Vaginal ring device

Abstract

The present disclosure discloses an intravaginal ring (IVR) device that is made of a barrier made of metal, polymer, or a combination of metal and polymer. The IVR is useful for contraception, treatment and / or prevention of sexually transmitted diseases, and treatment and / or prevention of bacterial infections. The IVR is resistant to deformation caused by absorption of vaginal fluids. Therefore, the IVR can perform better over a long period of time than other intravaginal rings that use copolymer silicone.

Description

[Technical field]

[0001] Related Applications This application is a Patent Cooperation Treaty application of U.S. application Ser. No. 17 / 331,119, filed May 26, 2021, which is a bypass continuation-in-part of PCT application Ser. No. PCT / US2020 / 061058, filed November 18, 2020, which claims priority to U.S. application Ser. No. 62 / 937,247, filed November 18, 2019, all of which are incorporated by reference in their entireties, including any drawings.

[0002] The present disclosure relates to the field of women's health. More particularly, the present disclosure relates to an intravaginal ring (IVR) device for use in contraception. The IVR device is comprised of a non-segmented or segmented ring made of an uncoated thermoplastic polymer surrounding a curved or flat non-resorbable barrier, which exhibits significantly less distortion of the ring structure due to absorption of vaginal fluids or moisture generated during storage prior to use, as compared to intravaginal ring devices made of a copolymer silicone matrix. [Background technology]

[0003] Intravaginal ring devices made with a copolymer silicone matrix may distort due to humidity or after a period of use in a subject, which may cause the IVR device to not fit the subject properly and, as a result, the intravaginal ring device may not function as well as a non-distorted device. Also, the incorporation of sperm inhibitors into the ring matrix may weaken the mechanical properties of the ring.

[0004] The present disclosure is directed to novel intravaginal ring devices having ring components and / or ring geometries that reduce or eliminate ring distortion over time that occurs in intravaginal ring devices made with a copolymer silicone matrix, which can result in better fit and more comfort for the subject using the device. Summary of the Invention

[0005] In one embodiment of the present disclosure, disclosed herein is an intravaginal ring (IVR) device having a flat, round or oval ring made of unsplit or split, uncoated thermoplastic elastomer, excluding copolymer silicone, which may contain one or more non-hormonal sperm inhibitors, antibacterial agents, antifungal agents and / or antiviral agents, and which surrounds a curved or flat non-resorbable metal barrier, polymer barrier, combination metal and polymer barrier, or barrier made of a perforated film, which is attached to the ring and does not completely occlude to allow the passage of uterine secretions.

[0006] In other embodiments, disclosed herein is an IVR device comprising a flat, circular or oval ring made of a non-segmented or segmented uncoated thermoplastic elastomer, excluding copolymer silicone, the ring containing one or more active ingredients and surrounding a curved or flat, non-resorbable metal barrier, polymeric barrier, combination metal and polymer barrier, or barrier made of a perforated film, which is attached to the ring and is not completely occluded to allow the passage of uterine secretions.

[0007] In another embodiment, the IVR device comprises a flat circular or oval ring made of a non-segmented or segmented uncoated thermoplastic elastomer, excluding copolymer silicone, which surrounds a curved or flat barrier made of a non-resorbable metal barrier, polymeric barrier, combination metal and polymer barrier, or perforated film, which is attached to the ring, and the metal and polymeric barrier and the perforated film comprise an active ingredient, and the barrier or perforated film does not completely occlude to allow the passage of uterine secretions.

[0008] In some embodiments, the IVR comprises a flat circular or oval ring made of a non-segmented uncoated thermoplastic elastomer, excluding copolymer silicone, which comprises one or more non-hormonal sperm inhibitors, which surround a curved non-resorbable polymeric barrier attached to the ring, and which covers the cervix when inserted into a subject. In other embodiments of this IVR device, the flat circular or oval intravaginal ring is made of a segmented uncoated thermoplastic elastomer. In some embodiments of the flat circular or oval intravaginal ring, the number of segmented ring segments is two or more.

[0009] In some embodiments, the uncoated thermoplastic elastomer of the flat, round or oval intravaginal ring is selected from one or more of styrene butadiene block copolymers, ethylene vinyl acetate copolymers, poly(methyl methacrylate), poly(butyl methacrylate), poly(vinyl chloride), nylon, soft nylon, poly(ethylene terephthalate) (PET), poly(ethylene), poly(acrylonitrile), polychlorotrifluoroethylene (PCTFE), poly(ethylene-vinyl ester), poly(ethylene vinyl acetate), poly(vinyl chloride-diethyl fumarate), polymers of acrylic and methacrylic esters, poly(amides), poly(vinyl chloride), PTFE (polytetrafluoroethylene), poly(urethane), polypropylene or other poly(olefins).

[0010] In some embodiments, the uncoated thermoplastic elastomer for the flat, round or oval intravaginal ring is selected from one or more of ethylene vinyl acetate copolymer (EVA), polyurethane, or polyethylene terephthalate (PET).

[0011] In some embodiments, the uncoated thermoplastic elastomer for the flat, round or oval intravaginal ring is EVA.

[0012] In some embodiments, the flat, round or oval IVR device has a polymeric barrier that is a mesh composed of one or more of metal, polyolefin, nylon, and / or silk. In some embodiments, the polyolefin is polypropylene or polyethylene. In other embodiments, the polymeric mesh of the flat, round or oval IVR device is a monofilament or multifilament polymer. In some embodiments of the flat, round or oval IVR device, the polymeric barrier or mesh comprises one or more sperm inhibitory metals and / or metal salts as an active ingredient. In some embodiments, the metal salt is selected from one or more of calcium chloride, magnesium chloride, ferrous sulfate, ferrous gluconate, iron amino acid chelate, copper sulfate, copper gluconate, silver nitrite, copper amino acid chelate, and copper oxide.

[0013] In some embodiments of the flat, round, or oval IVR device, the IVR device has a metal barrier comprising one or more of aluminum, copper, stainless steel, titanium, nickel, nickel titanium, and precious metals such as, but not limited to, gold, silver, platinum, or palladium. In some embodiments, when the metal barrier is composed of copper or silver, the metal barrier has a sperm-inhibiting effect. In some embodiments, the metal barrier is a monofilament or multifilament polymer.

[0014] In some embodiments, the flat, round or oval shaped IVR instrument comprises two or more sections.

[0015] In another embodiment, the flat, round or oval IVR device has a barrier that is a combination of metal and polymer, and the combination barrier is attached to a ring. In some embodiments of this aspect, the metal and / or polymer can be monofilament or multifilament. In some embodiments, the polymeric barrier portion is composed of one or more of polyolefin, nylon, and / or silk. In other embodiments, the polyolefin is polypropylene or polyethylene. In some embodiments, the metal portion of the barrier is composed of one or more of aluminum, copper, stainless steel, titanium, nickel, nickel titanium, gold, silver, platinum, or palladium. In some embodiments, the metal and / or polymeric portion of the barrier includes one or more sperm inhibitory metals and / or metal salts as active ingredients. In some embodiments, the metal salt is selected from one or more of calcium chloride, magnesium chloride, ferrous sulfate, ferrous gluconate, iron amino acid chelate, copper sulfate, copper gluconate, silver nitrite, copper amino acid chelate, and copper oxide.

[0016] In some embodiments of the flat, round or oval IVR device, the use of metal salts results in intravaginal ion concentrations ranging from about 0.5 to about 20 μM per day. In some embodiments, the sperm-inhibiting metal and / or metal salt is part of the ring. In other embodiments, the metal and / or metal salt is part of the barrier or mesh. In some embodiments, the metal ion release can act as both a sperm-inhibiting agent and an antimicrobial agent.

[0017] Also disclosed herein are flat, round or oval IVR devices in which the barrier is a perforated film. In some embodiments, the perforated film comprises multiple offset layers. In some embodiments, the perforated film is made of a polymer such as 1,2-polybutadiene, ethylene vinyl acetate, polyethylene, silicone gel, polyurethane, etc.

[0018] In some embodiments, the flat, round or oval IVR devices disclosed herein also contain ascorbic acid. In some embodiments, the ascorbic acid is part of a ring. In other embodiments, the ascorbic acid is part of a barrier, such as a metal barrier, a polymer barrier, a combination metal and polymer barrier, or a perforated film barrier.

[0019] In some embodiments, the flat, round, or oval IVR devices, polymeric barriers, metal barriers, metal / polymer combination barriers, or perforated film barriers disclosed herein have pores with sizes ranging from about 100 to 150 μm, 80 μm to about 150 μm, or about 80 μm to about 130 μm, or about 80 μm to about 90 μm, or about 80 μm to about 100 μm, or about 80 μm to about 110 μm, or about 80 μm to about 120 μm.

[0020] The term "about" is used herein to mean approximately, roughly, in the vicinity of, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value above and below (higher or lower) by a variance of 20%.

[0021] In some embodiments, the flat, round or oval IVR device has a removal tab, lanyard or tag or similar structure that aids in removing the ring after insertion. In some embodiments, the removal tab has a diameter of about 10 mm to about 20 mm in length and is integrated into the outer ring structure. In some embodiments, the tab is part of the ring and the tag is part of the barrier. In some embodiments, the tab is made of the same material as the ring and the tag is made of the same material as the barrier. In some embodiments, the lanyard is integrated into the barrier and extends about 30 mm distally from the intravaginal ring.

[0022] In some embodiments, the flat, round or oval ring has an active agent for preventing pregnancy and / or treating or preventing bacterial, fungal and / or viral infections. In some embodiments, the active agent is a non-hormonal or hormonal contraceptive, and the antiviral agent is used to treat or prevent one or more sexually transmitted diseases. In some embodiments, the antiviral agent is one or more of tenofovir, atanzanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, efavirenz, or nelfinavir. In some embodiments, the hormonal contraceptive is one or more of desogestrel, drospirenone, ethinyl estradiol, levonorgestrel, medroxyprogesterone acetate, norelgestromin, norethindrone, norgestimate, or norgestrel. In some embodiments, the intravaginal ring contains the active ingredient contained in discrete reservoirs as part of a thermoplastic elastomer and / or continuously coated with a polymer, as shown in FIG.

[0023] In another aspect of the present disclosure, the flat, round or oval shaped ring device is resistant to distortion of shape due to absorption of vaginal fluids and / or fluids contained in the packaging used to store the device prior to use.

[0024] In another aspect of the present disclosure, the flat, round or oval shaped ring device is resistant to distortion of shape due to absorption of vaginal fluids and / or fluids contained in the packaging used to store the device prior to use.

[0025] In some embodiments, a flat, circular ring intravaginal device absorbs about 95%, 90%, 85%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% less simulated vaginal fluid compared to an intravaginal ring made with a copolymer silicone matrix when both contain equivalent amounts and compositions of non-hormonal sperm inhibitors.

[0026] In some embodiments, when a flat, circular ring intravaginal device and an intravaginal ring made of a copolymer silicone matrix contain equivalent amounts and compositions of non-hormonal sperm inhibitors, the former device absorbs from about 1% to 95% less simulated vaginal fluid compared to the latter intravaginal ring, or anywhere between about 1% to 95% less.

[0027] In some embodiments of the present disclosure, disclosed herein is an IVR device comprising a saddle-shaped oval ring made of a non-segmented or segmented uncoated thermoplastic elastomer, excluding copolymer silicone, wherein the ring comprises one or more active ingredients, and wherein the ring surrounds a curved non-resorbable metal barrier, polymeric barrier, combination metal and polymer barrier, or barrier made of a perforated film, wherein the barrier is attached to the ring and does not completely occlude to allow the passage of uterine secretions.

[0028] In another embodiment, disclosed herein is an intravaginal ring device comprising a saddle-shaped oval ring made of a non-segmented or segmented uncoated thermoplastic elastomer, excluding copolymer silicone, said ring surrounding a barrier made of a curved or flat non-resorbable metal barrier, polymeric barrier, combination metal and polymer barrier, or perforated film, attached to the ring, wherein the metal and polymeric barrier and said perforated film optionally comprise an active ingredient, said barrier or perforated film does not completely occlude to allow the passage of uterine secretions.

[0029] In another embodiment, disclosed herein is an IVR device comprising a saddle-shaped oval ring made of a non-split, uncoated thermoplastic elastomer, excluding copolymer silicone, said ring comprising one or more non-hormonal sperm inhibitors, and the ring encircling a curved non-resorbable polymeric barrier attached to the ring and covering the cervix.

[0030] In another embodiment of the present disclosure, disclosed herein is an intravaginal ring device that is a saddle-shaped oval ring made of unsplit or split uncoated thermoplastic elastomer, excluding copolymer silicone. The saddle-shaped intravaginal ring contains one or more non-hormonal sperm inhibitors or hormonal contraceptives, and the saddle-shaped oval ring surrounds a curved non-resorbable metal barrier, polymer barrier, combination metal and polymer barrier, or barrier made of a perforated film, which is attached to the ring and does not completely occlude to allow the passage of uterine secretions.

[0031] In some embodiments, the thermoplastic elastomer of the saddle oval ring is selected from the group consisting of one or more of styrene butadiene block copolymers, ethylene vinyl acetate copolymers, poly(methyl methacrylate), poly(butyl methacrylate), poly(vinyl chloride), nylon, soft nylon, poly(ethylene terephthalate) (PET), poly(ethylene), poly(acrylonitrile), polychlorotrifluoroethylene (PCTFE), poly(ethylene vinyl ester), poly(ethylene-vinyl acetate), poly(vinyl chloride-diethyl fumarate), polymers of acrylic and methacrylic esters, poly(amides), poly(vinyl chloride), PTFE (polytetrafluoroethylene), poly(urethane), polypropylene or other poly(olefins).

[0032] In some embodiments, the uncoated thermoplastic elastomer for the saddle-type elliptical ring IVR device is selected from one or more of ethylene vinyl acetate copolymer, polyurethane, or PET.

[0033] In some embodiments, the saddle-shaped oval ring IVR device has a polymeric barrier mesh composed of one or more of polyolefin, nylon, and / or silk. In some embodiments, the polyolefin is polypropylene or polyethylene. In some embodiments, the polymeric barrier mesh is a monofilament or multifilament polymer. In some embodiments of the saddle-shaped oval ring IVR device, the polymeric barrier or mesh comprises one or more sperm-inhibiting metals and / or metal salts as an active ingredient. In some embodiments, the metal salts are selected from one or more of calcium chloride, magnesium chloride, ferrous sulfate, ferrous gluconate, iron amino acid chelate, copper sulfate, copper gluconate, silver nitrite, copper amino acid chelate, and copper oxide.

[0034] In some embodiments, the use of metal salts results in intravaginal ion concentrations ranging from about 0.5 to about 20 μM per day. In some embodiments, the sperm-inhibiting metal and / or metal salt is part of a ring. In other embodiments, the metal and / or metal salt is part of a barrier or mesh. In some embodiments, the metal ion release can act as both a sperm-inhibiting agent and an antibacterial agent.

[0035] In some embodiments, the saddle-type elliptical ring intravaginal device has a metal barrier comprising one or more of aluminum, copper, stainless steel, titanium, nickel, nickel titanium, and precious metals, such as, but not limited to, gold, silver, platinum, or palladium. In some embodiments, when the metal barrier is composed of copper or silver, the metal barrier has a sperm-inhibiting effect. In some embodiments, the metal barrier is a monofilament or multifilament polymer.

[0036] In some embodiments, the saddle-type oval ring intravaginal device comprises two or more sections.

[0037] In another embodiment, the saddle-shaped oval ring intravaginal device disclosed herein has a barrier that is a combination of metal and polymer, and the combination barrier is attached to the ring. In some embodiments, the metal and / or polymer can be monofilament or multifilament. In some embodiments, the polymeric barrier portion comprises one or more of polyolefin, nylon, and / or silk. In other embodiments, the polyolefin is polypropylene or polyethylene. In some embodiments, the metal portion of the barrier comprises one or more of aluminum, copper, stainless steel, titanium, nickel, nickel titanium, gold, silver, platinum, or palladium. In some embodiments, the metal and / or polymer portion of the barrier comprises one or more sperm-inhibiting metals and / or metal salts as active ingredients. In some embodiments, the metal salts are selected from one or more of calcium chloride, magnesium chloride, ferrous sulfate, ferrous gluconate, iron amino acid chelate, copper sulfate, copper gluconate, silver nitrite, copper amino acid chelate, and copper oxide.

[0038] Also disclosed herein is a saddle-shaped elliptical ring IVR device in which the barrier is a perforated film. In some embodiments, the perforated film comprises multiple offset layers. In some embodiments, the perforated film is made of a polymer such as 1,2-polybutadiene, ethylene vinyl acetate, polyethylene, silicone gel, or polyurethane.

[0039] In some embodiments, the saddle-type elliptical ring IVR devices disclosed herein also include ascorbic acid. In some embodiments, the ascorbic acid is part of the ring. In other embodiments, the ascorbic acid is part of a barrier, such as a metal barrier, a polymeric barrier, a combination metal and polymer barrier, or a perforated film barrier.

[0040] In some embodiments, the saddle-shaped, oval ring IVR devices, polymeric, metal, metal / polymer combination, or perforated film barriers disclosed herein have pores with sizes ranging from about 100 to 150 μm, 80 μm to about 150 μm, or about 80 μm to about 130 μm, or about 80 μm to about 90 μm, or about 80 μm to about 100 μm, or about 80 μm to about 110 μm, or about 80 μm to about 120 μm.

[0041] In some embodiments, the saddle-shaped oval ring IVR device has a removal tab, lanyard, tag, or similar structure to aid in removal of the ring after insertion. In some embodiments, the removal tab has a diameter of about 10 mm to about 20 mm in length and is integrated into the outer ring structure. In some embodiments, the tab is part of the ring and the tag is part of the barrier. In some embodiments, the tab is made of the same material as the ring and the tag is made of the same material as the barrier. In some embodiments, the lanyard is integrated into the barrier and extends about 30 mm distal to the intravaginal ring.

[0042] In some embodiments, the saddle-shaped oval ring IVR device has an active agent for preventing pregnancy and / or treating or preventing bacterial, fungal, and / or viral infections. In some embodiments, the active agent is a non-hormonal or hormonal contraceptive, and the antiviral agent is used to treat or prevent one or more sexually transmitted diseases. In some embodiments, the antiviral agent is one or more of tenofovir, atanzanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, efavirenz, or nelfinavir. In some embodiments, the hormonal contraceptive is one or more of desogestrel, drospirenone, ethinyl estradiol, levonorgestrel, medroxyprogesterone acetate, norelgestromin, norethindrone, norgestimate, or norgestrel. In some embodiments, the intravaginal ring comprises the active ingredient contained in discrete reservoirs as part of a thermoplastic elastomer and / or continuously coated with a polymer, as shown in FIG.

[0043] In some embodiments, the saddle-shaped oval ring intravaginal device absorbs less simulated vaginal fluid or water compared to an intravaginal ring made with a copolymer silicone matrix when both rings contain equal amounts and compositions of non-hormonal sperm inhibitors and ascorbic acid, if any.

[0044] In some embodiments, the simulated vaginal fluid absorption of a saddle-type oval ring intravaginal device is about 95%, 90%, 85%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% less than an intravaginal ring made with a copolymer silicone matrix when both rings contain equivalent amounts and compositions of non-hormonal sperm inhibitors.

[0045] In some embodiments, the water absorption of a saddle-type oval ring intravaginal device is about 1% to 95% less, or any range between about 1% to 95%, compared to an intravaginal ring made with a copolymer silicone matrix, when both rings contain equivalent amounts and compositions of non-hormonal sperm inhibitors. [Brief description of the drawings]

[0046] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The present disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0047] The drawings depict exemplary aspects of the disclosed aspects and embodiments, however, the scope of the invention is not limited to the specific embodiments disclosed in these drawings, which are for illustrative purposes only, since other embodiments may achieve similar results.

[0048] [Figure 1] FIG. 1 is a perspective view of an intravaginal ring device of the present disclosure having a curved polymeric barrier and a flat circular ring.

[0049] [Diagram 2] FIG. 2 is a side view of the intravaginal ring device of FIG. 1, also showing the rounded or curved cross-section of the ring.

[0050] [Diagram 3] FIG. 1 is a perspective view of an intravaginal ring device of the present disclosure having a saddle ring and a curved polymeric barrier.

[0051] [Figure 4] FIG. 4 is a side view of the intravaginal ring device of FIG. 3, also showing the rounded or curved cross-section of the saddle ring.

[0052] [Diagram 5] FIG. 2 is a perspective view of an intravaginal ring device of the present disclosure having a split ring, a curved polymeric barrier and a removal tap.

[0053] [Figure 6] FIG. 6 is a side view of the intravaginal device of FIG. 5, also showing the rounded or curved cross-section of the ring.

[0054] [Figure 7] 1A-1D are plan and cross-sectional views of the ring portion of an intravaginal device with drug-containing reservoirs formed in the ring body in various configurations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] Disclosed herein is an intravaginal ring (IVR) device. In some embodiments, the intravaginal ring device comprises a flat, round or oval ring made of unsegmented or segmented uncoated thermoplastic elastomer, excluding copolymer silicone. The ring surrounds a curved non-resorbable polymer barrier, metal barrier, combination metal and polymer barrier, or perforated film barrier attached to the ring and covers the cervix.

[0056] In other embodiments, the IVR device disclosed herein is a saddle-shaped oval ring made of a non-segmented or segmented uncoated thermoplastic elastomer that surrounds a curved non-resorbable polymeric, metal, metal and polymer combination, or perforated film barrier that is attached to the ring and covers the cervix.

[0057] In some embodiments, the IVR devices disclosed herein have a barrier that does not completely occlude to allow the passage of uterine secretions.

[0058] Thermoplastic elastomers, as used herein, are copolymers or blends of polymers having thermoplastic and elastomeric properties, excluding silicone polymers.

[0059] Thermoplastic polymers suitable for the IVR devices disclosed herein include polymers and copolymers that can be softened by heating and hardened by cooling within a temperature range characteristic of the polymer, i.e., crystalline melting or glass transition temperature, and, in the softened state, shaped by flowing into a molding or extrusion system. Thermoplastic polymers suitable for the present purposes are permeable to non-hormonal sperm inhibitors, ascorbic acid, antibacterial agents, antifungal agents, and absorb small amounts of vaginal fluids upon insertion into a subject.

[0060] Thermoplastic polymers that can be used to fabricate the IVR devices of the present disclosure include, by way of example and without limitation, ethylene vinyl acetate copolymers, poly(methyl methacrylate), poly(butyl methacrylate), poly(vinyl chloride), nylon, soft nylon, poly(ethylene terephthalate) (PET), poly(ethylene), PCTFE (polychlorotrifluoroethylene), poly(ethylene vinyl ester), poly(ethylene-vinyl acetate), poly(vinyl chloride-diethyl fumarate), polymers of acrylic and methacrylic esters, poly(amides), poly(vinyl chloride), poly(urethane), polypropylene, and other poly(olefins). These polymers and their physical properties are known to those skilled in the art and can be synthesized by the procedures disclosed in Encyclopedia of Polymer Science and Technology, Vol. 15, pp. 508-530, 1971, published by Interscience Publishers, Inc., New York, Polymers, Vol. 17, pp. 938-956, 1976, and Technical Bulletin SCR-159, 1965, published by Shell Corp. and the references cited therein.

[0061] In some embodiments, the ring of the IVR device of the present disclosure comprises one or more sperm-inhibiting metals and / or metal salts. The salts may be selected from one or more of calcium chloride, magnesium chloride, ferrous sulfate, ferrous gluconate, iron amino acid chelate, copper sulfate, copper gluconate, silver nitrite, copper amino acid chelate, and copper oxide.

[0062] In some embodiments, the barrier of the intravaginal device disclosed herein is a mesh composed of one or more of metal, polyolefin, nylon, and / or silk. In some embodiments, the metal has a sperm-inhibiting effect and / or an antibacterial effect by incorporating filaments such as copper or silver into the mesh / barrier. Other metals such as aluminum, stainless steel, titanium, nickel, nickel-titanium, and precious metals such as, but not limited to, gold, platinum, and palladium are useful for the mechanical strength of the barrier. In some embodiments, the metal mesh also includes one or more metal salts, such as iron salts to provide iron ions for the sperm-inhibiting effect. In some embodiments, the polyolefin is polypropylene or polyethylene. In some embodiments, the polymeric or metallic barrier is monofilament or multifilament. In some embodiments, the polymeric barrier mesh and / or metallic barrier mesh has pores with a size ranging from about 100 to 150 μm. In some embodiments, the polymeric or metallic barrier mesh has pores with sizes ranging from about 80 μm to about 150 μm, or from about 80 μm to about 130 μm, or from about 80 μm to about 90 μm, or from about 80 μm to about 100 μm, or from about 80 μm to about 110 μm, or from about 80 μm to about 120 μm.

[0063] In other embodiments, the barrier is made of a perforated film, which can be made of multiple layers with offset perforated layers. In some embodiments, the film can be made of a polymer, such as, but not limited to, 1,2-polybutadiene, ethylene vinyl acetate, polyethylene, silicone gel, polyurethane, etc. In some embodiments, metal filaments and / or metal salts are incorporated into at least the outermost perforated layer. In some embodiments, the perforated film has pores ranging in size from about 80 μm to about 150 μm, or from about 80 μm to about 130 μm, or from about 80 μm to about 90 μm, or from about 80 μm to about 100 μm, or from about 80 μm to about 110 μm, or from about 80 μm to about 120 μm.

[0064] The pore size of a polymer mesh, metal mesh or perforated film can be measured microscopically.

[0065] In one embodiment of the IVR device of the present disclosure, the intravaginal ring can use a multipurpose prevention technology (MPT) that combines prevention of unintended pregnancy and prevention of HIV and other sexually transmitted infections. In some embodiments, the intravaginal ring can include one or more portions, each portion containing a separate active ingredient, for example, an antiviral agent such as tenofovir, dapivirine, atanzanavir, darunavir, fos / amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, efavirenz, cabotegravir, or nelfinavir, or a non-hormonal contraceptive, such as a metal salt, for example, as described herein, or a hormonal contraceptive, such as segesterone, desogestrel, drospirenone, ethinyl estradiol, levonorgestrel, medroxyprogesterone acetate, norelgestromin, norethindrone, norgestimate, or norgestrel. In some embodiments, the concentration of the antiviral agent results in a dosage ranging from about 0.1 to about 10 mg per day, and in some embodiments, the concentration of the hormonal agent results in a dosage ranging from about 0.01 to about 2 mg per day.

[0066] In some embodiments of MPT, the non-hormonal agent is contained in or on the barrier mesh, such as by incorporation into the mesh material or spraying the non-hormonal agent onto the barrier mesh. In another embodiment, the barrier mesh contains a low-dose hormonal contraceptive instead of a non-hormonal metal salt. In another embodiment, the barrier mesh contains both a non-hormonal contraceptive and a low-dose hormonal contraceptive.

[0067] In some embodiments of the IVR disclosed herein, the active ingredient (API) can be placed in a preformed reservoir within the polymer ring, which can optionally be covered and sealed with additional polymeric structures using techniques known in the art, including but not limited to molding, gluing, welding, etc.

[0068] In some embodiments, the antiviral, antibacterial and / or antifungal agent is present in the ring portion of the IVR device. In other embodiments, the antiviral, antibacterial and / or antifungal agent is present only in the barrier of the IVR device. In some embodiments, the antiviral, antibacterial and / or antifungal agent is present in the barrier and / or ring of the IVR device.

[0069] In some embodiments, the IVR device absorbs less vaginal fluid from a subject using the device compared to an intravaginal ring device made from a copolymer silicone matrix.

[0070] The ability of the disclosed IVR device to absorb less vaginal fluid or water compared to a polysilicone vaginal ring can be tested in vitro using fluids such as water or simulated vaginal fluid. Example 6 provides a method for testing the absorption of simulated vaginal fluid by the IVR device.

[0071] In some embodiments, the IVR devices disclosed herein distort less than intravaginal ring devices made from a copolymer silicone matrix when used in a subject for a period of about 14 days to about 3 months or when stored in moisture sensitive packaging prior to use. Thus, the rings of the present disclosure maintain their shape longer than intravaginal ring devices made from a copolymer silicone matrix, resulting in better fit, performance and comfort in subjects using the devices of the present disclosure.

[0072] In some embodiments, the IVR comprises ascorbic acid.

[0073] In some embodiments, the IVR device can be used for at least 14 days.

[0074] In some embodiments, the intravaginal ring devices disclosed herein are non-resorbable in the subject.

[0075] In some embodiments, the devices disclosed herein can be used for about 30 days to about 31 days, or about 1 month to about 3 months, hi some embodiments, the devices disclosed herein can be removed between menstrual cycles, washed, and reused after multiple menstrual cycles.

[0076] Example 4 describes one embodiment of manufacturing an IVR device as disclosed herein with a sperm-inhibiting barrier. Example 4 also describes the fabrication of the barrier mesh using a 3D knitting machine.

[0077] Example 5 describes one embodiment of making an IVR device in which the ring contains a beneficial agent and the barrier mesh contains a sperm-inhibiting barrier.

[0078] In order to facilitate a more complete understanding of the present invention, several examples are set forth below. The following examples illustrate exemplary modes of making and practicing the present invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only, since alternative methods may be utilized to achieve similar results. EXAMPLES

[0079] Example 1 Flat Ring The barrier mesh of the ring device shown in Figure 1 is fabricated by extruding poly(propylene), nylon, or poly(ethylene) multifilament or monofilament and using a 3D knitting machine and warp knitting pattern to create a spherical cap shape. The outer diameter dimensions of the spherical cap shape are approximately 50 mm (millimeters) and the height is approximately 15 mm.

[0080] Alternatively, a multifilament or monofilament of sericin-free silk fibroin was knitted using a 3D knitting machine and warp knitting pattern to create a spherical cap-shaped shape in which the sphere is cut with a saddle rather than a flat surface (Figure 3). This spherical cap shape has an outer dimension of about 50 mm (millimeters) and a height of about 15 mm.

[0081] The intravaginal contraceptive ring device shown in FIG. 1 is prepared using poly(ethyl-co-vinyl acetate) (EVA), about 500 (milligram) mg of ferrous gluconate, and about 400 mg of ascorbic acid, which are dissolved together in about 10 mL of a non-polar solvent, such as dichloromethane, in a scintillation vial. A polymer mixture is then prepared by adding about 4000 mg of EVA to the solution and mixing the EVA / drug composition using a rotary shaker. The resulting mixture is solvent cast in dry ice using ethanol as the solvent. The solvent is allowed to evaporate overnight, and the dried EVA / drug mixture is ground into a powder. The EVA / drug powder is placed into an injection molding machine. The injection molding machine is heated to about 80°C. The barrier mesh is held in a stainless steel mold using an insert molding fixture, and then the molten EVA / drug composition is extruded into the stainless steel mold to produce a finished product with an outer diameter of about 55 mm and a cross section of about 4 mm.

[0082] Alternatively, an intravaginal contraceptive ring device as shown in FIG. 1 is made by a similar process as described above using polyurethane or polyethylene terephthalate as the ring material and copper gluconate and ascorbic acid as the sperm inhibitors. Example 2 Saddle ring

[0083] The barrier mesh of the ring device shown in Figure 3 is fabricated by extruding poly(propylene), nylon, or poly(ethylene) multifilament or monofilament and using a 3D knitting machine and warp knitting pattern to create a spherical cap shape with a portion of the sphere cut into a saddle shape rather than a flat surface (Figure 3). This spherical cap shape has outer dimensions of approximately 50 mm (millimeters) and a height of approximately 15 mm.

[0084] Alternatively, silk fibroin multifilaments or monofilaments without sericin were knitted using a 3D knitting machine and warp knitting pattern to form a spherical cap shape with a saddle-shaped cutout rather than a flat surface (Figure 3), with outer dimensions of approximately 50 mm (millimeters) and a height of approximately 15 mm. Example 3 Flat Ring with Removal Tab

[0085] The barrier mesh of the ring device is fabricated using the process in Example 1 above.

[0086] The intravaginal contraceptive ring device shown in Figure 5 is prepared using poly(ethyl-co-vinyl acetate) (EVA). Approximately 250 (milligram) mg of ferrous gluconate is dissolved in about 5 mL of a non-polar solvent such as dichloromethane in a scintillation vial. Approximately 2000 mg of EVA is then added to the solution and a polymer mixture is prepared by mixing the EVA / drug composition using a rotary shaker.

[0087] A semicircle of EVA / ascorbic acid is prepared by the process described above. The two semicircles are then fused together to form a complete circle with a semicircular cross-sectional shape with an outer diameter of approximately 55 mm.

[0088] The EVA is then placed into an injection molding machine. The mold is circular with an outer diameter of approximately 55 mm, with a release tab protruding from one side of the circle, and a semicircular cross-sectional diameter of approximately 4 mm. The injector is heated to approximately 80°C, forcing the molten EVA / ferric gluconate into a stainless steel mold. The two ring halves are then welded together with the barrier mesh in the middle to form the finished product.

[0089] Alternatively, the intravaginal contraceptive ring device shown in FIG. 5 can be fabricated using the same process as above, using polyurethane or polyethylene terephthalate as the ring material and copper gluconate and ascorbic acid as the sperm inhibitors. Example 4 IVR Ring Device with Sperm Inhibitory Barrier

[0090] The intravaginal ring device is manufactured using EVA polymer by injection molding in a similar manner to Example 1, however, no drugs or sperm inhibitors are incorporated into the polymer mixture prior to molding.

[0091] The barrier mesh of the ring device is fabricated by extruding poly(propylene), nylon, or poly(ethylene) multifilaments or monofilaments, and copper or silver multifilaments or monofilaments, and using a 3D knitting machine and warp knitting pattern to create a spherical cap shape that combines the polymer and metal filaments into one integrated structure. The outer diameter of the spherical cap shape is approximately 50 mm (millimeters) and the height is approximately 15 mm.

[0092] Alternatively, the barrier mesh of the ring device is fabricated by combining a metal salt (e.g., copper gluconate) with a suitable polymer in a manner similar to that described in Example 1, extruding a multifilament or monofilament of the composite metal salt / polymer filament, and using a 3D knitting machine and warp knitting pattern to create a spherical cap shape containing the sperm inhibitor. Example 5 IVR Ring Device with Active Substance and Sperm Inhibitory Barrier

[0093] The intravaginal contraceptive ring device shown in FIG. 1 is made by blending about 2200 g of poly(ethyl-co-vinyl acetate) (EVA) in dry powder form with about 800 g of active agent (e.g., cabotegravir). The polymer / drug powder premix is ​​fed into a screw extruder to produce drug-loaded polymer pellets. The extruder is operated at about 4 m / min, the melt temperature is about 85° C., and the melt pressure is about 35 bar. The EVA / drug pellets are fed into an injection molding apparatus. The injector is heated to about 80° C. The barrier mesh is held in a stainless steel mold using an insert molding fixture and the molten EVA / drug composition is extruded into the stainless steel mold to produce a finished product with an outer diameter of about 55 mm and a cross section of about 4 mm.

[0094] The barrier mesh of the ring device is fabricated by extruding poly(propylene), nylon, or poly(ethylene) multifilaments or monofilaments, and copper or silver multifilaments or monofilaments, and using a 3D knitting machine and warp knitting pattern to create a spherical cap shape that combines the polymer and metal filaments into one integrated structure. The outer diameter of the spherical cap shape is approximately 50 mm (millimeters) and the height is approximately 15 mm.

[0095] Alternatively, the barrier mesh of the ring device is fabricated by combining a metal salt (e.g., copper gluconate) with a suitable polymer in a manner similar to that described in Example 1, extruding a multifilament or monofilament of the composite metal salt / polymer filament, and using a 3D knitting machine and warp knitting pattern to create a spherical cap shape containing the sperm inhibitor. Example 6 Measurement of absorption of synthetic vaginal fluid

[0096] The IVR device of the present disclosure is weighed on an analytical balance. It is then immersed in about 100 mL of simulated vaginal fluid (SVF) at 37° C. for 14 to 35 days. For the preparation of simulated vaginal fluid, see, for example, Rastogi R. et al., (2016), Engineering and Characterization of Simplified Vaginal and Seminal Fluid Simulants, Contraception, 2016, 93(4), pp. 337-346. The ring is then removed from the simulated vaginal fluid, wiped with a Kimwipe, and reweighed. The ring is then placed in a vacuum oven to remove absorbed moisture. The ring is kept in the vacuum oven for a period of time to dry until it reaches a constant weight. Its final dry weight is recorded.

[0097] The same process is repeated for the control rings. Water absorption is quantified by subtracting the wet ring weight from the dry ring weight to obtain the weight of water absorbed per ring. The weight of water absorbed in the control ring is divided by the weight of water absorbed in the control ring to quantify the percentage reduction in water absorption.

[0098] The examples and embodiments described herein are intended to be illustrative, and various modifications or changes suggested to those skilled in the art are intended to be within the spirit and scope of this application and the appended claims.

Claims

1. A vaginal ring device comprising a saddle-shaped elliptical ring made of a thermoplastic elastomer without an undivided or divided coating, excluding copolymersilicone, wherein the ring contains one or more active ingredients, and the ring is surrounded by a curved non-absorbent metal barrier, a polymer barrier, a barrier that is a combination of one or more metals and one or more polymers, or a barrier made of a perforated film, the barrier is attached to the ring, and the barrier is not completely occluded to allow the passage of uterine secretions, a vaginal ring device.

2. The vaginal ring device according to claim 1, wherein the polymer barrier is a mesh composed of one or more of polyolefin, nylon, and / or silk.

3. The vaginal ring device according to claim 1 or 2, wherein the ring contains one or more sperm-suppressive metals and / or metal salts as active substances.

4. A vaginal ring device comprising a saddle-shaped elliptical ring made of a thermoplastic elastomer without an undivided or divided coating, excluding copolymersilicone, wherein the ring is surrounded by a curved or flat non-resorbable metal barrier, a polymer barrier, a barrier that is a combination of one or more metals and one or more polymers, or a barrier made of a perforated film, the barrier is attached to the ring, the metal barrier and the polymer barrier and the perforated film optionally contain an active ingredient, and the barrier or the perforated film is not completely occluded to allow the passage of uterine secretions, a vaginal ring device.

5. The vaginal ring device according to claim 4, wherein the metal barrier is a monofilament and / or a multifilament.

6. The vaginal ring device according to claim 4 or 5, wherein the metal barrier contains one or more sperm-suppressive metals as an active ingredient.

7. The vaginal ring device according to claim 4, wherein the polymer barrier is a mesh composed of one or more of polyolefin, nylon, and / or silk.

8. The vaginal ring device according to claim 4, wherein the perforated film contains a plurality of offset layers.

9. The vaginal ring device according to claim 4, wherein the ring contains two or more parts.

10. An intravaginal ring device comprising a flat, circular or oval ring made of a thermoplastic elastomer without a non-divided coating, excluding copolymersilicone, wherein said ring contains one or more non-hormonal sperm suppressants, said ring surrounds a curved non-absorbable polymer barrier attached to said ring, and when inserted into a subject, said ring covers the cervix.

11. The intravaginal ring device according to claim 10, wherein said ring contains one or more sperm-suppressive metals and / or metal salts.

12. An intravaginal ring device comprising a saddle-shaped oval ring made of a thermoplastic elastomer without a non-divided coating, excluding copolymersilicone, wherein said ring contains one or more non-hormonal sperm suppressants, said ring surrounds a curved non-absorbable polymer barrier attached to said ring, and said ring covers the cervix.

13. An intravaginal ring device made of a thermoplastic elastomer without a divided coating, excluding copolymersilicone, having a removable tab, and comprising a flat, circular or oval ring, wherein said ring contains one or more non-hormonal sperm suppressants, said ring surrounds a curved non-absorbable polymer barrier attached to said ring, and said ring covers the cervix when inserted into a subject.

14. When the intravaginal ring and an intravaginal ring device having two or more parts made of a copolymersilicone matrix contain non-hormonal sperm suppressants and ascorbic acid in equivalent amounts and compositions, after storage or after being inserted into a subject for more than one week, the intravaginal ring has less distortion compared to the intravaginal ring device made of the copolymersilicone matrix. The intravaginal ring device according to claim 13. A vaginal ring device comprising a saddle-shaped elliptical ring made of a thermoplastic elastomer without an undivided or divided coating, the ring surrounding a non-resorbable metal barrier, a polymer barrier, a barrier that is a combination of one or more metals and one or more polymers, or a barrier made of a perforated film, which is curved or flat, the barrier being attached to the ring, the metal barrier and the polymer barrier and the perforated film optionally containing an active ingredient, and the barrier or the perforated film not being completely occluded to allow passage of uterine secretions, a vaginal ring device.

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