agents, hormones, statins, beta blockers, ACE inhibitors, angiotensin receptor blockers, vitamins, steroids, biologics, anticancer drugs, allergy medications, anticoagulants, antiplatelet therapy agents, nonsteroidal anti-inflammatory drugs, vaccines, or combinations thereof.

25. 25. The drug delivery device of claim 24, wherein the one or more drugs is an antiretroviral drug.

26. The one or more drugs may be zidovudine, cabotegravir, dapivirine, fluticasone propionate, chlordiazepoxide, haloperidol, indomethacin, prednisone, ethinyl estradiol, acyclovir, tenofovir, atenolol, aminoglycosides, exenatide acetate, leuprolide acetate, acetylsalicylic acid (aspirin), levodopa, remdesivir, acyclovir, gaclovir, cyclosporine ...

25. The drug delivery device of claim 24, comprising ribavirin, lamivudine, dolutegravir, chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir, EV-100, EV-200, EV-300, EV-400, KD025, tenofovir, emtricitabine, elvitegravir, lenacapavir, islatravir, C5A, VRC01, or a combination thereof.

27. 27. The drug delivery device of claim 26, wherein the one or more drugs comprises tenofovir.

28. 28. The drug delivery device of claim 27, wherein the one or more drugs comprise tenofovir alafenamide or tenofovir disoproxil fumarate.

29. The drug delivery device of any one of claims 1 to 28, wherein the drug delivery device is a subcutaneous or intramuscular implant, an intravaginal ring, or a microarray patch.

30. A drug delivery device according to any one of claims 1 to 29, comprising one kernel.

31. A drug delivery device according to any one of claims 1 to 29, comprising a plurality of kernels.

32. The drug delivery device of any one of claims 1 to 31, wherein the kernel(s) comprises a defined microscopic or nanoscopic pore structure.

33. The drug delivery device according to any one of claims 1 to 32, wherein the kernel is a reservoir kernel.

34. 34. The drug delivery device of claim 33, wherein the reservoir kernel comprises a powder comprising one or more APIs.

35. 35. The drug delivery device of claim 34, wherein the powder comprises microscale or nanoscale drug carriers.

36. 36. The drug delivery device of claim 35, wherein the drug carrier is a bead, a capsule, a microgel, a nanocellulose, a dendrimer, or a diatom.

37. 34. The drug delivery device of claim 33, wherein the reservoir kernel comprises a paste comprising one or more peptide-drug conjugates.

38. 38. The drug delivery device of claim 37, wherein the paste comprises an oil vehicle, an ionic liquid, a phase inversion system, or a gel.

39. 39. The drug delivery device of claim 38, wherein the phase inversion system comprises a biodegradable polymer, a combination of phospholipids and medium chain triglycerides, or a lyotropic liquid crystal.

40. 40. The drug delivery device of claim 38, wherein the gel is a stimuli-responsive gel or a self-healing gel.

41. The drug delivery device according to any one of claims 1 to 32, wherein the kernel is a pellet, tablet or microtablet.

42. The drug delivery device of any one of claims 1 to 32, wherein the kernel comprises a fibre-based carrier.

43. 43. The drug delivery device of claim 42, wherein the fiber-based carrier comprises electrospun microfibers or electrospun nanofibers.

44. 44. The drug delivery device of claim 43, wherein the electrospun nanofiber is a Janus microfiber or a Janus nanofiber.

45. The drug delivery device of any one of claims 42 to 44, wherein the fiber-based carrier comprises random or oriented fibers.

46. 46. ​​The drug delivery device of claim 45, wherein the fiber-based carrier comprises a fiber bundle, a thread, a woven mat, or a nonwoven mat.

47. 43. The drug delivery device of claim 42, wherein the fiber-based carrier comprises rotary jet spun fibers, wet spun fibers, or dry jet spun fibers.

48. The drug delivery device of any one of claims 42 to 47, wherein the fiber-based carrier comprises glucose, sucrose, or a polymeric material.

49. The drug delivery device of any one of claims 1 to 32, wherein the kernel comprises a porous sponge.

50. 50. The drug delivery device of claim 49, wherein the porous sponge comprises silicon, a silica sol-gel material, a xerogel, a mesoporous silica, a polymeric microsponge, a polyurethane foam, a nanosponge, or an aerogel.

51. 51. The drug delivery device of claim 49 or 50, wherein the porous sponge comprises a porogen.

52. 52. The drug delivery device of claim 51, wherein the porogen comprises a fiber mat.

53. 53. The drug delivery device of claim 52, wherein the fiber mat comprises glucose or sucrose.

54. 52. The drug delivery device of claim 51, wherein the porogen comprises a peptide-drug conjugate.

55. The drug delivery device of any one of claims 49 to 54, wherein the porous sponge is impregnated with the peptide-drug conjugate.

56. 56. The drug delivery device of claim 55, wherein the porous sponge comprises a sponge material having an affinity for a solvent capable of dissolving the peptide-drug conjugate.

57. 57. The drug delivery device of claim 56, wherein the porous sponge comprises polydimethylsiloxane (PDMS).

58. A drug delivery device according to any one of claims 1 to 57, comprising one skin.

59. A drug delivery device according to any one of claims 1 to 57, comprising a plurality of skins.

60. 60. The drug delivery device of any one of claims 1 to 59, wherein the skin covers a portion of the device.

61. 60. The drug delivery device of any one of claims 1 to 59, wherein the skin covers the entire device.

62. The drug delivery device of any one of claims 1 to 61, wherein the skin comprises a rate-limiting skin.

63. 63. The drug delivery device of claim 62, wherein the skin is non-resorbable.

64. 64. The drug delivery device of claim 63, wherein the skin comprises a biocompatible elastomer.

65. 65. The drug delivery device of claim 64, wherein the skin comprises poly(dimethylsiloxane), silicone, one or more synthetic polymers, and / or a metal.

66. 66. The drug delivery device of claim 65, wherein the synthetic polymer is a poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, poly(siloxane), copolymers thereof, or combinations thereof.

67. 67. The drug delivery device of claim 66, wherein the polymer is expanded poly(tetrafluoroethylene) (ePTFE).

68. The drug delivery device of claim 6 , wherein the polymer is ethylene vinyl acetate (EVA).

69. 66. The drug delivery device of claim 65, wherein the metal is titanium, a nickel-titanium (nitinol) alloy, or stainless steel.

70. The drug delivery device of any one of claims 58 to 62, wherein the skin is resorbable.

71. 71. The drug delivery device of claim 70, wherein the skin comprises a biocompatible elastomer.

72. 72. The drug delivery device of claim 71, wherein the skin comprises poly(amide), poly(ester), poly(ester amide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sebacate), poly(lactic acid), poly(glycolic acid), (lactic acid-glycolic acid) copolymer, poly(caprolactone) (PCL), PCL derivatives, amino alcohol-based poly(ester amide) (PEA), poly(octane-diol citrate) (POC), copolymers thereof, or mixtures thereof.

73. 73. The drug delivery device of claim 72, wherein the polymer is crosslinked PCL.

74. 74. The drug delivery device of claim 73, wherein the crosslinked PCL comprises lysine diisocyanate or 2,2-bis(-caprolactone-4-yl)propane.

75. 74. The drug delivery device of claim 73, wherein the polymer comprises poly(caprolactone) / (lactic acid-co-glycolic acid) and tricalcium phosphate.

76. The drug delivery device of any one of claims 1 to 75, wherein the skin is fabricated via casting and etching, soft lithography, or microlithography.

77. 77. The drug delivery device of claim 76, wherein the skin is fabricated via microlithography.

78. 78. The drug delivery device of claim 76 or 77, wherein the skin comprises a defined surface morphology.

79. The drug delivery device of claim 78, wherein the defined surface morphology comprises a grid pattern.

80. The drug delivery device of any one of claims 1 to 79, wherein the defined pores are microscopic pores or nanoscopic pores.

81. 81. The drug delivery device of any one of claims 1 to 80, wherein the defined pores have a diameter of less than 2 nm.

82. 81. The drug delivery device of any one of claims 1 to 80, wherein the defined pores have a diameter of from 2 nm to 50 nm.

83. The drug delivery device of any one of claims 1 to 80, wherein the defined pores have a diameter greater than 50 nm.

84. A drug delivery device according to any one of claims 1 to 83 for implantation in the body of a patient.

85. 87. The drug delivery device of claim 86, wherein implantation within the body comprises implantation into a sterile anatomical compartment.

86. 86. The drug delivery device of claim 85, wherein the sterile anatomical compartment is selected from the subcutaneous space, the intramuscular space, the eye, the ear, and the brain.

87. 85. The drug delivery device of claim 84, wherein implantation within the body comprises implantation in a non-sterile anatomical compartment.

88. 88. The drug delivery device of claim 87, wherein the non-sterile anatomical compartment is selected from the vagina, the rectum, and the nasal cavity.

89. 89. A drug delivery device according to any one of claims 1 to 88, further comprising a shape adapted to be placed within the body of a patient.

90. 90. The drug delivery device of claim 89, wherein the device is in the shape of a capsule.

91. 91. The drug delivery device of claim 89 or 90, wherein the device comprises one or more reservoirs.

92. 92. The drug delivery device of claim 91, wherein the one or more reservoirs are separated into one or more compartments.

93. 93. The drug delivery device of claim 92, wherein the one or more reservoirs are separated into compartments by one or more rib structures.

94. A drug delivery device according to any one of claims 90 to 93, wherein the device further comprises one or more impermeable disc-shaped covers.

95. 95. The drug delivery device of claim 94, wherein the device comprises an outer sealing ring that forms a seal with the one or more covers.

96. 96. The device of claim 95, wherein the one or more covers include an outer lip that fits inside the sealing ring to form a seal.

97. A drug delivery device according to any one of claims 94 to 96, comprising one cover.

98. A drug delivery device according to any one of claims 94 to 96, comprising two covers.

99. A drug delivery device according to any one of claims 91 to 93, wherein the reservoir is sealed by the skin.

100. 100. The drug delivery device of claim 99, wherein the skin is attached to the device with an adhesive.

101. The drug delivery device of any one of claims 92 to 100, wherein the one or more kernels are disposed within the one or more compartments.

102. 90. The drug delivery device of claim 89, wherein the device is in the shape of a ring.

103. 103. The drug delivery device of claim 102, comprising one or more cylindrical core elements disposed within a first skin, the core element comprising a kernel and, optionally, a second skin.

104. 103. The drug delivery device of claim 102, comprising a molded lower structure including one or more compartments containing one or more kernels, and an upper structure coupled to the lower carrier to seal the multiple compartments.

105. 105. The drug delivery device of claim 104, wherein the skin covers the underlying carrier.

106. 105. The drug delivery device of claim 104, wherein the skin covers the lower structure and the upper structure.

107. 107. A drug delivery device according to any one of claims 102 to 106, comprising one or more lobes projecting inwardly from an outer edge of the annulus.

108. 108. The drug delivery device of claim 107, wherein the one or more compartments are disposed in the lobes.

109. 109. A drug delivery device as described in claim 107 or 108, comprising one or more recessed structures to facilitate sealing of the device.

110. A drug delivery device according to any one of claims 107 to 109, wherein the one or more compartments comprise ribs.

111. 111. A drug delivery device according to any one of claims 107 to 110, further comprising a protective mesh disposed on a surface of the device.

112. 112. A method of delivering one or more APIs to a subject in need thereof, said method comprising providing to said subject a drug delivery device according to any one of claims 1 to 111.

113. 113. The method of claim 112, wherein providing the drug delivery device comprises implanting the drug delivery device within the body of the subject.

114. 112. A method of treating or preventing a disease or disorder in a subject, the method comprising providing to the subject a drug delivery device according to any one of claims 1 to 111.

115. The method of claim 114, wherein the disease or disorder is an infectious disease, transplant rejection, a condition indicating hormonal therapy, a physiological or pathophysiological use, diabetes, an allergy or hypersensitivity, an autoimmune disorder, cancer, a hematological disease, a musculoskeletal disorder, a psychological or neurological disorder, a genetic disease, or a veterinary condition.

116. 116. The method of claim 115, wherein the disease or disorder is an infectious disease.

117. 117. The method of claim 116, wherein the infectious disease is HIV.

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