Non-hormonal contraceptive devices and methods of use thereof

Abstract

This specification describes a contraceptive device comprising a donut-shaped elastomer body and a bioactive agent bound to the elastomer body. The device may be inserted into the vaginal region of the female reproductive system by a person in need for preventive and / or emergency contraception.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 501,575, filed May 11, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] Field The present disclosure relates to devices and methods for non - hormonal contraception, particularly intravaginal contraceptive devices containing copper as a spermicide or spermiostatic agent.

Background Art

[0003] Background Current contraceptive options use barrier contraceptives, hormonal methods, and spermicides. Barrier contraceptives, such as condoms, contraceptive sponges, cervical caps, and diaphragms, are often ineffective due to misuse and are generally low in convenience. Hormonal methods, such as oral contraceptive pills, patches, rings, injections, implants, and intrauterine devices (IUDs), may be more reliable than barrier contraceptives, but are associated with an increased risk of breast cancer, cervical cancer, Crohn's disease, ulcerative colitis, lupus, multiple sclerosis, glucose metabolism disorders, decreased bone density, decreased libido, headaches, breakthrough bleeding, depression, anxiety, and suicide. Hormonal contraceptive methods using estrogen also increase the risk of deep vein thrombosis, pulmonary embolism, heart attack, and stroke. This limits the number of eligible women who are willing to use them. Spermicidal products containing compositions such as creams and jellies are also low in reliability, not attractive to use, and can be difficult. Both copper and hormonal IUDs require invasive clinical procedures to be inserted into and removed from the uterus. This can be painful and, for example, in developing countries or for people without appropriate health insurance, it may be difficult to access a provider who can perform the procedure.

[0004] Copper IUDs can also cause foreign body reactions and may result in more severe menstruation or dysmenorrhea, which is a significant deterrent for patients.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Therefore, there is a need for an effective, safe, and easy-to-use contraceptive option.

Means for Solving the Problems

[0006] Summary The present disclosure describes a novel contraceptive device configured to release an effective amount of at least one bioactive agent having spermicidal properties or sperm motility reducing properties into the vaginal region, cervical region, and endometrial region of a subject's female genital system when positioned within the vaginal region of the female genital system. As described herein, the term "vaginal region" may refer to the location of the device described herein, which is intended to be positioned at a high position within the vagina, thereby meaning that the "vaginal region" may refer to the region between the external uterine os and the vaginal orifice of the vagina. Within the scope in which different meanings are ascribed to the vaginal region, the meaning is readily anticipated by those skilled in the art when viewing the term in conjunction with the surrounding context and the terms of the particular claims.

[0007] The instruments described herein may be positioned within the vaginal region of the female reproductive system (i.e., the muscular vaginal canal, approximately 5–13 cm in length (which may vary from person to person)). The vaginal wall is covered with an outer fibrous outer membrane; a smooth muscle middle layer; and an inner mucosa. The middle and inner layers allow for vaginal dilation to accommodate the instrument. When the instrument is positioned high within the vagina (i.e., proximal to the cervical opening), a bioactive agent is released that impairs the metabolic processes and motility of sperm, thereby inhibiting sperm from fertilizing the egg. As described herein, the vaginal region may be defined as including the region between the external os and the vaginal opening (introitus) of the cervix, and the cervical region includes the internal os, endometrium, uterine vagina, and external os. Because the upper part of the vagina is in contact with the cervix (i.e., the narrow lower part of the uterus), bioactive agents may diffuse throughout the vaginal region, from the vaginal region to the cervical region, and from the cervical region into the endometrial region, preventing sperm from reaching the egg and / or fertilizing it.

[0008] The devices described herein offer advantages over current contraceptives. Firstly, because they can be manufactured without the use of hormones, they have none of the side effects associated with hormonal contraceptives such as Nuvaring®; secondly, because they can be positioned within the vaginal region of the female reproductive system rather than within the uterus, they do not cause foreign body reactions and inflammation of uterine tissue like copper IUDs; thirdly, unlike copper IUDs, because they are easy to use without requiring clinical insertion; fourthly, because they can be used for emergency contraception by those who need it, within approximately 120 hours of unprotected intercourse, which is not achievable with Nuvaring®. Furthermore, because the devices described herein can position the bioactive agent proximal to the cervix but within the vaginal region, allowing for maximum interaction between the bioactive agent and the environment within the cervix and vaginal region, and maximizing the spermicidal or sperm motility-reducing effectiveness of the devices compared to conventional devices, they can unexpectedly improve treatment outcomes. The device described herein can unexpectedly improve contraception without the use of hormone-like compounds, while providing the benefits of a ring positioned in the vaginal region, without placing a foreign object that causes adverse effects such as pain or inflammation in one region (i.e., an IUD in the uterus), by maximizing the concentration of a bioactive agent in three regions (vaginal region, cervical region, and uterus) to most effectively produce the result of spermicidal or reduced sperm motility. Therefore, the device described herein is unexpectedly superior to devices of the prior art.

[0009] In some embodiments, the contraceptives described herein include a donut-shaped elastomer body and at least one bioactive agent having spermicidal properties or sperm motility-reducing properties. The elastomer body may be permeable or impermeable. In some embodiments, the at least one bioactive agent exists as one or more segments bonded to the elastomer body. The outer surface of one or more segments may be in line with the outer surface of the elastomer body. In some embodiments, the at least one bioactive agent exists as a plurality of inclusions, where the donut-shaped elastomer body may have a plurality of inclusions interspersed thereon, each exposing the surface of the at least one bioactive agent. In some embodiments, the plurality of inclusions are embedded in the donut-shaped elastomer body, where the surface of the at least one bioactive agent may be partially exposed, not exposed, or a combination thereof. In some embodiments, the elastomer body has one or more holes into which a copper wire is inserted. In some embodiments, the elastomer body has one or more holes and apertures, and at least one bioactive agent is stored in the aperture as a solid or solution. The bioactive agent may come into contact with the environment of the vaginal region through its exposed surface, permeable membrane, or permeable elastomer body.

[0010] In some embodiments, at least one bioactive agent includes a copper-containing agent. In some embodiments, at least one bioactive agent is copper, a copper alloy, or a copper salt. In some embodiments, at least one bioactive agent is copper. In some embodiments, the total exposed surface area of ​​copper is approximately 50 to 1000 mm². 2In some embodiments, the intrauterine copper concentration may be approximately 3.0–20 μg / g or approximately 3.0–20.0 μg / ml (dry weight) (and in the range between thereof) from the third day after insertion of the device described herein until the time of removal of the contraceptive described herein (e.g., up to 1 month, up to 6 months, up to 1 year, up to 2 years, up to 3 years, up to 4 years, and up to approximately 5 years). In some embodiments, the intrauterine copper concentration is approximately 0.5–5.0 μg / g or approximately 0.5–5.0 μg / ml (wet weight) from the third day after insertion of the device described herein until the fifth year. In some embodiments, the intrauterine copper concentration rises for at least approximately one week after insertion of the device described herein. In some embodiments, the copper release of the device described herein lasts for at least approximately one week. In some embodiments, the Pearl index of the device described herein may be approximately 0.8–5.0.

[0011] In some embodiments, the contraceptives described herein may be used in combination with one or more vaginal health enhancers. In some embodiments, one or more vaginal health enhancers may be administered before, simultaneously with, or after the contraceptives described herein are administered. In some embodiments, the devices described herein may be used for prophylactic contraception before sexual intercourse. In some embodiments, the devices described herein may be used for emergency contraception within approximately 10, 12, 20, 24, 48, 72, or 120 hours after unprotected sexual intercourse.

[0012] This specification also describes a method for making contraceptives.

[0013] These and other features, aspects, and advantages of this embodiment will be understood by referring to the following description, drawings, and appended claims.

[0014] Brief explanation of the drawing Here, as an example, we refer to the attached drawings illustrating an example of an embodiment of this application. [Brief explanation of the drawing]

[0015] [Figure 1A]The methods and instruments described herein are useful examples for describing the female reproductive system in which they may be used. [Figure 1B] This shows the region where copper ions concentrate when using the instrument described herein, compared to several commercially available instruments. [Figure 1C] This document shows the location within the female reproductive system where the device described herein is used, compared to several commercially available devices. [Figure 2] An exemplary contraceptive device as an intravaginal ring according to embodiments of this disclosure is shown. [Figure 3] An exemplary vaginal ring embedded with a copper-containing agent according to an embodiment of the present disclosure is shown. [Figure 4A] An exemplary intravaginal ring having at least one copper-containing segment according to embodiments of the present disclosure is shown. [Figure 4B] An exemplary vaginal ring having at least one copper-containing segment according to embodiments of the present disclosure is shown. [Figure 4C] An exemplary intravaginal ring having at least one copper-containing segment according to embodiments of the present disclosure is shown. [Figure 4D] An exemplary intravaginal ring having at least one copper-containing segment according to embodiments of the present disclosure is shown. [Figure 4E] An exemplary intravaginal ring having at least one copper-containing segment according to embodiments of the present disclosure is shown. [Figure 5A] Figure 4A shows a cross-sectional view of an exemplary vaginal ring according to an embodiment of the present disclosure. [Figure 5B] This is a perspective view of an exemplary copper-containing segment according to an embodiment of the present disclosure. [Figure 5C] This is a cross-section of an exemplary copper-containing segment according to an embodiment of the present disclosure. [Figure 6A] Figure 4A shows a side view of the vaginal ring according to an embodiment of the present disclosure. [Figure 6B] Figure 6A shows a cross-sectional view of the vaginal ring according to an embodiment of the present disclosure. [Figure 7A] This disclosure illustrates exemplary embodiments of a vaginal ring according to the present disclosure. [Figure 7B] An exemplary embodiment of the molded thermoplastic framework of the vaginal ring shown in Figure 7A according to an embodiment of the present disclosure is shown. [Figure 8] This flowchart shows an exemplary method of using a contraceptive according to embodiments of the present disclosure. [Modes for carrying out the invention]

[0016] Similar reference numerals may have been used in different drawings to indicate similar components.

[0017] Detailed explanation This specification describes a novel contraceptive that can be positioned within the vaginal region of the female reproductive system of a person requiring it, and, after being positioned, releases at least one bioactive agent having spermicidal or sperm motility-reducing properties into the vaginal region, cervical region, and endometrial region for prophylactic and / or emergency contraception. In some embodiments, the contraceptive described herein is an intravaginal ring comprising a donut-shaped elastomer body and at least one bioactive agent bonded to the elastomer body. In some embodiments, the at least one bioactive agent exists as a plurality of intercalations scattered or embedded in the elastomer body. In some embodiments, the at least one bioactive agent exists as one or more segments bonded within the donut-shaped elastomer body. The outer surface of one or more segments may be in line with the outer surface of the elastomer body. In some embodiments, the elastomer body has one or more holes into which the at least one bioactive agent is placed. In some embodiments, the elastomer body has one or more holes and / or apertures, and at least one bioactive agent can be stored in the aperture as a solid or solution. In some embodiments, the contraceptives described herein further include a barrier.

[0018] In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 3.0 to 10.0 mm and an outer diameter of about 30 to 90 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 4.0 to 10.0 mm and an outer diameter of about 40 to 80 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 4.0 to 9.0 mm and an outer diameter of about 50 to 60 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 5.5 to 9.0 mm and an outer diameter of about 55 to 60 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 5.7 to 6.1 mm or 6.3 to 7.5 mm and an outer diameter of about 55 to 60 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 6.35 mm and an outer diameter of about 55 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 5.6 mm and an outer diameter of about 59.7 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 6.2 mm and an outer diameter of about 57.6 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 7.9 mm and an outer diameter of about 57.6 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 9.0 mm and an outer diameter of about 55 mm. In some embodiments, the vaginal ring described herein has a cross-sectional diameter of about 4.0 mm and an outer diameter of about 54 mm. In some embodiments, the inner diameter can be in the range of about 25 mm to 70 mm, about 35 to 55 mm, about 40 to about 60 mm, about 25 to about 35 mm, about 35 to about 70 mm, and in between. In some embodiments, the outer diameter can be in the range of approximately 35mm to 80mm, approximately 45 to 60mm, approximately 50 to approximately 65mm, approximately 25 to approximately 35mm, approximately 50 to approximately 70mm, and in between.

[0019] In some embodiments, the elastomer body is made of a biocompatible polymer material, which can be permeable or impermeable. In some embodiments, the elastomer body is made of silicone. The silicone elastomer can be permeable or impermeable.

[0020] In some embodiments, at least one bioactive agent is present as a plurality of inclusions. In some embodiments, the elastomeric body has a plurality of inclusions scattered therein, exposing the entire surface of the inclusions (see, for example, FIG. 3). In some embodiments, the plurality of inclusions are embedded in the elastomeric body, where the surface of the inclusions is partially exposed or not exposed. In some embodiments, the total exposed surface area of the plurality of inclusions is about 50-1000 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 200-600 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 380-600 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 380-400 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 400-500 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 394 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 425 mm 2 ². In some embodiments, the total exposed surface area of the plurality of inclusions is about 473 mm 2 ².

[0021] In some embodiments, at least one bioactive agent is present as one or more segments attached to the elastomeric body (see, for example, FIGS. 4A-4E). In some embodiments, the elastomeric body further includes a thermoplastic support ring. In some embodiments, the biocompatible polymer material is molded over the thermoplastic support ring to form the elastomeric body. The molding can be achieved by overmolding, insert molding, or 3D printing. In some embodiments, the thermoplastic support ring can be used to attach one or more bioactive agent-containing segments thereto, connecting the elastomeric body to the one or more segments. In some embodiments, the total outer surface area of the one or more bioactive agent-containing segments is about 50-1000 mm 2In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 200-600 mm². 2 In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 380-600 mm². 2 In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 380-400 mm². 2 In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 400-500 mm². 2 In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 394 mm². 2 In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 425 mm². 2 In some embodiments, the total outer surface area of ​​one or more bioactive agent-containing segments is approximately 473 mm². 2 In some embodiments, the arc of one or more bioactive agent-containing segments is approximately 40 to 60 degrees. In some embodiments, the arc of one or more bioactive agent-containing segments is approximately 45 to 50 degrees.

[0022] In some embodiments, at least one bioactive agent is positioned as a solution in a permeable storage vessel, where it is released by diffusion into the vaginal region through the storage vessel. In some embodiments, the elastomer body has holes and apertures, where the apertures can be used as storage vessels.

[0023] In some embodiments, at least one bioactive agent is a copper-containing agent. Examples of copper-containing agents include, but are not limited to, copper metal, copper alloy, copper salt, or any combination thereof. Copper salts may be copper sulfate, copper gluconate, copper amino acid chelates, and copper oxide. In some embodiments, at least one bioactive agent is a copper metal. In some embodiments, at least one bioactive agent may contain one or more copper salts as a solid. In some embodiments, at least one bioactive agent may contain one or more copper salts and one or more non-copper spermicides as a solid. The solid, when embedded in an elastomer ring and positioned within the vaginal region, can diffuse into the vaginal, cervical, and endometrial regions. In some embodiments, at least one bioactive agent may contain one or more copper salts in solution. In some embodiments, at least one bioactive agent may contain one or more copper salts and one or more non-copper spermicides in solution. The solution may be stored in a permeable storage container, which, once positioned therein, diffuses both the copper salt and the non-copper spermicide into the vaginal area. Examples of non-copper spermicides, but not limited to, include nonoxynol-9, menfegol, boric acid, citrate, zinc sulfate, potassium permanganate, and benzalkonium chloride.

[0024] In some embodiments, at least one bioactive agent may further comprise one or more vaginal health promoters, which may be vaginal probiotics, prebiotics, acidifiers, and combinations thereof. The vagina is home to a standard population of microorganisms (i.e., the vaginal microbiome) that help protect against infection by pathogens, yeasts, or other organisms that may enter the vagina. The administration of certain prebiotics and / or vaginal microbiome may promote microbial growth and is therefore beneficial in promoting or maintaining a healthy vaginal environment. Furthermore, maintaining an acidic pH value (below 4.5) with acid may also protect the vagina from infection. Examples of vaginal microbiota strains that may be administered to subjects as described herein include, but are not limited to, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus reuteri, and Bifidobacterium longum. Examples of prebiotics include, but are not limited to, lactitol, inulin, lactulose, and oligosaccharides. Examples of acidifying agents include, but are not limited to, lactic acid, acetic acid, ascorbic acid, aspartic acid, citric acid, folic acid, potassium sorbate, and boric acid. In some embodiments, the acidifying agent is lactic acid. In some embodiments, at least one bioactive agent may be released at a controlled rate over a predetermined period of time.

[0025] In some embodiments, one or more vaginal health enhancers may be mixed with the spermicidal bioactivators described above. In some embodiments, one or more vaginal health enhancers are kept separate from the spermicidal bioactivators. For example, one or more vaginal health enhancers are stored in a separate storage container from the storage container in which the spermicidal bioactivators are stored.

[0026] In some embodiments, the contraceptive described herein is positioned in the vaginal region of the female genital system for a period of one week to one year (or less than two weeks in the case of emergency contraception), and thereafter the contraceptive is removed from the vaginal region of the female genital system for a period of one to three weeks or longer. In some embodiments, the contraceptive is inserted into the vaginal region of the female genital system for a period of one week, and thereafter the contraceptive is removed from the vaginal region of the female genital system for a period of one week. In some embodiments, the contraceptive is inserted into the vaginal region of the female genital system for a period of two weeks, and thereafter the contraceptive is removed from the vaginal region of the female genital system for a period of one week. In some embodiments, the contraceptive is inserted into the vaginal region of the female genital system for a period of two weeks, and thereafter the contraceptive is removed from the vaginal region of the female genital system for a period of two weeks. In some embodiments, the contraceptive is inserted into the vaginal region of the female reproductive system for a period of three weeks, and then removed from the vaginal region of the female reproductive system for a period of one to two weeks. In some embodiments, the contraceptive is positioned within the vaginal region of the female reproductive system for a period of one month, and then removed from the vaginal region of the female reproductive system for a period of one to three weeks or more. In some embodiments, the contraceptive is attached to the vaginal region of the female reproductive system during ovulation. In some embodiments, the contraceptive is attached to the vaginal region of the female reproductive system as needed. In some embodiments, the contraceptive is attached to the vaginal region of the female reproductive system for a period of one year, and then removed from the vaginal region of the female reproductive system for a period of one to three weeks or more. In some embodiments, the contraceptive can be reused monthly for up to one year. For example, a contraceptive may be inserted into the vaginal region of the female reproductive system for 1 to 3 weeks per month, then removed for 1 to 3 weeks, and reused for approximately 1 to 3 weeks the following month, or at other similar intervals that would be readily conceivable by those skilled in the art in light of the disclosures contained herein.

[0027] The contraceptive devices described herein can be used before sexual intercourse for preventative contraception. These devices are as effective as conventional copper IUDs, but have far fewer side effects due to their distance from the uterus and duration of use. Specifically, unlike copper IUDs, the devices described herein are not positioned in the uterus and are not left in the body for more than five years. Furthermore, these devices are hormone-free and therefore do not have the side effects associated with hormonal methods.

[0028] The contraceptives described herein, like copper IUDs, can be used for emergency contraception within 120 hours of intercourse. For example, the contraceptives can be used within approximately 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, or any time in between. Thanks to ease of insertion and low-risk foreign body reactions (such as those resulting from copper IUDs inserted into the uterus), the embodiments described herein offer advantages over conventional devices that use copper ions and do not provide readily available emergency contraception. For example, as further described herein, copper IUDs are not readily available as emergency contraceptives because their insertion requires a clinical setting and supervision by a medical professional such as a physician. The contraceptives described herein are more readily available and convenient than copper IUDs because they can be positioned within the vaginal region of the female reproductive system by the person who needs them and do not require a clinical setting.

[0029] In some embodiments, one or more vaginal health enhancers may be used in conjunction with the devices described herein. For example, they may be administered before, during, and after use of the devices described herein to maintain and restore a healthy vaginal environment. In some embodiments, one or more vaginal health enhancers may be administered when the devices described herein are removed in order to restore a healthy vaginal environment.

[0030] The terms used herein are for illustrative purposes only and are not intended to limit any particular embodiment. As used herein and in the appended claims, the singular forms "a," "an," and "the" also include plural referents unless the context clearly indicates otherwise.

[0031] In this disclosure, “female reproductive system” or “uterine reproductive system” may refer to the reproductive system of any person capable of becoming pregnant. As used herein, the female reproductive system is not limited to individuals identified as female, but rather is recognized as a common term for the reproductive capacity and the physiological system that supports reproduction, including organs such as the uterus, ovaries, fallopian tubes, vagina and cervix.

[0032] In this disclosure, “sperm motility inhibitor” or “spermicide” may mean a substance that exerts a contraceptive effect by inhibiting or reducing the normal cellular function of sperm, for example, by inhibiting sperm motility and / or survival, thereby preventing sperm from fertilizing an egg. As used herein, sperm motility inhibitors or spermicides may be used alone or in combination with other contraceptives to prevent unwanted pregnancies.

[0033] In this disclosure, “bioactive agent” may refer to a substance that affects the function or behavior of a living organism’s cells. Bioactive agents may be metals, chemical compounds, pharmaceutical products (e.g., drugs), and enzymes.

[0034] In this disclosure, the “Pearl Index” refers to a statistical measure of pregnancy rate and is calculated using the following formula: Pearl Index = (Number of pregnancies × 12) × 100 / (Number of women in the study × Study period in months). A lower Pearl Index indicates a lower pregnancy rate and better birth control.

[0035] In this disclosure, the unit "μg / g" is equivalent to "μg / ml" because 1g of sample is approximately 1ml, "wet weight" refers to the weight of the collected sample as is, and "dry weight" refers to the weight of the sample after it has been dried before analysis.

[0036] In this disclosure, “elastomer” or “elastomer material” may mean a natural or synthetic polymer that has elastic properties, i.e., can return to its original shape after the load is removed.

[0037] In this disclosure, “thermoplastic material” may mean any material that has the properties of a plastic material when heated (e.g., soft, flexible, moldable, etc.) and hardens or solidifies when cooled.

[0038] In this disclosure, “molding” may mean covering and securing one object to another, and “overmolding” may mean an injection molding technique for manufacturing a single component comprising two or more materials, such as covering and molding one thermoplastic material to another.

[0039] As used herein, “exposed surface” and “outer surface” are interchangeable, and “foreign body response” and “foreign body reaction” are interchangeable.

[0040] As used herein, “copper,” “copper metal,” and “pure copper metal” are interchangeable and may refer to materials containing at least 99.9% copper.

[0041] Where used herein, “about” means including variations of ±30%, ±20%, ±10%, ±5%, ±1%, ±0.5%, ±0.1%, or any variation appropriate for functioning as expected by a person skilled in the art. The numerical ranges referred to herein will be readily expected by a person skilled in the art based on the context in which they are used in the disclosures contained herein.

[0042] An exemplary technical solution of this disclosure is described below with reference to the attached drawings. Similar reference numerals may be used in different drawings to indicate similar components.

[0043] Figure 1A shows an example of a female reproductive system 100 in which the methods and apparatus described herein may be used according to embodiments of the present disclosure. System 100 is simplified for easy understanding and simple reference in embodiments included herein. The main internal organs of the female reproductive system 100 include the uterus 110, ovaries 120, fallopian tubes 130, vagina (or vaginal tract) 140, and cervix 150. The cervix 150 is the slender lower part of the uterus 110 that protrudes into the vagina 140. During fertilization, sperm travel along the vaginal tract 140 and enter the uterus 110 through the cervix 150. The cervix produces mucus secretion, which becomes thin and sticky under the influence of high systemic plasma estrogen concentrations, and these secretions can facilitate the movement of sperm through the reproductive tract. An unfertilized ovum (e.g., egg) stored in one of the two ovaries 120 is released into the respective fallopian tube 130 and travels toward the uterus 110. Generally, the ovum may be fertilized by sperm within the fallopian tube 130, and the fertilized egg may reach the uterus and implant in the inner wall of the uterus 110 (e.g., the endometrium). Following implantation, the fertilized egg may develop into an embryo and then into a fetus.

[0044] Figure 1B shows that when a copper IUD is inserted, copper ions are concentrated in the uterus 110, shown as a shaded area, and that when the devices described herein are positioned, copper ions are concentrated in the vaginal and cervical regions and the uterus 110, shown as a dotted area.

[0045] Figure 1C shows the positions of the copper IUD, Nuvaring®, and the devices described herein when placed within the female reproductive system. The copper IUD is placed in the uterus 110, the Nuvaring® ring is placed deep within the cervical region, and the devices described herein are placed within the vaginal region.

[0046] Figure 2 shows an exemplary contraceptive as described herein. The contraceptive is a vaginal ring 200 comprising a donut-shaped elastomer body 210.

[0047] Figure 3 shows exemplary vaginal rings according to several embodiments of the present disclosure. The vaginal ring 300 has a donut-shaped elastomer body 310 and a plurality of copper-containing inclusions 320. In some embodiments, the copper-containing inclusions 320 contain a bioactive agent including copper, such as copper metal or a copper alloy. In some embodiments, the copper-containing inclusions 320 are scattered on the surface of the elastomer body 310 and dispersed throughout the elastomer body 310 so that the entire surface of the copper-containing inclusions 320 is exposed. When the vaginal ring 300 is positioned in the vaginal or cervical region of the female reproductive system 100, the copper-containing inclusions 320 are exposed to the environment within the vaginal region, resulting in the release of copper ions into the vaginal region, as well as the cervical and endometrial regions. In some embodiments, the copper-containing inclusions 320 are embedded in the elastomer body 310 and dispersed throughout the elastomer body 310 so that the copper-containing inclusions 320 are partially exposed or not exposed. When the vaginal ring 300 is positioned within the vaginal region of the female reproductive system 100, copper ions are released into the vaginal region through the elastomer body 310. The size, number, and spacing of the copper-containing inclusions 320 scattered or embedded in the body 310 are not particularly limited, and their orientation can be determined to optimize the total surface area and positioning of the copper-containing inclusions 320 in order to optimally control the release of a dose of copper-containing material very close to the cervix (thus conferring contraceptive activity), thereby providing improved contraception compared to conventional devices in which the released copper cannot be positioned in this region. In some embodiments, the total exposed surface area of ​​the copper-containing inclusions 320 is approximately 50 to 1000 mm². 2 Approximately 200-600mm 2 Approximately 380-600mm 2 Approximately 380-400mm 2 Approximately 400-500mm 2 , about 394mm 2 , about 473mm 2 , or approximately 425mm 2 The total exposed surface area, unexposed inclusions, and combinations thereof can be adjusted to control the rate of copper ion release that can be expected to those skilled in the art in consideration of the disclosures herein.

[0048] Figures 4A–4E show exemplary intravaginal rings according to several embodiments of the present disclosure. The intravaginal ring (400) shown in Figures 4A–4E has a donut-shaped elastomer body 410 and one or more copper-containing segments 420. One or more copper-containing segments 420 are connected to or bonded to the elastomer body 410. The outer surface of one or more copper-containing segments 420 may be aligned with the outer surface of the elastomer body 410 (as described, for example, with respect to Figure 5). When the intravaginal ring 400 is positioned in the vaginal region of the female reproductive system 100, the copper-containing segments 420 are exposed to the environment of that region, and as a result, copper ions are released by diffusion into the vaginal region, as well as into the cervical and endometrial regions. The outer surface of one or more copper-containing segments 420 may be coated with a permeable membrane, the outer surface of which is aligned with the outer surface of the elastomer body 410. The permeable membrane may be used to control the rate of copper ion release.

[0049] In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 50 to 1000 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 200-600 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 380-600 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 380-400 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments is approximately 400-500 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 394 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 425 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 473 mm². 2In some embodiments, the arc of one or more copper-containing segments 420 is approximately 40 to 60 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 45 to 55 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 45 to 50 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 45 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 50 degrees. In some embodiments, the total outer surface area of ​​one or more copper-containing segments and the total outer surface area of ​​the elastomer body exist in a ratio of approximately 1:100 to 1:1, approximately 1:50 to 1:1, approximately 1:20 to 1:1, approximately 1:10 to 1:1, approximately 1:5 to 1:1, and any range in between. In certain embodiments, the vaginal ring 400 has a cross-sectional diameter of approximately 4 mm, an outer diameter of approximately 54 mm, a single copper-containing segment 420 with an arc of approximately 45 degrees, and approximately 473 mm 2 The outer surface area of ​​the single copper-containing segment 420 is as follows. In another particular embodiment, the vaginal ring 400 has a cross-sectional diameter of approximately 4.8 mm, an outer diameter of approximately 55 mm, and an outer surface area of ​​approximately 394 mm. 2 The outer surface area of ​​the single copper-containing segment 420 is as follows. In another particular embodiment, the vaginal ring 400 has a single copper-containing segment 420 with a cross-sectional diameter of approximately 6.35 mm, an outer diameter of approximately 55 mm, and an arc of approximately 50 degrees, and approximately 425 mm 2The vaginal ring 400 has the outer surface area of ​​a single copper-containing segment 420. The vaginal ring 400 may contain one copper-containing segment 420 (as in Figure 4A), two copper-containing segments 420 (as in Figure 4B), three copper-containing segments 420, four copper-containing segments 420 (as in Figure 4C), six copper-containing segments 420 (as in Figure 4D), twelve copper-containing segments 420 (as in Figure 4E), or more, or any number in between. Although each copper-containing segment 420 in Figures 4B-4E is shown to be the same size, it is understood that each copper-containing segment 410 of the vaginal ring 400 may be of different sizes. The size and number of copper-containing segments 420 may be determined based on the desired dose or release rate of copper ions into the vaginal, cervical, and endometrial regions, and / or the desired level of flexibility of the vaginal ring 400 for ease of insertion and retention of the vaginal ring in the desired position. In some embodiments, the copper-containing segments 420 may be arranged in an alternating pattern, for example, alternating with sections of the elastomer body 410, based on a desired level of flexibility of the vaginal ring 400 for ease of insertion.

[0050] Figure 5A shows a cross-sectional view of the vaginal ring 400 of Figure 4A. The vaginal ring 400 includes an elastomer body 410 and one or more copper-containing segments 420. In some embodiments, each copper-containing segment 420 may be an arched and tubular component and have a hollow cavity 422 extending along the length of the copper-containing segment 420, and projections 424 at each end for securing the copper-containing segment 420 to the elastomer body 410. In some embodiments, the projections 424 may be barbs long enough to grip the inner diameter portion of the elastomer body 410 and seal the connection. In some embodiments, the copper-containing segment 420 is made of copper metal. In some embodiments, the copper-containing segment 420 in Figure 5A may be made of a hard or thermoplastic material having properties that allow bonding with the elastomer material. In some embodiments, the copper-containing segment 420 may be made of a hard material and its surface may be coated with copper.

[0051] In some embodiments, the vaginal ring 400 may be assembled by inserting a barb 424 into an elastomer body 410, where the barb 424 is long enough to grip the inner diameter portion of the elastomer body 410 and seal the connection. In some embodiments, the vaginal ring 400 may be assembled by molding (e.g., overmolding), where the elastomer body 410 is molded directly onto the projection 424, thereby directly bonding the elastomer body 410 to the copper-containing segment 420. In some embodiments, the projection 424 may extend to a sufficient length to provide a sufficient surface area for bonding to the elastomer body 410. In some embodiments, during molding, a hollow cavity 422 may be filled with elastomer material to mechanically lock the copper-containing segment 420 to the elastomer body 410. The copper-containing segment 420 may be secured by other means as readily assumed by those skilled in the art in consideration of the disclosures contained herein.

[0052] Figure 5B is a perspective view of a copper-containing segment 420 according to an embodiment of the present disclosure. The copper-containing segment 420 comprises a metal or thermoplastic core, the outer surface of which is coated with a copper layer 426. The metal or thermoplastic core may be between two protrusions 424. The thickness of the copper layer 426 may be determined based on a desired dose or release rate of copper ions into the vaginal, cervical, and endometrial regions. For example, the thickness of the copper layer 426 may be about 0.1 mm to 1 cm, about 0.5 mm to 5 mm, about 1 mm to 5 mm, about 1 mm to about 2.5 mm, or any range in between. In some embodiments, the metal or thermoplastic core may be first coated with the copper layer 426 and then bonded to the elastomer body 410 by inserting the protrusions 424 into the elastomer body 410. In some embodiments, the protrusions 424 may include friction-inducing elements, such as barbs, to help fix and retain the thermoplastic core within the elastomer layer. Alternatively, the elastomer body 410 may be formed into protrusions 424 of a metal or thermoplastic core, and then the copper layer 426 may be coated onto the core. The copper coating and copper layer may be a copper alloy or pure copper metal, among the many copper compositions described herein.

[0053] Figure 5C is a cross-sectional view of the copper-containing segment 420 of Figure 5B according to an embodiment of the present disclosure. The copper-containing segment 420 includes a hollow cavity 422 extending along the length of the copper-containing segment 420 and projections 424 extending from each end of the copper-containing segment 420.

[0054] Figure 6A shows a side view of the vaginal ring of Figure 4A according to an embodiment of the present disclosure. The vaginal ring 400 comprises an elastomer body 410 and one or more copper-containing segments 420. One or more copper-containing segments 420 may be bonded to the elastomer body 410 via a metal or thermoplastic support ring 428.

[0055] In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 50 to 1000 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 200-600 mm².2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 380-600 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 380-400 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 400-500 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 394 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 425 mm². 2 In some embodiments, the total outer surface area of ​​one or more copper-containing segments 420 is approximately 473 mm². 2 In some embodiments, the arc of one or more copper-containing segments 420 is approximately 40 to 60 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 45 to 55 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 45 to 50 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 45 degrees. In some embodiments, the arc of one or more copper-containing segments 420 is approximately 50 degrees. In certain embodiments, the vaginal ring 400 has a cross-sectional diameter of approximately 4 mm, an outer diameter of approximately 54 mm, a single copper-containing segment 420 with an arc of approximately 45 degrees, and approximately 473 mm 2 The outer surface area of ​​the single copper-containing segment 420 is as follows. In another particular embodiment, the vaginal ring 400 has a cross-sectional diameter of approximately 4.8 mm, an outer diameter of approximately 55 mm, and an outer surface area of ​​approximately 394 mm. 2 The outer surface area of ​​the single copper-containing segment 420 is as follows. In another particular embodiment, the vaginal ring 400 has a single copper-containing segment 420 with a cross-sectional diameter of approximately 6.35 mm, an outer diameter of approximately 55 mm, and an arc of approximately 50 degrees, and approximately 425 mm 2 The outer surface area of ​​a single copper-containing segment 420 is as follows. In yet another specific embodiment, the vaginal ring 400 has a cross-sectional diameter of about 6.35 mm, an outer diameter of about 55 mm, and two copper-containing segments 420, each with an arc of about 50 degrees, and about 425 mm 2The total outer surface area of ​​the two copper-containing segments 420 is as follows. In yet another specific embodiment, the vaginal ring 400 has a cross-sectional diameter of about 4 mm, an outer diameter of about 54 mm, and two copper-containing segments 420, each with an arc of about 45 degrees, and about 473 mm 2 The total outer surface area of ​​the two copper-containing segments 420 is as follows. In some embodiments, the total outer surface area of ​​one or more copper-containing segments and the total outer surface area of ​​the elastomer body are in a ratio of about 1:100 to 1:1, about 1:50 to 1:1, about 1:20 to 1:1, about 1:10 to 1:1, about 1:5 to 1:1, and any range in between.

[0056] Figure 6B shows a cross-sectional view of the vaginal ring of Figure 6A according to an example of the present disclosure. The vaginal ring 400 includes an elastomer body 410 molded on a support ring 428 and one or more copper-containing segments 420. The support ring 428 may be made of metal or a thermoplastic material. In some embodiments, the support ring 428 is made of a thermoplastic material. In some embodiments, the support ring 428 has a ring body and two enlarged ends, where the ring body provides a support structure on which the elastomer body can be molded (or molded over the elastomer body), and the two enlarged ends allow the copper-containing segments 420 to be bonded to the elastomer body 410. In some embodiments, the support ring 428 has a ring body and two ends of the same size as the ring body.

[0057] In some embodiments, the elastomer body 410 is molded over the ring body of the support ring 428, and subsequently, the barbs 424 of the copper-containing segment 420 are inserted into the enlarged ends of the support ring 428 to ensure connection between the elastomer body 410 and the copper-containing segment 420. In some embodiments, the copper-containing segment 420 may be mounted on the support ring 428 by inserting each end of the support ring 428 into the hollow cavity 422 of the copper-containing segment 420 before molding the elastomer body 410 over the support ring 428. In some embodiments, the copper-containing segment 420 may be mounted on the support ring 428 by inserting each end of the support ring 428 into a metal or thermoplastic core positioned between two protrusions 424 before molding the elastomer body 410 over the support ring 428. The copper-containing segment 420 can be made of copper metal and copper alloys. In some embodiments, the copper-containing segment 420 can be made of copper metal. In some embodiments, the copper is Cu101 containing approximately 99.99% copper. In some embodiments, the elastomer body is made of silicone.

[0058] Figure 7A shows an exemplary embodiment of an intravaginal ring according to an embodiment of the present disclosure. The intravaginal ring 700 has an elastomer body 710, one or more holes 720 in the elastomer body 710, and a copper-containing agent within the elastomer body. The elastomer body 710 is made of a biocompatible polymer. In some embodiments, the elastomer body 710 is a silicone elastomer which may be permeable or impermeable. In the exemplary embodiment, the intravaginal ring 700 is shown having 13 round holes 720, but the holes 720 may be incorporated into the intravaginal ring 700 and may be of other shapes and quantities. For example, the holes 720 may have the shapes of oval, triangular, rhombus, square, rectangular, trapezoidal, pentagonal, hexagonal, or octagonal, or any combination thereof. The number of holes 720 may be 1, 2, 3, 4, 5, 6, 7, or more. When the vaginal ring 700 is positioned within the vaginal region of the female reproductive system 100, the hole 720 can expose the copper-containing agent to the fluid in that region, releasing copper ions into the vaginal region, cervical region, and endometrial region.

[0059] Figure 7B shows an exemplary copper-containing material within the vaginal ring 700 of Figure 7A according to an embodiment of the present disclosure. In some embodiments, the copper-containing material is a copper wire, indicated as 750, without an aperture 760. The total outer surface of the copper wire is approximately 50 mm 2 ~1000mm 2 , about 200mm 2 ~600mm 2 , about 380mm 2 ~600mm 2 , about 380mm 2 ~400mm 2 Approximately 400mm 2 ~500mm 2 , and any range between them. In some embodiments, a thermoplastic frame 750 is used, having one or more apertures 760 that fit into the hole 720, as shown in Figure 7B. One or more apertures 760 may be storage containers for storing copper-containing agents, which may be copper metal, copper alloy, solid copper salt, or copper-salt solution. In some embodiments, copper metal, copper alloy, solid copper salt, or a combination thereof may be filled into one or more apertures 760 and have an outer surface that, when positioned within the vaginal region, is exposed to the environment of that region. The total outer surface of the copper metal, copper alloy, and solid copper salt is about 50 mm 2 ~1000mm 2 , about 200mm 2 ~600mm 2 , about 380mm 2 ~600mm 2 , about 380mm 2 ~400mm 2 Approximately 400mm 2 ~500mm 2 , and any range between them. In some embodiments, the copper-salt solution in the permeable membrane may be stored in one or more apertures 760. In some embodiments, about 50 to 1000 mm 2 Doses derived from copper-containing agents exposed to the copper may be used.

[0060] In some embodiments, the copper wire may be placed inside the elastomer body 710 during its preparation, or it may be inserted into the hole 720 after the elastomer body 710 has been prepared. In some embodiments, the elastomer body 710 is molded on a thermoplastic frame 750, and the copper-containing material is filled into one or more apertures 760.

[0061] In some embodiments, the contraceptives of this disclosure further include a barrier, such as a diaphragm contraceptive. In some embodiments, the contraceptive may be a ring that is not a barrier-type contraceptive, such as a diaphragm contraceptive. In some embodiments, the contraceptives described herein are not barrier-type contraceptives. In some embodiments described herein, the contraceptive is not saucer-shaped. In some embodiments of the contraceptives described herein, the contraceptive does not form a barrier across the opening of the cervix. In some embodiments, the barrier may include a flexible body positioned within the vaginal region of the female reproductive system 100 to provide a physical barrier against sperm migration and fertilization, and a bioactive agent containing copper embedded in the flexible body. In some embodiments, the bioactive agent is a copper wire coiled along the outer edge of the flexible body, where the surface of the copper wire is exposed to the environment of the vaginal region to release copper ions to interfere with sperm migration and fertilization. The barrier provides the additional benefit of combining a physical barrier that prevents sperm from passing through the cervix with the spermicidal effect of copper for highly effective contraception.

[0062] Figure 8 shows a method of using the contraceptive described herein. Method 800 begins with step 802, in which the contraceptive is inserted into the vaginal region of the female genital system 100 by the person who needs it and / or with the help of an instrument applicator. In some embodiments, the contraceptive described herein can be easily inserted by the person who needs it, rather than by a clinical professional or in a clinical setting, unlike conventional copper IUDs (which may be painful and unsuitable for use as emergency contraception) which require clinical administration. The contraceptive described herein may be used for planned contraception and / or emergency contraception. The contraceptive described herein may be inserted into the vaginal region before or within 120 hours of intercourse and may remain in place for a period of two weeks, three weeks, or one year, or any period in between.

[0063] In step 804, in response to exposure to the environment of the vaginal region of the female reproductive system 100, the copper-containing bioactive agent may be released at a specific rate into the vaginal region, cervical region, and endometrial region to exert a spermicidal or sperm motility-reducing effect on sperm that may be present in the vagina and / or cervical region. In some embodiments, the copper-containing bioactive agent is released at a controlled rate and / or controlled dose. In some embodiments, the contraceptive device described herein is configured to continuously release the copper-containing bioactive agent for a predetermined period, for example, to provide a reliable method of contraception for the entire predetermined period. In some embodiments, the predetermined period is from one day to four weeks or longer.

[0064] In some embodiments, the intrauterine copper concentration is approximately 3.0–20 μg / g or approximately 3.0–20.0 μg / ml (dry weight) from day 3 to year 5 after insertion of the device described herein. For example, intrauterine copper concentrations (dry weight) are approximately 3.9–4.2 μg / g, 3.5 μg / g, 3.9 μg / g, 4.0 μg / g, 4.1 μg / g, 4.2 μg / g, 4.3 μg / g, 4.4 μg / g, 4.5 μg / g, 5.0 μg / g, 5.5 μg / g, 6.0 μg / g, 6.5 μg / g, 7.0 μg / g, 7.5 μg / g, 8.0 μg / g, 8.5 μg / g, 9.0 μg / g, 9.5 μg / g, 10.0 μg / g, and 10.5 μg. The amount may be 11.0 μg / g, 11.5 μg / g, 12.0 μg / g, 12.5 μg / g, 13.0 μg / g, 13.5 μg / g, 14.0 μg / g, 14.5 μg / g, 15.0 μg / g, 15.5 μg / g, 16.0 μg / g, 16.5 μg / g, 17.0 μg / g, 17.5 μg / g, 18.0 μg / g, 18.5 μg / g, 19.0 μg / g, 19.5 μg / g, 20.0 μg / g, or any amount in between. In some embodiments, the intrauterine copper concentration (dry weight) on the third day after insertion of the device described herein is approximately 3.9 to 10.0 μg / g. For example, the intrauterine copper concentration on the third day after insertion of the instrument described herein may be approximately 3.9-4.2 μg / g, 3.9 μg / g, 4.0 μg / g, 4.1 μg / g, 4.2 μg / g, 4.3 μg / g, 4.4 μg / g, 4.5 μg / g, 5.0 μg / g, 5.5 μg / g, 6.0 μg / g, 6.5 μg / g, 7.0 μg / g, 7.5 μg / g, 8.0 μg / g, 8.5 μg / g, 9.0 μg / g, 9.5 μg / g, 10.0 μg / g, or any amount in between.

[0065] In some embodiments, the intrauterine copper concentration may be approximately 0.5–5.0 μg / g (dry weight) or approximately 0.5–5.0 μg / ml (wet weight) from the third day after insertion of the instrument described herein until removal of the instrument (e.g., 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or up to approximately 5 years or longer). The intrauterine copper concentration (wet weight) can be approximately 0.8-1.8 μg / g, 0.9-1.8 μg / g, 10.5 μg / g, 0.6 μg / g, 0.7 μg / g, 0.8 μg / g, 0.9 μg / g, 1.0 μg / g, 1.01 μg / g, 1.2 μg / g, 1.3 μg / g, 1.04 μg / g, 1.5 μg / g, 1.6 μg / g, 1.7 μg / g, 1.8 μg / g, 1.9 μg / g, 2.0 μg / g, 2.5 μg / g, 3.0 μg / g, 3.5 μg / g, 4.0 μg / g, 4.5 μg / g, 5.0 μg / g, or any amount in between. In some embodiments, the intrauterine copper concentration three days after insertion of the instrument described herein is approximately 0.9 to 3.0 μg / g (wet weight). For example, the intrauterine copper concentration three days after insertion of the instrument described herein may be approximately 0.8 to 1.8 μg / g, 0.9 to 1.8 μg / g, 0.9 μg / g, 1.0 μg / g, 1.1 μg / g, 1.2 μg / g, 1.3 μg / g, 1.4 μg / g, 1.5 μg / g, 1.6 μg / g, 1.7 μg / g, 1.8 μg / g, 1.9 μg / g, 2.0 μg / g, 2.5 μg / g, 3.0 μg / g, or any amount in between.

[0066] While the intrauterine copper concentration increases after insertion of the copper-containing device described herein, it is understood that the copper concentration may reach an equilibrium level, as described herein, that maintains an effective copper concentration in the cervical region, vaginal region, and / or uterus for the duration that the contraceptive device described herein remains in the target vaginal region. In some embodiments, the intrauterine copper concentration increases for about one week, two weeks, three weeks, six months, one year, two years, three years, or longer after insertion of the device described herein.

[0067] In some embodiments, the copper emission of the apparatus described herein ranges from about one week to five years. For example, the copper emission of the apparatus described herein may be about one week, two weeks, three weeks, one month, two months, six months, one year, two years, three years, four years, five years, or any time in between.

[0068] In some embodiments, the Pearl index of the instrument described herein may be about 0.8 to 5, about 0.8 to 1.5, about 0.9 to 1.4, about 0.8 to 1.3, about 1.0 to 1.5, about 0.9 to 1.1, about 0.8 to 1.0, about 1.0 to 3.5, about 0.9 to 4.5, about 1.8 to 5.0, or about 1.1 to 1.2. For example, the Pearl index of the instrument described herein may be about 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, or any value in between.

[0069] In step 806, in response to reaching a predetermined period of time, or instead in response to the user deciding that they no longer wish to use the contraceptive, the contraceptive may be removed from the vaginal area of ​​the female genital system by the person who needs it. In some embodiments, the contraceptive may be removed from the vaginal area with the help of an instrument applicator or removal tool. In some embodiments, the contraceptive may be easily removed by the person who needs it, but not by a clinical professional or in a clinical setting.

[0070] This disclosure describes methods and processes in a specific order of steps, but one or more steps of the methods and processes may be appropriately omitted or modified. One or more steps may be appropriately performed in an order other than that described.

[0071] This disclosure may be provided in other specific forms without departing from the subject matter of the claims. The exemplary embodiments described are in all respects descriptive and not restrictive. Selected features from one or more of the embodiments described above may be combined to create alternative embodiments not explicitly described, and features suitable for such combinations are understood to be within the scope of this disclosure.

[0072] All values ​​and sub-ranges within the disclosed scope are also disclosed. Furthermore, while the systems, apparatus, and processes disclosed and shown herein may include a certain number of elements / components, the systems, apparatus, and assemblies may be modified to include additional or fewer such elements / components. For example, any of the disclosed elements / components may be referred to in the singular, but the embodiments disclosed herein may be modified to include multiple such elements / components. The subject matter described herein is intended to encompass and include all preferred modifications in the art. [Examples]

[0073] Examples Example 1: Animal study to evaluate the effectiveness of contraceptives The contraceptive device shown in Figure 4A was studied in animals for its effectiveness by determining copper concentrations in vaginal fluid and the uterus. The study was conducted by Charles River Laboratories. The device has an outer diameter of approximately 55 mm and a cross-sectional diameter of approximately 4.8 mm (3 / 16”). The exposed surface area of ​​the copper segment within the device is approximately 394 mm². 2 The instruments were boiled in deionized water at 100°C (±1°C) for approximately 5 minutes, and then sealed in sterile bags before study. Female sheep (S. Ovis aries, Dorset × Rideau Arcott Hybrids strain, supplied by Bakerstone) were used due to their physiological and anatomical similarities to the human reproductive system. Two young adult sheep (2-4.5 years old), weighing 70-75 kg, were selected for the study.

[0074] Prior to the study, both sheep were acclimatized to their environment for 21 days, during which time they were placed together in a room with a concrete floor covered with chip bedding and given pellets (ENVIGO Teklad Ruminant Food or equivalent) and tap water. To induce estrus and ovulation, Estrumate (prostaglandin; 1 mL) was injected intramuscularly 11 days prior to the study (-11 days), and then Estrumate (prostaglandin, 1 mL) and Novormon (equine chorionic gonadotropin, 2 mL) were injected 1 day prior to the study (-1 day). Between -11 and -1 days, the sheep were accustomed to being suspended for at least three sessions during the estrus synchronization period.

[0075] On the first day of the study (Day 0), one contraceptive was inserted into each sheep and firmly positioned as high and horizontal as possible within the cranial vaginal cavity to prevent slippage. Prior to insertion, vaginal fluid and vaginal swabs were collected as baseline vaginal samples for assessing the copper concentration in the vagina. Vaginal fluid was collected in a sterile tube by touching the vaginal wall with the sterile tube. Vaginal swabs were collected by gently sliding the swab to a high position in the cranial vaginal cavity, touching the vaginal wall with the swab head, and gently rotating the swab at least five times clockwise to absorb as much moisture as possible. On Day 1 (24-48 hours after insertion), Day 2 (48-72 hours after insertion), and Day 3 (72-80 hours after insertion), vaginal fluid and swabs were collected from both sheep each day using the method described above. The weight of the tube and swab was measured before and after collection to determine the net weight of the collected vaginal fluid and vaginal swabs. The collected vaginal fluid and vaginal swabs were flash-frozen on dry ice and stored at -80°C until copper concentration analysis was performed.

[0076] On day 3, an endometrial biopsy was performed on one sheep using laparoscopy. Under anesthesia, the base of the right uterine horn was incised using Halstead hemostatic agent, and a sterile flocked-headed swab was introduced through this incision to collect endometrial secretions. After collection, the swab was placed in a tube. The net weight of the collected endometrial swab sample was determined by weighing both the tube and the swab before and after collection. The endometrial sample was flash-frozen on dry ice and then stored in a -80°C freezer. After swab removal, pipette endometrial biopsies were performed to collect endometrial secretions from both uterine horns. All samples were placed in separate, appropriately identified sterile tubes, placed on dry ice, and stored in a -80°C freezer.

[0077] Copper concentrations were measured in vaginal fluid, vaginal swabs, and endometrial samples using inductively coupled plasma mass spectrometry (ICPMS). For pipette endometrial biopsy samples, copper concentration was first measured based on the wet weight of the sample (using the collected sample as is), and then subsequently based on the dry weight of the sample (the collected sample was dried before analysis). Each sample was measured three times, and the copper concentration was reported as mean ± standard deviation. The results are shown in Tables 1-3 below.

[0078] Table 1 shows that copper concentrations in vaginal swabs and vaginal fluid increased significantly every day from day 0 to day 3, and also on day 3, indicating very high copper concentrations in the vagina. Table 2 shows that on day 3, the copper concentrations in the right uterine horn were approximately 0.9 μg / g (wet weight) and 4.2 μg / g (dry weight), and in the left uterine horn were approximately 1.04 μg / g (wet weight) and 3.9 μg / g (dry weight). Table 3 shows that on day 3, the copper concentration in the right uterine horn was approximately 0.89 μg / g (wet weight), and in the left uterine horn was approximately 1.74 μg / g (wet weight). The total copper surface area was 175 mm². 2It has been reported that a copper IUD produced a copper concentration of approximately 0.67 μg / g (wet weight) in the human uterus 1 to 6 months after IUD insertion. Similarly, (i) the contraceptive effectiveness of this copper IUD is 92.2%, (ii) the Pearl index of another copper IUD with the same total copper surface area is 0.96, and (iii) the total copper surface area is 200 mm². 2 NOVA-T® (i.e., copper IUD) has been reported to have a pregnancy rate of 1.26 / 100 patients-year (i.e., equally effective in contraception), and (iv) an intrauterine copper concentration of 3.9 μg / g (dry weight) or less may be effective in contraception. The contraceptive described herein produced uterine copper concentrations of at least approximately 0.90 μg / g (wet weight, thereby exceeding the wet weight threshold of 0.67 μg / g considered to be an effective copper concentration based on prior art copper IUDs) and 3.9 μg / g (dry weight) on day 3, thus demonstrating that the contraceptive described herein is quite effective in contraception both as prophylactic contraception and for emergency contraception. Considering that copper concentrations were achieved in the uterus and vagina on day 3, the contraceptives described herein can be used for emergency contraception and are more effective than reported copper IUDs, because copper IUDs take a much longer time (i.e., at least one month) to release such high concentrations of copper, and these high copper concentrations are only in the uterus and not in the vagina.

[0079] [Table 1]

[0080] [Table 2]

[0081] [Table 3]

[0082] Example 2: Human study to evaluate the effectiveness of contraceptives The effectiveness of the contraceptive used in Example 1 was evaluated in humans by determining the copper concentration in vaginal fluid and the uterus.

[0083] On the first day of the study, a contraceptive device was inserted into the vagina of a biological woman. On day 3 and on day 3 after device insertion, a vaginal swab was collected by inserting the soft tip end of a sterile swab (from the STI kit test) into the vagina approximately 2 inches (5 cm) beyond the vaginal opening, rotating the swab for 10–30 seconds, and ensuring that the swab made firm contact with the vaginal wall so that moisture could be absorbed by the swab. On day 3 after device insertion, an endometrial biopsy was performed by a licensed gynecologist using a standard procedure, and an endometrial biopsy sample was collected. Copper concentrations in the vaginal swab and uterus were analyzed using ICPMS. The results are shown in Table 4.

[0084] The results show that (i) the copper concentration in the vagina increased from day 3 to day 5, which is consistent with the results from sheep vaginas, and (ii) on day 5, the copper concentration in the uterus was approximately 1.12 μg / g (wet weight) and 4 μg / g (dry weight), which is similar to the copper concentration in the sheep uterus on day 3 in Example 1. The results further demonstrate the effectiveness of the device described herein for emergency contraception, as it can be used for prophylactic contraception due to the copper concentration on day 3 and because the release is prolonged.

[0085] [Table 4]

[0086] Example 3: Animal studies to evaluate the safety, tolerance, and effectiveness of contraceptives. The contraceptives shown in Figure 4A or Figure 4B will be studied for their safety, tolerance, and effectiveness in animals. Sheep weighing 45-100 kg and aged 1-4.5 years with 0-2 previous pregnancies will be acquired in January of the study year. The study will be conducted from March to June, as this is the typical breeding month. The sheep will be given free-range food and water at the same frequency and will be kept indoors on a 12 / 12 light / dark cycle for 6 weeks prior to the study and throughout the study period. A total of 20 sheep will be randomly divided into two groups: Group A will accept the contraceptives, and Group B will be the control group. The size of the contraceptive to be inserted will be determined by measuring the vaginal dimensions of each sheep.

[0087] On day 1 of the study, five sheep from Group A were anesthetized and a contraceptive device was inserted into each of their vaginal areas. On day 2, estrus was induced in all sheep by either (i) progesterone treatment followed by exposure to rams after being separated from them for at least 6 weeks, or (ii) progesterone followed by treatment with pregnant mare serum gonadotropin. On day 5 of the study, frozen ram sperm were thawed in a 37°C water bath for 30 seconds, and then the sperm motility and morphology were analyzed under a microscope to ensure that the ram sperm was suitable for use. Sixty hours after estrus induction, all sheep were artificially inseminated with ram sperm. On day 35, all sheep were evaluated for pregnancy. On day 36, estrus was induced in non-pregnant sheep, and 60 hours later, they were artificially inseminated again with ram sperm.

[0088] The effectiveness of the contraceptives described herein for emergency contraception will also be evaluated. Twenty-four hours after insemination, five more sheep from Group A will be anesthetized and contraceptives will be inserted. Seventy-two hours after insemination, yet another five sheep from Group A will be anesthetized and contraceptives will be inserted. One hundred and twenty hours after insemination, the last five sheep from Group A will be anesthetized and contraceptives will be inserted.

[0089] On day 71, all sheep will be evaluated for pregnancy using serological testing. From day 1 to day 71, vaginal fluid will be collected to determine copper concentration. Throughout the study, sheep from Group A will be monitored for signs of adverse effects such as infection and irritation through weekly vaginal examinations by a veterinarian.

[0090] Example 4: Safety, tolerance, and effectiveness of contraceptives in humans The contraceptives described herein and those shown in either Figure 4A or Figure 4B will be evaluated in critical clinical trials regarding their safety, tolerance, and effectiveness.

[0091] A total of 200 individuals aged 18-40 will participate in the study. All participants are capable of becoming pregnant, are in good overall health, have regular menstrual cycles of 24-32 days, are willing to become pregnant if devices fail, are willing to discontinue any current method of contraception, are willing to have regular sexual intercourse throughout their cycle, and are capable of giving informed consent. The study will be conducted in accordance with the ethical principles outlined in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2).

[0092] Each participant will insert a contraceptive device into their vagina and leave it in place for three weeks of their menstrual cycle, remove it on day 26 of their cycle, and leave it removed until day 5 of the following menstrual cycle. Data will be collected at various points in time throughout the study period. Prior to the start of the study, basic demographic and medical information will be collected from each participant. During the study, participants will be scheduled for regular follow-up visits at week 2, month 1, month 2, month 3, month 5, and month 7, which will include clinical evaluation, clinical examination, and completion of questionnaires to assess pregnancy rates, safety, tolerance, and any adverse events. Specific data collected will include serum copper and pregnancy tests, swabs to check vaginal pH, vaginal copper concentration, and overall vaginal tissue health, ease of insertion, comfort, irritation, partner comments (if applicable), ease of removal, and responses to questionnaires regarding any concerns about use during sexual intercourse. Descriptive statistics will be used to summarize demographic characteristics and basic data. Safety and tolerance will be assessed by examining the incidence and severity of adverse events reported by participants. Properly document and analyze pregnancy rates.

[0093] Example 5: Efficacy of emergency contraception in humans This specification evaluates the effectiveness of the contraceptive devices described herein and shown in either Figure 4A or Figure 4B in emergency contraception, compared to copper IUDs.

[0094] Individuals aged 18-40 will participate in the study. Participants will be divided into two groups. Within five days of intercourse, one group will have a contraceptive device described herein inserted into their vagina, and the other group will have a copper IUD inserted. From day 1 to day 5 after insertion, copper concentrations in the vagina and uterus of participants in both groups will be determined. Data including pregnancy tests and swabs to check vaginal pH will also be collected and analyzed.

Claims

1. A contraceptive device configured to be inserted into the vagina of the female reproductive system of a subject, wherein the contraceptive device is: A donut-shaped elastomer body and; Bonded to the elastomer body is at least one bioactive agent having spermicidal properties or sperm motility-reducing properties. Includes, A contraceptive device configured to release an effective amount of the at least one bioactive agent to the vaginal region, cervix region, and endometrial region of the female reproductive system when positioned within the vaginal region of the female reproductive system.

2. The contraceptive device according to claim 1, wherein the at least biological agent is a copper-containing agent.

3. The contraceptive device according to claim 2, wherein the copper-containing agent is copper, a copper alloy, a copper salt, or a combination thereof.

4. The contraceptive device according to claim 3, wherein the copper-containing agent is copper.

5. The contraceptive according to claim 4, wherein the elastomer body has copper scattered as a plurality of intercalations, and the surface of the copper is in contact with the environment of the vaginal region of the female reproductive system.

6. The contraceptive device according to claim 1, wherein the at least one bioactive agent further comprises one or more vaginal health promoters.

7. The contraceptive device according to claim 6, wherein the one or more vaginal health promoters are selected from the group consisting of acidifying agents, vaginal microbiota, prebiotics, or combinations thereof.

8. The contraceptive device according to claim 7, wherein the acidifying agent is lactic acid.

9. The contraceptive according to claim 7, wherein the vaginal microbiota is Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus reuteri, Bifidobacterium longum, or a combination thereof.

10. A method for emergency contraception: The emergency contraceptive is inserted into the vaginal region of the female reproductive system after sexual intercourse, wherein the emergency contraceptive comprises a donut-shaped elastomer body and at least one bioactive agent having spermicidal properties or sperm motility-reducing properties, which is bonded to the elastomer body. Methods that include...

11. The method according to claim 10, wherein the at least biological agent is a copper-containing agent.

12. The method according to claim 11, wherein the copper-containing agent is copper, a copper alloy, a copper salt, or a combination thereof.

13. The method according to claim 12, wherein the copper-containing agent is copper.

14. The method according to claim 13, wherein the copper is bonded to the elastomer body as one or more segments.

15. The method according to claim 14, wherein the elastomer body has a cross-sectional diameter of about 3.0 to 10 mm and an outer diameter of about 30 to 90 mm.

16. The method according to claim 14, wherein the arc of one or more copper segments is approximately 40 to 60 degrees.

17. The total outer surface area of ​​the one or more copper segments mentioned above is approximately 50 to 1000 mm². ２ The method according to claim 14.

18. The method according to claim 10, wherein the emergency contraceptive device is used in combination with one or more vaginal health promoters.

19. The method according to claim 18, wherein the one or more vaginal health promoters are selected from the group consisting of acidifying agents, vaginal microbiota, prebiotics, or combinations thereof.

20. The method according to claim 19, wherein the acidifying agent is lactic acid.

21. The method according to claim 19, wherein the vaginal microbiota is Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus reuteri, Bifidobacterium longum, or a combination thereof.

22. The method according to claim 10, wherein the at least one bioactive agent further comprises one or more vaginal health promoters.

23. The method according to claim 10, wherein the emergency contraceptive is positioned within the vaginal region of the female reproductive system for a period of less than two weeks within 120 hours of sexual intercourse, and thereafter the contraceptive is removed from the vaginal region of the female reproductive system for a period of one to three weeks or more.

24. The method according to claim 10, wherein the emergency contraceptive is positioned within the vaginal region of the female reproductive system for a period of one week to one year within 120 hours of sexual intercourse, and thereafter the contraceptive is removed from the vaginal region of the female reproductive system for a period of one to three weeks.

25. The method according to claim 10, wherein the emergency contraceptive is positioned within the vaginal region of the female reproductive system within 48 hours of intercourse for the purpose of emergency contraception.

26. The method according to claim 10, wherein the emergency contraceptive is positioned within the vaginal region of the female reproductive system within 24 hours of intercourse for the purpose of emergency contraception.

27. A method of planned contraception: The method involves inserting a contraceptive device into the vaginal region of the female reproductive system before sexual intercourse, wherein the contraceptive device comprises a donut-shaped elastomer body and at least one bioactive agent having spermicidal properties or sperm motility-reducing properties, which is bonded to the elastomer body. Methods that include...

28. The method according to claim 27, wherein the contraceptive is positioned in the vaginal region of the female reproductive system for a period of one week to one year prior to sexual intercourse, and thereafter the contraceptive is removed from the vaginal region of the female reproductive system for a period of one to three weeks or more.

29. A method for making contraceptives: To provide a thermoplastic support ring; The process involves molding an elastomer material by placing it over the thermoplastic support ring to form a donut-shaped elastomer body having two ends; To provide arched and tubular copper metals including two barbs; Insert the barbs into each end of the elastomer body. Methods that include...

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