Vaginal drug delivery devices

Abstract

This disclosure relates to the use of intravaginal devices for delivering bioactive compounds at controlled rates over extended periods, and to methods for manufacturing such devices. The devices are biocompatible and biostable and are useful in patients (humans and animals) for delivering appropriate bioactive substances to tissues or organs.

Description

Technical Field

[0001] Statement Regarding Government Interests This invention was made with government support under U19AI113048 and R01HD101344 awarded by the National Institutes of Health (NIH), and 7200AA22CA00002 awarded by the United States Agency for International Development (USAID). The government has certain rights in this invention.

[0002] This disclosure generally relates to the field of intravaginal sustained release drug delivery devices.

Background Art

[0003] Drug delivery is an important area of medicine. The safety and effectiveness of many drugs are directly related to how they are administered. Current modes of drug delivery, such as topical application, oral delivery, and intramuscular, intravenous, and subcutaneous injections, can result in high and low blood concentrations and / or shortened half-lives in the blood. In some cases, achieving therapeutic effectiveness with these standard administrations requires large amounts of drug that can cause toxic side effects. Technologies related to controlled drug release have been attempted to avoid some of the pitfalls of conventional treatments. Their goal is to deliver drugs in a continuous and sustained manner. Additionally, locally controlled drug release applications are site- or organ-specific (e.g., controlled intravaginal delivery) and can minimize systemic exposure to the drug.

[0004] Traditional routes of administration present problems in that they require strict patient compliance, such as when drugs like antibiotics, hormones, vitamins, and antiretroviral drugs for HIV prevention and treatment are administered orally, or when the route of administration is by injection, requiring repeated visits to a doctor. These methods of administration are particularly problematic when the patient is a child, elderly, or when the drug must be administered long-term, such as in the case of weekly allergy injections. For many adults, compliance with medication is problematic simply because they forget to take their medication. Furthermore, weekly injections prevent many people from receiving necessary treatment because weekly visits to the clinic interfere with their activities and schedules. In other words, adherence to frequent dosing is burdensome for users and has emerged as a significant factor in explaining the heterogeneous efficacy outcomes of many therapeutic and prophylactic regimens. Sustained-release or "long-acting" drug formulations have significant potential as a means of reducing the frequency of dosing and thereby increasing the efficacy of regimens.

[0005] Implantable microdevice reservoir delivery systems do not require user intervention and therefore overcome the compliance concerns mentioned above. In recent years, the development of microdevices for local drug delivery has been a steadily progressing field. The activation of drug release can be controlled passively or actively. They are theoretically capable of delivering drugs at a controlled rate for months, and in some cases for years, and often involve polymer materials. Implants of polymer materials as drug delivery systems have been known for some time. Implantable delivery systems of polymer materials are known, for example, in relation to the delivery of contraceptives, either as subcutaneous implants or intravaginal rings (IVRs). Conventional 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 benefits.

[0006] Intravaginal rings have been used since the late 1960s for the topical administration of therapeutic drugs, primarily hormonal and, more recently, antiretroviral drugs. Since Duncan's 1968 patent application (U.S. No. 3,545,439), the geometric shape of toroidal IVRs has remained essentially unchanged. There is still a need for more economical, practical, and efficient methods for developing, fabricating, and manufacturing drug delivery systems that can be used transvaginally in solid or semi-solid formulations. This disclosure is generally in the field of implantable drug delivery devices, and more particularly in the field of devices for the controlled release of drugs from intravaginally implantable devices. [Overview of the Initiative]

[0007] According to a first exemplary aspect of the present disclosure, provided herein is a vaginal implant device configured to provide continuous drug delivery to a patient, the vaginal implant device comprising: a scaffold having one or more lobes and one or more hinged areas disposed between the one or more lobes; one or more cassettes disposed within each of the one or more lobes; and one or more active pharmaceutical ingredients (APIs) disposed within each of the one or more cassettes.

[0008] According to a second exemplary aspect of the present disclosure, provided herein is a vaginal implant device configured to provide continuous drug delivery to a patient, the vaginal implant device comprising: a scaffold having one or more lobes; one or more cassettes disposed within one or more lobes; and one or more APIs disposed within one or more cassettes, each of which cassettes is defined by a cap and a base coupled to the cap, and further comprises a reservoir defined between the cap and base of each of the one or more cassettes; the one or more APIs are disposed within each of the reservoirs of the one or more cassettes; each of the one or more cassettes comprises a membrane disposed within each of the reservoirs of the one or more cassettes; and each cap comprises one or more first holes for exposing the respective membrane to the patient's vaginal fluid.

[0009] According to a third exemplary aspect of the present disclosure, provided herein is a vaginal implant device configured to provide continuous drug delivery to a patient, the vaginal implant device comprising: a scaffold including one or more lobes; one or more cassettes disposed within one or more lobes; and one or more APIs disposed within reservoirs of one or more cassettes, each of which comprises a cap and a base coupled to the cap, thereby defining a reservoir, wherein (i) each cap has one or more first holes, one or more first ribs supported by one or more edges of the cap, and one or more pins, and each base has an angled lip, one or more second holes disposed opposite to one or more pins of the cap, and one or more second ribs supported by one or more edges of the base, or (ii) each base has one or more first holes, one or more first ribs supported by one or more edges of the base, and one or more pins Each cap has an angled lip, one or more second holes located opposite one or more pins on the base, and one or more second ribs supported by one or more edges of the cap; each of one or more cassettes further comprises a membrane disposed between the base and the cap, one or more first holes on each cap or base expose the respective membrane to the patient's vaginal fluid, one or more pins on each cap or base are sized to accommodate one or more second holes on each respective base or cap, each lobe of the scaffold comprises one or more first grooves and one or more second grooves, one or more first ribs on each cap or base are sized to accommodate each of the one or more first grooves, one or more second ribs on each base or cap are sized to accommodate each of the one or more second grooves, and the angled lip on each base or cap is configured to assist in the alignment of the respective membrane between the base and the cap.

[0010] Also provided are methods for treating or preventing a patient's disease or disorder, which include administering a vaginal implant device disclosed herein to the patient, and using the vaginal implant device disclosed herein, for example, to treat or prevent a patient's disease or disorder. [Brief explanation of the drawing]

[0011] [Figure 1] This document presents examples of vaginal implant device designs used in clinical trials to evaluate the insertion, mating, and removal of vaginal implant devices. [Figure 2A-2C] This document presents alternative vaginal implant device designs used in clinical trials to evaluate the insertion, mating, and removal of vaginal implant devices. [Figure 3A-3C] This shows an example of a membrane-based vaginal implant device design. [Figure 4A-4D] This document details an example of a membrane-based vaginal implant device design with a thermoplastic / silicone hybrid drug reservoir. [Figure 5A-5C] This document details an example of a membrane-based vaginal implant device design with an all-silicone drug reservoir design. [Figure 6A-6C] This shows an alternative design for a vaginal implant device. [Figure 7] This document details the alternative reservoir design incorporated into the vaginal implant device. [Figure 8A-8B] This shows an alternative design for a vaginal implant device. [Figures 9A-9C] This document details alternative designs for vaginal implant devices. [Figure 10] This document presents an exemplary embodiment of a next-generation intravaginal ring design. [Figure 11A-11D] This document presents an alternative exemplary embodiment of a next-generation intravaginal ring design having a separate API compartment. [Figures 12A-12E] This exhibits an alternative exemplary embodiment of a next-generation intravaginal ring design having separate API compartments with non-toroidal geometric shapes. [Figures 13A-13E]This document presents an alternative exemplary embodiment of a next-generation intravaginal ring design with a non-circular cross-section, having separate API compartments and separate skins. [Figure 14] This document presents an exemplary embodiment of a next-generation reservoir implant design. [Modes for carrying out the invention]

[0012] A vaginal implant device configured to provide continuous drug delivery to a patient is provided herein. Also provided are methods for treating or preventing a patient's disease or disorder, which include administering a vaginal implant device configured to provide continuous drug delivery to the patient, and using, for example, a vaginal implant device configured to provide continuous drug delivery in a patient for the treatment of diseases and disorders.

[0013] All references cited herein are incorporated in their entirety by reference to ensure their completeness. Unless otherwise defined, technical and scientific terms used herein have the same meanings as those generally 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.1 and 2,20 thed., McGraw-Hill (New York, NY, 2018), Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology, 3 rd ed., 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, DNA and Genome Technology, 3 rd ed., Wiley-Blackwell (Hoboken, NJ, 2012) provides those skilled in the art with a general guide for many of the terms used in this application.

[0014] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of this disclosure. Indeed, this disclosure is not limited to the methods and materials described in any way. For the purposes of this disclosure, certain terms are defined below.

[0015] "Treatment" and "prevention" and related terms, including but not limited to, the treatment, prevention, reduction in the likelihood of having, reduction in the severity of, and / or delay in the progression of a medical condition in a subject, hereinafter also referred to as a "symptom". Such a condition or symptom can be corrected by the use of one or more agents administered through a sustained-release drug delivery device.

[0016] These conditions, i.e., signs, are further described in "Device Use and Application" and can include infectious diseases (e.g., human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), herpes simplex virus (HSV) infection, hepatitis virus infection, respiratory virus infection (influenza virus and coronavirus, such as, but not limited to, 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, but are not limited to these in any form.

[0017] Additionally, the present disclosure provides administrations of biological agents such as proteins and peptides for the treatment or prevention of various disorders such as conditions treatable with leuprolide (e.g., anemia caused by bleeding from uterine leiomyomas, fibroids in the uterus, and central precocious puberty), exenatide for the treatment of diabetes, and histrelin acetate for the treatment of central precocious puberty. A more detailed list of exemplary examples of potential uses of the present disclosure is provided in "Device Use and Applications".

[0018] As used herein, the term "HIV" includes HIV-1 and HIV-2.

[0019] As used herein, the term "agent" includes any drug or prodrug and any thing including but not limited to these.

[0020] As used herein, the terms "drug", "pharmaceutical", and "therapeutic agent" are used synonymously.

[0021] As used herein, the term "API" means an active pharmaceutical ingredient including the agents described herein.

[0022] The terms “vaginal implant device,” “drug delivery system,” “implant,” and “vaginal ring” are used synonymously herein unless otherwise indicated and include devices used in the vagina.

[0023] As used herein, the term "IVR" means an intravaginal ring including the embodiments described herein.

[0024] "Permeability" refers to a measure of the ability of a therapeutic agent to pass through a thermoplastic polymer.

[0025] As used herein, “mammal” refers to any member of the mammalian species, including but not limited to humans and non-human primates (e.g., chimpanzees and other apes and monkey species), domesticated animals (e.g., cattle, sheep, pigs, goats, and horses), domesticated animals (e.g., dogs and cats), and laboratory animals (e.g., rodents such as mice, rats, and guinea pigs). This term does not indicate a specific age. Therefore, adults and newborns are intended to be included within the scope of this term.

[0026] With the aforementioned background in mind, in various embodiments, this disclosure teaches vaginal implantable devices, systems, and methods for treating, preventing, reducing the likelihood of having, reducing the severity of, and / or delaying the progression of a condition in question (e.g., disease or disorder).

[0027] Vaginal implant device This disclosure provides an intravaginal ring (IVR), which is a vaginal implantable device configured to provide continuous drug delivery to a patient. Also provided are methods for treating or preventing a patient's disease or disorder, comprising administering the vaginal implantable device disclosed herein to the patient. Furthermore, the use of the vaginal implantable device disclosed herein for treating or preventing a disease or disorder in a patient is also provided.

[0028] In some embodiments, a vaginal implant device is provided that is configured to provide continuous drug delivery to a patient, and the vaginal implant device is A scaffold comprising one or more lobes, and one or more hinged areas disposed between the one or more lobes, One or more cassettes are placed inside one or more robes, The device comprises one or more active pharmaceutical ingredients (APIs) each disposed within one or more cassettes.

[0029] Furthermore, a vaginal implant device is provided that is configured to provide continuous drug delivery to the patient, and the vaginal implant device is A platform with one or more robes, One or more cassettes are placed inside one or more robes, It comprises one or more APIs, each located within one or more cassettes, Each of one or more cassettes is defined by a cap and a base coupled to the cap, and further comprises a reservoir defined between the cap and base of each of the one or more cassettes, and one or more APIs are disposed within each of the reservoirs of the one or more cassettes. Each of the one or more cassettes comprises a membrane disposed in the reservoir of each of the one or more cassettes, and each cap comprises one or more first holes for exposing the respective membrane to the patient's vaginal fluid.

[0030] Furthermore, a vaginal implant device is provided that is configured to provide continuous drug delivery to the patient, and the vaginal implant device is A platform with one or more robes, One or more cassettes are placed inside one or more robes, It comprises one or more APIs, each located within the reservoir of one or more cassettes, Each of one or more cassettes comprises a cap and a base coupled to the cap, thereby defining a reservoir, (i) each cap having one or more first holes, one or more first ribs supported by one or more edges of the cap, and one or more pins, and each base having an angled lip, one or more second holes disposed on the opposite side of one or more pins of the cap, and one or more second ribs supported by one or more edges of the base, or (ii) each base having one or more first holes, one or more first ribs supported by one or more edges of the base, and one or more pins, and each cap having an angled lip, one or more second holes disposed on the opposite side of one or more pins of the base, and one or more second ribs supported by one or more edges of the cap, Each of the one or more cassettes further comprises a membrane disposed between the base and the cap, and one or more first holes in each cap or base expose each membrane to the patient's vaginal fluid. One or more pins on each cap or base are sized to fit into one or more second holes on each respective base or cap. Each of the scaffolding ropes is provided with one or more first grooves and one or more second grooves, One or more first ribs on each cap or base are sized to fit into one or more first grooves. One or more second ribs on each base or cap are sized to fit into one or more second grooves, and the angled lips on each base or cap are configured to assist in the alignment of the respective membranes between the base and the cap.

[0031] In one embodiment, the vaginal implant device (Figure 1) is an IVR 10 having a circular outer circumference and one or more lobes 11 extending inward toward the center of the ring. The IVR has two main components: a carrier scaffold 13 that determines the overall IVR geometry and defines the lobes, and cassettes 12 disposed within each lobe, with one or more cassettes per lobe, which function as independent drug delivery devices. The vaginal implant device may include one lobe, preferably two lobes, or alternatively three lobes, up to four lobes. In some embodiments, the vaginal implant device may include one lobe, two lobes, three lobes, four lobes, five lobes, six lobes, seven lobes, or eight lobes. In some embodiments, the scaffold includes an elastomer. The scaffold may be made of any suitable biocompatible elastomer, such as, but not limited to, silicone, ethylene-co-vinyl acetate, or polyurethane. In some embodiments, the elastomer includes silicone, ethylene-co-vinyl acetate, polyurethane, thermosetting polyester (TPE), photocurable perfluoropolyether (PFPE), copolymers thereof, or combinations thereof. In some embodiments, the elastomer includes silicone. In some embodiments, the silicone includes polydimethylsiloxane (PDMS). The elastomer hardness should be such that the elastomer provides flexibility to the scaffold but retains sufficient flexural stiffness to secure the IVR in the vaginal fornix. The elastomer hardness value may be in the range of Shore A 20 to 80, preferably Shore A 30 to 60, more preferably 40 to 50. For humans, the scaffold diameter is in the range of 45 to 70 mm, preferably 50 to 60 mm, most preferably 55 to 58 mm.

[0032] In some embodiments, the scaffold includes a biodegradable material to reduce the environmental impact of the vaginal implant device. Medical-grade biodegradable materials are well known in the art and include, but are not limited to, poly(lactic acid), poly(glycolic acid), poly(lactic acid-coglycolic acid), poly(caprolactone) (PCL), and mixtures thereof. Other curable bioabsorbable elastomers include PCL derivatives, amino alcohol-based poly(esteramide) (PEA), and poly(octane-diol citrate) (POC). PCL polymers may require additional crosslinking agents, such as lysine diisocyanate or 2,2-bis(caprolactone-4-yl)propane, to obtain elastomeric properties. Other biodegradable materials include bio-based and renewable plastics, such as those supplied by Neste and Server Pharma Solutions.

[0033] The scaffolding region located between the lobes (and therefore the cassette 12) is a hinge region 14 in which the ring bends during insertion and while positioned within the vaginal fornix.

[0034] In a non-limiting embodiment, when inserting a two-lobe IVR, the IVR is held between the thumb and index finger such that the thumb contacts the outer circumference of the IVR at the center of one lobe and the index finger contacts the outer circumference of the IVR along the center of the opposite lobe. When the thumb and index finger are brought together, the IVR folds along the hinge region, and the two cassette surfaces on the same side of the IVR move toward each other and nearly touch, folding the IVR nearly in half. The IVR is inserted so that one end (of the hinge region) enters the vagina first, hinge-side down, and is pushed with one or more fingers until it is fully in the vaginal fornix and away from the narrower pubic region. In another non-limiting embodiment, for a single-lobe IVR, the hinge region is located in the ring portion directly adjacent to each side of the lobe. In yet another non-limiting embodiment, for a four-lobe IVR, there are four hinge regions, and when the IVR is positioned, only two opposing hinges will be bent. In another non-limiting embodiment, in the case of a three-lobe IVR, the three lobes are generally asymmetrical in size and position so that the hinge regions opposite each other across the ring are folded approximately along the center of the ring for insertion and within the vaginal fornix. Other embodiments for inserting the IVRs disclosed herein will be obvious to those skilled in the art.

[0035] The dimensions and geometry of the hinge region play a surprisingly important role in the ability to easily insert and remove the IVR, as well as in the fit and comfort of the IVR. In one embodiment of the IVR shown in Figures 3A–3C, the thickness of the scaffolding in the hinge region 31 and the cassette region 32 is the same. In this embodiment 30, the hinge region provides an open area that helps maintain a uniform bending radius when the IVR is bent, allowing the ring to be grasped during removal using a single finger in a hook-like manner. The thickness of the scaffolding may range from about 3 mm to about 8 mm, preferably about 5 mm to about 7 mm, and most preferably about 6 mm. In some embodiments, the scaffolding has an average thickness of about 3 mm to about 10 mm, about 5 mm to about 8 mm, about 5.5 mm to about 6.5 mm, or about 6 mm. In some embodiments, the scaffolding has an average thickness of about 6 mm. In another embodiment shown in Figures 2A to 2C, the scaffold has a taper within the hinge region such that the thickness of the cassette region 22 is greater than the thickness of the hinge region 23. The taper may begin directly adjacent to each hinge region and end before reaching the center of the hinge, resulting in a hinge that tapers to a central constant-diameter section at the center of the hinge. Varying the thickness of the central hinge region and the length of each tapered section changes the hinge bending radius and therefore the user's ability to grasp the intravaginal IVR with a single finger for removal. A longer taper in the hinge region and a smaller thickness in the central hinge region results in a smaller bending radius, making it more difficult to hook the ring with a finger for removal. A shorter taper results in a larger bending radius. In one embodiment, the hinge region has a circular cross-sectional geometry. In an alternative embodiment, the cross-sectional geometry of the hinge region may be non-circular. In one embodiment, the inner radius of the hinge region may be constant. In another embodiment, the inner radius of the hinge region may be non-constant so that a recess is formed inside the hinge region, which can help increase the open space for gripping the IVR with a finger when the IVR is folded. In some embodiments, the vaginal implant device has a diameter of about 45 to about 70 mm, or about 50 to 60 mm, or about 56 mm.

[0036] In some embodiments, the hinge region may include a mechanism to assist in ring removal by providing a larger surface and geometric shape to help grip the ring. The removal assistance mechanism may include one or more protrusions that interrupt the smooth scaffolding surface and enhance the ability to grip the ring for removal. The protrusions may cover part or all of the hinge region. In an alternative embodiment, the removal assistance mechanism may include one or more dimples that cover part or all of the surface of the hinge region. In yet another alternative embodiment, the removal assistance mechanism may include raised portions disposed on one or both sides of the hinge region.

[0037] The thickness of the cassette region plays a surprisingly important role in the comfort and ease of insertion and removal of the IVR. The cassette thickness can be about 4 mm to about 8 mm, preferably about 5 mm to about 7 mm, and most preferably about 5.8 mm to about 6.3 mm. In some embodiments, one or more cassettes have an average thickness of about 6 mm. In some embodiments, one or more cassettes have an average thickness of about 8 mm. When folded for insertion, the cassette thickness determines the width of the IVR during insertion and, together with the hinge shape (see above), determines the bending radius of the hinge region, which is an important factor in the ease of removal.

[0038] The cassette may be formed from any suitable biocompatible rigid material. In some cases, the cassette includes, but is not limited to, polycarbonate (PC), thermoplastic polyurethane (TPU), polyethylene (PE), polyvinylidene fluoride (PVDF), and polyether ether ketone (PEEK). In some embodiments, the elastomer includes polylactic acid (PLA), polylactic acid-coglycolic acid (PLGA), ethylene-covinyl acetate (EVA), high viscosity rubber (HCR), silicone, polymethyl methacrylate (PMMA), polycarbonate (PC), thermoplastic polyurethane (TPU), polyethylene (PE), polyvinylidene fluoride (PVDF), polyether ether ketone (PEEK), cyclic olefin copolymer (COC), polystyrene (PS), polyvinyl chloride (PVC), and polyethylene terephthalate glycol (PETG), their copolymers, or combinations thereof. The cassette may also be formed from biodegradable materials as described above with respect to scaffolding. To maximize the possible drug load of the IVR, the cassette may be filled with a band of 1–6 mm, preferably 2–5 mm, more preferably 3–4 mm, that completely surrounds the sides of the cassette, leaving the top and bottom of the cassette exposed. In another embodiment, the cassette may be significantly smaller than the lobe, allowing two or more cassettes to be arranged in a single lobe. Each cassette is formed from a base and a cap, which are assembled so that a portion of the IVR scaffold is positioned between them to fix the cassette to the base and form a drug reservoir within the cassette. A rate-controlled release membrane is disposed in the drug reservoir of the cassette and positioned between the base and the cap so that the drug contained therein can diffuse through the membrane and exit the cassette through a hole in the cap. In some embodiments, the drug includes a solid, paste, or liquid formulation. The position of the cassette within the scaffold is maintained by scaffold retaining grooves, one on the bottom surface of the scaffold for the base and the other on the top surface for the cap. These retaining grooves engage with corresponding rib structures that continue continuously along the outer circumference of both the base and the cap.The cassette base and cap include a structure that interlocks, allowing the cap to be attached to the base and thus locking the cassette onto the platform (see below).

[0039] In one embodiment (Figures 4A to 4D), the bottom and sides of the drug reservoir are fully integrated into the cassette base 43 such that the reservoir sidewalls extend through the cassette opening of the scaffold and contact the cap 41 to seal the cassette and membrane 42. In a second embodiment (Figures 5A to 5C), the cassette base 51 serves as the reservoir bottom, and the reservoir sidewalls 52 are formed from a structure molded into the scaffold that contacts the base along its entire circumference. The membrane 54 is positioned between the rigid cap 53 and the reservoir wall (made of, for example, elastomer), so that the wall 52 helps to seal the membrane, thus forming a drug reservoir in the space enclosed by the base, the scaffold wall structure, and the membrane. As shown in Figure 7, a pin 71 extending from a cap through-hole formed in the scaffolding may engage with a corresponding hole 72 in the base to provide sufficient compression of the base, membrane, and cap against the elastomer reservoir wall to bond the base to the cap and seal the drug reservoir. The cap pin may be permanently fixed to the base hole using an adhesive or welding process (e.g., induction welding, ultrasonic welding, or laser welding). In a third embodiment (Figures 6A-6C), the drug reservoir wall 61 and bottom 62 are incorporated into the scaffolding so that the drug formulation does not come into contact with a rigid base. In this embodiment, the base and cap incorporate the same pin-and-hole approach for assembling the cassette and provide compressive force to seal the membrane against the reservoir wall. It will be understood that the cap only contacts the membrane around its outer edge, and most of the membrane is recessed so that it does not come into contact with the cap. The hole provides a pathway for vaginal fluid to reach the membrane, but the entire membrane surface inside the seal with the cassette is exposed to the vaginal fluid (because fluid can enter between the membrane and the cap portion other than the hole). At least a portion of the membrane is exposed to the patient's vaginal fluid. In some embodiments, about 25% to about 100% of the membrane is exposed to the patient's vaginal fluid. In some embodiments, about 50% to about 75% of the membrane is exposed to the patient's vaginal fluid. In some embodiments, about 65% to about 70% of the membrane is exposed to the patient's vaginal fluid. In some embodiments, the membrane contains a non-absorbent polymer.In some embodiments, the non-absorbent polymer includes poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), fluorinated polymer, poly(siloxane), copolymers thereof, or combinations thereof. In some embodiments, the non-absorbent polymer includes poly(ethylene-co-vinyl acetate), ethylene vinyl acetate (EVA), poly(tetrafluoroethylene), copolymers thereof, or combinations thereof. In some embodiments, the non-absorbent polymer includes stretched poly(tetrafluoroethylene) (ePTFE). In some embodiments, the membrane includes an absorbent polymer. In preferred embodiments, the absorbent polymer is selected from poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(caprolactone) (PCL), and mixtures thereof. Other curable bioabsorbable elastomers include PCL derivatives, amino alcohol-based poly(esteramide) (PEA), and poly(octane-diol citrate) (POC). PCL-based polymers may require additional crosslinking agents, such as lysine diisocyanate or 2,2-bis(-caprolacton-4-yl)propane, to obtain elastomeric properties.

[0040] An alternative IVR design positions a single drug delivery cassette at the center of an elastomer ring, as shown in embodiments of Figures 8A–8B and 9A–9C. The cassette provides the drug delivery function, and the elastomer ring helps to retain the device in the vaginal fornix without contributing to the drug delivery function of the IVR. Embodiment 2, discussed below, provides an implementation of this design in an IVR sized for use in macaque monkeys, used in non-human primate studies during the development of a drug delivery device intended for human use. The design and mechanism realized in the macaque IVR may be applied to an IVR appropriately scaled for humans. For macaque-sized IVRs, the outer diameter of the IVR is in the range of 22–32 mm, preferably 25–30 mm, most preferably 27.5 mm. For humans, the outer diameter is in the range of 45–70 mm, preferably 50–60 mm, most preferably 55–58 mm. The cross-sectional diameter of the ring is 3 to 5 mm, preferably 4.5 mm, for macaque-sized IVRs, and 4 to 8 mm, preferably 6 mm, for human-sized IVRs. The elastomer hardness must provide flexibility to the scaffold but retain sufficient flexural rigidity to secure the IVR in the vaginal fornix. The elastomer hardness value may be in the range of Shore A 20 to 80, preferably Shore A 30 to 60, more preferably 40 to 50.

[0041] In the embodiments shown in Figures 9A to 9C, the central drug delivery cassette comprises four components: (1) a cassette shell 94 that provides primary structural support to the cassette and holds it at the center of the ring; (2) a reservoir 95 that fits into the cassette shell and holds a drug formulation 93; (3) a rate-controlled release membrane 92 that seals along the upper rim 96 of the reservoir; and (4) a rigid cap 91 that compresses the membrane against the reservoir rim and is bonded to the shell. In some embodiments, the shell and cap include a rigid biocompatible material, such as those described for the lobe IVR base and cap (see above). The reservoir elastomer is typically silicone, but any biocompatible elastomer polymer with suitable properties, such as those described for the scaffold (see above), may be used. The cassette shell comprises two appendages or wing-like structures extending from each end and embedded in the scaffold to secure the cassette at the center of the ring. The scaffold and shell are a single piece of two materials manufactured using overmolding techniques well known in the art. First, the shell is manufactured by standard thermoplastic injection molding. Next, the pre-fabricated shell is placed in the cavity within the scaffold mold, and the scaffold is molded around the shell using either liquid injection molding (LIM) technique for silicone elastomers or thermoplastic molding technique for thermoplastic elastomers. The cassette may be any shape, including but not limited to circular, elliptical, or rectangular. For macaque-sized IVRs, a rectangular cassette with rounded corners is preferred, maximizing reservoir size while still allowing easy insertion and removal without compromising the ring scaffold's ability to compress against the vaginal wall and perform retention through pressure. For human-sized IVRs of this design, oval, elliptical, or “football” shaped cassettes are preferred geometric shapes, similar to those described for lobe-shaped IVRs. The thickness of the assembled cassette should be 50–150%, preferably 100–133%, of the thickness of the scaffold.

[0042] Next-generation vaginal implant device design The following terms are related to the next-generation vaginal implant devices described in this section.

[0043] A "kernel" is defined as one or more compartments that contain one or more APIs and occupy a large portion of the device volume.

[0044] A "matrix system" is a specific type of kernel defined as a system in which one or more therapeutic agents are uniformly distributed within a matrix material and have no release barriers other than diffusion from the matrix material.

[0045] A "reservoir system" is a specific type of kernel defined as a system in which one or more therapeutic agents are formulated with excipients and enter a central compartment.

[0046] "Skin" is defined as a low-volume element of a drug delivery system that covers part or all of the kernel. In some cases, skin refers to the outer portion of a drug delivery system that is in contact with the external environment. The terms "skin," "membrane," and "layer" are used synonymously herein.

[0047] "Speed-limiting skin" is a specific embodiment of skin defined by a part of a system that includes a polymer having relatively low permeability to therapeutic agents.

[0048] In other embodiments, the implantable devices disclosed herein for vaginal drug delivery include the following elements:

[0049] One or more compartments that contain one or more APIs and constitute a substantial portion of the device volume, also known as the "kernel", One or more skin layers that cover one or more kernels and meet one or more of the following requirements, and are transparent to the API: a) To function as a diffusion limiting barrier to control the release of API from the central compartment, b) Protect the central compartment from one or more components of the external environment, c) Provide structural support to the device.

[0050] The skin comprises a continuous film covering all or part of the device. The film is not perforated with macroscopic (>250 μm) orifices or channels that are generated during device manufacturing (e.g., via mechanical punching).

[0051] A defined microscopic pore structure. The pore structure is 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 is defined as follows:

[0052] Microporous with defined pores having a diameter of less than 2 nm, Mesoporous with defined pores having a diameter of 2-50 nm, Macroporous with defined pores exceeding 50 nm in diameter, typically less than 250 μm.

[0053] Provided herein is a drug delivery device comprising (a) one or more kernels comprising one or more active pharmaceutical ingredients (APIs), and (b) one or more skins comprising a continuous membrane, wherein one or more kernels and / or skins comprise a defined pore, and the pore is not mechanically fabricated.

[0054] In some cases, the device comprises one kernel. In some embodiments, the device comprises multiple kernels.

[0055] In some cases, one or more kernels have defined microscopic or nanoscale pore structures. In some cases, the kernel is a reservoir kernel.

[0056] In some cases, the reservoir kernel contains a powder containing one or more APIs. In some cases, the reservoir kernel contains a powder containing one API. In some cases, the reservoir kernel contains a powder containing two or more APIs. In some cases, the powder contains a microscale or nanoscale drug carrier. In some cases, the powder contains a microscale drug carrier. In some cases, the powder contains a nanoscale drug carrier. In some cases, the drug carrier is a bead, capsule, microgel, nanocellulose, dendrimer, or diatom.

[0057] The device that embodies these elements includes a hierarchical structure based on three levels of organization.

[0058] Primary structure: Based on the components and physicochemical properties of the materials that make up the kernel and skin of the implant. This includes, but is not limited to, elements such as the composition, molecular weight, degree of crosslinking, hydrophobic / hydrophilicity, and rheological properties of polymers or elastomers, as well as the physicochemical properties of drugs such as solubility, logarithmic P, and potency.

[0059] Secondary structure: The complex microstructure of the kernel and / or skin. This includes, but is not limited to, properties such as the size, shape, and structure of drug particles (e.g., core-shell architecture), the fibrous structure of the drug or excipient in the kernel, and the pore properties of the sponge-based kernel material or porous skin (pore density, pore size, pore shape, etc.).

[0060] Tertiary structure: The macroscopic geometric shape and architecture of an implantable device. This includes, but is not limited to, the size and shape of the implant, the dimensions of the kernel and skin (thickness, diameter, etc.), the layers of the kernel and / or skin, and their relative orientation.

[0061] Incorporating these elements into a portable drug delivery device determines the controlled, sustained, intravaginal delivery characteristics of one or more APIs.

[0062] Devices such as those described herein are intended to remain in place for a period ranging from one day to over one year, delivering one or more APIs during this period of use. In certain exemplary, non-limiting embodiments, the device is used vaginally as an IVR and delivers one or more APIs for one to three months.

[0063] Additional details regarding exemplary embodiments are provided below.

[0064] Geometric shape of next-generation implants In another non-limiting embodiment, as shown in Figure 10, a device for vaginal use, such as IVR 100, has a toroidal geometric shape with an outer diameter of 40–70 mm and a cross-sectional diameter of 2–10 mm. Preferred IVR outer diameters are 50–60 mm or 54–56 mm and cross-sectional diameters of 3–8 mm or 4–6 mm. The cross-sectional shape of the IVR can be square, rectangular, triangular, or other shapes other than circular, such as IVR 104. The IVR may include a separate compartment for containing a drug and other components of the drug delivery function, which are connected by sections of elastomer material that help to hold the compartments in a ring-like orientation and allow the IVR, for example IVR 105, to be retained in the vagina. In another embodiment, the central compartment may contain a drug delivery device having an outer ring that functions solely to retain the device, for example IVR 106, in the vaginal cavity. The drug delivery function may be included in a module inserted into the central compartment through opening 107, which has multiple large openings that allow the drug to exit the central compartment but do not play a role in controlling the drug release rate. In an alternative embodiment, both the ring and the central compartment may contain the drug delivery component.

[0065] In one embodiment, one or more cylindrical core elements, including or consisting of kernels, with or without a skin, are held within a perforated carrier. In some cases, the skin includes a non-medicinal elastomer. The core elements are inserted into the carrier through the perforations. Additional perforations within the carrier allow the kernels to interact with vaginal fluid, but the perforations do not play a role in controlling the rate of drug release. In the alternative embodiments shown in Figures 11A–11D, the IVR 110 comprises a molded substructure 112 having one or more distinct compartments, which may include one or more kernels 113. The bottom of each compartment is a drug-permeable membrane, which serves as a skin to regulate drug release from the kernels. The superstructure 111 of the IVR 110 is coupled to the carrier 112 to seal the compartments and form a ring structure. Matching protrusions and recesses may be positioned around the inner and outer circumferences of the upper and lower portions of the IVR to facilitate assembly and sealing of the device during manufacturing. Alternatively, both the upper and lower structures may include a skin to allow drug release from the top and bottom surfaces of the IVR. In the alternative embodiments shown in Figures 12A–12E, the IVR 120 includes compartments contained within lobes projecting inward from the circular outer rim of the IVR. The lower portion 121 includes kernels 125 within one or more compartments 123, the bottom surfaces of which are drug-permeable and serve as a skin. The upper portion 122 is coupled to the lower structure and may include matching recessed structures 124 to facilitate sealing of the upper and lower compartmental portions. Alternatively, recessed areas of the upper portion may serve as an additional drug-permeable membrane to allow drug release from both the top and bottom surfaces of the IVR. In another embodiment shown in Figures 13A–13E, the IVR 130 includes a lower structure containing one or more compartments 131, each containing one or more kernels. The compartments are sealed to the carrier body and surrounded by a separate membrane material 132 that serves as a release rate-controlling skin. An additional protective mesh 133 may be present on top of the skin to protect it from puncture. A sealing ring or other structure 134 may be used to hold the skin and mesh in place on top of the kernel compartment.The compartments may include ribs 135 to further subdivide the compartments covered by one skin structure and to provide support to the skin and mesh.

[0066] In some cases, the device has a torus shape. In some cases, the device comprises one or more cylindrical core elements disposed within a first skin, the core elements comprising a kernel and optionally a second skin.

[0067] In some cases, the device comprises a molded substructure containing one or more compartments, each containing one or more kernels, and a superstructure coupled to a lower carrier to seal the compartments. In some cases, a skin covers the lower carrier. In some cases, the skin covers the substructure and the superstructure.

[0068] In some cases, the device comprises one or more lobes projecting inward from the outer edge of the torus. In some cases, the device comprises two lobes projecting inward from the outer edge of the torus. In some cases, one or more compartments are disposed on the lobes. In some cases, the device comprises one or more recessed structures in one part and corresponding protruding structures in another part to facilitate sealing of the device. In some cases, one or more compartments include ribs. In some cases, the device further comprises a protective mesh disposed on the surface of the device.

[0069] In such alternative IVR designs, the implant kernel is the primary device component that houses the API. Several exemplary, non-limiting systems are disclosed below.

[0070] Next-generation implant matrix system In one embodiment, the implant kernel includes a matrix-type design. In the matrix design, the active pharmaceutical ingredient (API) is distributed throughout the kernel as a solution in an elastomer. In another embodiment, the API 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. In one embodiment, the size distribution of the solid particles is monodisperse. In one embodiment, the solid particles include or consist of nanoparticles (average diameter < 100 nm). In one embodiment, the average diameter of the particles is 100 to 500 nm. Preferred average particle diameters can be in the ranges of 0.5 to 50 μm, 0.5 to 5 μm, 5 to 50 μm, 1 to 10 μm, 10 to 20 μm, 20 to 30 μm, 30 to 40 μm, and 40 to 50 μm. Other suitable average particle diameters can be in the ranges 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, rhombuses, cubes, and irregular shapes.

[0071] In one embodiment, the implant core includes, or comprises, a plurality of modular kernels assembled into a single device, each module being a matrix-type component containing one or more active pharmaceutical ingredients. In one embodiment, the modules may be directly joined to each other (e.g., ultrasonically welded) or separated by an impermeable barrier to prevent drug diffusion between segments.

[0072] At least a portion of the matrix-type devices disclosed herein are covered with one or more skins.

[0073] In one embodiment, the implant includes a reservoir-type design 140, as shown in Figure 14. In the reservoir implant, one or more kernels 141 are filled with the active pharmaceutical ingredient (API). The kernels may extend the entire length of the device or a portion of the device length. In some embodiments, the kernels are partially or completely surrounded by a skin 142 that forms a barrier to drug diffusion, i.e., slows the rate of drug release from the device. Thus, the release of the API from such an implant depends on the penetration (i.e., molecular dissolution and subsequent diffusion) of the kernel-filled API through the outer sheath or skin. The drug release rate can be adjusted by changing the thickness of the rate-controlling skin, as well as the composition of the skin. The drug release kinetics from a reservoir-type implant range from zero to primary, depending on the properties of the kernel and skin.

[0074] At least a portion of the porous devices disclosed herein are covered with one or more skins.

[0075] The next-generation vaginal implant device design is fully described in WO2021 / 108722, and its disclosure is incorporated herein by reference in its entirety.

[0076] film The devices disclosed herein comprise one or more membranes and / or skins. As used herein, the term “skin” refers to a membrane that partially or entirely covers the kernel of the devices described in the “Alternative Vaginal Implant Device Designs” section above.

[0077] The in vitro and in vivo drug release profiles of the implants disclosed herein are generally nonlinear, with an initial burst of drug release followed by a low sustained release period. In certain indications, it may be desirable to linearize the drug release characteristics of the implant. In embodiments of the implants disclosed herein, the membrane or skin is rate-limiting. In one embodiment, the membrane or skin comprises a biocompatible elastomer as described herein. The composition and thickness of the membrane or skin determine the degree of linearization of drug release and the rate of drug release. The thickness of the membrane or skin can be, for example, in the range of 5 to 700 μm. Preferred thicknesses of the membrane or skin can be in the ranges of 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 thickness of the film or skin 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 thickness of the film or skin is 30 μm, 50 μm, or 80 μm.

[0078] In some embodiments, the API-containing compartment (e.g., reservoir) comprises one membrane or skin. In other embodiments, the API-containing compartment (e.g., reservoir) comprises multiple membranes or skins. In some embodiments, the API-containing compartment (e.g., reservoir) comprises 2 to 20 membranes or skins. In some embodiments, these membranes or skins comprise or consist of the same material having the same or different thicknesses. In some embodiments, these membranes or skins comprise or consist of one or more different materials having the same or different thicknesses.

[0079] In one embodiment, the membrane or skin is non-absorbent. It may be formed from medical-grade silicone, as is known to those skilled in the art. Other examples of suitable non-absorbent materials include, but are not limited to, poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(ethylene-co-vinyl acetate), poly(vinyl acetate), or ethylene vinyl acetate (EVA), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, polyvinylidene fluoride (PVDF), poly(siloxane), copolymers thereof, and combinations thereof.

[0080] In one embodiment, one or more membranes or skins comprise or consist of a non-absorbent polymer stretched poly(tetrafluoroethylene) (ePTFE), also known in the art as Gore-Tex.

[0081] In some embodiments, the membrane or skin comprises a biodegradable or bio-erosive polymer. Examples of suitable biodegradable or bio-erosive materials include synthetic polymers selected from poly(amide), poly(ester), poly(esteramide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sevacate), copolymers thereof, and mixtures thereof. In preferred embodiments, the absorbent polymer is selected from poly(lactic acid), poly(glycolic acid), poly(lactic acid-coglycolic acid), poly(caprolactone) (PCL), and mixtures thereof. Other curable bioabsorbable elastomers include PCL derivatives, amino alcohol-based poly(esteramide) (PEA), and poly(octane-diol citrate) (POC). PCL-based polymers may require additional crosslinking agents, such as lysine diisocyanate or 2,2-bis(caprolactone-4-yl)propane, to obtain elastomeric properties.

[0082] In one embodiment, a membrane or skin used to modulate or control the drug release rate from the kernel, and the release kinetics (e.g., zero-order vs. first-order or second-order), are microfabricated using methods known in the art, such as additive manufacturing, and described herein. In some embodiments, the membrane or skin comprises a poly(caprolactone) / poly(lactic acid-coglycolic acid) scaffold blended with tricalcium phosphate constructed using solid freeform fabrication (SFF) technology. In another embodiment, the membrane or skin comprises or comprises a nanostructured elastomer thin film formed by casting and etching a sacrificial template agent known in the art (e.g., zinc oxide nanowires). In yet another embodiment, the membrane or skin comprises or comprises one or more elastomer thin films fabricated via highly reproducible, controllable, and scalable microfabrication methods. These include microelectromechanical systems (MEMS), nanoelectromechanical systems (NEMS), and microfluidics and nanofluidics known in the art. One embodiment known in the art as soft lithography involves the production of a master having patterned features, which may be reproduced in an elastomer material by replica molding. Simply put, a substrate (typically a silicon wafer) is coated with a photoresist (a photoactive polymer commonly used in photolithography, e.g., SU-8) and exposed to UV radiation through a photomask to generate a desired pattern in the photoresist. The resist is then developed and the substrate is etched so that the desired pattern is reproduced on the substrate in the form of negatives (i.e., channels and depressions in areas exposed to UV and not protected by the photoresist). The film or skin is then produced by replica molding using the patterned master. An elastomer resin is poured onto the patterned silicon master of SU-8, and the curing of the material on the master yields the desired pattern. Suitable elastomers include, but are not limited to, polydimethylsiloxane (PDMS, silicone), thermosetting polyester (TPE), and photocurable perfluoropolyether (PFPE).In another embodiment, the patterned film or skin is manufactured using an embossing technique. The patterned master (stamp) is manufactured by methods known in the art, including soft lithography (see above), micromachining, laser processing, electro-electrical discharge machining (EDM), electroplating, or electroforming. The elastomer in the form of a thin sheet is pressed onto the master with a heated hydraulic press to replicate the master pattern of the elastomer. Suitable elastomers for embossing include, but are not limited to, polylactic acid (PLA), polylactic acid-coglycolic acid (PLGA), ethylene-covinyl acetate (EVA), high viscosity rubber (HCR) silicone, polymethyl methacrylate (PMMA), polycarbonate (PC), cyclic olefin copolymer (COC), polystyrene (PS), polyvinyl chloride (PVC), and polyethylene terephthalate glycol (PETG).

[0083] In some cases, the membrane or skin is non-absorbent. In some cases, the membrane or skin contains a biocompatible elastomer. In some cases, the membrane or skin contains poly(dimethylsiloxane), silicone, one or more synthetic polymers, and / or metals. In some cases, the synthetic polymers are 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 stretched poly(tetrafluoroethylene) (ePTFE) or ethylene vinyl acetate (EVA). In some cases, the polymer is stretched poly(tetrafluoroethylene) (ePTFE). In some cases, the polymer is ethylene vinyl acetate (EVA).

[0084] In some cases, the film or skin is metallic, and the metallic material is titanium or stainless steel. In some cases, the metallic material is titanium. In some cases, the metallic material is stainless steel.

[0085] In some cases, the membrane or skin is absorbent. In some cases, the membrane or skin contains a biocompatible elastomer. In some cases, the membrane or skin contains poly(amide), poly(ester), poly(esteramide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sevacate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-coglycolic acid), poly(caprolactone) (PCL), PCL derivatives, amino alcohol-based poly(esteramide) (PEA), poly(octane-diol citrate) (POC), copolymers thereof, or mixtures thereof. In some cases, the polymer is cross-linked PCL. In some cases, the cross-linked PCL contains lysine diisocyanate or 2,2-bis(caprolactone-4-yl)propane. In some cases, the polymer contains poly(caprolactone) / poly(lactic acid-coglycolic acid) and tricalcium phosphate.

[0086] In some cases, the polymer is a hydrophilic polyether-based thermoplastic polyurethane, such as the Tecophilic® series polymers manufactured by Lubrizol. In some cases, the hydrophilic polyurethane can absorb water up to an equilibrium water content of 20% to 1000%. In some cases, the equilibrium water content is 20% to 150%. In some cases, the equilibrium water content is 20% to 100%. In some cases, the equilibrium water content is 20%, 35%, 60%, or 100%.

[0087] In some cases, the film or skin is manufactured by casting and etching, soft lithography, or microlithography.

[0088] In some cases, the film or skin includes a defined surface morphology. In some cases, the defined surface morphology includes a grid pattern.

[0089] In some cases, the defined pores are microscopic or nanoscale pores.

[0090] 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 greater than 50 nm.

[0091] In some cases, the membrane or skin includes a fibrous mat. Methods for producing such nanofiber mats are well known in the art, as described in Brochocka et al. (Materials (Basel), 2020 13(3):712), which are incorporated herein by reference in their entirety, and include spunbound processes, such as those used to produce spunbond polypropylene (SBPP). In a non-limiting example, SBPP is produced by bonding sheets of extruded polypropylene using a process called calendering. The sheets are passed between rollers at high temperature and pressure until the desired weight and thickness are achieved. The result is a material with long, loosely bonded fibers and large pores. Other processes based on spunbond production are also known in the art, including spunbond meltblown spunbond (SMS), which has one or more layers of meltdown nonwoven fabric between nanowoven mats.

[0092] In another embodiment, the film or skin comprises a material having a pattern of laser-drilled holes. In one preferred embodiment, the film material comprises polydimethylsiloxane (PDMS), and the microscopic holes are generated using a femtosecond pulse-width laser. Alternatively, the holes may be generated using a picosecond pulse-width laser. The defined holes have a diameter of less than 250 μm. In some cases, the defined holes have a diameter of 1 μm, 2 μm, 3 μm, 4 μm, or 5 μm. In some cases, the defined pores have a diameter of 5 μm to 250 μm. In some cases, the defined pores have a diameter of 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 75 μm, 100 μm, 150 μm, 200 μm, or 250 μm. The laser-drilled holes occupy a defined pitch pattern. In some cases, the pitch may be more than five times the hole diameter. In some cases, the pitch may be more than twice the hole diameter. In some cases, the pitch may be more than one time the hole diameter. In another embodiment, the undrilled film is manufactured as part of the cassette, and the laser-drilled holes are added later, thereby avoiding the sealing of separate films within the cassette.

[0093] In another embodiment, the membrane comprises a polymer blend in which one component is a water-insoluble polymer and the other component is a water-soluble polymer. When the membrane is exposed to water from vaginal fluid during use of the IVR or during part of the manufacturing process, the water-soluble polymer leaches out of the membrane, creating a porous membrane structure. The water-soluble polymer may account for 5% to 75%, preferably 10% to 70%, more preferably 20% to 60%, and most preferably 30% to 40% of the membrane mass.

[0094] Vaginal implant device materials In one embodiment, the vaginal implantable drug delivery device disclosed herein comprises one or more suitable thermoplastic polymers, elastomer materials suitable for pharmaceutical applications. Examples of such materials are known in the art and described in the literature.

[0095] In one embodiment, the implant elastomer material is non-absorbent. It may contain medical-grade poly(dimethylsiloxane) or silicone, as is known to those skilled in the art. Exemplary silicones include, but are not limited to, fluorosilicones, i.e., polymers having a siloxane skeleton and fluorocarbon pendant groups such as poly(3,3,3-trifluoropropylmethylsiloxane). Other examples of suitable non-absorbent materials include poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), EVA, poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), poly(tetrafluoroethylene), and other fluorinated polymers including ePTFE, poly(siloxane), copolymers thereof, and synthetic polymers selected from combinations thereof.

[0096] In another embodiment, the implantable elastomer material is absorbable. In one embodiment of an absorbable device, the membrane or skin is formed from a biodegradable or bioerosive polymer. Examples of suitable absorbable materials include synthetic polymers selected from poly(amide), poly(ester), poly(esteramide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sevacate), copolymers thereof, and mixtures thereof. In one embodiment, the absorbable polymer is selected from poly(lactic acid), poly(glycolic acid), poly(lactic acid-coglycolic acid), PCL, and mixtures thereof. Other curable bioabsorbable elastomers include PCL derivatives, amino alcohol-based PEA, and POC. PCL-based polymers may require additional crosslinking agents, such as lysine diisocyanate or 2,2-bis(-caprolacton-4-yl)propane, to obtain elastomeric properties.

[0097] In one embodiment of the implantable drug delivery system described herein, the elastomer material may be any thermoplastic polymer or elastomer material suitable for pharmaceutical use, such as silicone, low-density polyethylene, EVA, polyurethane, and styrene-butadiene-styrene copolymer, and includes a suitable thermoplastic polymer or elastomer material.

[0098] In certain embodiments, the elastomer material is EVA. The EVA can be any commercially available EVA, such as products available under the trade names Elvax, Evatane, Lupolen, Movriton, Ultrathene, and Vestypar.

[0099] Small to medium-sized drug molecules (M ≤ 600 g mol) -1 The permeability of EVA copolymers to VA is primarily determined by the vinyl acetate to ethylene ratio. Low VA-content EVA copolymers are substantially less permeable than high VA-content membranes or skins and therefore exhibit rate-limiting properties when used as membranes or skins. EVA copolymers with a VA content of 19% w / w or less (≤19% w / w) are substantially less permeable than polymers with a VA content of 25% w / w or more (>25% w / w).

[0100] In some embodiments, the scaffold comprises a first thermoplastic polymer and a second thermoplastic polymer. 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 another embodiment, the first thermoplastic polymer has a vinyl acetate content of 28-40% vinyl acetate. In yet another embodiment, the first thermoplastic polymer has a vinyl acetate content of 28-33% vinyl acetate. 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 another embodiment, the second thermoplastic polymer has a vinyl acetate content of 28-40% vinyl acetate. In yet another embodiment, the second thermoplastic polymer has a vinyl acetate content of 28-33% vinyl acetate. In one embodiment, the second thermoplastic polymer has a vinyl acetate content of 28%. In another embodiment, the second thermoplastic polymer has a vinyl acetate content of 33%.

[0101] 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 of less than 28%. In yet another embodiment, the second thermoplastic polymer has a vinyl acetate content of 9-28% vinyl acetate. In yet another embodiment, the second thermoplastic polymer has a vinyl acetate content of 9-18% vinyl acetate. 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%.

[0102] It should be noted that when a specific vinyl acetate content, e.g., 15%, is mentioned, it refers to the manufacturer's target content, and the actual vinyl acetate content may vary by plus or minus 1% or 2% from the target content. Those skilled in the art will understand that suppliers may use internal analytical methods to determine the vinyl acetate content, and therefore offsets may exist between methods.

[0103] Pharmaceutical considerations Drug formulations may include essentially any therapeutic, prophylactic, or diagnostic agent that would be useful for local delivery to a body cavity.

[0104] Targeting in vivo pharmacokinetics and pharmacokinetic profiles Drug formulations may provide a time-regulated release profile or a more continuous or consistent release profile. Pulsating release can be achieved from multiple APIs administered simultaneously or staggered over time. For example, different degradable membranes or skins can be used to alternate the release of one or more drugs from each of several cassettes or kernels over time.

[0105] API Selection The drug formulation may include essentially any therapeutic, prophylactic, or diagnostic agent that would be useful for delivery to an anatomical compartment. The implantable drug delivery devices disclosed herein include at least one pharmaceutically active substance, including but not limited to agents used in the art to treat or prevent the signs described herein, and combinations thereof. In one embodiment, the drug delivery device includes two or more pharmaceutically active substances. In this case, the pharmaceutically active substances may be the same or different hydrophilic or hydrophobic.

[0106] Non-exclusive examples of hydrophobic pharmaceutically active substances include cabotegravir, dapivine, fluticasone propionate, chlordiazepoxide, haloperidol, indomethacin, prednisone, and ethinylestradiol. Non-exclusive examples of hydrophilic pharmaceutically active substances include acyclovir, tenofovir, atenolol, aminoglycosides, exenatide acetate, leuprolide acetate, acetylsalicylic acid (aspirin), and levodopa.

[0107] In some cases, the pharmaceutically active substance is an antibacterial agent. In some cases, the antibacterial agent is a broad-spectrum antibacterial agent. A non-specific example of an antibacterial agent is azithromycin.

[0108] In some cases, the pharmaceutically active substance is an antiviral agent. Non-specific examples of antiviral agents include remdesivir (Gilead Sciences), acyclovir, ganciclovir, and ribavirin, as well as combinations thereof. In some cases, the pharmaceutically active substance is an antiretroviral drug. In some cases, antiretroviral drugs are used to treat HIV / AIDS. Non-specific examples of antiretroviral drugs include protease inhibitors, reverse transcription inhibitors, interchain transfer inhibitors, integrase inhibitors, and maturation inhibitors.

[0109] In some cases, pharmaceutically active substances are drugs that affect immune and fibrotic processes. Non-exclusive examples of drugs that affect immune and fibrotic processes include inhibitors of Rho-related coiled coil kinase 2 (ROCK2), such as KD025 (Kadmon).

[0110] In some cases, the pharmaceutically active substance 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 sirtuin inhibitors restores cellular metabolism and immunity in the human host.

[0111] The pharmaceutically active substances described herein may be administered individually or in combination. Combinations of pharmaceutically active substances may be administered using one lobe, multiple lobes, or a cassette. In some cases, the implants described herein contain one pharmaceutically active substance. In some cases, the implants described herein contain two or more pharmaceutically active substances. In some cases, the implants described herein contain a combination of pharmaceutically active substances.

[0112] In one embodiment, HIV and HBV can be treated and / or prevented using one or more implants that deliver potent antiviral agents, including but not limited to a combination of tenofovir alafenamide, lamivudine (3TC), and dolutegravir (DTG).

[0113] In one embodiment, an interventional radiology (IVR) delivering two or more APIs against HIV may be advantageous. Non-limiting examples include tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination with a third anti-HIV compound from a different mechanical class, such as DTG, elvitegravir, antiviral peptide C5A, and other antimicrobial peptides, as well as a broadly neutralizing antibody 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.

[0114] In some cases, one or more active pharmaceutical ingredients are antiretroviral agents, antimicrobial agents, antibacterial agents, antiviral agents, hormones, contraceptives, statins, beta-blockers, ACE inhibitors, angiotensin receptor blockers, vitamins, steroids, biologics, anticancer agents, allergy medications, anticoagulants, antiplatelet therapies, nonsteroidal anti-inflammatory drugs, vaccines, or combinations thereof. In some cases, one or more active pharmaceutical ingredients include antiviral agents. In some cases, one or more active pharmaceutical ingredients include zidovudine, cabotegravir, dapivine, fluticasone propionate, chlordiazepoxide, haloperidol, indomethacin, prednisone, ethinylestradiol, 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 combinations thereof. In some cases, one or more active pharmaceutical ingredients include tenofovir. In some cases, one or more active pharmaceutical ingredients include contraceptives. In some cases, the contraceptives include etonogestrel, estradiol, or a combination thereof.

[0115] The suitability of any given pharmaceutically active substance is not limited or predicted by any given medical use, but rather is a function of the following non-limiting parameters:

[0116] Potency; the potency of the API determines whether it can be formulated for interventional radiology (IVR) and whether it can maintain pharmacologically relevant concentrations in key anatomical compartments over the targeted duration of use.

[0117] The amount of API that can be formulated into implant payloads (IVR), along with the potency of the API, is a major limiting factor in selecting an API for a given indication.

[0118] Solubility; the water solubility of the API must be such that delivery via IVR is achievable at the target rate. The solubility of the API, and therefore the release rate, can also be regulated (increased or decreased) by preparing pharmaceutically acceptable salts using appropriate excipients, by conjugation to prodrugs all known in the art, and by using the formulation strategies described above.

[0119] Local toxicity; the local toxicity profiles of many APIs assumed in the disclosed applications will be determined before formulation into interventional radiology (IVR), especially when FDA-approved drugs are used. Therefore, local toxicity is the greatest safety concern in these cases and can limit the delivery rate of the API. In some cases, the drug may have a low therapeutic index (TI), making it impossible to control the drug release rate from the IVR to deliver a safe and effective concentration within the target pharmacological compartment.

[0120] Costs; API costs and / or manufacturing costs may be limiting in certain cases.

[0121] Developing silico predictions of implant specifications for any given API and medical application, as well as target product profiles, is extremely challenging, as is known in the art for other sustained-release drug delivery technologies, and typically requires preclinical trials followed by pharmacological clinical validation from a pharmacokinetic (PK) and pharmacodynamic (PD, safety, and efficacy) perspective.

[0122] API formulations A drug formulation may consist solely of the drug, or it may contain one or more other drugs and / or one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art and include viscosity modifiers, volume extenders, surfactants, dispersants, disintegrants, penetrants, diluents, binders, anti-adhesives, lubricants, flow enhancers, pH adjusters, antioxidants and preservatives, as well as other inactive components of the formulation intended to facilitate the handling of the drug and / or affect the drug's release kinetics.

[0123] In some embodiments, binders and / or disintegrants may include, but are not limited to, starch, gelatin, carboxymethylcellulose, croscarmellose sodium, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, 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, anti-adhesive or lubricant may include, but are not limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium behenate. In some embodiments, flow enhancers may include, but are not limited to, fumed silica, talc, and magnesium carbonate. In some embodiments, pH adjusters may include, but are not limited to, citric acid, lactic acid, and gluconic acid. In some embodiments, antioxidants and preservatives may include, but are not limited to, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), cysteine, methionine, vitamin A, vitamin E, sodium benzoate, and parabens.

[0124] Effect of excipients on API release The devices disclosed herein may include excipients to facilitate and / or control the release of APIs from the device. Non-limiting examples of these excipients include PEG and TEC. The release kinetics of the API are intended to be modulated by incorporating different excipients into the devices disclosed herein. That is, the release kinetics of the API can be tuned over a wide range by changing the properties and / or amount of the excipients contained therein. In some cases, the device contains a low concentration of excipient, e.g., about 0% to about 30% by weight. In some cases, the excipient is a polyether or ester. In some cases, the excipient is PEG or TEC. In some cases, the device contains PEG to achieve a lower sustained release of the API. In some cases, the device contains TEC to achieve a more immediate, larger dose of API.

[0125] Drug preparations APIs can be formulated by any conventional method known to those skilled in the art to achieve a desired release and / or therapeutic profile. In some embodiments, APIs can be formulated as solids, semi-solid preparations (e.g., pastes), or liquids. In some embodiments, APIs can be dispersed in a fibrous carrier or a porous sponge.

[0126] In some cases, the API is formulated as a solid. In some cases, the solid is a powder. In some cases, the powder contains a drug carrier at the microscale (1–1,000 μm cross-section) or nanoscale (1–1,000 nm cross-section). The drug carrier is a particulate material containing the API either internally or on its surface. Non-limiting examples of such carriers known in the art include, but are not limited to, beads, capsules, microgels including, but not limited to, chitosan microgels, nanocellulose, dendrimers, and diatoms. The carrier is filled or coated with the API by impregnation or by other methods known in the art (e.g., lyophilization, rotary solvent evaporation, spray drying).

[0127] In another embodiment, the solid comprises one or more pellets or microtablets. In these embodiments, it may be desirable to maximize the drug load and minimize the use of excipients. However, the use of excipients can provide beneficial physical properties such as lubrication and binding during tableting. In some cases, the kernel comprises a pellet. In some cases, the kernel comprises a microtablet.

[0128] Semi-solid preparation (paste) In some cases, solid API particles are blended or mixed with one or more liquids, gels, or excipients to form a semi-solid preparation or paste. This embodiment has the advantage of allowing the formulation to be easily dispensed into a reservoir, which provides manufacturing advantages. The properties of the excipients may also affect the drug release kinetics from the preparation. The paste is contained within an IVR structure such as a cassette (e.g., within a reservoir in the cassette). The paste can be isolated from the external environment by one or more membranes or skins, as described herein.

[0129] In one embodiment, the liquid excipient includes an oil having a history of pharmaceutically active use, including subcutaneous or intramuscular use. Non-limiting examples of such oils include triethyl citrate (TEC), glyceryl monooleate, polyethylene glycol (PEG; e.g., PEG-300 and PEG-400), and vegetable oils (e.g., sunflower oil, castor oil, sesame oil, etc.). The paste may contain API particles and a single liquid, or 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 adjust 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 active pharmaceutical ingredient from the kernel, and therefore the implantation release rate. Certain excipients can be used to increase the solubility of the drug in water, while others can decrease it. In some cases, excipients can provide drug stabilization. Exemplary excipients are described in more detail herein. In another embodiment, the paste described above may include a blend of two or more APIs for the purpose of delivering two or more active pharmaceutical ingredients from a single kernel.

[0130] In another embodiment, the excipient includes a so-called "ionic liquid," which is widely defined in the art as a salt that melts below 100°C and consists only of ions. The selection of cations strongly influences the properties of the ionic liquid and often defines its stability. The chemical properties and functionality of the ionic liquid are generally controlled by the selection of anions. In one embodiment, the concentration of active pharmaceutical ingredient particles in the paste is 5-99% w / w, with preferred concentrations ranging from 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.

[0131] Phase inversion systems, based on phospholipids alone or in combination with medium-chain triglycerides and pharmaceutically acceptable water-miscible solvents, are also known in the art to form solid or semi-solid deposits when in contact with physiological fluids and are used to constitute the kernel of the disclosed devices. In some embodiments, the phase inversion system comprises one or more phospholipids. In some cases, the phase inversion system comprises one or more phospholipids in combination with one or more medium-chain triglycerides (MCTs). 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 those supplied by ABITEC Corporation. In one embodiment, the concentration of active pharmaceutical ingredient particles in the paste is, for example, 5 to 99% w / w, and preferred concentrations are in the ranges of 5 to 10% w / w, 10 to 25% w / w, 25 to 35% w / w, 35 to 50% w / w, 50 to 60% w / w, 60 to 70% w / w, 70 to 80% w / w, 80 to 90% w / w, and 90 to 99% w / w.

[0132] In some embodiments, the phase inversion system includes one or more soluble liquid crystals. In another, non-limiting set of embodiments, excipient formulations constituting a kernel paste-drug suspension yield soluble liquid crystals upon contact with physiological fluids. Certain lipid-based systems, such as monoglycerides, including but not limited to the following compounds 1-5, form soluble liquid crystals in the presence of water. These systems self-assemble into an ordered intermediate phase containing nanoscale water channels, while the remainder of the three-dimensional structure is hydrophobic. [ka]

[0133] In one embodiment, a soluble lipid system can be used to form a paste formulation suspension with active pharmaceutical ingredient particles. In one embodiment, the concentration of active pharmaceutical ingredient particles in the paste is, for example, 5 to 99% w / w, and preferred concentrations are in the ranges of 5 to 10% w / w, 10 to 25% w / w, 25 to 35% w / w, 35 to 50% w / w, 50 to 60% w / w, 60 to 70% w / w, 70 to 80% w / w, 80 to 90% w / w, and 90 to 99% w / w.

[0134] In another non-limiting embodiment, the paste comprises a shape-memory self-repairing gel, as known to those skilled in the art. A shape-retaining, injectable hydrogel based on a polysaccharide scaffold (e.g., alginate, chitosan, HPMC, hyaluronic acid) and optionally non-covalently bonded to nanoparticles (non-pharmaceutical or pharmaceutical) forms part of this embodiment for semi-solid preparations. In one embodiment, the physically crosslinking nanoparticles include or consist of API nanoparticles. In one embodiment, the concentration of the active pharmaceutical ingredient particles in the paste is 5 to 99% w / w, with preferred concentrations ranging from 5 to 10% w / w, 10 to 25% w / w, 25 to 35% w / w, 35 to 50% w / w, 50 to 60% w / w, 60 to 70% w / w, 70 to 80% w / w, 80 to 90% w / w, and 90 to 99% w / w.

[0135] In one embodiment of the present disclosure, the paste comprises a stimulus-responsive gel. Such a gel changes its physical properties (e.g., from liquid to viscous gel or solid) in response to external or internal stimuli, including but not limited to temperature, pH, mechanical (i.e., thixotropic), electrical, electrochemical, magnetic, electromagnetic (i.e., light), and ionic intensity. In one non-limiting embodiment of a heat-sensitive polymer suitable for kernel formulations, it comprises or comprises 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 drug delivery. In one embodiment, the concentration of active pharmaceutical ingredient particles in the paste is 5-99% w / w, and preferred concentrations are in the ranges of 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.

[0136] A device comprising a paste containing one or more APIs is provided herein. The paste may optionally comprise an oily excipient, an ionic liquid, a phase inversion system, or a gel. The paste may optionally comprise an oily excipient. The paste may optionally comprise an ionic liquid. The paste may optionally comprise a phase inversion system. The paste may optionally comprise a gel.

[0137] In some cases, the phase inversion system includes a combination of biodegradable polymers, phospholipids, and medium-chain triglycerides, or soluble liquid crystals. In some cases, the phase inversion system includes biodegradable polymers. In some cases, the phase inversion system includes a combination of phospholipids and medium-chain triglycerides. In some cases, the phase inversion system includes soluble liquid crystals.

[0138] In some cases, the gel is a stimuli-responsive gel or a self-healing gel. In some cases, the gel is a stimuli-responsive gel. In some cases, the gel is a self-healing gel.

[0139] In some embodiments, multiple reservoir modules are joined together to form a single implant. In some embodiments, segments are separated by an impermeable barrier to prevent drug diffusion between segments.

[0140] Fiber-based system In another embodiment, the IVR comprises one or more APIs dispersed in a high-surface-area fiber-based carrier suitable for tissue manipulation, chemotherapeutic agent delivery, and wound management devices. In one embodiment, the high-surface-area carrier comprises fibers fabricated by electrospray. In one embodiment, the high-surface-area carrier comprises electrospun fibers, including but not limited to electrospun nanofibers.

[0141] Electrospan drug-containing fibers can have a number of configurations. For example, in one embodiment, the API is embedded in a fiber, which is a miniaturized version of the matrix system described above. In another exemplary embodiment, the API fiber system is fabricated by coaxial electrospinning to give a core-shell structure, which is a miniaturized version of the reservoir system described above. Fabrication of core-shell fibers by coaxial electrospinning results in the encapsulation of water-soluble drugs, such as biomolecules, including but not limited to proteins and peptides. In yet another exemplary embodiment, Janus nanofibers can be prepared. Janus fibers consist of two or more distinct surfaces having different physical or chemical properties, and in the simplest case, are two fibers coaxially bonded along their edges. In some embodiments, it may be advantageous to modify the fibers by surface functionalization.

[0142] Electrospinning may also be used to produce membranes or skins. In one embodiment, a membrane or mat of electrospun fibers collected on a rotating plate or drum may be used as a membrane or skin.

[0143] The above paragraph describes an embodiment incorporating fibers produced by electrospinning, but additional non-limiting embodiments use the same approach to incorporate fibers formed by alternative spinning methods. In one embodiment, a rotary jet spinner, a perforated reservoir rotating at high speed, propels a jet of liquid material outward from the reservoir orifice toward the surface of a stationary cylindrical collector. The fibrous material may be thermally liquefied by melting, resulting in a process similar to that used in cotton candy machines, or it may be dissolved in a solvent to enable fiber production at low temperatures (i.e., without melting the material). Before impact, the jet is stretched, dried, and finally solidified to form a mat or bundle of nanoscale fibers on the collector surface. The fibrous material may include, or consist of, pharmaceutically acceptable excipients such as glucose or sucrose, or polymer materials, e.g., absorbent or non-absorbent polymers described herein. In another embodiment, the solid drug and excipient or polymer are pre-mixed as a solid and formed into a fibrous mat by spinning. The rotary jet spinning method is known in the art.

[0144] In another embodiment, the fibers may be produced by a wet spinning method. In wet spinning, the fibers are formed by extruding a polymer solution through a small needle spinneret into a fixed or rotating coagulation bath containing, or comprising, a solvent that has low polymer solubility but is miscible with the polymer solution solvent. Dry jet wet spinning is a similar process in which initial fibers are formed in the air before being collected in the coagulation bath.

[0145] Provided herein are devices in which the API is dispersed in a fiber-based carrier. In some cases, the fiber-based carrier includes electrospun microfibers or nanofibers. In some cases, the fiber-based carrier includes electrospun microfibers. In some cases, the fiber-based carrier includes electrospun nanofibers. In some cases, the electrospun nanofibers are Janus microfibers or nanofibers. In some cases, the electrospun nanofibers are Janus microfibers. In some cases, the electrospun nanofibers are Janus nanofibers.

[0146] In some cases, the fiber-based carrier contains random or oriented fibers. In some cases, the fiber-based carrier contains random fibers. In some cases, the fiber-based carrier contains oriented fibers.

[0147] In some cases, the fiber-based carrier includes bundles of fibers, yarns, woven mats, or nonwoven mats. In some cases, the fiber-based carrier includes bundles of fibers, yarns, woven mats, or nonwoven mats. In some cases, the fiber-based carrier includes bundles of fibers. In some cases, the fiber-based carrier includes yarns of fibers. In some cases, the fiber-based carrier includes woven mats of fibers. In some cases, the fiber-based carrier includes nonwoven mats of fibers.

[0148] In some cases, the fiber-based carrier includes rotary jet-spun, wet-spun, or dry jet-spun fibers.

[0149] In some cases, the fibers contain glucose, sucrose, or polymer materials. In some cases, the fibers contain glucose. In some cases, the fibers contain sucrose. In some cases, the fibers contain polymer materials. In some cases, the polymer materials include absorbent or non-absorbent polymer materials as specified herein, for example, 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 contains stretched poly(tetrafluoroethylene) (ePTFE) or ethylene vinyl acetate (EVA). In some cases, the polymer contains stretched poly(tetrafluoroethylene) (ePTFE). In some cases, the polymer is ethylene vinyl acetate (EVA). In some cases, the polymers include poly(amide), poly(ester), poly(esteramide), poly(anhydride), poly(orthoester), polyphosphazene, pseudo-poly(amino acid), poly(glycerol-sevacate), poly(lactic acid), poly(glycolic acid), poly(lactic acid-coglycolic acid), poly(caprolactone) (PCL), PCL derivatives, amino alcohol-based poly(esteramide) (PEA), poly(octane-diol citrate) (POC), copolymers thereof, or mixtures thereof.

[0150] Porous sponge system In some embodiments, the API is dispersed in a porous support structure. The support has a porous microstructure (pore diameter 1 to 1,000 μm). In some embodiments, the support has a porous nanostructure (pore diameter 1 to 1,000 nm). In yet other embodiments, the support has both a porous microstructure and a nanostructure. Examples of these micropores include, but are not limited to, silica sol-gel materials, zero-gels, mesoporous silica, polymer microsponges including polydimethylsiloxane (PMDS) sponges and polyurethane foams, nanosponges including cross-linked cyclodextrins, and sponges including electrospun nanofiber sponges and aerogels. In some embodiments, the porous sponge includes silicone, silica sol-gel materials, zero-gels, mesoporous silica, polymer microsponges, polyurethane foams, nanosponges, or aerogels. In some embodiments, the porous sponge includes silicone. In some embodiments, the porous sponge includes silica sol-gel materials, zero-gels, mesoporous silica, polymer microsponges, polyurethane foams, nanosponges, or aerogels.

[0151] In other embodiments, the API is dispersed in a porous metal structure. Porous metal materials may be used, including but not limited to titanium and nickel-titanium (NiTi or nitinol) alloys in structural forms including forms, tubes, and rods. Such materials have been used in other applications, including bone replacement materials, filter media, and as structural components in aerospace and aeronautics. These materials possess desirable properties for drug 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 their original shape from significant and seemingly plastic deformation when a specific stimulus such as heat is applied) and superelastic properties (the alloy deforms reversibly by the formation of a stress-induced phase under load, which becomes unstable when the load is removed and returns to its original phase and shape). In the case of NiTi alloys, these properties are due to the conversion between the low-temperature monoclinic isotope (martensite phase) and the high-temperature cubic (austenite) phase. Porous NiTi materials maintain shape memory and / or superelastic properties. Both mechanical properties and corrosion resistance are determined by the chemical composition of the titanium alloy. Surface treatments, including chemical treatment, plasma etching, and heat treatment, may be used to increase or decrease the bioactivity of Ti and Ti alloy porous materials.

[0152] There are few examples of drug-loaded nanoporous coatings on implantable or implantable devices that have been used for sustained drug delivery. In these cases, drug release is directly from a thin coating (similar to a drug-release stent) rather than from the bulk implant material (porous or solid), and these systems typically exhibit primary dissolution kinetics.

[0153] In one embodiment, a sponge structure known in and for drugs is incorporated by impregnation using methods known in the art. In one non-limiting example, the API is introduced into an inner sponge microarchitecture using a liquid medium having affinity for the sponge material. For example, polydimethylsiloxane (PDMS) is a highly hydrophobic and commonly used material in the art. Thus, a PDMS sponge can be readily impregnated with a nonpolar solvent solution of the API and subsequently dried. Multiple impregnation cycles allow for the accumulation of the drug within the device. In another non-limiting embodiment, the solvent acts as a vehicle for filling the sponge with a drug particle suspension. In a relevant embodiment, a biomolecule (e.g., a peptide or protein) is suspended in n-hexane and impregnated into a PDMS sponge, which is then dried at room temperature in a vacuum oven. Multiple impregnation-drying cycles are used to increase the drug load. In a non-limiting example, a suspension of VRC01, a broad-spectrum neutralizing antibody against HIV, in n-hexane is impregnated into a PDMS sponge. In another non-limiting example, a suspension of tenofovir alafenamide in n-hexane is impregnated into a PDMS sponge.

[0154] In some embodiments, the sponge is magnetic, for example, to allow remotely induced drug release.

[0155] In one embodiment, the sponge pore is fabricated in situ during use using a template excipient. Several porogens are known in the art and have been used to produce porous structures. Methods for fabricating the pore during use (i.e., in vivo) include, but are not limited to, including excipient particles in an implant kernel that dissolves when exposed to bodily fluids such as subcutaneous and cervical fluids. As used herein, the solid particles may be in crystalline or amorphous form. 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 include or consist of nanoparticles (average diameter < 100 nm). In one embodiment, the average diameter of the particles may be in the range of 1–10 nm, 10–25 nm, 25–100 nm, and 100–500 nm. Suitable average particulate diameters can be in the ranges 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 diameters can be in the ranges of 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, rhomboids, cubes, and irregular shapes. The above template particles may contain, or consist of, salts (e.g., sodium chloride), sugars (e.g., glucose), or other water-soluble excipients known to those skilled in the art. Those skilled in the art will know how to produce such particles of well-defined shapes and sizes. The mass ratio of pore-forming particles to API in the kernel is in the range of 100 to 0.01. More specifically, the above ratio can be in the range of 100 to 20, 20 to 5, or 5 to 1. In other embodiments, the ratio can be in the range of 1 to 0.2, 0.2 to 0.05, or 0.05 to 0.01.

[0156] In one non-limiting embodiment, the pologen includes a fibrous mat as described above. In another embodiment, the pologen includes a microfiber mat. In yet another embodiment, the pologen includes a nanofiber mat. The fibrous mat is manufactured by methods 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 fibrous material may include or consist of one or more biocompatible polymers (absorbent and non-absorbent) as enumerated herein. The fibrous material may also include or consist of pharmaceutically acceptable excipients such as glucose (i.e., cotton candy).

[0157] In one non-limiting embodiment, pologen particles are fused by exposure to a suitable solvent vapor. Particle fusion may be required to yield an open-cell sponge architecture, which can be desirable. The fusion solvent can be a polar solvent such as water, or an organic solvent ranging from polar (e.g., methanol) to non-polar (e.g., hexane), depending on the solubility of the template agent. The solvent vapor is generated by any preferred method, such as heating, using a suitable container such as a Buchner funnel with or without a filter, or by a column of suspended pologen particles in contact with the vapor using a screen, mesh, or perforated plate. The exposure time can be experimentally determined to achieve the desired degree of particle fusion.

[0158] In some embodiments, the pores are formed during manufacturing (i.e., before use) by immersing the device in a suitable fluid (e.g., water or an organic solvent) to dissolve the pologen.

[0159] In some embodiments, pores may be formed as a result of mechanical, temperature, or pH changes after transplantation / use.

[0160] In one non-limiting embodiment, one or more drugs constitute a sponge template agent. When the drugs are released from the device, a sponge is formed. In one embodiment, the drug template agent includes a mat of microneedles.

[0161] In one non-limiting embodiment, the sponge is composed of PDMS, and the hydrophobic microchannels are modified using methods known in the art, such as chemical treatment and plasma treatment. In another embodiment, a binder is used between the internal PDMS microchannels and the surface modifier to adjust the internal surface properties of the sponge. Surface modifier chemicals are well known in the art. In one non-limiting embodiment, 3-aminopropyl)triethoxysilane is used as a binder to attach proteins to the PDMS surface.

[0162] Provided herein are devices in which an API is supported in a porous sponge. In some cases, the porous sponge includes silicone, silica sol-gel material, zero gel, mesoporous silica, polymer microsponge, polyurethane foam, nanosponge, or aerogel. In some cases, the porous sponge includes silicone. In some cases, the porous sponge includes silica sol-gel material. In some cases, the porous sponge includes zero gel. In some cases, the porous sponge includes mesoporous silica. In some cases, the porous sponge includes polymer microsponge. In some cases, the porous sponge includes polyurethane foam. In some cases, the porous sponge includes nanosponge. In some cases, the porous sponge includes aerogel.

[0163] In some cases, the porous sponge contains a pologen. In some cases, the pologen contains a fibrous mat. In some cases, the fibrous mat contains glucose. In some cases, the pologen contains an API. In some cases, the porous sponge is impregnated with an API. In some cases, the porous sponge contains a sponge material having an affinity for a solvent that can dissolve the API. In some cases, the porous sponge contains polydimethylsiloxane (PDMS).

[0164] Targeted IVR specifications The amount of pharmaceutically active substance incorporated into an IVR can also be calculated as a pharmaceutically effective amount, and the device of this implant contains a pharmaceutically effective amount of one or more pharmaceutically active substances. "Pharmacologically effective" means an amount sufficient to produce the desired physiological or pharmacological change in the subject. This amount varies depending on factors such as the potency of the particular pharmaceutically active substance, the density of the pharmaceutically active substance, the shape of the implant, the desired physiological or pharmacological effect, and the intended duration of treatment.

[0165] In some embodiments, the pharmaceutically active substance is present in amounts ranging from about 1 mg to about 25,000 mg per implant device. This includes embodiments in which the amount of pharmaceutically active substance 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 per implant device.

[0166] The size of the drug depot determines the maximum amount of pharmaceutically active substance in the IVR. A typical IVR weighs less than 10g, meaning that the maximum amount of pharmaceutically active substance per implant device of this nature will also be less than 10g.

[0167] In certain embodiments of the implantable drug delivery device described herein, the first therapeutic agent is present in the kernel at a concentration of about 0.1% to 99% w / w. In other embodiments, the first therapeutic agent is present in the kernel at concentrations of about 0.1% to 1% w / w, about 1% to 5% w / w, about 5% to 25% w / w, about 25% to 45% w / w, about 45% to 65% w / w, about 65% to 100% w / w, about 65% to 75% w / w, or about 75% to 85% w / w, or about 85% to 99% w / w.

[0168] In certain embodiments, the intravaginal drug delivery system described herein can release the contained therapeutic agent over a period of 1, 2, 3, 4, 5, or 6 weeks. In certain embodiments, the implantable drug delivery system described herein can release the contained therapeutic agent over a period of 8, 10, 12, or 14 weeks. In certain embodiments, the implantable drug delivery system described herein can release the contained therapeutic agent over a period of 1, 2, 3, or 6 months. In certain embodiments, the implantable drug delivery system described herein can release the contained therapeutic agent over a period of 1, 2, 3, or 4 years.

[0169] In certain embodiments of the vaginal drug delivery devices described herein, the second therapeutic agent is present in the membrane or skin at a concentration of about 5–50% w / w. In other embodiments, the second therapeutic agent is present in the membrane or skin at a concentration of about 10–50% w / w, about 20–50% w / w, about 10%, 30%, or 50% w / w of the membrane or skin.

[0170] In certain embodiments, the vaginal drug delivery systems described herein are stable at room temperature. As used herein, “room temperature” is somewhere between approximately 18°C ​​and approximately 30°C. As used herein, the physically implantable drug delivery systems are systems that can be stored at approximately 18–30°C for at least approximately one month.

[0171] Vaginal ring fabrication Methods for manufacturing vaginal drug delivery systems are also described herein.

[0172] Manufacturing of vaginal rings with drugs and / or excipients in polymer dispersions Reservoir IVR manufacturing Methods for manufacturing a reservoir-designed vaginal drug delivery system are also described herein.

[0173] In one embodiment of a reservoir-type IVR, the API and any other solid drug or excipient can be filled into the IVR shell as a powder or slurry using a filling method known in the art. In another embodiment, the solid activator and carrier can be compressed into a microtablet / tablet form using means common in the art to maximize the filling of the activator.

[0174] Manufacturing of porous IVR components One or more porous materials can be used in IVR manufacturing as described in detail above. In one embodiment, the API permeable portion of the IVR device is formed from a porous membrane of polyurethane, silicone, or other suitable elastomer material. Open-cell foams and their fabrication are known to those skilled in the art. Open-cell foams may be fabricated using a cell-opening step, which involves using a blowing agent present during the manufacturing process, typically carbon dioxide or hydrogen gas, or a low-boiling point liquid, to form closed pores in the polymer, followed by breaking the seals between cells and forming an interconnected porous structure in which diffusion can occur. An alternative embodiment involves using a breath-figure method to fabricate an ordered porous polymer membrane for API release. In this method, a hexagonal array of micrometer pores is obtained by droplet condensation during rapid solvent evaporation carried out under a wet flow. Porous membranes may also be fabricated using a porogen leaching method, in which case the polymer is mixed with a salt or other soluble particles of controlled size to form the desired shape before casting, spin coating, extrusion, or other treatment. Next, the polymer composite is immersed in a suitable solvent, as is known in the art, to leach out the pologen particles, leaving a porous structure controlled by the number and size of the leached pologen particles. A preferred approach is to use water-soluble particles and water as solvents for pologen leaching and removal. Using this technique, a highly porous scaffold can be formed with a porosity value of up to 93% and an average pore diameter of up to 500 μm. A variation of this method is melt molding, which involves filling a mold with polymer powder and pologen and heating the mold above the glass transition temperature of the polymer to form a scaffold. After removal from the mold, the pologen is leached out to form a porous structure with independently controlled morphology (from pologen) and shape (from the mold).

[0175] Porous membranes can also be formed using a phase separation process. A second solvent is added to the polymer solution (quenching), causing phase separation of the mixture to form a polymer-rich phase and a polymer-deficient phase. The polymer-rich phase solidifies and the polymer-deficient phase is removed, leaving a highly porous polymer network, whose micro and macro structures are controlled by parameters such as polymer concentration, temperature, and quenching rate. A similar approach is freeze-drying, where the polymer solution is cooled to a freezing state, the solvent forms ice crystals, and the polymer aggregates in the interstitial space. The solvent is removed by sublimation, resulting in an interconnected porous polymer structure. A final method for forming porous polymer membranes is to create an open-cell network using a stretching process.

[0176] Additive manufacturing of IVR components Additive manufacturing (colloquially referred to as 3D printing technology in the art) is one of the fastest-growing applications for plastic processing. Components that make up Interactive Vehicle Regeneration (IVR) can be manufactured by additive techniques that enable the acquisition of complex, asymmetric three-dimensional structures using 3D printing devices and methods, such as those known to those skilled in the art. Currently, there are three main methods of additive manufacturing: stereolithography (SLA), selective laser sintering (SLS), and fused deposition modeling (FDM).

[0177] The SLA process requires a photopolymer, a liquid plastic resin, which is then cured by an ultraviolet (UV) laser. SLA machines require an excess amount of photopolymer to complete the print and can translate CAD models into printer assembly instructions using a common G-code format. SLA machines typically store the excess photopolymer in a tank beneath the print bed, and as the printing process progresses, the bed is lowered into the tank, curing the continuous layer 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 several hours or even days to complete. Additionally, the uniqueness and limited availability of photopolymers result in relatively high material costs. In one embodiment, one or more components of an IVR (Interactive Visual Resonance) are manufactured by the SLA process.

[0178] The SLS process is similar to SLA, forming parts layer by layer using a high-energy pulsed laser. However, in SLS, the process begins with a tank filled with bulk material in powder form. As printing continues, the bed lowers itself with each new layer, advantageously supporting the overhangs of the upper layers with excess bulk powder not used in forming the lower layers. To facilitate processing, the bulk material is typically heated to just below its transition temperature to allow for faster particle fusion and printing movement, as described in the art. In one embodiment, one or more components of an IVR are manufactured by the SLS process.

[0179] Porous metal materials formed by conventional sintering can suffer from the inherent brittleness of the final product and limited control over pore shape and distribution. Additive manufacturing techniques can overcome some of these limitations, improving control over various pore parameters and mechanical properties, and enabling the fabrication of parts with complex shapes and geometric forms. These include powder bed techniques such as SLS and selective laser melting (SLM). Aluminum and titanium composites can be fabricated by SLS with controlled porosity and mechanical properties by varying the laser power; at low power (25-40W), the material exhibits higher porosity and lower mechanical strength, while at higher laser power (60-100W), macroporous and dense parts produced from IVR structural designs are formed. Advanced manufacturing processes may also be based on layered fabrication to additively fabricate parts. CAD / CAM-based layered fabrication techniques have found applications in the fabrication of nearly net shapes of porous parts with controlled porosity. Electron beam melting (EBM) and direct metal laser sintering (DMLS) processes enable the direct digital fabrication of porous custom titanium interventional radiology (IVR) components with controlled porosity and desired external and internal properties. While typically used in aerospace applications, the systems can be easily extended for use in the manufacture of medical IVRs. EBM is a direct CAD-to-metal rapid prototyping process that allows for the creation of dense, porous metal components by melting metal powder layer by layer with an electron beam, directly solidifying the metal powder into a predetermined 3D structure. SLS and SLM processes are similar but use lasers to melt the powder, typically creating denser structures. Direct 3D deposition and sintering of Ti alloy fibers can produce scaffolds with controlled porosity of 100–700 μm, with total porosity reaching 90%. An alternative is laser-engineered net shaping (LENS), an additive manufacturing technique developed to produce metal parts directly from computer-aided design (CAD) solid models using metal powder injected into a molten pool created by a focused, high-power laser beam.

[0180] Rather than using lasers to form polymers or sintered particles together, FDM works by extruding and positioning continuous layers of material from a polymer molten mass at high temperatures, allowing adjacent layers to cool and bond together before the next layer is deposited. In fused fiber processing (FFF), the most common FDM approach, polymer in the form of filaments is continuously fed to a heated printhead print, thereby melting and depositing onto the print surface. The printhead moves in a horizontal plane to deposit the polymer in a single layer, and either the printhead or the printing platform moves along a vertical axis to initiate a new layer. A second FDM approach uses a printhead design based on a conventional single-screw extruder to melt polymer granules (powder, flakes, or pellets), and the polymer molten mass is extruded through a nozzle, thereby depositing onto the print surface, similar to FFF. This approach allows the use of standard polymer materials in their granular form without the need to first process the filament through a separate extrusion step. In one embodiment, one or more components of an IVR are manufactured by the FDM and / or FFF process.

[0181] In another embodiment, Arburg Plastic Free Forming (APF) is an additive manufacturing technique used in IVR (Interventional Vehicle Refining) production. In this embodiment, a plasticizing cylinder with a single screw is used to produce a homogeneous polymer molten material, similar to the process of thermoplastic injection molding. The polymer molten material is supplied under pressure from the screw cylinder to a piezoelectrically operated deposition nozzle. The nozzle discharges individual polymer droplets of controlled size to pre-calculated positions, building each layer of a three-dimensional polymer print from the molten droplets. The screw and nozzle assembly is fixed in place, and a build platform holding the printed part is moved along three axes to control the droplet deposition positions. The droplets bond together upon cooling to form a solid part. This technique can operate at high temperatures (approximately 300°C) and high pressures (approximately 400 bar). One advantage of the APF method is its direct compatibility with many of the processes used in injection molding and extrusion (e.g., granular polymer raw materials, no organic solvents).

[0182] In another embodiment, droplet deposition modeling (DDM) is used as an additive manufacturing technique, well known in the art for inkjet systems, which involves creating separate flows of material during deposition.

[0183] A preferred additive manufacturing method for forming three-dimensional structures, avoiding continuous layer deposition, is to use Continuous Liquid Interface Fabrication (CLIP), a technique developed by Carbon3D. In CLIP, a three-dimensional object is constructed from a high-speed, continuous flow of liquid resin that is continuously polymerized using UV light under controlled oxygen conditions to form a monolithic structure with the desired geometric shape. The CLIP process can produce solid parts drawn from the resin at speeds of several hundred millimeters per hour. IVR scaffolds containing complex geometric shapes may be formed using CLIP from a variety of materials, including polyurethane and silicone.

[0184] Device usage and applications The primary purpose of the interventional radiology (IVR) systems described herein is to deliver one or more APIs for the treatment, prevention, reduction of the likelihood of having, reduction of the severity of, and / or delay of the progression of a medical condition in a subject, also referred to hereafter as “sign.” In some cases, the target anatomical compartment is the vagina. In other cases, the target body compartment is the systemic circulation. The primary purpose is enhanced by the related intention to improve patient compliance by reducing problems in adherence to treatment and prophylaxis associated with more frequent dosing regimens. Thus, this disclosure relates to multiple signs. Exemplary, non-limiting examples of such signs are provided below in abstract form. Based on these examples, a person skilled in the art can adapt the disclosed technology to other signs. A person skilled in the art will recognize whether such signs involve local drug delivery (i.e., the vagina is the target drug compartment) or systemic drug delivery (i.e., the drug enters the systemic circulation through the vagina).

[0185] Infectious diseases including multiple overlapping infections: In some cases, patients requiring treatment for a disease or disorder disclosed herein, such as an infectious disease, may exhibit symptoms of that disease or disorder. In some cases, patients requiring treatment for a disease or disorder disclosed herein, such as an infectious disease, may be asymptomatic. Patients requiring treatment for a disease or disorder disclosed herein can be identified by those skilled in the art, such as a physician or nurse.

[0186] HIV prophylaxis using one or more suitable antiretroviral agents, including biological agents, and / or one or more vaccines and / or adjuvants delivered from an interventional radiology (IVR); and treatment using one or more suitable antiretroviral agents, including biological agents delivered from an IVR.

[0187] Sexually transmitted infections (STIs), including but not limited to the prevention or treatment of both active and chronic activity, with one or more suitable antimicrobial agents delivered via interventional radiology (IVR). Exemplary but not limited examples of STIs include gonorrhea, chlamydia, genital lymphogranuloma, syphilis including multidrug-resistant (MDR) organisms, hepatitis C virus, and herpes simplex virus.

[0188] Bacterial vaginitis (BV), as well as other microbial vaginal conditions, including but not limited to the prevention or treatment of both active and chronic activity, by one or more suitable agents delivered via interventional radiology (IVR).

[0189] Prevention or treatment of both active and chronically active hepatitis B virus (HBV) with one or more suitable antiviral agents delivered via interventional radiology (IVR).

[0190] Prevention or treatment of both active and chronic herpes simplex virus (HSV) and varicella-zoster virus (herpes zoster) zingles by one or more suitable antiviral agents delivered via interventional radiology (IVR).

[0191] Prevention or treatment of both active and chronic cytomegalovirus (CMV) and congenital CMV infection using one or more appropriate antiviral agents delivered via interventional radiology (IVR).

[0192] Prevention or treatment of malaria, both active and chronic, by one or more suitable antimicrobial agents delivered via interventional radiology (IVR).

[0193] Prevention or treatment of tuberculosis, including multidrug-resistant (MDR) and broadly drug-resistant (XDR) tuberculosis, with both active and chronic activity, by one or more suitable antimicrobial agents delivered via interventional radiology (IVR).

[0194] Treatment or management of acne with one or more suitable drugs delivered via interventional radiology (IVR).

[0195] Prevention or treatment of respiratory viral infections, including but not limited to influenza viruses and coronaviruses, such as SARS-CoV-2.

[0196] Influenza spreads globally in seasonal outbreaks, killing hundreds of thousands or even millions of people annually in pandemic years. For example, three influenza pandemics occurred in the 20th century, killing tens of millions of people, each of which was caused by the emergence of a new virus strain in humans. Often, these new strains result from the spread of existing influenza viruses to humans from other animal species. Influenza viruses are RNA viruses belonging to the Orthomyxoviridae family, which include five genera: influenza A, influenza B, influenza C, Isavirus, and Togottovirus. Influenza A viruses can be subdivided into different serotypes based on antibody responses to these viruses. The serotypes identified in humans are ordered by the number of known human pandemic deaths and 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 (pandemic threat during the 2007-08 flu season), H7N7 (a rare zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2, H7N3, and H10N7. Influenza B causes seasonal influenza, influenza C causes localized epidemics, and both influenza B and C are less common than influenza A.

[0197] Coronaviruses are a common family of viruses that cause a variety of diseases in humans, ranging from the common cold to severe acute respiratory syndrome (SARS). Coronaviruses can also cause many diseases in animals. Coronaviruses are enveloped positive-strand RNA viruses, named for their characteristic crown-like appearance in electron micrographs. Coronaviruses are classified as a family within the order of nidoviruses, which are viruses that replicate using a set of nested mRNA. The coronavirus subfamily is further divided into four genera: alpha, beta, gamma, and delta coronaviruses. Human coronaviruses (HCoV) belong to two genera: alpha coronaviruses (including HCoV-229E and HCoV-NL63) and beta coronaviruses (including HCoV-HKU1, HCoV-OC43, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), and SARS-CoV-2).

[0198] Transplant-graft rejection: Post-transplant therapy for chronic immunosuppression with one or more suitable drugs delivered via interventional radiology (IVR).

[0199] Hormone therapy: Contraception containing estrogen and progestin by one or more suitable drugs delivered via IVR, Infertility treatment using one or more suitable drugs delivered via IVR. Hormone replacement with one or more suitable drugs delivered via IVR. Testosterone replacement with one or more suitable drugs delivered via IVR. Thyroid replacement / blocker, delivered via IVR by one or more suitable drugs. Hormone therapy to regulate triglycerides (TG) using one or more suitable drugs delivered via IVR. Chronic pharmacological support for all transgender individuals (all stages from cis-trans) using one or more suitable drugs delivered via IVR.

[0200] Physiology and pathophysiology: Gastrointestinal (GI) symptoms, including but not limited to diarrhea, pancreatic failure, cirrhosis, fibrosis of all organs; GI organ-associated parasitic diseases, and treatment / management of gastroesophageal reflux disease (GERD), with one or more suitable drugs delivered via interventional radiology (IVR). Cardiovascular symptoms, including but not limited to the treatment / management of hypertension (HTN) (e.g., using statins or equivalents), cerebrovascular / peripheral vascular disease, stroke / embolism / arrhythmia / deep vein thrombosis (DVT) (e.g., using anticoagulants and anti-atherosclerotic cardiovascular disease (ASCVD) agents), and congestive heart failure (CHF) (e.g., using beta-blockers, ACE inhibitors, and angiotensin receptor blockers), with one or more suitable agents delivered via interventional radiology (IVR). Treatment of pulmonary symptoms by one or more suitable agents delivered via interventional radiology, including but not limited to treatment of sleep apnea, asthma, long-term pneumonia, pulmonary HTN, fibrosis, and pneumonia. Treatment / management of bone signs, including but not limited to chronic pain (joints and bones including the sternum), osteomyelitis, osteopenia, cancer, idiopathic chronic pain, and gout, by one or more suitable agents delivered via interventional radiology (IVR). Treatment / management of urological symptoms with one or more suitable agents delivered via interventional radiology, including but not limited to bladder cancer, cervical cancer including radiation therapy resistance, chronic infections (of the entire urinary tract), chronic cystitis, interstitial cystitis, endometriosis, pelvic pain, and incontinence. Cholesterol management with one or more suitable medications delivered via IVR. Metabolic symptoms caused by one or more suitable medications delivered via IVR, including but not limited to the treatment / management of weight gain, weight loss, obesity, malnutrition (substitution), osteopenia, vitamin deficiencies (B vitamins / D), folic acid, and smoking / drug reduction / cessation.

[0201] Diabetes: Treatment and management of diabetes (type 1 and type 2) with one or more suitable drugs (including peptide drugs) delivered via IVR. Allergies and hypersensitivity reactions accompanied by desensitization often require repeated exposure to low doses. Type: Type I (IgE-mediated reaction), Type II (antibody-mediated cytotoxic reaction), Type III (immune complex-mediated reaction), and Type IV delayed-type hypersensitivity reactions caused by one or more suitable drugs delivered via IVR. Hypersensitivity reactions (HSR) caused by one or more suitable drugs delivered via IVR, One or more suitable agents delivered via IVR, including antibiotics, biological agents (drug and antibody portions), chemotherapy (e.g., platin), progesterone, and other treatments known in the art as described in [translate]. Food allergies (e.g., nuts, shellfish) can be treated with one or more suitable medications delivered via IVR. As an alternative to allergy vaccination, the administration of allergy medication using one or more suitable drugs provided by an IVR was recommended for individuals with severe allergic reactions that do not respond to conventional medications, those who experience significant drug side effects, those whose lives are interrupted by allergies / insect bites, or those whose allergies may be life-threatening: anaphylaxis. Autoimmune diseases are often classified as chronic inflammatory diseases:

[0202] Treatment and management of Crohn's disease and ulcerative colitis with one or more suitable agents (e.g., biologics) delivered via IVR. Treatment and management of rheumatoid arthritis (RA) with one or more suitable drugs (e.g., biological agents) delivered via interventional radiology (IVR). Treatment and management of multiple sclerosis (MS) with one or more suitable agents (e.g., biologics) delivered via interventional radiology (IVR). Treatment and management of psoriasis with one or more suitable agents (e.g., biologics) delivered via IVR. Treatment and management of lupus with one or more suitable agents (e.g., biologics) delivered via IVR. Treatment and management of autoimmune thyroiditis with one or more suitable drugs (e.g., biological agents) delivered via interventional radiology (IVR).

[0203] Oncology: Chronic or subchronic cancer management with chemotherapy and targeted therapy (e.g., Ig) using one or more suitable agents delivered via interventional radiology (IVR).

[0204] Blood disorders: Treatment / management of hemophilia A with one or more suitable drugs (e.g., factor VIII orthologs) delivered via IVR. Administration of anticoagulants and / or antiplatelet therapy with one or more suitable drugs delivered via IVR. Treatment / management of leukemia / lymphoma and bone marrow transplantation (MBT) therapy with one or more suitable drugs delivered via interventional radiology (IVR). Iron supplementation therapy with one or more suitable drugs delivered via IVR. Fibroproliferative disorders required blockade.

[0205] Musculoskeletal symptoms: Delivery of one or more anti-inflammatory drugs (e.g., NSAIDs) from IVR, Delivery of low-dose prednisone from IVR, Opioid addiction / pain management with one or more suitable medications delivered via IVR. Hypertrophic fibrosis / scar tissue.

[0206] Psychological and neurological disorders: Treatment and management of depression with one or more suitable drugs delivered via IVR. Treatment and management of schizophrenia and related conditions with one or more suitable drugs delivered via IVR. Treatment and management of bipolar disorder with one or more suitable drugs delivered via IVR. Treatment and management of dythymic disorder with one or more suitable drugs delivered via IVR. Treatment and management of seizure control with one or more suitable drugs delivered via IVR. Treatment and management of ADD / ADHD and attention deficit hyperactivity disorder with one or more suitable drugs delivered via IVR. Treatment and management of early-onset (child / adolescent), substance use, physical, sexual, and emotional abuse, PTSD, and anxiety with one or more suitable medications delivered via IVR. Treatment and management of seizures, including but not limited to epilepsy and traumatic brain injury, by one or more suitable drugs delivered via IVR. Treatment and management of Parkinson's disease with one or more suitable drugs delivered via IVR. Treatment and management of Alzheimer's disease with one or more suitable drugs delivered via interventional radiology (IVR).

[0207] Genetic disorders: Treatment of congenital gene defects, including genetic excess disorders, with one or more suitable drugs delivered via IVR. Treatment of primary immunodeficiency (e.g., agammaglobulinemia, secretory IgA deficiency, sIgA deficiency) with one or more suitable drugs delivered via IVR. Treatment of severe combined immunodeficiency (SCID) including, but not limited to, enzyme replacement therapy (ERT) with pegylated bovine ADA (PEG-ADA) delivered via IVR. Muscular dystrophy treated and managed with one or more suitable drugs delivered via IVR. Treatment or management of Duchenne disease with one or more suitable drugs (e.g., eteplirsen) delivered via IVR. Treatment or management of Pompe disease, including ERT such as intravenous administration of recombinant human alpha-glucosidase acid with one or more suitable agents delivered via IVR. Treatment or management of Gaucher disease, including ERT, with one or more suitable drugs delivered via IVR.

[0208] In the above treatment, one or more beneficial living microorganisms (i.e., probiotics) and / or metabolites (i.e., prebiotics) are delivered as APIs.

[0209] Veterinary signs including all mammals, including but not limited to dogs, cats, horses, pigs, sheep, goats, and cattle.

[0210] In one embodiment, the IVR serves multiple purposes, targeting two or more symptoms simultaneously. An example of such a multipurpose drug delivery IVR involves the prevention of HIV infection by delivery of one or more antiretroviral agents and contraception by delivery of one or more contraceptives. In another embodiment, the multipurpose drug delivery IVR protects against multiple diseases using a single agent. Intravaginal delivery of a peptide broadly active against viruses is used to prevent HIV, HSV, and HPV infections, among other viruses. The peptide can also be combined with other agents (e.g., contraceptives and / or antiviral agents) in the IVR as a multipurpose preventive technique. In another non-limiting embodiment, systemic delivery of ivermectin from the drug delivery IVR disclosed herein can be used to treat parasitic infections as well as certain neurological disorders such as seizures and epilepsy.

[0211] In one embodiment, one of the administered drugs is a contraceptive, such as a hormonal contraceptive known in the art. In another embodiment, the contraceptive is non-hormonal, as known to those skilled in the art. In one preferred embodiment, the non-hormonal contraceptive is active against sperm. For example, ferrous gluconate induces sperm fixation. In another non-limiting example, the non-hormonal contraceptive is a small molecule such as an inhibitor of soluble adenylyl cyclase (sAC:ADCY10), which is essential for male infertility. Other non-limiting examples of non-hormonal contraceptives for men known in the art target EPPIN and cyclin-dependent kinase 2 (CDK2), which are surface proteins on human sperm that have essential reproductive functions. In another embodiment, the non-hormonal contraceptive contains polyvalent IgG with high cohesiveness to capture actively motile sperm. In another embodiment, the contraceptive is administered in combination with one or more APIs targeting different symptoms, such as but not limited to antiviral, antibacterial, antifungal, or antimicrobial agents.

[0212] This disclosure also provides a method for delivering an API to a target via an IVR device of this disclosure, including a kernel containing an excipient and an API. In some cases, the API is delivered in a consistent sustained-release profile. In some cases, the excipient is PEG or TEC.

[0213] Provided herein are methods for delivering one or more APIs to a patient in need thereof, the method comprising implanting a vaginal device disclosed herein into the patient's body. In some cases, the device delivers one or more APIs over a period of 1 to 12 months. In some cases, one or more APIs are delivered over a period of 1 to 3 months. In some cases, the device delivers one or more APIs over a period of 3 to 12 months. In some cases, the device delivers one or more APIs over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the device delivers one API over a period of 1 to 12 months. In some cases, one API is delivered over a period of 1 to 3 months. In some cases, the device delivers one API over a period of 3 to 12 months. In some cases, the device delivers one API over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some cases, the device delivers two or more APIs over a period of 1 to 12 months. In some cases, the device delivers two or more APIs over a period of 1 to 3 months. In some cases, the device delivers two or more APIs over a period of 3 to 12 months. In some cases, the device provides two or more APIs over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0214] In some cases, the API contains a hydrophobic or hydrophilic drug. In some cases, the API contains a hydrophobic drug. In some cases, the API contains a hydrophilic drug. 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).

[0215] Further consideration Conventional IVR designs involve the dissolution of the API in an elastomer, a so-called "matrix design." In some exemplary embodiments disclosed in the art, for example, in the contraceptive IVR NuvaRing®, the matrix is ​​surrounded by a thermoplastic polymer skin. Other conventional IVR designs well known in the art involve a solid API kernel surrounded by a continuous elastomer sheath, a so-called "reservoir design." In some exemplary embodiments disclosed in the art, the elastomer sheath comprises polyurethane, and the API is contained as a powder or microtablet.

[0216] Non-conventional IVR designs generally involve API tablets inserted into an elastomer scaffold, which is an approach used for drug delivery from IVRs. In some exemplary embodiments disclosed in the art, the tablets are not coated with a polymer skin, and drug release occurs through one or more channels formed in an elastomer support that is impermeable to the API. In some embodiments of the IVR designs disclosed herein, the polymer skin does not contain macroscopic (>250 μm) orifices or channels generated during device manufacturing (e.g., via mechanical punching). In yet another exemplary embodiment disclosed in the art, the tablets are coated with a polymer skin, and drug release occurs through one or more channels formed in an elastomer support that is impermeable to the API. In some embodiments of the IVR designs disclosed herein, the API does not contain a coated tablet.

[0217] Other examples of non-traditional IVR designs include complex, open geometric shapes fabricated by additive manufacturing. These designs are essentially versions of matrix-type devices, consisting of interconnected high-surface-area strands of API polymer dispersions.

[0218] The subject matter of this disclosure differs from and offers greater advantages over previously used devices and methods. Various features are described in detail above and below “Implantable Drug Delivery Devices”. Some exemplary non-limiting innovations embodied by various embodiments of this disclosure include:

[0219] Equivalents This disclosure should not be limited 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 this disclosure, as will be obvious to those skilled in the art. In addition to those enumerated herein, functionally equivalent methods, systems, and apparatus within the scope of this disclosure will be obvious 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. This disclosure is limited only by the conditions of the appended claims, along with the entire scope of equivalents to which such claims are entitled. This disclosure is not limited to specific methods, reagents, compound compositions, or biological systems, which are, of course, subject to change. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting. For any and all purposes, including providing written explanations, as will be understood to those skilled in the art, the entire scope disclosed herein also encompasses any and all possible partial scopes and combinations of partial scopes.

[0220] Those skilled in the art will readily see that many modifications can be made to the preferred embodiments without departing from the scope of the preferred embodiments. All matters included herein are intended to be illustrative of the disclosure, not limiting.

[0221] Various aspects and embodiments are disclosed herein, but other aspects and embodiments will be obvious to those skilled in the art. All references cited herein are incorporated by reference in their entirety. [Examples]

[0222] Example 1 - Clinical evaluation of placebo IVR A placebo-based interventional radiology (IVR) of the design disclosed herein was evaluated in a small clinical trial. A total of 12 participants were enrolled; 6 had prior IVR experience, and 6 had never used an IVR before. Women self-inserted the IVR at the clinic and were asked to perform a series of activities (e.g., coughing, straining, deeply bending their knees, jumping in place, lifting a 10-pound weight) 10 times, and to ascend and descend approximately 50 steps if possible. After the IVR remained in place for approximately one hour, clinical evaluations (e.g., pelvic examination, endoscopic examination, colposcopy, ultrasound) were performed. Participants removed the IVR as instructed and returned it to the trial staff for analysis. Participants then completed a short questionnaire (15-30 minutes) before leaving the clinic.

[0223] The first three participants used a placebo IVR, specifically the one shown in Figure 1, with a cassette region height of 8.0 mm, tapering to a diameter of 6.0 mm at the center of the hinge region (the arc-shaped silicone segment connecting the cassettes), and having a silicone durometer value of 60 A. Participants were able to easily insert the IVR but were unable to remove it. Two of the three women required assistance. One participant experienced some discomfort during transvaginal ultrasound with the IVR in place. The discomfort was suspected to be caused by the rigidity of the silicone IVR scaffold, the stiffness of the polycarbonate cassette, or a combination of both.

[0224] The surprising results described above led to a sophisticated IVR design, as shown in Figure 2, specifically a constant-diameter hinge region (an arc-shaped silicone segment connecting the cassettes) with a cassette height of 6.0 mm and a thickness of 6.0 mm, and a silicone durometer value of 50A or 40A (i.e., two prototypes). Both IVRs were evaluated by the remaining nine participants, who were able to insert and remove the devices without any difficulty and experienced no discomfort during transvaginal ultrasound. The results of the IVR fitting study clearly demonstrate that subtle changes in IVR design and mechanical properties can have significant and inconspicuous effects during use that are not predictable in advance by those skilled in the art. The optimal hinge diameter and geometric shape, as well as the cassette height, could not have been predicted without conducting the study. Surprisingly, slight changes in IVR stiffness (i.e., lower durometer values) eliminated previously experienced discomfort during transvaginal ultrasound, while cassette stiffness played no role.

[0225] Example 2 - Study on non-human primates (macaques) The IVR designs disclosed herein, shown in Figures 8A-B and 9A-C, were manufactured with dimensions suitable for use in pigtails and rhesus monkeys during the preclinical development of a vaginal ring drug delivery product. In this example, the elastomer ring was made from 40A durometer silicone (Elkem LSR 4340) and had an outer diameter of 27.5 mm and a cross-sectional diameter of 4.5 mm. The overmolded cassette shell had internal dimensions of 6.2 mm x 9.3 mm and a height of 3.7 mm. The reservoir was molded from 70A durometer silicone (Elkem LSR 4370) with internal reservoir dimensions of 8.5 mm length x 5 mm width x 3.7 mm depth. The cap and shell were injection molded from polycarbonate plastic (Lexan HP1-112). The assembled cassette had a thickness of 5.9 mm.

[0226] To determine the optimal IVR dimensions, a fit study of macaque IVRs was conducted in rhesus monkeys. IVRs with ring outer diameters of 25, 27.5, and 30 mm were prepared in all the other dimensions mentioned above. All three IVRs could be inserted and removed and did not appear to cause discomfort to the animals. Removal of the 27.5 mm and 25 mm IVRs was not more difficult than that of the 30 mm IVR, and as a result, 27.5 mm was selected as the optimal diameter for macaque IVRs in future studies.

[0227] Macau pharmacokinetic and safety studies were conducted using macaque-sized interventional radiologists (IVRs) in rhesus monkeys. Fourteen macaque IVRs were prepared using a drug formulation of the experimental antiretroviral drug SAMT-247 blended 1:1 with monoolein (Myverol 18-92K, Kerry Inc., Beloit WI). 150 mg of the SAMT formulation was dispensed into each reservoir. A rate-controlled release membrane was placed on top of the reservoir, and the membrane was sealed in place with a cassette cap. The release membrane had a thickness of 250 μm and a density of 0.49 g / cm². 3 It was fabricated from stretched polytetrafluoroethylene (ePTFE) with an average density of 41 mm². 2 That was the case.

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Claims

1. A vaginal implant device configured to provide continuous drug delivery to a patient, A scaffold comprising one or more lobes, and one or more hinged areas disposed between the one or more lobes, One or more cassettes are disposed within each of the one or more robes, A vaginal implant device comprising one or more active pharmaceutical ingredients (APIs) disposed within one or more cassettes.

2. The vaginal implant device according to claim 1, wherein each of the one or more hinge regions has a first thickness, and each of the one or more lobes has a second thickness equal to the first thickness.

3. The vaginal implant device according to claim 1, wherein each of the one or more hinge regions has a first thickness, and each of the one or more lobes has a second thickness greater than the first thickness.

4. The vaginal implant device according to any one of claims 1 to 3, wherein each of the one or more cassettes is defined by a cap and a base coupled to the cap, and each of the one or more cassettes further comprises a reservoir defined between the cap and the base of each of the one or more cassettes, and one or more APIs are disposed within the reservoir of each of the one or more cassettes.

5. The vaginal implant device according to claim 4, wherein each of the one or more cassettes further comprises a membrane disposed in the reservoir, and each cap comprises one or more holes for exposing each of the membranes to the patient's vaginal fluid.

6. A vaginal implant device configured to provide continuous drug delivery to a patient, wherein the vaginal implant device is A platform equipped with one or more robes, One or more cassettes are disposed within each of the one or more robes, The system comprises one or more active pharmaceutical ingredients (APIs) disposed within one or more cassettes, Each of the one or more cassettes is defined by a cap and a base coupled to the cap, and further comprises a reservoir defined between the cap and the base of each of the one or more cassettes, and one or more APIs are disposed within the reservoir of each of the one or more cassettes. A vaginal implant device in which each of the one or more cassettes comprises a membrane disposed in the reservoir of each of the one or more cassettes, and each cap comprises one or more first holes for exposing the respective membrane to the patient's vaginal fluid.

7. The vaginal implant device according to claim 6, wherein one of the cap and the base has one or more second holes, and the other of the cap and the base has one or more pins disposed in the one or more second holes, respectively, and configured to connect the base to the cap.

8. The vaginal implant device according to claim 6 or 7, wherein each of the lobes of the scaffold comprises one or more first grooves and one or more second grooves, each cap comprises one or more first ribs sized to fit into the one or more first grooves, and each base comprises one or more second ribs sized to fit into the one or more second grooves.

9. A vaginal implant device configured to provide continuous drug delivery to a patient, wherein the vaginal implant device is A platform equipped with one or more robes, One or more cassettes are disposed within each of the one or more robes, The cassette comprises one or more active pharmaceutical ingredients (APIs) disposed in the reservoirs of one or more cassettes, Each of the one or more cassettes comprises a cap and a base coupled to the cap, thereby defining the reservoir, and (i) each cap has one or more first holes, one or more first ribs supported by one or more edges of the cap, and one or more pins, and each base has an angled lip, one or more second holes disposed on the opposite side of the one or more pins of the cap, and one or more second ribs supported by one or more edges of the base, or (ii) each base has one or more first holes, one or more first ribs supported by one or more edges of the base, and one or more pins, and each cap has an angled lip, one or more second holes disposed on the opposite side of the base, and one or more second ribs supported by one or more edges of the cap, Each of the one or more cassettes further comprises a membrane disposed between the base and the cap, and one or more first holes in each cap or base expose each of the membranes to the patient's vaginal fluid. Each cap or base is sized so that one or more pins are positioned in the one or more second holes of each base or cap. Each of the lobes of the scaffolding is provided with one or more first grooves and one or more second grooves, and each cap or base is sized so that one or more first ribs are positioned in each of the one or more first grooves. A vaginal implant device in which one or more second ribs of each base or cap are sized to fit into the respective one or more second grooves, and the angled lip of each base or cap is configured to assist in the alignment of the respective membranes between the base and the cap.

10. The vaginal implant device according to claim 9, wherein one or more lobes are provided with grooves for accommodating the rib structure that traverses one or more edges of the cap element and / or the base element, thereby clamping the cassette to the scaffold.

11. The vaginal implant device according to claim 9 or 10, further comprising a raised portion disposed on the inner surface of the cap, thereby forming a seal between the membrane, the cap, and the base.

12. The vaginal implant device according to any one of claims 9 to 11, further comprising one or more partitions on the opposite side of the cap for dividing the reservoir into one or more chambers.

13. The vaginal implant device according to any one of claims 9 to 12, wherein the one or more first holes are rectangular, circular, or oval in shape.

14. The vaginal implant device according to any one of claims 9 to 13, wherein about 25% to about 100% of each of the membranes of the cassette is exposed to the patient's vaginal fluid through the one or more first holes.

15. The vaginal implant device according to any one of claims 9 to 14, wherein the membrane has an outer edge portion that contacts the cassette and a central portion that is separated radially inward from the outer edge portion and does not contact the cassette.

16. The vaginal implant device according to any one of claims 1 to 15, wherein the membrane comprises a non-absorbable polymer.

17. The vaginal implant device according to claim 16, wherein the non-absorbent polymer includes poly(ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane), poly(ethylene), fluorinated polymer, poly(siloxane), copolymers thereof, or combinations thereof.

18. The vaginal implant device according to claim 16 or 17, wherein the non-absorbable polymer includes poly(ethylene-co-vinyl acetate), ethylene vinyl acetate (EVA), poly(tetrafluoroethylene), copolymers thereof, or combinations thereof.

19. The vaginal implant device according to claim 18, wherein the non-absorbable polymer comprises stretched poly(tetrafluoroethylene) (ePTFE).

20. The vaginal implant device according to any one of claims 1 to 15, wherein the membrane comprises an absorbent polymer.

21. The vaginal implant device according to claim 20, wherein the absorbent polymer includes poly(lactic acid), poly(glycolic acid), poly(lactic acid-coglycolic acid), poly(caprolactone) (PCL), PCL derivatives, amino alcohol-based poly(esteramide) (PEA), poly(octane-diol citrate) (POC), or a combination thereof.

22. The vaginal implant device according to any one of claims 1 to 21, wherein the scaffold is formed of an elastomer.

23. The vaginal implant device according to claim 22, wherein the elastomer comprises silicone, ethylene-covinyl acetate, polyurethane, thermosetting polyester (TPE), photocurable perfluoropolyether (PFPE), copolymers thereof, or combinations thereof.

24. The vaginal implant device according to claim 22 or 23, wherein the elastomer comprises polydimethylsiloxane (PDMS).

25. The vaginal implant device according to claim 24, wherein the PDMS has a durometer value of approximately 30A to approximately 60A.

26. The vaginal implant device according to claim 24 or 25, wherein the PDMS has a durometer value of approximately 40A to approximately 50A.

27. The vaginal implant device according to any one of claims 1 to 26, wherein one or more of the cassettes are made of a thermoplastic material.

28. The vaginal implant device according to claim 27, wherein the thermoplastic material includes polylactic acid (PLA), polylactic acid-coglycolic acid (PLGA), ethylene-covinyl acetate (EVA), high viscosity rubber (HCR), silicone, polymethyl methacrylate (PMMA), polycarbonate (PC), thermoplastic polyurethane (TPU), polyethylene (PE), polyvinylidene fluoride (PVDF), polyether ether ketone (PEEK), cyclic olefin copolymer (COC), polystyrene (PS), polyvinyl chloride (PVC), and polyethylene terephthalate glycol (PETG), copolymers thereof, or combinations thereof.

29. The vaginal implant device according to claim 27 or 28, wherein the thermoplastic material includes polycarbonate (PC).

30. The vaginal implant device according to any one of claims 1 to 29, wherein the one or more active pharmaceutical ingredients are an antiretroviral agent, an antimicrobial agent, an antibacterial agent, an antiviral agent, a hormone, a contraceptive, a statin, a beta-blocker, an ACE inhibitor, an angiotensin receptor blocker, a vitamin, a steroid, a biological agent, an anticancer agent, an allergy agent, an anticoagulant, an antiplatelet therapy agent, a nonsteroidal anti-inflammatory drug, a vaccine, a microorganism, a metabolite, or a combination thereof.

31. The vaginal implant device according to claim 30, wherein the one or more active pharmaceutical ingredients include an antiviral agent.

32. The one or more active pharmaceutical ingredients mentioned above include zidovudine, cabotegravir, dapivine, fluticasone propionate, chlordiazepoxide, haloperidol, indomethacin, prednisone, ethinylestradiol, acyclovir, tenofovir, atenolol, aminoglycoside, exenatide acetate, leuprolide acetate, acetylsalicylic acid (aspirin), levodopa, remdesivir, acyclovir, and ganci. A vaginal implant device according to claim 30, comprising Clovir, ribavirin, lamivudine, dolutegravir, chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir, EV-100, EV-200, EV-300, EV-400, KD025, tenofovir, emtricitabine, elvitegravir, renacapavir, islatravir, C5A, VRC01, or a combination thereof.

33. The vaginal implant device according to claim 31 or 32, wherein the one or more active pharmaceutical ingredients include tenofovir.

34. The vaginal implant device according to claim 30, wherein one or more active pharmaceutical ingredients include a contraceptive.

35. The vaginal implant device according to claim 34, wherein the contraceptive comprises etonogestrel, estradiol, or a combination thereof.

36. The vaginal implant device according to claim 34 or 35, wherein the contraceptive includes a non-hormonal contraceptive.

37. The vaginal implant device according to claim 36, wherein the non-hormonal contraceptive comprises ferrous gluconate, a soluble adenylyl cyclase inhibitor (sAC:ADCY10), an EPPIN inhibitor, cyclin-dependent kinase 2 (CDK2), polyvalent IgG, or a combination thereof.

38. The vaginal implant device according to any one of claims 1 to 37, wherein the scaffold has an average thickness of approximately 3 to approximately 10 mm.

39. The vaginal implant device according to claim 37, wherein the scaffold has an average thickness of approximately 6 mm.

40. A vaginal implant device according to any one of claims 1 to 39, having a diameter of approximately 45 to 70 mm.

41. A vaginal implant device according to claim 40, having a diameter of approximately 56 mm.

42. The vaginal implant device according to any one of claims 1 to 41, wherein one or more cassettes have an average thickness of about 4 to about 10 mm.

43. The vaginal implant device according to claim 42, wherein one or more cassettes have an average thickness of about 6 mm.

44. The vaginal implant device according to claim 42, wherein one or more cassettes have an average thickness of approximately 8 mm.

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