Systems for Providing Birth Control

Abstract

The present disclosure relates to a vaginal system for preventing pregnancy comprising segesterone acetate and ethinyl estradiol, the vaginal system being configured for thirteen 28-day product use cycles.

Description

[Technical Field]

[0001] The present disclosure relates to a vaginal system for preventing pregnancy that is comprised of a progestin, such as segesterone acetate, and an estrogen, such as ethinyl estradiol, configured for thirteen 28-day product use cycles. [Background technology]

[0002] Oral contraceptive use is widespread among the female population, but the need to remember to take a daily pill and the inconvenience of having to get frequent refills can reduce compliance and undermine its effectiveness.

[0003] The use of subcutaneous brachial implants and intrauterine devices (IUDs) as a means of administering contraception has been considered as a way to overcome these drawbacks, as they remain effective for more than a year. However, these devices have their own drawbacks in that the insertion and removal of the implants and IUDs requires the services of a medical professional, such as a doctor, nurse, or physician's assistant.

[0004] An intravaginal ring is a circular item containing a medication (drug) that can be introduced into the vagina in a simple manner without medical assistance. For example, NuvaRing® is designed to be used in a single 28-day cycle. NuvaRing® is discarded on the 21st day, and a new ring is inserted at the beginning of the next 28-day cycle. This product provides one month of contraception without the need to remember to take a daily pill, but regular prescription refills are still required throughout the year. Summary of the Invention

[0005] In a first aspect, the present disclosure provides a reusable vaginal system for preventing pregnancy, the system comprising a silicone elastomer ring body and two cores, the cores containing a total of about 103 mg segesterone acetate and about 17.4 mg ethinyl estradiol; The system is configured to release an average of about 0.15 mg / day of segesterone acetate and an average of about 0.013 mg / day of ethinyl estradiol, or a bioequivalent thereof, for up to thirteen 21-day cycles, A vaginal system is provided in which about 80% to about 90% of the ethinyl estradiol is recoverable from the system after about 18 months of storage at 25°C and 60% relative humidity.

[0006] In a first embodiment of the first aspect, the system is configured to release an average of about 0.15 mg / day of segesterone acetate and about 0.013 mg / day of ethinyl estradiol, or bioequivalents thereof, into the vagina of a female subject in need thereof for up to thirteen 21-day cycles, respectively.

[0007] In a second embodiment of the first aspect, one of the two cores contains segesterone acetate, and the other contains segesterone acetate and ethinyl estradiol. In a third embodiment of the first aspect, the core containing segesterone acetate and ethinyl estradiol is cured at a temperature of about 60°C to about 90°C. In a fourth embodiment of the first aspect, the core containing segesterone acetate and ethinyl estradiol is cured at a relative humidity of about 1% to about 2%. In a fifth embodiment of the first aspect, the core containing segesterone acetate and ethinyl estradiol is aged for at least 30 days before being assembled into the ring body.

[0008] In a sixth embodiment of the first aspect, the silicone elastomer has a hydride / vinyl ratio before curing of from about 1:1 to about 1.3:1.

[0009] In a seventh embodiment of the first aspect, the silicone elastomer ring body has a platinum concentration of about 3 ppm to about 10 ppm. In an eighth embodiment of the first aspect, the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm. In a ninth embodiment of the first aspect, the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

[0010] In a second aspect, the present disclosure provides a multi-component 13-cycle vaginal system for preventing pregnancy, the system comprising: a silicone elastomer ring body adapted to receive first and second drug-containing cores, the ring body comprising a silicone elastomer having a platinum concentration of about 3 ppm to about 10 ppm; a first core and a second core containing a total of about 103 mg of segesterone acetate and about 17.4 mg of ethinyl estradiol; the system is configured to release an average of about 0.15 mg / day of segesterone acetate and an average of about 0.013 mg / day of ethinyl estradiol, or a bioequivalent amount of either or both, for up to thirteen 21-day cycles, A multi-component, 13-cycle vaginal system is provided in which about 80% to about 90% of the ethinyl estradiol is recoverable from the system after about 18 months of storage at 25°C and 60% relative humidity.

[0011] In a first embodiment of the second aspect, the system is configured to release an average of about 0.15 mg / day of segesterone acetate and about 0.013 mg / day of ethinyl estradiol, or bioequivalents thereof, into the vagina of a female subject in need thereof for up to thirteen 21-day cycles, respectively.

[0012] In a second embodiment of the second aspect, the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm. In a third embodiment of the second aspect, the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

[0013] In a fourth embodiment of the second aspect, the silicone elastomer has a hydride / vinyl ratio before curing of from about 1:1 to about 1.3:1.

[0014] In a fifth embodiment of the second aspect, one of the two cores contains segesterone acetate and the other contains segesterone acetate and ethinyl estradiol. In a sixth embodiment of the second aspect, the core containing segesterone acetate and ethinyl estradiol is cured at a temperature of about 60°C to about 90°C. In a seventh embodiment of the second aspect, the core containing segesterone acetate and ethinyl estradiol is cured at a relative humidity of about 1% to about 2%. In an eighth embodiment of the second aspect, the core containing segesterone acetate and ethinyl estradiol is aged for at least 30 days before being assembled into the ring body.

[0015] In a third aspect, the present disclosure provides a multi-component vaginal system for preventing pregnancy, the system comprising: a silicone elastomer ring body adapted to receive first and second drug-containing cores, the ring body comprising a silicone elastomer having a hydride / vinyl ratio of about 1:1 to about 1.3:1 before curing and a platinum concentration of about 3 ppm to about 10 ppm; a first core and a second core containing a total of about 103 mg of segesterone acetate and about 17.4 mg of ethinyl estradiol; the system is configured to release an average of about 0.15 mg / day of segesterone acetate and an average of about 0.013 mg / day of ethinyl estradiol, or a bioequivalent amount of either or both, for up to thirteen 21-day cycles; A multi-component vaginal system is provided in which less than about 10% to about 20% of the ethinyl estradiol is hydrosilylated with unreacted hydrosilane in the ring body after about 18 months of storage at 25°C and 60% relative humidity.

[0016] In a first embodiment of the third aspect, the system is configured to release an average of about 0.15 mg / day of segesterone acetate and about 0.013 mg / day of ethinyl estradiol, or bioequivalents thereof, into the vagina of a female subject in need thereof for up to thirteen 21-day cycles, respectively.

[0017] In a second embodiment of the third aspect, the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm. In a third embodiment of the third aspect, the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

[0018] In a fourth embodiment of the third aspect, one of the two cores contains segesterone acetate and the other contains segesterone acetate and ethinyl estradiol. In a fifth embodiment of the third aspect, the core containing segesterone acetate and ethinyl estradiol is cured at a temperature of about 60°C to about 90°C. In a sixth embodiment of the third aspect, the core containing segesterone acetate and ethinyl estradiol is cured at a relative humidity of about 1% to about 2%. In a seventh embodiment of the third aspect, the core containing segesterone acetate and ethinyl estradiol is aged for at least 30 days before being assembled into the ring body.

[0019] In a fourth aspect, the present disclosure provides a reusable 13-cycle vaginal system for preventing pregnancy, the system comprising a silicone elastomer ring body and two drug-containing cores, each core comprising segesterone acetate, ethinyl estradiol, or a combination thereof; the silicone elastomer ring body has a Shore A hardness of about 25 to about 30, an average fatigue parallel to the core of about 95%, and an average fatigue perpendicular to the core of about 98%; the system is configured to release an average of about 0.15 mg / day of segesterone acetate and an average of about 0.013 mg / day of ethinyl estradiol, or a bioequivalent amount of either or both, for up to thirteen 21-day cycles, A reusable, 13-cycle vaginal system is provided in which approximately 80% to approximately 90% of the ethinyl estradiol is recoverable from the system after approximately 18 months of storage at 25°C and 60% relative humidity.

[0020] In a first embodiment of the fourth aspect, the system is configured to release an average of about 0.15 mg / day of segesterone acetate and about 0.013 mg / day of ethinyl estradiol, or bioequivalents thereof, into the vagina of a female subject in need thereof for up to thirteen 21-day cycles, respectively.

[0021] In a second embodiment of the fourth aspect, the silicone elastomer ring body has an average fatigue parallel to the core of about 95%. In a third embodiment of the fourth aspect, the silicone elastomer ring body has an average fatigue perpendicular to the core of about 98%.

[0022] In a fourth embodiment of the fourth aspect, the silicone elastomer ring body has a platinum concentration of about 3 ppm to about 10 ppm. In a fifth embodiment of the fourth aspect, the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm. In a sixth embodiment of the fourth aspect, the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

[0023] In a seventh embodiment of the fourth aspect, the silicone elastomer ring body has a hydride / vinyl ratio before curing of from about 1:1 to about 1.3:1.

[0024] In a fifth aspect, the present disclosure provides a multi-component 13-cycle vaginal system for preventing pregnancy, the system comprising: a silicone elastomer ring body comprising a silicone elastomer having, prior to cure, a hydride / vinyl ratio of about 1:1 to about 1.3:1 and a platinum concentration of about 3 ppm to about 10 ppm; a first core comprising second and third silicone elastomers, the second and third silicone elastomers being impregnated with a first amount of segesterone acetate particles having a particle size distribution of D90 equal to or less than 10 micrometers and D50 equal to or less than 5 micrometers; a second core comprising a fourth silicone elastomer, the fourth silicone elastomer being impregnated with a second amount of segesterone acetate particles and an amount of ethinyl estradiol particles, the ethinyl estradiol particles having a particle size distribution of 100% at most 15 micrometers, 99% at most 12.5 micrometers, 95% at most 10 micrometers, and 40% at most 1.3 micrometers; the second, third, and fourth silicone elastomers collectively contain about 103 mg of segesterone acetate and about 17.4 mg of ethinyl estradiol; The ring system is configured to release an average of 0.15 mg / day of segesterone acetate and an average of 0.013 mg / day of ethinyl estradiol, or a bioequivalent amount of either or both, for up to 13 21-day cycles, A multi-component, 13-cycle vaginal system is provided in which less than about 10% to about 20% of the ethinyl estradiol is hydrosilylated with unreacted hydrosilane in the ring body after about 18 months of storage at 25°C and 60% relative humidity.

[0025] In a first embodiment of the fifth aspect, the system is configured to release an average of about 0.15 mg / day of segesterone acetate and about 0.013 mg / day of ethinyl estradiol, or bioequivalents thereof, into the vagina of a female subject in need thereof for up to thirteen 21-day cycles, respectively.

[0026] In a second embodiment of the fifth aspect, the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm. In a third embodiment of the fifth aspect, the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

[0027] In a fourth embodiment of the fifth aspect, at least 75% of the segesterone acetate comprises segesterone acetate polymorphic Form I.

[0028] In a fifth embodiment of the fifth aspect, the segesterone acetate comprises up to 25% of segesterone acetate polymorph Form II.

[0029] In a sixth embodiment of the fifth aspect, the second core is cured at a temperature of about 60° C. to about 90° C. In a seventh embodiment of the fifth aspect, the second core is cured at a relative humidity of about 1% to 2%. In an eighth embodiment of the fifth aspect, the second core is aged for at least 30 days before being assembled into the ring body.

[0030] In a sixth aspect, the present disclosure provides a 13-cycle vaginal system for preventing pregnancy, the ring system comprising: a silicone elastomer ring body; segesterone acetate particles having a particle size distribution of D90 less than or equal to 10 micrometers, D50 less than or equal to 5 micrometers, and D10 less than or equal to 0.6 micrometers; ethinyl estradiol particles having a particle size distribution of 100% up to 15 micrometers, 99% up to 12.5 micrometers, 95% up to 10 micrometers, and 40% up to 1.3 micrometers, The system provides a 13-cycle vaginal system containing a total of about 103 mg of segesterone acetate and about 17.4 mg of ethinyl estradiol.

[0031] In a first embodiment of the sixth aspect, at least 75% of the segesterone acetate is segesterone acetate polymorphic Form I. In a second embodiment of the sixth aspect, at least 95% of the segesterone acetate is acetate polymorphic Form I.

[0032] In a third embodiment of the sixth aspect, up to 25% of the segesterone acetate is acetate polymorph Form II. [Brief explanation of the drawings]

[0033] [Figure 1A] FIG. 1 is a diagram of a vaginal system disclosed herein. [Figure 1B] FIG. 1 is a diagram of a vaginal system disclosed herein.

[0034] [Figure 2] 1 is an XRPD comparison of the ethinyl estradiol / segesterone acetate core with the history patterns of segesterone acetate polymorphic Forms I and II.

[0035] [Figure 3] 1 is an XRPD comparison of ethinyl estradiol with the calculated patterns of ethinyl estradiol hemihydrate and anhydrous ethinyl estradiol.

[0036] [Figure 4] FIG. 1 is a schematic diagram of a platinum catalyzed reaction to form a ring body elastomer.

[0037] [Figure 5] FIG. 1 is a schematic diagram of the reaction between ethinyl estradiol and components of the ring body elastomer.

[0038] [Figure 6A] 13C-solid state NMR spectrum of 17α-ethynyl-13C2-estradiol (20,21-13C2 labeled, 99.1% isotopic enrichment).

[0039] [Figure 6B] FIG. 13C-Solid State NMR spectrum of NuSil™ MED4-4224 (9:1 mixture of Part A:Part B).

[0040] [Figure 7A] 13C-solid state NMR spectrum of the EE-13C2 silicone sample before solvent extraction.

[0041] [Figure 7B] 13C-solid state NMR spectrum of the EE-13C2 silicone sample after solvent extraction.

[0042] [Figure 8A] FIG. 1 is a diagram of the upper and lower rigs used to measure tensile strength and elongation.

[0043] [Figure 8B] FIG. 10 shows tensile measurement orientations parallel and perpendicular to the ring core.

[0044] [Figure 8C] 1 shows the ring mounted for tensile strength and elongation measurements parallel to the ring core.

[0045] [Figure 8D] 1 shows the ring mounted for tensile strength and elongation measurements perpendicular to the ring core.

[0046] [Figure 9A] FIG. 10 shows compression measurement orientations parallel and perpendicular to the ring core.

[0047] [Figure 9B] FIG. 1 shows a compression probe instrument of a compression rig.

[0048] [Figure 9C] FIG. 1 shows a lower compression rig.

[0049] [Figure 9D] FIG. 1 shows a lower compression rig including nylon straps.

[0050] [Figure 9E] 1 shows the ring mounted for compression measurements parallel to the ring core.

[0051] [Figure 9F] 1 shows the ring mounted for compression measurements normal to the ring core.

[0052] [Figure 10A] The structures of the identified NES and EE degradation products are shown.

[0053] [Figure 10B] The structures of the identified NES and EE degradation products are shown.

[0054] [Figure 10C] The structures of the identified NES and EE degradation products are shown.

[0055] [Figure 10D] The structures of the identified NES and EE degradation products are shown. DETAILED DESCRIPTION OF THE INVENTION

[0056] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0057] As used herein, the term "or" indicates a logical branch (i.e., and / or) and not an exclusive branch unless expressly indicated as such by the terms "either," "unless," "alternatively," and words of similar effect.

[0058] As used herein, the term "about" refers to ±10% of the stated value, unless otherwise specified.

[0059] The term "bioequivalent" has the meaning defined in 21 C.F.R. § 320.1(e) and refers to the absence of significant differences in the rate and extent to which the active ingredient or active moiety of pharmaceutical equivalents or pharmaceutical substitutes becomes available at the site of drug action when administered at the same molar dose under similar conditions in well-designed studies. Where there are intentional differences in rate (e.g., in certain sustained-release dosage forms), certain pharmaceutical equivalents or substitutes may be considered bioequivalent if there are no significant differences in the extent to which the active ingredient or active moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or active moiety becomes available at the site of drug action is intentional, reflected in the proposed labeling, is not essential to achieving effective body drug concentrations for chronic use, and is not considered medically significant to the drug. In practice, two products may differ in AUC or C max are considered bioequivalent if the 90% confidence interval is between 80.00% and 125.00%.

[0060] As used herein, the term "compatibility" refers to the ability of two or more items of different chemical composition to repeatedly contact each other over an extended period of time, such as about one year, without adverse effects on any of the items that contact each other during that period. Exemplary adverse effects that do not occur when two or more items are compatible include, but are not limited to, a chemical reaction between the two or more items, increased brittleness in one or more of the items, fracture of one or more of the items, expansion or contraction of one or more of the items, breakage of one or more of the items, hardening of one or more of the items, softening of one or more of the items, erosion of one or more of the items, and / or a decrease in the functionality of one or more of the items, such as a change in the rate of drug release from one of the items.

[0061] As used herein, the phrase "cumulative 2 hours" refers to multiple periods that total 2 hours.

[0062] As used herein, the term "day" refers to a 24-hour period.

[0063] As used herein, the term "elongation" refers to the increase in length that a material undergoes under tension before failure. The procedure used to measure the elongation of a subject vaginal ring is described in Example 5 herein.

[0064] As used herein, "ethinyl estradiol" and "EE" refer to the compound having the established name 19-nor-17α-pregna-1,3,5(10)-triene-20-yne-3,17-diol, molecular formula C 20 H 24 It refers to the compound O2 and has the following structure: [ka] The physical form of the compound is a white to slightly yellowish-white crystalline powder. The compound is substantially insoluble in water, freely soluble in alcohol, and soluble in alkaline solutions. In certain embodiments, the EE comprises a crystalline form that melts at about 181°C to about 186°C. In some embodiments, the EE comprises a crystalline form that melts at about 141°C to about 146°C.

[0065] As used herein, the term "fatigue" refers to the weakening of a material caused by repeated application of load. The procedure used to measure fatigue of the vaginal rings described in this disclosure is described in Example 6 herein.

[0066] As used herein, the phrase "first period" refers to the 21 day period during which the vaginal system described herein is inside the subject's vagina during a product use cycle.

[0067] As used herein, the term "hydrosilylation" refers to the catalytic addition of a Si-H bond to an unsaturated bond.

[0068] As used herein, the term "polyisoprene" refers to a polymer of isoprene, the polymer having the following structure: [ka]

[0069] As used herein, the phrase "product use cycle" refers to the combined number of days for the first period and the second period. In one embodiment of the present disclosure, the product use cycle for the vaginal systems described herein is 28 days.

[0070] As used herein, the term "relative humidity" refers to the amount of water vapor present in the air expressed as a percentage of the amount required for saturation at the same temperature.

[0071] As used herein, the term "fertility" refers to the ability of a female to produce offspring.

[0072] As used herein, the phrase "room temperature" refers to a temperature between 15°C and 30°C.

[0073] As used herein, the phrase "second period" refers to the 5-7 days during which the vaginal system is outside the subject's vagina during a product use cycle. The second period is a non-overlapping period immediately following the first period and is a "no-dose" interval. That is, the subject does not receive either SA or EE during this period.

[0074] As used herein, "segesterone acetate," "SA," and "NES" refer to the compound having the established name 16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3,20-dione, molecular formula C 23 H 30 It refers to the compound O4 and has the following structure: [ka] The physical form of the compound is a white or off-white powder. The compound is slightly soluble in n-hexane, soluble in ethyl acetate and methanol, and freely soluble in acetone (USP classification). Segesterone acetate is sold under the trade name NESTORONE®.

[0075] As used herein, the term "subject" refers to a human female of reproductive potential.

[0076] As used herein, the term "substantially pure" refers to a polymorph of a compound that is greater than about 90% pure, meaning that the polymorph contains no more than about 10% of any other compound or any other form of the compound.

[0077] As used herein, the term "tensile strength" refers to a material's resistance to longitudinal stress, measured in force per unit of cross-sectional area, due to the maximum load that a given material can withstand in the direction of its length without breaking. The procedure used to measure tensile strength is described in Example 5 herein.

[0078] As used herein, the term "unacceptable EE burst" refers to an EE burst of about 0.13 mg or more (i.e., about 10 times or more the average amount of EE released by the vaginal system per day).

[0079] As used herein, the term "vaginal system" refers to a device inserted into the vagina to prevent pregnancy. In one embodiment of the present disclosure, the vaginal system comprises a vaginal ring. In another embodiment of the present disclosure, the vaginal system comprises a progestin / estrogen combined hormonal contraceptive (CHC). In another embodiment of the present disclosure, the vaginal system is a segesterone acetate and ethinyl estradiol system.

[0080] In an exemplary embodiment, each vaginal system is individually packaged in an aluminum pouch. Typically, the pouch is made from a laminate material including, from the outside to the inside, polyester, aluminum foil, and polyethylene. A compact case that is inert to the vaginal system may be provided to the patient for storing the system.

[0081] In some embodiments, the vaginal systems described herein contain about 90 mg to about 120 mg of segesterone acetate (SA). In some embodiments, the vaginal systems described herein contain about 95 mg to about 115 mg of SA. In some embodiments, the vaginal systems described herein contain about 100 mg to about 110 mg of SA. In some embodiments, the vaginal systems described herein contain about 103 mg of SA. In some embodiments, the vaginal systems described herein contain 103 mg of SA.

[0082] In some embodiments, the vaginal systems described herein contain about 10 mg to about 25 mg of ethinyl estradiol (EE). In some embodiments, the vaginal systems described herein contain about 15 mg to about 20 mg of EE. In some embodiments, the vaginal systems described herein contain about 17.4 mg of EE. In some embodiments, the vaginal systems described herein contain 17.4 mg of EE.

[0083] In some embodiments, the vaginal system described herein contains 103 mg of SA and 17.4 mg of EE. In certain embodiments, the system may release an average of about 0.15 mg / day of SA and 0.013 mg / day of EE intravaginally over 21 days of each product use cycle for up to 13 product use cycles (a total of 273 days). Each product use cycle is 28 days long, comprising a 21-day first period and a 7-day second period. Typically, the vaginal system is self-inserted into the vagina by the subject during the first period and removed during the second period. The day of the week on which the vaginal system is first inserted during the first period, i.e., day 1, is the change day of the vaginal system. The day of the week on which the vaginal system is removed to begin the second period, i.e., day 22, is also referred to as the change day of the vaginal system. Each vaginal system is designed to be used for up to 13 product use cycles (one year) before being discarded.

[0084] In some embodiments, the vaginal systems described herein can release an average of about 0.15 mg / day of SA and an average of about 0.013 mg / day of EE, or bioequivalents thereof.

[0085] The vaginal system provides SA and EE at the approximate rates described above, although SA and EE may diffuse from the vaginal system at release rates that vary over time. In certain embodiments, the daily in vitro release rates of SA and EE are higher during the first 24-48 hours of use in each given product use cycle, achieving a somewhat lower steady state with continued use over the following days of each product use cycle. Based on the residual drug content in the vaginal system used in clinical trials for 13 product use cycles, a total of approximately 41.3 mg of SA and approximately 3.4 mg of EE are released during this period. Thus, approximately 60% of SA and approximately 80% of EE remain in the vaginal system at the end of 13 product use cycles. For reasons explained later in this disclosure, it was surprising that such a proportionally larger amount of EE is required in the vaginal system compared to SA. Structure of the vaginal system

[0086] Generally, the vaginal systems described herein are of a suitable size and shape for insertion into the vagina. The systems typically include at least two components: a ring body and one or more cores. The cores are shaped in a manner suitable for containment within the ring. The ring body is typically made of one or more polymeric materials, such as one or more silicone elastomers, and is generally adapted to receive or be co-extruded with at least one drug-containing core. The at least one drug-containing core may be made of the same or a different polymeric material as the ring body. The core may contain an active ingredient, such as an EE, an SA, or a combination thereof, that dissolves, distributes (i.e., as a solid), or dissolves and distributes throughout the at least one core. When combined, the ring body and the at least one core provide the user with the active ingredient at a release rate sufficient to provide effective birth control over 13 product use cycles.

[0087] In some embodiments, the vaginal system of the present disclosure releases an average of about 0.15 mg / day of SA and 0.013 mg / day of EE intravaginally over a 21-day period during each product use cycle for up to 13 product use cycles (273 days total). In some embodiments, the system releases an average of about 0.15 mg / day of SA and 0.013 mg / day of EE intravaginally over a 21-day period during each product use cycle for up to 13 product use cycles (273 days total) and includes one core. In other embodiments, the system releases an average of about 0.15 mg / day of SA and 0.013 mg / day of EE intravaginally over a 21-day period during each product use cycle for up to 13 product use cycles (273 days total) and includes multiple cores. In some embodiments, the system releases an overall average of about 0.15 mg / day of SA and 0.03 mg / day of EE intravaginally over a 21-day period during each product use cycle for up to 13 product use cycles (273 days total) and includes two, three, or four cores. In certain embodiments, the system releases an overall average of about 0.15 mg / day of SA and 0.013 mg / day of EE intravaginally over a 21-day period during each product use cycle for up to 13 product use cycles (273 days total) and includes two cores.

[0088] Although the ring body can be manufactured without an active agent such as SA or EE before the first product use cycle, in certain embodiments, the link body can be prepared to include SA, EE, or both in addition to or instead of the core, provided that the vaginal system as a whole intravaginally releases an average of about 0.15 mg / day of SA and 0.013 mg / day of EE during the 21-day period of each product use cycle for up to 13 product use cycles (273 days total). However, if the ring body is manufactured without an active agent, it is understood that either or both active agents can diffuse from the core into the ring body before the first product use cycle.

[0089] In certain embodiments, the vaginal systems of the present disclosure are ring-shaped having an overall (external) diameter, an internal diameter, and a cross-sectional diameter. In some embodiments, the ring has an overall (external) diameter of about 40 mm to about 70 mm. In other embodiments, the ring has an overall diameter of about 45 mm to about 65 mm. In other embodiments, the ring has an overall diameter of about 50 mm to about 60 mm. In other embodiments, the ring has an overall diameter of about 53 mm to about 59 mm. In some embodiments, the ring has an overall diameter of about 56 mm.

[0090] In certain embodiments, the ring has an inner diameter of about 25 mm to about 55 mm. In other embodiments, the ring has an inner diameter of about 30 mm to about 50 mm. In other embodiments, the ring has an inner diameter of about 35 mm to about 45 mm. In some embodiments, the ring has an inner diameter of about 40 mm.

[0091] In certain embodiments, the vaginal system of the present disclosure is ring-shaped and has a cross-sectional diameter of about 3 mm to about 10 mm. In other embodiments, the ring has a cross-sectional diameter of about 3.5 mm to about 9.5 mm. In other embodiments, the ring has a cross-sectional diameter of about 4 mm to about 9 mm. In other embodiments, the ring has a cross-sectional diameter of about 5 mm to about 9 mm. In other embodiments, the ring has a cross-sectional diameter of about 6 mm to about 9 mm. In other embodiments, the ring has a cross-sectional diameter of about 7 mm to about 9 mm. In other embodiments, the ring has a cross-sectional diameter of about 8 mm to about 9 mm. In some embodiments, the ring has a cross-sectional diameter of about 8.4 mm.

[0092] Sizing of the vaginal system is an important component in system design. Because the system is inserted into a woman's vagina, the vaginal system cannot be too large or too small to make insertion and / or withdrawal more difficult. Similarly, the cross-sectional diameter of the vaginal system is another design component that can be adjusted to provide optimal drug delivery and comfort, so that the system is not viewed aesthetically as "bulky" by the woman or felt in the vagina.

[0093] The vaginal system typically adopts the shape of a ring body, such as, by way of example only, when the ring body is ring-shaped. While the vaginal system can be ring-shaped, in some embodiments, the vaginal system can be an elliptical or oval torus, a Bohemian dome, a lemon shape, an "eight-sided," an ellipsoid, a cardiac surface, a sphere, a spheroid, or any other shape suitable for insertion into a subject's vagina. In some embodiments, the vaginal system can be circular or spherical. In some embodiments, the vaginal system can be polygonal in shape. In some embodiments, the vaginal system can be rectangular, triangular, hexagonal, pentagonal, rectangular, triangular prism, or spherical. Any shape suitable for vaginal insertion can be selected or used to provide maximum comfort to the user without departing from the teachings provided in this disclosure.

[0094] Regardless of its shape, in certain embodiments, the vaginal system includes one or more channels adapted to receive at least one core. When the ring body includes two or more cores, the channels adapted to receive the cores can be on opposite sides of the ring body. In other embodiments, the channels adapted to receive the cores are adjacent to each other within the ring body. In some embodiments, the channels adapted to receive the cores abut each other. In some embodiments, both channels adapted to receive the cores are located in the same half of the ring body.

[0095] The release rate of the agent(s) contained within the core is affected by the length of the path the agent(s) must travel to diffuse from the system to the subject. For example, a shorter diffusion path within the ring body may provide an increased release rate, while a longer diffusion path may provide a decreased release rate. Therefore, the amount of active agent(s) contained within the core must be balanced against the diffusion path length, among other considerations. In some embodiments, the channel adapted to receive the core has a length of about 10 mm to about 40 mm. In other embodiments, the channel adapted to receive the core has a length of about 15 mm to about 35 mm. In other embodiments, the channel adapted to receive the core has a length of about 20 mm to about 35 mm. In other embodiments, the channel adapted to receive the core has a length of about 25 mm to about 30 mm. In other embodiments, the channel adapted to receive the core has a length of about 27 mm.

[0096] The channel(s) adapted to receive at least one core may be of any suitable shape. For example, in some embodiments, the channel(s) adapted to receive the core(s) may be a bore, such as a cylindrical bore, adapted to receive an appropriately shaped cylindrical or spherical core. In other embodiments, the channel(s) may be adapted to receive a core(s) shaped like a rectangular prism, including a square prism, or a core(s) shaped like a cone, triangular prism, triangular pyramid, rectangular pyramid, pentagonal prism, hexagonal prism, heptagonal prism, or any other three-dimensional shape suitable for fabrication. In some embodiments, the channel(s) may be adapted to receive a disk-shaped core(s). In certain embodiments, the channel(s) may be adapted to receive a cylindrical core or a core shaped like a rectangular prism.

[0097] In some embodiments, the channel(s) adapted to receive at least one core are adapted to receive a cylindrical core having a diameter of about 1 mm to about 7 mm. In other embodiments, the channel(s) adapted to receive at least one core are adapted to receive a cylindrical core having a diameter of about 2 mm to about 6 mm. In other embodiments, the channel(s) adapted to receive at least one core are adapted to receive a cylindrical core having a diameter of about 2 mm to about 5 mm. In other embodiments, the channel(s) adapted to receive at least one core are adapted to receive a cylindrical core having a diameter of about 2 mm to about 4 mm. In other embodiments, the channel(s) adapted to receive at least one core are adapted to receive a cylindrical core having a diameter of about 3 mm.

[0098] In some embodiments, the core is co-extruded with the ring body elastomer, hi other embodiments, the core can be extruded or formed and cured by injection molding, and the ring body elastomer is extruded to encase the core.

[0099] In certain embodiments, the vaginal system of the present disclosure is ring-shaped, has an overall diameter of 56 mm, and a cross-sectional diameter of 8.4 mm. In some embodiments, the system includes two channels, each approximately 3 mm in diameter and approximately 27 mm in length, each adapted to receive a steroid-containing core of appropriate size and shape. Examples of such embodiments are shown in Figures 1A and 1B.

[0100] It is understood that in certain embodiments, the channels are formed in the ring when the ring body is prepared by either injection molding or extrusion, while in other embodiments, the channels are formed around the core during extrusion or injection molding of the ring body. core

[0101] In certain embodiments, the vaginal system contains about 50 to about 150 mg of SA and about 5 to about 35 mg of EE distributed throughout one or more cores. In certain embodiments, the vaginal system contains about 75 to about 125 mg of SA and about 10 to about 25 mg of EE distributed throughout one or more cores. In certain embodiments, the vaginal system contains about 90 to about 115 mg of SA and about 15 to about 20 mg of EE distributed throughout one or more cores. In some embodiments, the vaginal system contains about 103 mg of SA and about 17.4 mg of EE distributed throughout one or more cores. In certain embodiments, the vaginal system contains about 50 to about 150 mg of SA and about 5 to about 35 mg of EE distributed throughout a single core. In certain embodiments, the vaginal system contains about 75 to about 125 mg of SA and about 10 to about 25 mg of EE distributed throughout a single core. In certain embodiments, the vaginal system contains about 90 to about 115 mg of SA and about 15 to about 20 mg of EE distributed across a single core. In some embodiments, the vaginal system contains about 103 mg of SA and about 17.4 mg of EE distributed across a single core. In certain embodiments, the vaginal system contains about 50 to about 150 mg of SA and about 5 to about 35 mg of EE distributed across multiple cores. In certain embodiments, the vaginal system contains about 75 to about 125 mg of SA and about 10 to about 25 mg of EE distributed across multiple cores. In certain embodiments, the vaginal system contains about 90 to about 115 mg of SA and about 15 to about 20 mg of EE distributed across multiple cores. In some embodiments, the vaginal system contains about 103 mg of SA and about 17.4 mg of EE distributed across multiple cores. In some embodiments, the SA is distributed across one core and the EE is distributed across separate cores. In some embodiments, the SA is distributed across one core and the EE is distributed across multiple cores. In some embodiments, the SA is distributed throughout multiple cores and the EE is distributed throughout a separate core. In certain embodiments, the vaginal system contains about 50 to about 150 mg of SA and about 5 to about 35 mg of EE distributed across two or more cores. That is, each core in the system contains both the SA and the EE.In certain embodiments, the vaginal system contains about 75 to about 125 mg of SA and about 10 to about 25 mg of EE distributed among two or more cores. That is, each core in the system contains both SA and EE. In certain embodiments, the vaginal system contains about 90 to about 115 mg of SA and about 15 to about 25 mg of EE distributed among two or more cores. That is, each core in the system contains both SA and EE. In yet another embodiment, the vaginal system contains about 103 mg of SA and about 17.4 mg of EE, each distributed among two or more cores. That is, each core in the system contains both SA and EE.

[0102] In certain embodiments, the vaginal system includes two cores that collectively contain 103 mg of SA and 17.4 mg of EE. In one such embodiment, one core contains 17.4 mg of EE and a portion of the SA drug load. In this embodiment, the other core contains the remainder of the SA drug load. Of course, both cores may contain both active substances. In some embodiments, the EE drug load is contained in the first core, and the SA drug load is divided between two or more cores.

[0103] In some embodiments, the vaginal system contains about 103 mg of SA distributed across the two cores and about 17.4 mg of EE distributed across only one of the two cores, such that one core contains only SA and the other core contains both SA and EE. In certain embodiments, the SA is distributed between the two cores in a ratio of about 90:10 to about 10:90. In other embodiments, the SA is distributed between the two cores in a ratio of about 80:20 to about 20:80. In other embodiments, the SA is distributed between the two cores in a ratio of about 70:30 to about 30:70. In other embodiments, the SA is distributed between the two cores in a ratio of about 60:40 to about 40:60. In other embodiments, the SA is distributed between the two cores in a ratio of about 50:50. In certain embodiments, the SA is distributed between the two cores in a ratio of about 55:45 to about 45:55. In another embodiment, the SA is distributed between the two cores in a ratio of approximately 55:45.

[0104] In a typical embodiment, EE is present in one core and substantially or completely absent from the second core. However, in other embodiments, EE is distributed between the two cores in a ratio of about 99:1 to about 1:99. In other embodiments, EE is distributed between the two cores in a ratio of about 95:5 to about 5:95. In certain embodiments, EE is distributed between the two cores in a ratio of about 90:10 to about 10:90. In other embodiments, EE is distributed between the two cores in a ratio of about 80:20 to about 20:80. In other embodiments, EE is distributed between the two cores in a ratio of about 70:30 to about 30:70. In other embodiments, EE is distributed between the two cores in a ratio of about 60:40 to about 40:60. In other embodiments, EE is distributed between the two cores in a ratio of about 50:50.

[0105] In some embodiments, the vaginal system includes a first core containing about 40% to about 60% SA by weight. In some embodiments, the first core contains about 45% to about 55% SA by weight. In certain embodiments, the first core contains about 50% SA by weight.

[0106] In some embodiments, the first core has a diameter of about 1 mm to about 5 mm. In some embodiments, the first core has a diameter of about 2 mm to about 4 mm. In some embodiments, the first core has a diameter of about 3 mm. In certain embodiments, the first core has a length of about 9 mm to about 13 mm. In certain embodiments, the first core has a length of about 10 mm to about 12 mm. In some embodiments, the first core has a length of about 11 mm.

[0107] In some embodiments, the vaginal system includes a second core containing about 30% to about 50% SA by weight. In some embodiments, the second core contains about 35% to about 45% SA by weight. In some embodiments, the second core contains about 40% SA by weight. In some embodiments, the second core also contains about 5% to about 20% EE by weight. In some embodiments, the second core contains about 10% to about 14% EE by weight. In some embodiments, the second core contains about 12% EE by weight. In some embodiments, the second core has a diameter of about 1 mm to about 5 mm. In some embodiments, the second core has a diameter of about 2 mm to about 4 mm. In some embodiments, the second core has a diameter of about 3 mm. In some embodiments, the second core has a length of about 16 mm to about 20 mm. In some embodiments, the second core has a length of about 17 mm to about 19 mm. In some embodiments, the second core has a length of about 18 mm.

[0108] In certain embodiments, the vaginal system core comprises one or more polymers. In certain embodiments, the vaginal system core comprises one or more polymers selected from polystyrene, thermoplastic polymers (including but not limited to, poly(methyl methacrylate), acrylonitrile butadiene styrene, nylon, polylactic acid, polybenimidazole, polycarbonate, polyethersulfone, polyoxymethylene, polyetherketone, polyetherimide, polyethylene, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polyvinyl chloride, polyvinylidene fluoride, and Teflon), and elastomers (including but not limited to, natural and synthetic polyisoprene, polybutadiene, chloroprene, butyl rubber ( The vaginal system core may comprise one or more polymers selected from the group consisting of ethylene / propylene rubber (including halogenated derivatives thereof), styrene butadiene, nitrile rubber (including halogenated derivatives thereof), ethylene / propylene rubber (including both melt blends and reactor blends (block copolymers) of ethylene and propylene), epichlorohydrin rubber, polyacrylic rubber, silicone elastomer, fluorosilicone rubber, fluoroelastomer (e.g., VITON, TECNOFLON, FLUOREL, AFAS, and DAI-EL), perfluoroelastomer, polyether block amide, chlorosulfonated polyethylene, and ethylene vinyl acetate ("EVE"). In some embodiments, the core comprises EVA. In some embodiments, the core comprises one or more elastomers, and the elastomer is a silicone elastomer. In some embodiments, the core comprises a blend of silicone and other elastomers. In some embodiments, the vaginal system core comprises a single silicone elastomer. In other embodiments, the vaginal system core is composed of multiple silicone elastomers. In some embodiments, one or more of the cores comprises a single silicone elastomer and one or more of the cores comprises multiple silicone elastomers.

[0109] In some embodiments, the silicone elastomer includes one or more agents to increase viscosity. In some embodiments, the one or more agents to increase viscosity can be diatomaceous earth, cellulose, talc, and / or silica (e.g., fumed silica or colloidal silica). In some embodiments, the agent to increase viscosity is diatomaceous earth.

[0110] In some embodiments, the vaginal systems described herein comprise a condensation-cured silicone elastomer core. In some embodiments, the vaginal systems comprise an addition-cured silicone elastomer core. In some embodiments, the vaginal systems comprise one or more condensation-cured silicone elastomer cores and one or more condensation-cured silicone elastomer cores.

[0111] In some embodiments, the vaginal system includes a first core comprising one or more condensation-cured silicone elastomers. In some embodiments, the first core comprises two condensation-cured silicone elastomers. In some embodiments, one or both of these condensation-cured silicone elastomers may contain one or more agents to increase its viscosity. In some embodiments, the one or more agents to increase viscosity may be diatomaceous earth, cellulose, talc, and / or silica (e.g., fumed silica or colloidal silica). In some embodiments, the agent to increase viscosity is diatomaceous earth.

[0112] In some embodiments, the condensation-cured silicone elastomer can be NuSil™ MED-6381. In certain embodiments, this condensation-cured silicone elastomer can be prepared from three components: "Part A," "Part B," and a tin catalyst. In some embodiments, Part A contains >90% hydroxyl-terminated dimethylsiloxane and dimethylsilicone (CAS No. 70131-67-8). In some embodiments, Part B contains >90% tetrapropyl orthosilicate (CAS No. 682-01-9). In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, dioctyldilauryltin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate.

[0113] In certain embodiments, the condensation-cured silicone elastomer can be NuSil™ MED-6382. In certain embodiments, this condensation-cured silicone elastomer can be prepared from two components: "Part A" and a tin catalyst. In some embodiments, Part A includes siloxane, silicone, and <1% amorphous fumed silica (CAS No. 112945-52-5). In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, dioctyldilauryltin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate.

[0114] In further embodiments, the condensation-cured silicone elastomer can be NuSil™ MED-6630 (formerly known as DDU-4352). In certain embodiments, this condensation-cured silicone elastomer can be prepared from two components, "Part A" and a tin catalyst. In some embodiments, Part A comprises a siloxane and a silicone. In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, dioctyldilaurytin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate.

[0115] In further embodiments, the condensation-cured silicone elastomer can be NuSil™ MED3-6603. In certain embodiments, the condensation-cured silicone elastomer can be prepared from three components: "Part A," "Part B," and a tin catalyst. In some embodiments, Part A comprises a polydimethylsiloxane backbone. In some embodiments, Part B comprises a crosslinker. In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, dioctyldilaurytin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate.

[0116] In some embodiments, the condensation-cure silicone elastomer can be NuSil™ MED-6385. In certain embodiments, this condensation-cure silicone elastomer can be prepared from two components, "Part A" and a tin catalyst. In some embodiments, Part A includes dimethylsiloxane, dimethylsilicone (CAS No. 70131-67-8), 20-25% diatomaceous earth (CAS No. 68855-54-9), <5% silicic acid, tetrapropyl ester (CAS No. 682-01-9), and <1% amorphous fumed amorphous silica (CAS No. 112945-52-5). In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, di-octyldilauryltin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate.

[0117] In yet further embodiments, the condensation-cured silicone elastomer can be NuSil™ MED3-6385. In certain embodiments, this condensation-cured silicone elastomer can be prepared from three components: "Part A," "Part B," and a tin catalyst. In some embodiments, Part A includes a polydimethylsiloxane polymer backbone and diatomaceous earth. In some embodiments, Part B includes a crosslinker. In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, di-octyldilauryltin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate.

[0118] Each of these polymers is commercially available and is referenced in one or more drug master files.

[0119] In certain embodiments, the first silicone elastomer of the primary core is NuSil™ MED-6385. In some embodiments, the second silicone elastomer of the primary core is NuSil™ MED-6603 (formerly known as DDU-4352). In some embodiments, the tin catalyst is dibutyltin dilaurate.

[0120] In certain embodiments, the first core comprises an SA uniformly dispersed or distributed throughout a silicone elastomer comprising at least two condensation-cured silicone elastomers. In certain embodiments, the core can be prepared by combining a first silicone elastomer with a second silicone elastomer, adding the SA, and blending the resulting mixture. In certain embodiments, the SA can be added in portions. After thorough mixing, a curing agent can be added, and the resulting mixture can be further blended. In some embodiments, the curing agent can be a tin catalyst. In certain embodiments, the tin catalyst can be di-n-butylbutoxychlorotin, dibutyldiacetoxytin, dibutyltin dilaurate, dimethyltin dineodecanoate, dioctyldilauryltin, tetramethyltin, dioctylbis(2-ethylhexylmaleate)tin, or stannous octoate. In some embodiments, the tin catalyst is stannous octoate or dibutyltin dilaurate. In some embodiments, the curing agent can be dibutyltin dilaurate. In some embodiments, the curing agent is NuSil™ MED-6603 Part B. In some embodiments, the blended mixture, also referred to as a pre-core mixture, can be formed into a string and subjected to curing conditions.

[0121] In certain embodiments, the pre-core mixture may be formed into a string by injection molding. In some embodiments, the pre-core mixture may be formed into a string by extrusion. In certain embodiments, the string may be cured at a temperature of about room temperature to about 140°C. In some embodiments, the string may be cured at a temperature of about 40°C to about 135°C. In certain embodiments, the string may be cured at a temperature of about 50°C to about 130°C. In some embodiments, the string may be cured at a temperature of about 55°C to about 125°C. In some embodiments, the string may be cured at a temperature of about 60°C to about 120°C.

[0122] In some embodiments, the amount of time the string cures increases with decreasing curing temperature. In certain embodiments, the string may be cured for about 10 minutes to about 70 minutes. In certain embodiments, the string may be cured for about 20 minutes to about 60 minutes. In some embodiments, the string may be cured for about 25 minutes to about 50 minutes. In some embodiments, the string may be cured for about 30 minutes to about 45 minutes. In some embodiments, the string may be cured for about 30 minutes. In some embodiments, the string may be cured for about 45 minutes. In some embodiments, the string may be cured at about 120°C for about 30 minutes. In some embodiments, the string may be cured at about 60°C for about 45 minutes.

[0123] In some embodiments, the cured product may be post-cured at room temperature for at least 2 days. In some embodiments, the cured product may be post-cured at room temperature for at least 3 days. In some embodiments, the cured product may be post-cured at room temperature for at least 4 days. In some embodiments, the cured product may be post-cured at room temperature for at least 5 days. In some embodiments, the cured product may be post-cured at room temperature for at least 6 days. In some embodiments, the cured product may be post-cured at room temperature for at least 7 days. In some embodiments, the cured product may be post-cured at room temperature for at least 8 days. In some embodiments, the cured product may be post-cured at room temperature for at least 9 days. In some embodiments, the cured product may be post-cured at room temperature for at least 10 days.

[0124] In certain embodiments, the strings may be cut after post-curing to provide cores suitable for providing the desired SA and EE release rates disclosed herein. Because the length and diameter of the core may affect the release rate of the drug, the amount of a particular drug added to a particular core must be balanced against the length and diameter of that core to ensure the release rate disclosed herein is achieved. In some embodiments, the strings may be cut to lengths of about 8 mm to about 14 mm. In some embodiments, the strings may be cut to lengths of about 9 mm to about 13 mm. In some embodiments, the strings may be cut to lengths of about 10 mm to about 12 mm. In some embodiments, the strings may be cut to lengths of about 11 mm. In some embodiments, the weight of the first core may be about 70 to about 120 mg. In some embodiments, the weight of the first core may be about 80 to about 100 mg. In some embodiments, the weight of the first core may be about 85 mg to about 95 mg. In some embodiments, the weight of the first core is about 90 mg.

[0125] In certain embodiments, the first core may contain about 25 mg to about 75 mg of SA. In some embodiments, the first core may contain about 35 mg to about 65 mg of SA. In some embodiments, the first core may contain about 40 mg to about 50 mg of SA. In some embodiments, the first core contains about 45 mg of SA or 43 mg to 47 mg of SA.

[0126] Segesterone acetate has been found to exist in at least two polymorphic unsolvated forms: polymorphic form I and polymorphic form II. Polymorphic forms I and II can be obtained by crystallization under conditions known in the art (see Hungarian Patent No. Hu0004967, Modifications A and B, respectively). The XRPD patterns for each polymorph are shown in Figure 2, comparing a representative core containing both EE and SA with the respective hysteresis patterns of forms I and II.

[0127] In some embodiments, the SA used in the vaginal systems described herein can be a pure or substantially pure single polymorph, such as polymorphic Form I or polymorphic Form II. However, in some embodiments, the SA used in the vaginal systems described herein can include a mixture of polymorphs. For example, in some embodiments, the SA can include about 60% to about 99% by weight of polymorphic Form I, with the remainder being other known polymorphs, amorphous SA, or a combination thereof. In some embodiments, the SA can include about 70% to about 99% polymorphic Form I. In some embodiments, the SA can include about 80% to about 99% polymorphic Form I. Each of the specified percentages is a weight percent.

[0128] In some embodiments, the SA contained within each core of the vaginal system may comprise about 1% to about 40% by weight of polymorphic Form II, with the remainder being other known polymorphs, amorphous SA, or combinations thereof. In some embodiments, the SA may comprise about 1% to about 30% polymorphic Form II. In some embodiments, the SA may comprise about 1% to about 20% polymorphic Form II. In some embodiments, the SA may contain a detectable amount of polymorphic Form II, but less than 10% polymorphic Form II. All percentages above are by weight.

[0129] The applicant surprisingly discovered that the SA particle size is important for obtaining an elastomeric core mixture, i.e., a pre-core mixture, suitable for extrusion and injection molding. If the SA particles are too large, the resulting pre-core mixture is too soft and unsuitable for extrusion and / or injection molding. Alternatively, if the SA particle size is too small, the resulting pre-core mixture is too hard for extrusion and / or injection molding. The particle size also affects the rate at which the compound is solubilized into the core, ultimately affecting the release profile of the SA from the system to the patient.

[0130] In some embodiments, the SA contained within each core of the vaginal systems described herein can be micronized. In some embodiments, the SA contained within each core can have a particle size distribution such that at least 95% of the particles have a particle size between about 0.1 micrometers and about 25 micrometers, between about 0.1 micrometers and about 24 micrometers, between about 0.1 micrometers and about 23 micrometers, between about 0.1 micrometers and about 22 micrometers, between about 0.1 micrometers and about 21 micrometers, or between about 0.1 micrometers and about 20 micrometers.

[0131] In some embodiments, the SA contained within each core can have a particle size distribution in which about 90% of the particles have a particle size between about 0.5 micrometers and about 15 micrometers, between about 0.5 micrometers and about 14 micrometers, between about 0.5 micrometers and about 13 micrometers, between about 0.5 micrometers and about 12 micrometers, between about 0.5 micrometers and about 11 micrometers, or between about 0.5 micrometers and about 10 micrometers.

[0132] In some embodiments, the SA contained within each core may have a particle size distribution in which about 50% of the particles have a particle size between about 0.5 micrometers and about 10 micrometers, between about 0.5 micrometers and about 9 micrometers, between about 0.5 micrometers and about 8 micrometers, between about 0.5 micrometers and about 7 micrometers, between about 0.5 micrometers and about 6 micrometers, or between about 0.5 micrometers and about 5 micrometers.

[0133] In certain embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 100 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 90 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 80 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 70 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 60 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 50 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 40 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 30 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 20 micrometers. In some embodiments, the SA contained within each core may have a particle size distribution such that 99% or more of the particles are less than 10 micrometers.

[0134] In certain embodiments, the SA contained within each core may have a D90 of about 100 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 90 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 80 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 70 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 60 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 50 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 40 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 30 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 20 micrometers or less. In certain embodiments, the SA contained within each core may have a D90 of about 15 micrometers or less. In certain embodiments, the SA contained within each core may have a D90 of about 12 micrometers or less. In some embodiments, the SA contained within each core may have a D90 of about 10 micrometers or less. In certain embodiments, the SA contained within each core may have a D90 of about 8 micrometers or less. In certain embodiments, the SA contained within each core may have a D90 of about 6 micrometers or less.

[0135] In certain embodiments, the SA may have a D50 of about 75 micrometers or less. In certain embodiments, the SA may have a D50 of about 65 micrometers or less. In certain embodiments, the SA may have a D50 of about 55 micrometers or less. In certain embodiments, the SA may have a D50 of about 45 micrometers or less. In certain embodiments, the SA may have a D50 of about 35 micrometers or less. In certain embodiments, the SA may have a D50 of about 25 micrometers or less. In certain embodiments, the SA may have a D50 of about 15 micrometers or less. In some embodiments, the SA may have a D50 of about 10 micrometers or less. In some embodiments, the SA may have a D50 of about 8 micrometers or less. In some embodiments, the SA may have a D50 of about 5 micrometers or less. In some embodiments, the SA may have a D50 of about 3 micrometers or less. In some embodiments, the SA may have a D50 of about 2 micrometers or less.

[0136] In certain embodiments, the SA may have a D10 of about 50 micrometers or greater. In some embodiments, the SA may have a D10 of about 40 micrometers or greater. In some embodiments, the SA may have a D10 of about 30 micrometers or greater. In some embodiments, the SA may have a D10 of about 20 micrometers or greater. In some embodiments, the SA may have a D10 of about 10 micrometers or greater. In some embodiments, the SA may have a D10 of about 5 micrometers or greater. In some embodiments, the SA may have a D10 of about 3 micrometers or greater. In some embodiments, the SA may have a D10 of about 1 micrometer or greater. In some embodiments, the SA may have a D10 of about 0.6 micrometers or greater. In some embodiments, the SA may have a D10 of about 0.5 micrometers or greater. In some embodiments, the SA may have a D10 of about 0.4 micrometers or greater.

[0137] In certain embodiments, the SA contained within each core may have a D90 of about 80 micrometers or less, a D50 of about 45 micrometers or less, and a D10 of about 10 micrometers or more. In some embodiments, the SA contained within each core may have a D90 of about 40 micrometers or less, a D50 of about 25 micrometers or less, and a D10 of about 5 micrometers or more. In some embodiments, the SA contained within each core may have a D90 of about 20 micrometers or less, a D50 of about 15 micrometers or less, and a D10 of about 1 micrometer or more. In some embodiments, the SA contained within each core may have a D90 of about 10 micrometers or less, a D50 of about 5 micrometers or less, and a D10 of about 0.6 micrometers or more. In some embodiments, the SA contained within each core may have a D90 of about 8 micrometers or less, a D50 of about 3 micrometers or less, and a D10 of about 0.4 micrometers or more. In some embodiments, the SA contained within each core may have a D90 of about 6 micrometers or less, a D50 of about 2 micrometers or less, and a D10 of about 0.2 micrometers or more.

[0138] In certain embodiments, the vaginal system includes a secondary core comprising SA and EE. In some embodiments, the secondary core includes one or more condensation-cured silicone elastomers. In some embodiments, the secondary core includes a single condensation-cured silicone elastomer. In some embodiments, the condensation-cured silicone elastomer is selected from the group consisting of NuSil™ MED-6603 (formerly known as DDU-4352), NuSil™ MED3-6603, NuSil™ MED-6381, NuSil™ MED-6382, and NuSil™ MED-6385, as described elsewhere herein. In certain embodiments, the secondary core includes NuSil™ MED-6603 (formerly known as DDU-4352). This material is commercially available.

[0139] In certain embodiments, the secondary core comprises a single elastomer, SA, and EE. In some embodiments, the secondary core can be prepared by blending the elastomer with EE. In some embodiments, SA is added to the blend in portions. In some embodiments, the resulting mixture containing the elastomer, EE, and SA can be divided into smaller portions before treatment with the curative. In some embodiments, the curative can be a tin catalyst. In some embodiments, the curative can be dibutyltin dilaurate. In some embodiments, the curative is NuSil™ MED-6603 Part B. In some embodiments, the resulting mixture can be extruded into a string after addition of the curative.

[0140] Applicant surprisingly discovered that the temperature and relative humidity at which the secondary core is cured can be important to the rate at which EE is released on day 1 of the first product use cycle. Higher curing temperatures and higher relative humidity during the curing process cause an unacceptable EE burst on day 1. This effect was not observed with cores containing only SA. In certain embodiments, strings containing EE and SA can be cured at temperatures below about 120°C. In some embodiments, the strings can be cured at temperatures from about room temperature to about 115°C. In some embodiments, the strings can be cured at temperatures from about 40°C to about 110°C. In some embodiments, the strings can be cured at temperatures from about 50°C to about 100°C. In some embodiments, the strings can be cured at temperatures from about 60°C to about 90°C. In some embodiments, the strings can be cured at temperatures of about 90°C or higher. In some embodiments, the strings can be cured at temperatures of about 60°C to about 90°C.

[0141] In some embodiments, the amount of time the string cures increases with decreasing cure temperature. In certain embodiments, the string may be cured for about 5 minutes to about 60 minutes. In some embodiments, the string may be cured for about 25 minutes to about 50 minutes. In some embodiments, the string may be cured for about 30 minutes to about 45 minutes. In some embodiments, the string may be cured for about 30 minutes or more. In some embodiments, the string may be cured at about 90°C for about 10 minutes. In some embodiments, the string may be cured at about 60°C for about 15 minutes to about 20 minutes.

[0142] In certain embodiments, the string may be cured at a relative humidity of less than about 5%. In certain embodiments, the string may be cured at a relative humidity of less than about 4%. In some embodiments, the string may be cured at a relative humidity of less than about 3%. In some embodiments, the string may be cured at a relative humidity of less than about 2%. In some embodiments, the string may be cured at a relative humidity of about 1% to about 2%. In some embodiments, the string may be cured at a relative humidity of about 1.8%.

[0143] In some embodiments, the cured product may be post-cured at room temperature for at least 2 days. In some embodiments, the cured product may be post-cured at room temperature for at least 3 days. In some embodiments, the cured product may be post-cured at room temperature for at least 4 days. In some embodiments, the cured product may be post-cured at room temperature for at least 5 days. In some embodiments, the cured product may be post-cured at room temperature for at least 6 days. In some embodiments, the cured product may be post-cured at room temperature for at least 7 days. In some embodiments, the cured product may be post-cured at room temperature for at least 8 days. In some embodiments, the cured product may be post-cured at room temperature for at least 9 days. In some embodiments, the cured product may be post-cured at room temperature for at least 10 days.

[0144] In some embodiments, the string may be cut after the post-cure period to provide a core. In some embodiments, the string may be cut to a length of about 15 mm to about 21 mm. In some embodiments, the string may be cut to a length of about 16 mm to about 20 mm. In some embodiments, the string may be cut to a length of about 17 mm to about 19 mm. In some embodiments, the string may be cut to a length of about 18 mm. In certain embodiments, the weight of the second core may be about 115 mg to about 175 mg. In certain embodiments, the weight of the second core may be about 125 mg to about 165 mg. In some embodiments, the weight of the second core may be about 135 mg to about 155 mg. In some embodiments, the weight of the second core may be about 145 mg.

[0145] In certain embodiments, the second core may contain about 40 mg to about 80 mg of SA. In certain embodiments, the second core may contain about 50 mg to about 70 mg of SA. In some embodiments, the second core may contain about 50 mg to about 60 mg of SA. In some embodiments, the second core may contain about 55 mg to about 60 mg of SA. In some embodiments, the second core may contain about 58 mg of SA, or 56 to 60 mg of SA.

[0146] In some embodiments, the second core may contain about 14 mg to about 25 mg of EE. In some embodiments, the second core may contain about 15 mg to about 20 mg of EE. In some embodiments, the second core may contain about 16 mg to about 19 mg of EE. In some embodiments, the second core may contain about 15 mg to about 18 mg of EE. In some embodiments, the second core may contain about 16 mg to about 18 mg of EE. In some embodiments, the second core may contain about 17.4 mg of EE, or 17.2 to 17.6 mg of EE.

[0147] Crystalline forms of EE and multiple crystalline EE hydrates are known in the literature (see, e.g., Pheasant, R., "Polymorphism of 17-Ethinylestradiol," J. Am. Chem. Soc. 1950, 72(9), pp. 4303-4304 and Guguta, C. et al., Cryst. Growth Des. 2008, 8(3), pp. 823-831, both of which are incorporated by reference in their entireties). A comparison of the XRPD pattern of EE API with the calculated XRPD patterns of EE hemihydrate and anhydrous EE is shown in FIG. 3. In some embodiments, the EE contained within the second core comprises one or more anhydrous forms. In some embodiments, the EE contained within the second core comprises one or more hemihydrate forms. In some embodiments, the EE contained within the second core comprises a mixture of one or more anhydrous forms and one or more hemihydrate forms. In certain embodiments, the EE contained within the second core comprises a crystalline form that melts at about 181° C. to about 186° C. In some embodiments, the EE comprises a crystalline form that melts at about 141° C. to about 146° C. In yet other embodiments, the EE contained within the second core comprises a mixture of a crystalline form that melts at about 181° C. to about 186° C. and a crystalline form that melts at about 141° C. to about 146° C., wherein the weight ratio of these crystalline forms ranges from about 99:1 to about 1:99.

[0148] As discussed herein, particle size affects the rate at which the compound is solubilized in the core, ultimately affecting the release profile of the EE from the system to the patient. In some embodiments, the EE contained within the second core of the vaginal system may be micronized. In some embodiments, the EE contained within the second core may have a maximum particle size of about 10 micrometers to about 20 micrometers. In some embodiments, the EE contained within the second core may have a maximum particle size of about 11 micrometers to about 19 micrometers. In some embodiments, the EE contained within the second core may have a maximum particle size of about 12 micrometers to about 18 micrometers. In some embodiments, the EE contained within the second core may have a maximum particle size of about 13 micrometers to about 17 micrometers. In some embodiments, the EE contained within the second core may have a maximum particle size of about 14 micrometers to about 16 micrometers. In some embodiments, the EE may have a maximum particle size of about 15 micrometers.

[0149] In some embodiments, the EE may have a particle size distribution in which about 99% of the particles have a maximum particle size between about 11 micrometers and about 15 micrometers. In some embodiments, the EE may have a particle size distribution in which about 99% of the particles have a maximum particle size between about 12 micrometers and about 14 micrometers. In some embodiments, the EE may have a particle size distribution in which about 99% of the particles have a maximum particle size between about 12 micrometers and about 13 micrometers. In some embodiments, the EE may have a particle size distribution in which about 99% of the particles have a maximum particle size between about 12 micrometers and about 13 micrometers. In some embodiments, the EE may have a particle size distribution in which about 95% of the particles have a maximum particle size between about 8 micrometers and about 13 micrometers. In some embodiments, the EE may have a particle size distribution in which about 95% of the particles have a maximum particle size between about 9 micrometers and about 12 micrometers. In some embodiments, the EE may have a particle size distribution in which about 95% of the particles have a maximum particle size between about 9 micrometers and about 11 micrometers. In some embodiments, the EE may have a particle size distribution in which about 95% of the particles have a maximum particle size between about 10.0 micrometers. In some embodiments, the EE may have a particle size distribution in which about 50% of the particles have a maximum particle size between about 1 micrometer and about 4 micrometers. In some embodiments, the EE may have a particle size distribution in which about 50% of the particles have a maximum particle size between about 2 micrometers and about 4 micrometers. In some embodiments, the EE may have a particle size distribution in which about 50% of the particles have a maximum particle size between about 3 micrometers. In some embodiments, the EE may have a particle size distribution in which not more than about 40% of the particles have a particle size of not more than about 2 micrometers. In some embodiments, the EE may have a particle size distribution in which not more than about 40% of the particles have a particle size of not more than about 1.5 micrometers. In some embodiments, the EE may have a particle size distribution in which not more than about 40% of the particles have a particle size of not more than about 1.3 micrometers.

[0150] Surprisingly, it has been discovered that aging of the second core during assembly into the ring body affects the initial burst of EE on day 1. For example, new cores have been shown to result in unacceptable EE burst on day 1. In certain embodiments, after curing, one or more of the cores may be stored for at least 8 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 10 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 12 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 14 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 16 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 18 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 20 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 21 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 22 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 23 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 24 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 25 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 26 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 27 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 28 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 29 days before assembly into the ring body.In certain embodiments, after curing, one or more of the cores may be stored for at least 30 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 31 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 32 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 33 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 34 days before assembly into the ring body. In certain embodiments, after curing, one or more of the cores may be stored for at least 35 days before assembly into the ring body.

[0151] In certain embodiments, the shaping of the pre-core mixture, cutting of the resulting cores, and / or storage of the resulting cores may be carried out at a temperature of about 10° C. to about 40° C. In certain embodiments, the shaping of the pre-core mixture, cutting of the resulting cores, and / or storage of the resulting cores may be carried out at a temperature of about 15° C. to about 35° C. In certain embodiments, the shaping of the pre-core mixture, cutting of the resulting cores, and / or storage of the resulting cores may be carried out at a temperature of about 15° C. to about 30° C. In some embodiments, the shaping of the pre-core mixture, cutting of the resulting cores, and / or storage of the resulting cores may be carried out at a temperature of about 20° C. to about 25° C.

[0152] In some embodiments, forming the pre-core mixture, cutting the resulting cores, and / or storing the resulting cores may be performed at a relative humidity of about 10% or greater. In some embodiments, forming the pre-core mixture, cutting the resulting cores, and / or storing the resulting cores may be performed at a relative humidity of about 20% or greater. In some embodiments, forming the pre-core mixture, cutting the resulting cores, and / or storing the resulting cores may be performed at a relative humidity of about 30% or greater. In some embodiments, forming the pre-core mixture, cutting the resulting cores, and / or storing the resulting cores may be performed at a relative humidity of about 40% or greater.

[0153] In some embodiments, the core of the vaginal system described herein is prepared in accordance with the guidelines outlined in the United States Pharmacopeial Convention, particularly USP <905> Complies with. Ring body

[0154] The vaginal system ring body typically comprises one or more polymers. In certain embodiments, the ring body is made of a material selected from the group consisting of polystyrene, thermoplastic polymers (including but not limited to poly(methyl methacrylate), acrylonitrile butadiene styrene, nylon, polylactic acid, polybenimidazole, polycarbonate, polyethersulfone, polyoxymethylene, polyetherketone, polyetherimide, polyethylene, polyphenylene oxide, polyphenylene sulfide, polypropylene, polystyrene, polyvinyl chloride, polyvinylidene fluoride, and Teflon), and elastomers (including but not limited to natural and synthetic polyisoprene, polybutadiene, chloroprene, butyl rubber (including halogenated derivatives thereof), and the like). The ring body may comprise one or more polymers selected from: ethylene / propylene rubber (including conductors), styrene butadiene, nitrile rubber (including halogenated derivatives thereof), ethylene / propylene rubber (including both melt blends and reactor blends (block copolymers) of ethylene and propylene), epichlorohydrin rubber, polyacrylic rubber, silicone elastomer, fluorosilicone rubber, fluoroelastomer (e.g., VITON, TECNOFLON, FLUOREL, AFAS, and DAI-EL), perfluoroelastomer, polyether block amide, chlorosulfonated polyethylene, ethylene vinyl acetate ("EVE"). In some embodiments, the ring body comprises EVA. In some embodiments, the ring body comprises one or more elastomers, where the elastomer is a silicone elastomer. In some embodiments, the ring body comprises a blend of silicone and other elastomers. In some embodiments, the ring body comprises a single silicone elastomer. In other embodiments, the ring body comprises multiple silicone elastomers. In some embodiments, the ring body comprises a condensation cure silicone elastomer. In other embodiments, the ring body comprises an addition cure silicone elastomer.

[0155] In some embodiments, the ring body comprises a silicone addition-cure elastomer. Addition-cure silicone elastomers typically comprise a vinyl-terminated silicone polymer, a platinum catalyst, and a silyl hydrogenation crosslinker. Silicone addition-cure elastomers are generally supplied as a two-part system that must be intimately mixed to initiate curing. That is, in other embodiments, the addition-cure silicone elastomer can be provided as a premixed non-polymerized starting material with a separate catalyst, or in three separate component parts that are subsequently mixed in the appropriate ratio.

[0156] In certain embodiments, the ring body comprises a medical-grade addition-cure silicone elastomer having a platinum concentration of about 1 ppm to about 15 ppm. In certain embodiments, the ring body comprises a medical-grade addition-cure silicone elastomer having a platinum concentration of about 2 ppm to about 12 ppm. In certain embodiments, the ring body comprises a medical-grade addition-cure silicone elastomer having a platinum concentration of about 2 ppm to about 10 ppm. In some embodiments, the addition-cure silicone elastomer can be a polysiloxane elastomer containing about 2 ppm to about 10 ppm of platinum. In some embodiments, the polysiloxane elastomer can be a diorganopolysiloxane elastomer containing about 2 ppm to about 10 ppm of platinum. In some embodiments, the diorganopolysiloxane elastomer can be a dimethylpolysiloxane elastomer containing about 2 ppm to about 10 ppm of platinum. As discussed in more detail below, it has surprisingly been discovered that the concentration of platinum in the ring body appears to play a role in controlling the release rate of EE in the vaginal system. Platinum concentrations above or below the specified range can result in an increased rate of EE sequestration, while insufficient platinum can result in the release of excessive EE and the associated side effects associated with excess estradiol.

[0157] In addition to having a particular platinum concentration, the addition-cured silicone elastomer may also include one or more opacifying agents, one or more pigments, one or more anti-degradants, one or more fillers, or a combination thereof.

[0158] In certain embodiments, addition-cured silicone elastomers having specific platinum concentrations can be prepared from two components, "Part A" and "Part B." In some embodiments, the first part (Part A) contains an uncured vinyl-terminated silicone polymer and a platinum catalyst, which acts as a curing agent. In some embodiments, the second part (Part B) contains an uncured vinyl-terminated silicone polymer and a hydride crosslinker. In certain embodiments, the ratio of hydride crosslinker ("hydride") to vinyl-terminated polymer ("vinyl") in both Part A and Part B is from about 1:2 to about 5:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 4:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 3:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 2:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 1.5:1. In some embodiments, the hydride / vinyl ratio is from about 1:1 to about 1.3:1. In some embodiments, the hydride / vinyl ratio is from about 1:1 to about 1.2:1.

[0159] Increasing the ratio of Part A to Part B has been found to increase both the tensile strength and elongation of the cured elastomer without affecting the Shore A hardness. Therefore, an appropriate ratio of Part A to Part B can be selected to provide an elastomer that is flexible enough to facilitate insertion and removal, yet durable enough to withstand the physical stresses of use. In certain embodiments, the ring body elastomer can be prepared by mixing Part A to Part B in a ratio of about 8:1 to about 12:1. In certain embodiments, an addition-cure silicone elastomer can be prepared by mixing Part A to Part B in a ratio of about 9:1 to about 11:1. In certain embodiments, an addition-cure silicone elastomer can be prepared by mixing Part A to Part B in a ratio of about 9.5:1 to about 10.5:1. In certain embodiments, an addition-cure silicone elastomer can be prepared by mixing Part A to Part B in a ratio of about 10:1.

[0160] In some embodiments, the addition-cure silicone elastomer having the recited platinum concentration can be NuSil™ MED-4870. NuSil™ MED-4870 can be prepared by mixing two components, "Part A" and "Part B." In addition to siloxane and silicone, Part A of this embodiment can include 30-40% trimethylsilylsilane amine (CAS No. 68909-20-6). Part B of this embodiment can include dimethylsiloxane and dimethylsilicone, as well as 30-40% trimethylsilylsilane amine (CAS No. 68909-20-6) and a platinum catalyst.

[0161] In some embodiments, the addition-cure silicone elastomer having a platinum concentration within the specified range can be NuSil™ DDU-4320. Similar to other addition-cure silicone elastomers, NuSil™ DDU-4320 can be prepared by mixing two components, "Part A" and "Part B," in the appropriate ratio. In this embodiment, Part A can include 40-50% vinyl-terminated dimethyl siloxane and dimethyl silicone (CAS No. 68952-0001), 10-20% amorphous fumed amorphous silica (CAS No. 112945-52-5), and <1% hydroxyl to 1% hydroxyl-terminated dimethyl and methyl vinyl siloxane and silicone (CAS No. 67923-19-7). In some embodiments, Part B comprises 40-50% vinyl-terminated dimethylsiloxanes and dimethylsilicones (CAS No. 68952-0001), 30-40% ethenyldimethylsilyloxy- and trimethylsilyloxy-modified silica (CAS No. 68988-89-6), 10-20% amorphous fumed amorphous silica (CAS No. 112945-52-5), <1% silicic acid tetraethyl ester (CAS No. 68988-57-8), <1% 1-ethynylcyclohexanol (CAS No. 78-27-3), and <1% hydroxyl-terminated dimethyl and methylvinyl siloxanes and silicones (CAS No. 67923-19-7).

[0162] In some embodiments, an addition-cure silicone elastomer having a platinum concentration within the specified range can be MED4-4224 (formerly known as DDU-4331). As noted above, this addition-cure silicone elastomer can be prepared by mixing two components, "Part A" and "Part B," in the appropriate ratio. In this embodiment, Part A contains 65-75% mono(vinyl)-terminated dimethylsiloxane and dimethylsilicone (CAS No. 68952-00-1), 15-20% amorphous fumed amorphous silica (CAS No. 112945-52-5), and <5% titanium dioxide (CAS No. 137463-67-7). Part B, in this embodiment, comprises 65-75% mono(vinyl) terminated dimethyl siloxanes and dimethyl silicones (CAS No. 68952-00-1), 10-15% siloxanes and silicones (dimethyl and methyl) (CAS No. 68037-59-2), and a platinum catalyst.

[0163] In some embodiments, the silicone elastomer is NuSil™ MED4-4224 (formerly known as DDU-4331). In some embodiments, in addition to the above ingredients, NuSil™ MED4-4224 includes one or more opacifying agents. In some embodiments, the opacifying agent is titanium dioxide. In some embodiments, NuSil™ MED4-4224 includes about 4% by weight of TiO2.

[0164] In some embodiments, the component parts of the addition-cure silicone elastomer may be mixed, then molded into a ring body, and subjected to curing conditions to form the ring body. In some embodiments, the ring body may be cured at a temperature of about 120°C to about 180°C. In some embodiments, the ring body may be cured at a temperature of about 130°C to about 170°C. In some embodiments, the ring body may be cured at a temperature of about 140°C to about 160°C. In some embodiments, the ring body is cured at a temperature of about 145°C to about 155°C. In some embodiments, the ring body may be cured for about 20 to about 210 seconds. In some embodiments, the ring body may be cured for about 30 to about 200 seconds. In some embodiments, the ring body may be cured for about 40 to about 190 seconds. In some embodiments, the ring body may be cured for about 50 to about 190 seconds. In some embodiments, the ring body may be cured for about 60 to about 180 seconds. In some embodiments, the ring body may be cured for about 180 seconds.

[0165] In certain embodiments, the cured elastomeric ring body has a specific gravity of about 1 to about 1.5. In some embodiments, the cured elastomeric ring body has a specific gravity of about 1.05 to about 1.4. In some embodiments, the cured elastomeric ring body has a specific gravity of about 1.05 to about 1.3. In some embodiments, the cured elastomeric ring body has a specific gravity of about 1.05 to about 1.25. In some embodiments, the cured elastomeric ring body has a specific gravity of about 1.05 to about 1.20. In some embodiments, the cured elastomeric ring body has a specific gravity of about 1.07 to about 1.17. In some embodiments, the cured elastomeric ring body has a specific gravity of about 1.08 to about 1.11.

[0166] In certain embodiments, the ring body may be allowed to rest after removal from the mold and before inserting the core. In some embodiments, the ring body may be allowed to rest at a temperature of about 10°C to about 40°C. In some embodiments, the ring body may be allowed to rest at a temperature of about 15°C to about 35°C. In some embodiments, the ring body may be allowed to rest at a temperature of about 15°C to about 30°C. In some embodiments, the ring body may be allowed to rest at a temperature of about 19°C to about 25°C. In some embodiments, the ring body may be allowed to rest for a period of about 10 to about 45 days. In some embodiments, the ring body may be allowed to rest for a period of about 20 to about 40 days. In some embodiments, the ring body is allowed to rest for about 30 days.

[0167] As described elsewhere herein, the ring body includes one or more channels adapted to receive an active impregnated core. In certain embodiments, the channels adapted to receive the cores may be created in the ring body during the molding process. Alternatively, any suitable means for creating the channels after the molding process can be used. For example, in some embodiments, the channels may be prepared by a laser or by using a suitable cutting mechanism, such as a metal blade or high-pressure water. In some embodiments, the channels may be created by puncturing. In some embodiments, the channels may be created by drilling. An appropriate mechanism for introducing one or more channels into the ring body can be selected depending on the placement and size of the channels, as well as other factors. As described elsewhere herein, the channel(s) adapted to receive the core(s) may be a bore, such as a cylindrical bore, adapted to receive an appropriately shaped cylindrical or spherical core. In other embodiments, the channel(s) may be adapted to receive a core(s) shaped like a rectangular prism, including, for example, a square prism, or a core(s) shaped like a cone, triangular prism, triangular pyramid, rectangular pyramid, pentagonal prism, hexagonal prism, heptagonal prism, or any other three-dimensional shape suitable for fabrication. In some embodiments, the channel(s) may be adapted to receive a disk-shaped core(s). In particular embodiments, the channel(s) may be adapted to receive a cylindrical core or a core shaped like a rectangular prism.

[0168] Curing results in hardening of the resulting ring body. In certain embodiments, the cured ring body has an average elongation parallel to the core of about 350 to about 550%. In some embodiments, the cured ring body has an average elongation parallel to the core of about 375 to about 525%. In some embodiments, the cured ring body has an average elongation parallel to the core of about 400 to about 500%. In some embodiments, the cured ring body has an average elongation parallel to the core of about 418%. In certain embodiments, the cured ring body has an average elongation perpendicular to the core of about 350 to about 550%. In some embodiments, the cured ring body has an average elongation perpendicular to the core of about 375 to about 525%. In some embodiments, the cured ring body has an average elongation perpendicular to the core of about 400 to about 500%. In some embodiments, the cured ring body has an average elongation perpendicular to the core of about 474%.

[0169] In a particular embodiment, the hardened ring body has a strength of about 9,000 N / mm 2 ~approx. 10,000N / mm 2 In some embodiments, the hardened ring body has an average tensile strength parallel to the core of about 9,100 N / mm 2 ~9,750N / mm 2 In some embodiments, the hardened ring body has an average tensile strength parallel to the core of about 9,200 N / mm 2 ~Approx. 9,500N / mm 2 In some embodiments, the hardened ring body has an average tensile strength parallel to the core of about 9,300 N / mm 2 ~approx. 9,400N / mm 2 In some embodiments, the hardened ring body has an average tensile strength parallel to the core of about 9,312 N / mm 2 In a particular embodiment, the hardened ring body has an average tensile strength parallel to the core of about 10,000 N / mm 2 ~approx. 11,000N / mm 2 In some embodiments, the hardened ring body has an average tensile strength perpendicular to the core of about 10,100 N / mm 2~Approx. 10,750N / mm 2 In some embodiments, the hardened ring body has an average tensile strength perpendicular to the core of about 10,200 N / mm 2 ~Approx. 10,500N / mm 2 In some embodiments, the hardened ring body has an average tensile strength perpendicular to the core of about 10,300 N / mm 2 ~approx. 10,400N / mm 2 In some embodiments, the stiffening ring body has an average tensile strength perpendicular to the core of about 10,369 N / mm 2 has an average tensile strength perpendicular to the core of

[0170] In certain embodiments, the hardened ring body has an average fatigue parallel to the core of about 80 to about 110%. In certain embodiments, the hardened ring body has an average fatigue parallel to the core of about 85 to about 105%. In some embodiments, the hardened ring body has an average fatigue parallel to the core of about 90 to about 100%. In some embodiments, the hardened ring body has an average fatigue parallel to the core of about 95%. In certain embodiments, the hardened ring body has an average fatigue perpendicular to the core of about 80 to about 100%. In some embodiments, the hardened ring body has an average fatigue perpendicular to the core of about 85 to about 100%. In some embodiments, the hardened ring body has an average fatigue perpendicular to the core of about 90 to about 100%. In some embodiments, the hardened ring body has an average fatigue perpendicular to the core of about 98%.

[0171] In some embodiments, the cured elastomer has a Shore A hardness of about 10 to about 50. In some embodiments, the cured elastomer has a Shore A hardness of about 15 to about 45. In some embodiments, the cured elastomer has a Shore A hardness of about 20 to about 40. In some embodiments, the cured elastomer has a Shore A hardness of about 25 to about 35. In some embodiments, the cured elastomer has a Shore A hardness of about 25 to about 30. Assembly of the vaginal system

[0172] Depending on the configuration, the vaginal system can be completed by inserting the appropriate number of appropriately aged cores into channels or other structures in the ring body adapted to receive the core(s). In some embodiments, one or more suitable medical adhesives can be added to secure the cores within the ring body. In some embodiments, the medical adhesive can be added before the cores are added. In some embodiments, the medical adhesive can be added after the cores are added, and in certain embodiments, the medical adhesive can be added before or after the cores are added. In certain embodiments, the medical adhesive can be a one-part acetoxy (alkyltriacetoxysilane) or alcohol (alkoxy) crosslinking cure system. These one-part adhesives are cured in the presence of ambient humidity. In some embodiments, the acetoxy cure system utilizes a tin catalyst; in other embodiments, the acetoxy cure system does not utilize a tin catalyst. In other embodiments, the medical adhesive can be a UV-cure (solvent-free) adhesive. Such adhesives are known in the art and include photoinitiators that initiate crosslinking upon exposure to UV radiation between 200 and 500 nm.

[0173] Medical adhesives can be purchased from vendors such as NuSil and Elkem. In some embodiments, the medical adhesive used can be NuSil™ MED-1134, which contains 15-25% trimethylsilane amine (CAS No. 68909-20-6) and <5% methylsilanetriol triacetate (CAS No. 4253-34-3). In some embodiments, the channels can be sealed with additional medical adhesive. In certain embodiments, for ring bodies containing two channels, the ring can be assembled by adding medical adhesive to each channel, inserting one core, typically an aged core, into each channel, and adding additional medical adhesive to the channels once the cores have been added.

[0174] In some embodiments, the rings may be assembled at a temperature of about 10°C to about 35°C. In some embodiments, ring assembly may occur at a temperature of about 15°C to about 30°C. In certain embodiments, ring assembly may occur at a relative humidity of about 40% to about 95%. In certain embodiments, ring assembly may occur at a relative humidity of about 45% to about 90%. In some embodiments, ring assembly may occur at a relative humidity of about 50% to about 80%. In some embodiments, ring assembly may occur at a relative humidity of about 50% to about 75%. In some embodiments, ring assembly may occur at a relative humidity of about 50% to about 65%. In some embodiments, ring assembly may occur at a relative humidity of about 55%.

[0175] In some embodiments, the vaginal system may be assembled by extruding the ring body around one or more cores.

[0176] In some embodiments, the assembled vaginal system can be cured at room temperature for a period of about 1 to about 14 days. In some embodiments, the assembled vaginal system can be cured at room temperature for a period of about 2 to about 10 days. In some embodiments, the assembled vaginal system can be cured for a period of about 3 to about 7 days.

[0177] In certain embodiments, the assembled vaginal system has a total weight of about 6 grams to about 15 grams. In some embodiments, the assembled vaginal system has a total weight of about 6 grams to about 10 grams. In some embodiments, the assembled vaginal system has a total weight of about 8 grams to about 10 grams. In some embodiments, the assembled vaginal system has a total weight of about 9 grams.

[0178] In certain embodiments, the assembled vaginal system may be packaged in a pouch. In some embodiments, the pouch comprises aluminum. In some embodiments, the ring may be packaged at a temperature of about 10°C to about 35°C. In some embodiments, packaging may occur at a temperature of about 15°C to about 30°C. In some embodiments, packaging may occur at a relative humidity of 40% or greater. In some embodiments, packaging may occur at a relative humidity of about 40% to about 90%. In some embodiments, packaging may occur at a relative humidity of about 50% to about 80%. In some embodiments, packaging may occur at a relative humidity of about 50% to about 70%. In some embodiments, packaging may occur at a relative humidity of about 55%.

[0179] In other embodiments, the packaged vaginal system may be matured at a temperature of about 10°C to about 35°C. In certain embodiments, the packaged vaginal system may be matured at a temperature of about 15°C to about 30°C. In certain embodiments, the maturation time may be about 15 to about 60 days. In certain embodiments, the maturation time may be about 25 to about 40 days. In some embodiments, the maturation time may be about 28 to about 35 days.

[0180] In some embodiments, the vaginal systems described herein operate when the EE and SA are partially solubilized in the core in which they are contained, then diffuse from the core into the ring body, and finally diffuse from the ring body to the patient. The system is complex, and the rate of solubilization must be controlled to deliver the appropriate amount of each agent for each of 13 28-day product use cycles. If too much of the agent dissolves in either the core or the ring body, excessive drug will be released; if too little of the EE or SA dissolves in the core or ring body, insufficient release will occur. Long-term ring stability is also essential. That is, the selected polymer system must be compatible with both the SA and the EE so that sufficient amounts of both are available to provide the desired release rates of both active agents over 13 product use cycles, especially since the vaginal system, once placed in the vagina, will be repeatedly exposed to heat and humidity over a 21-day period.

[0181] Surprisingly, it was discovered that the amount of SA recoverable from the vaginal systems stored for 24 months at 25°C and 60% relative humidity remained essentially constant, while the amount of EE recoverable from the systems decreased in a time-dependent manner. This was quite surprising, as a similar trend was not observed during long-term stability studies on pre-assembled cores. In fact, the entire amount of EE was found to be recoverable from the cores by extraction even after extended storage.

[0182] Without being bound by any particular theory, it is believed that the platinum distributed throughout the ring body causes a catalytic reaction between excess / unreacted hydrosilanes present in the cured ring body elastomer and the terminal acetylene groups in the EE as it diffuses into the ring body during maturation of the system. This process binds the EE to the ring body elastomer, making it unavailable for release from the ring, resulting in a decrease in the recoverable amount of EE over time. This process is shown schematically in Figures 4 and 5. Figure 4 illustrates, for example, a process for preparing the ring body morphology under catalytic conditions using an exemplary addition-cured silicone elastomer. While this process is generally complete under the conditions described herein, the silicone elastomer resulting from the platinum-catalyzed reaction will yield an elastomer with the platinum catalyst distributed throughout, along with a certain amount of unreacted hydrosilane present on the polymer backbone. Without being bound by theory, it is believed that these hydrosilanes are randomly distributed throughout the ring body along with the platinum catalyst, which is more uniformly distributed because it is not believed to be linked to the polymer itself. The EE is partially dissolved in the core, and partially dissolved in the core over the life of the vaginal system, and migrates from the core through the ring body. The majority of the EE successfully migrates from the ring body into the subject's vagina, providing EE over the course of multiple product use cycles. However, a certain number of EE molecules interact with both the platinum catalyst and the hydrosilane distributed throughout the ring body, resulting in the structure shown in Figure 5.

[0183] To determine whether the amount of residual hydride in the ring body elastomer contributes to this phenomenon, the effect of the hydride / vinyl ratio of the uncured elastomer on the in vitro release of EE at day 1 at 6 and 12 months was investigated. Results showed that higher hydride / vinyl ratios (>1:1) resulted in lower EE release at day 1 than lower hydride / vinyl ratios (<1:1). Surprisingly, Applicant discovered that hydride / vinyl ratios <1 led to an EE "burst" resulting in unacceptably high day 1 releases at 6 and 12 months. Alternatively, hydride / vinyl ratios of about 1:1 to about 1.3:1 provided acceptable EE release profiles over the same time periods.

[0184] In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 25% to about 85% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 25% to about 80% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 30% to about 75% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 35% to about 65% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 35% to about 60% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 35% to about 55% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 35% to about 50% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of <1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 40% to about 45% higher than the day 1 release before storage.

[0185] In some embodiments, a hydride / vinyl ratio of >1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 15% lower to about 25% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of >1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 10% lower to about 20% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of >1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 5% lower to about 15% higher than the day 1 release before storage. In some embodiments, a hydride / vinyl ratio of >1:1 results in a day 1 release after 6 months of storage at 25°C and 60% relative humidity that is about 2% lower to about 19% higher than the day 1 release before storage. In some embodiments, at hydride / vinyl ratios >1:1, the release on day 1 after 6 months of storage at 25° C. and 60% relative humidity is about 1% to about 15% higher than the release on day 1 before storage. In some embodiments, at hydride / vinyl ratios >1:1, the release on day 1 after 6 months of storage at 25° C. and 60% relative humidity is about 1% to about 10% higher than the release on day 1 before storage. Thus, unexpectedly, some hydrosilylation of the EE appears to be necessary to achieve an acceptable EE release profile over the course of 13 product use cycles.

[0186] Moreover, it has been surprisingly discovered that when using NuSil™ MED4-4224, a 10:1 ratio of component Part A to component Part B must have a narrow range of hydride / vinyl ratios to obtain consistent EE emissions over 13 product use cycles. In certain embodiments, this hydride / vinyl ratio can be from about 1:2 to about 5:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 4:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 3:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 2:1. In some embodiments, the hydride / vinyl ratio is from about 1:1.5 to about 1.5:1. In some embodiments, the hydride / vinyl ratio is from 1:1 to 1.3:1. In some embodiments, the hydride / vinyl ratio is from 1:1 to 1.2:1. The hydride to vinyl ratio can be controlled by specifying the amount of vinyl terminated dimethylsiloxane and dimethylsilicone in the pre-cured elastomer at the time of order.

[0187] As previously mentioned, there are additional factors that contribute to the amount of EE released from a system on day 1 of each product use cycle. EE particle size influences the rate at which the compound is solubilized into the core, ultimately affecting the drug release profile from the system. Furthermore, it was surprisingly discovered that the temperature and relative humidity at which the EE-containing cores are cured influence the amount of EE released on day 1. A curing temperature of 120°C resulted in unacceptably excessive release. Humidity levels also had an unpredictable effect, with certain curing temperatures requiring lower relative humidity to ensure acceptable amounts of EE release on day 1.

[0188] The combination of particle size, conditions under which the core is cured, and the hydride / vinyl ratio in the ring body elastomer all contribute to the rate of EE release from the vaginal system over 13 product use cycles and also contribute to the system's stability over time. Therefore, each of these factors must be balanced to ensure an appropriate release profile over 13 product use cycles and adequate long-term stability. Too much hydride in the ring body elastomer reduces the amount of EE available in the system, especially after long-term storage. Conversely, too little hydride, high curing temperatures, and high humidity during core curing will result in an excessively high EE burst on day 1.

[0189] The vaginal systems disclosed herein are reusable for 13 product use cycles and are sufficiently stable for at least 18 months of storage at 25°C and 60% relative humidity. In certain embodiments, about 80 to about 95% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 81 to about 94% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 82 to about 93% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 83 to about 92% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 84 to about 91% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25° C. and 60% relative humidity. In some embodiments, about 85 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25° C. and 60% relative humidity.

[0190] In certain embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, or about 18 months of storage at 25°C and 60% relative humidity. In certain embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 months, about 12 months, and / or about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 9 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 12 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 15 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 6 to about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 12 to about 15 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 12 to about 18 months of storage at 25°C and 60% relative humidity. In some embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 15 to about 18 months of storage at 25° C. and 60% relative humidity. In still further embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 18 to about 24 months of storage at 25° C. and 60% relative humidity. In yet other embodiments, about 80 to about 90% of the EE incorporated into the system during manufacturing can be recovered from the system after about 24 to about 30 months of storage at 25° C. and 60% relative humidity.In yet another embodiment, about 80 to about 90% of the EE incorporated into the system during manufacture can be recovered from the system after about 24 to about 36 months of storage at 25° C. and 60% relative humidity. In a particular or preferred embodiment, after 18 months of storage, a sufficient amount of EE can be recovered to ensure an average release of about 0.013 mg / day over all 13 product use cycles.

[0191] While the majority of EE not recovered within one of the above-specified time periods is believed to involve EE reaction with unreacted hydrosilane, both EE and SA are susceptible to degradation within one of the above time periods. As a result, the ring body and core may contain, but are not limited to, 6α-OH-EE, 6β-OH-EE, 6α-OH-NES, 6β-OH-NES, 17β-estradiol, NES ST-alcohol, NES iso-ST-alcohol, 6,7-didehydro-EE and 9,11-didehydro-EE, estrone, Δ 6 The compounds may contain certain amounts of degradation products, including 3-(2-hydroxy-2-methyl-2-phenyl-2-propanol-1-one, 3-(2-hydroxy-2-methyl-2-phenyl-2-propanol-1-one), ...

[0192] In certain embodiments, the total percentage of EE and SA degradation products after 24 months of storage is detectable but not greater than 5 LCAP. In certain embodiments, the total percentage of EE and SA degradation products after 24 months of storage is detectable but not greater than 4 LCAP. In some embodiments, the total percentage of EE and SA degradation products after 24 months of storage is not greater than 3 LCAP. In some embodiments, the total percentage of EE and SA degradation products after 24 months of storage is detectable but not greater than 2 LCAP. In some embodiments, the total percentage of EE and SA degradation products after 24 months of storage is detectable but not greater than 1 LCAP.

[0193] In certain embodiments, the total percentage of EE and SA degradation products after 36 months of storage is detectable but not greater than 5 LCAP. In certain embodiments, the total percentage of EE and SA degradation products after 36 months of storage is detectable but not greater than 4 LCAP. In some embodiments, the total percentage of EE and SA degradation products after 36 months of storage is detectable but not greater than 3 LCAP. In some embodiments, the total percentage of EE and SA degradation products after 36 months of storage is detectable but not greater than 2 LCAP. In some embodiments, the total percentage of EE and SA degradation products after 36 months of storage is detectable but not greater than 1 LCAP. Embodiments described herein minimize the amount of impurities contained in the vaginal system after about 18 to about 36 months of storage.

[0194] In addition to the various aspects of the vaginal ring system described herein, additional aspects of the vaginal ring system are described in U.S. Patent Application No. 16 / 265,222, which is incorporated herein by reference in its entirety, including, in particular, paragraphs

[0006] ,

[0007] ,

[0009] -

[0016] ,

[0020] -

[0025] ,

[0027] -

[0038] ,

[0040] ,

[0062] -

[0069] , and claims 1-14 thereof.

[0195] The vaginal systems described herein are further described in detail with reference to the examples provided below. These examples are for illustrative purposes only and should not be construed as limiting the embodiments described herein. Rather, the embodiments should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein. [Example]

[0196] Example 1: XRPD investigation XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer with an incident beam of Cu radiation generated using an Optix long, fine-focus source. An elliptically gradient multilayer mirror was used to focus Cu Kα X-rays through the specimen onto the detector. Prior to analysis, a silicon specimen (NIST SRM640e) was analyzed to confirm that the position of the observed Si 111 peak matched the NIST-certified position. Core samples were prepared for analysis by slicing them into thin disks using a razor blade. Sample specimens were sandwiched between 3 μm-thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits in the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.2.2b. Data acquisition parameters for each pattern are displayed above the images in the data section of this report, including the divergence slit (DS) in front of the mirror. XRPD patterns were acquired over a 2θ range of approximately 7° to 26°.

[0197] Figures labeled "Image by PatternMatch v3.0.4" were generated using unvalidated software. Example 2: EE- for NMR investigations 13 C2 Preparation of silicone elastomer samples

[0198] MED4-4224 (formerly known as DDU-4331) was supplied by NuSil™ Technology LLC (Carpinteria, CA, USA). 13 C2-estradiol (20,21- 13 Labeled with C2, 99.1% isotopic enrichment) (EE- 13 C2) was purchased from Cambridge Isotope Laboratories, Inc. (Andover, MA, USA). 13 Micronization of C2 was achieved by manual grinding using a mortar and pestle.

[0199] An EE-free silicone elastomer mixture was prepared by intimately mixing Part A and Part B (9:1) in a DAC150FVK-Z Speedmixer™ (3000 rpm, 30 seconds). 13 Silicone elastomer mixtures formulated with C2 (2% w / w) were prepared similarly, except for extended high-speed mixing at 3000 rpm for 60 seconds to achieve distribution of the drug powder within the silicone elastomer. The elastomer mixture was poured onto a glass plate fitted with a cellulose acetate release liner and a 1 mm spacer. After pouring, a second acetate release liner and glass plate were placed on top, and the mixture was compressed to form a thin, viscous film. Non-drug silicone elastomer samples were cured in a 150°C oven for 10 minutes. Despite adjustments to the cure conditions (>20 hours at a final temperature of 130°C), EE- 13 The C2 formulated silicone sample only partially cured to form a gum-like consistency material due to EE inhibition of the curing reaction. Example 3: Cured EE- 13 Solvent extraction of EE from C2 silicone elastomer samples

[0200] 13To increase the sensitivity of detecting any bound EE using C solid-state NMR, the unbound EE fraction was extracted from silicone elastomer samples. Elastomer samples were placed in individually labeled glass vials. CDCl or acetone (10–40 mL, depending on the EE formulation) was added to each extraction flask. The flasks were sealed and stored at ambient temperature for 24 hours, with periodic manual shaking. This extraction protocol was repeated three times using fresh volumes of solvent to ensure complete extraction of unbound EE. The elastomer samples were removed from the solvent and 13 The mixture was dried overnight by solvent evaporation in preparation for C solid-state NMR analysis. Example 4: EE- 13 NMR spectrum of a silicone elastomer sample containing C2

[0201] Figure 7A shows the EE- 13 C2 silicone sample 13 C-solid state NMR spectrum is shown. 13 Chemical shifts associated with the C-labeled ethynyl group are visible at 75 ppm and 87 ppm. A second set of strong signals is observed at 125 ppm and 153 ppm. These signals at 125 ppm and 153 ppm are due to the EE- 13 These were not observed in the C2 or elastomer reference spectra (Figures 6A and 6B, respectively), and were 13 This is due to the newly formed vinylene carbon generated from the hydrosilylation reaction between the ethynyl group at C2 and the hydrosilane group in the silicone elastomer (Figure 4). 13 Analysis of C2 with elastomeric materials revealed that the unbound EE- 13 The ethynyl signals associated with C2 (75 ppm and 87 ppm) were no longer visible in the post-extraction samples (Fig. 7B), indicating unbound EE- 13It was confirmed that the C2 fraction was successfully removed via solvent extraction. More interestingly, the new vinylene signals at 125 ppm and 153 ppm were still observed and showed no decrease in intensity compared to the unextracted sample (Figure 7A), clearly indicating that they must be due to bound EE, since they cannot be removed from the silicone elastomer by solvent extraction. Thus, Figures 7A and 7B show that the EE- 13 We provide direct evidence of the formation of an irreversible covalent bond between the ethynyl group of C2 and the hydrosilane group of the addition-cured silicone elastomer. Example 5: Tensile strength and elongation tests

[0202] Tensile strength and elongation tests were performed on a calibrated Stable Micro Systems TA.XTPlus texture analyzer (Figure 8A) equipped with a TEXTURE1-1 tensile rig using the Texture Index 32 software program and a 50 kg (PL / CEL5) load cell. The instrument parameters used for tensile strength testing are listed in Table 1. [Table 1]

[0203] The ring bodies, without the core, were allowed to equilibrate to room temperature before testing. The cross-sectional diameters and inner diameters of 10 rings were measured for calculations.

[0204] Ten rings were measured parallel to the core channel along the 0° line, and ten additional rings were measured perpendicular to the core channel along the 90° line (Figure 8B). The instrument was started, and a 50 kg load cell was attached to the instrument according to the procedures in the instrument's instruction manual. The correct screws were ensured to be used to attach the black rig holder to the instrument. The screws were at least 30 mm long and fully inserted into the countersunk holes in the rig holder (Figure 8C). Force calibration and / or daily checks were performed according to the procedures in the instruction manual. The upper rig was lowered to a position just above the lower rig, ensuring that the upper and lower rigs were aligned. Height calibration was performed according to the procedures in the instrument's instruction manual.

[0205] To perform measurements parallel to the core, a single ring was placed on the upper and lower rigs according to the machine instructions, with the channel openings facing upwards. One channel opening was visible on each side of the upper rig (Figure 8C). Measurements were performed according to the instrument instructions, and the process was repeated for the remaining nine rings.

[0206] To perform measurements perpendicular to the core, a single ring was placed in the upper and lower rigs according to the machine instructions, with the channel openings facing outward toward the operator. Both channel openings were visible during setup (Figure 8D). Measurements were performed according to the instrument instructions, and the process was repeated for the remaining nine rings.

[0207] The tensile strength σ was calculated for each ring according to the following formula: σ = (F × 4) ÷ (2 × π × d 2 ) where F is the breaking force (N) and d is the average cross-sectional diameter of the ring body (mm) measured for 10 rings.

[0208] Inner circumference of the ring, C int (nm) was calculated according to the following formula: C int =d i ×π In the formula, d i is the average inner diameter (mm) of the ring measured from 10 rings described herein.

[0209] The elongation at break, E, was calculated for each ring according to the following formula: E=(2l+2r+C roll -C int ) ÷ C int ×100 with a compound according to the formula: l is the final distance between the upper and lower rigs (mm); r is the distance between the centers of the rollers at height calibration (15 mm); Croll is the circumference of the roller (47 mm), and C int is the inner circumference of the ring (mm).

[0210] The results of the tensile strength test are shown in Table 2. The results of the elongation study are shown in Table 3. [Table 2] [Table 3] Example 6: Fatigue Test

[0211] Compression force, fatigue, and seal integrity tests were performed on a calibrated Stable Micro Systems TA.XTPlus texture analyzer equipped with a TEXTURE 1-2 compression rig with a 9 mm slit and a lower compression rig with a 202 mm x 4.8 mm nylon strap (Figures 9A, 9B, and 9C). A 5 kg (PL / CEL 5) load cell, a 75 mm (SMS P / 75) compression probe, and a high-load platform (HDP / 90) were used, along with Texture Exponent 32 software. The instrument parameters used for the compression analysis are listed in Table 4. [Table 4]

[0212] The ring bodies, without the core, were allowed to equilibrate to room temperature for at least 3 hours prior to testing. Ten rings were measured parallel to the core channel along the 0° line, and ten additional rings were measured perpendicular to the core channel along the 90° line (Figure 9D). The instrument was started and a 5 kg load cell was attached to the instrument. The compression rig was attached according to the instrument's instructions. Calibration and / or daily checks were performed according to the instrument's instructions. The compression probe was lowered to just above the lower rig to ensure that the slits in the probe instrument and the lower rig were aligned. Alternatively, the heavy-duty platform was adjusted to ensure alignment.

[0213] To perform measurements parallel to the core, a single ring was mounted and secured as shown in Figure 9E, with the channel opening facing upwards and the ring fitting into the slit. The ring was secured by straps but could be rotated. One channel opening was visible on each side of the compression probe. It was important that the rings were mounted perpendicular to the rig. The compression plate was carefully lowered to just above the ring without compressing it. A measurement was performed and the process was repeated for the remaining nine rings.

[0214] To perform measurements perpendicular to the core, a single ring was mounted as shown in Figure 9F, and the ring was fitted into the slit with the channel openings facing outward. The ring was held in place by straps, but it was possible to rotate it. Both channel openings were visible during setup. It was important that the ring was mounted perpendicular to the rig. The compression probe was carefully lowered to just above the ring without compressing it. A measurement was taken, and the process was repeated for the remaining nine rings.

[0215] For each set of 10 rings, the average force in Newtons (N) was calculated for the 1st compression and the 1000th compression.

[0216] Fatigue due to cyclic load per ring (percentage of compressive force chain) ΔF according to the formula c was calculated. ΔF c =100×F 1000 ÷F1 In the formula, F1 is the compression force of the first compression, F 1000 is the compression force of the 1000th compression.

[0217] No effect on the seal integrity of the rings tested was observed.

[0218] The results of the fatigue test investigation are shown in Table 5. [Table 5] Example 7: Extraction Procedure to Determine Recoverable EE and NES After Any Period of Storage solution: Diluent: Methanol / Water 58 / 42v / v Dry NES and EE before weighing (100-105°C, 3 hours) EE stock solution: Dissolve 25.0 mg of EE and dilute to 250.0 mL with methanol (replicates, EE1 and EE2) NES stock solution: Dissolve 50.0 mg of NES and dilute to 100.0 mL with methanol (replicates, NES1 and NES2) Standard solution: S1: Dilute 5.0 mL of NES1 and 4.0 mL of EE1 to 50.0 mL with diluent. S2: Dilute 6.0 mL of NES2 and 5.0 mL of EE2 to 50.0 mL with diluent. S3: Dilute 8.0 mL of NES1 and 7.0 mL of EE1 to 50.0 mL with diluent. S4: Dilute 10.0 mL of NES2 and 9.0 mL of EE2 to 50.0 mL with diluent. System Suitability Solution (SST Solution): 5.0 mL acetone + 7.0 mL NES1 + 6.0 mL EE1 diluted to 50.0 mL with diluent. Extraction Procedure: The ring was cut into 8 pieces, each of which was split lengthwise and then transferred to an Erlenmeyer flask. 140 mL of acetone was added to the flask (the weight of the flask was recorded before and after the addition of acetone). The flask was then capped. The flask was shaken at 180 rpm for 24 hours (weight was recorded after extraction). · 2.5 mL of extraction medium was diluted to 25.0 mL with diluent (test solution), and then a sample was pulled for HPLC analysis. Liquid chromatography column Analytical column: Discovery C8, 5 μm, 150 × 4.6 mm (Supelco) Precolumn: Supelguard, Discovery C8, 5 μm, 20 × 4.0 mm (Supelco) Stationary phase: End-capped C8 (5 μm particle size) USP L7 ·Temperature: 30℃ Mobile phase: Methanol / water 58 / 42, isocratic elution ·Flow rate: 1.2mL / min Detection (assay): NES UV 240nm, EE UV 280nm Detection (identity): PDA (photodiode array detector) scanning 220~310nm, NES 240nm, EE 280nm ·Injection: 20μL Runtime: 15 minutes System suitability: SST solution ·Area accuracy (n=5):RSD(%)≦2.0 Peak tailing (T): 0.8≦T≦1.5 Blank injection: No interfering peaks Retention time: EE approx. 7 minutes and NES approx. 9 minutes Results Assay: The average value of three different rings is reported and expressed as mg EE / ring and mg NES / ring. Content uniformity results: calculate the average value of 10 different rings. <905> Report according to the guidelines outlined in the , with or without remarks. · Identity result: If the retention times of the test and standard solutions match in the assay and the UV spectra of the EE / NES in the test solution and the PDA library match, report without remarks; otherwise, report with remarks. Example 8: Determination of SA and EE Degradation Products standard Ethinylestradiol (EE), working standard Nestorone® (NES), working standard 17β-estradiol (structure shown in Figure 10B) Estrone estradiol (structure shown in Figure 10D) Δ6-Nestrone estradiol (structure shown in Figure 10D) NES ST-alcohol estradiol (structure shown in Figure 10C) reagent Methanol, HPLC grade Acetone, PA ·Water, purified Acetonitrile, gradient grade solution Dry NES and EE before weighing (100-105°C, 3 hours) NES stock solution: Dissolve 75.0 mg of NES and dilute to 50.0 mL with methanol (replicates SSA1 and SSA2) EE stock solution: Dissolve 15.0 mg of EE and dilute to 50.0 mL with methanol (replicates, SSB1 and SSB2) Standard solution: S5: Dilute 5.0 mL of SSA1 and 5.0 mL of SSB1 with methanol to 50.0 mL S4: Dilute 7.0 mL of S5 with methanol to 10.0 mL S3: Dilute 2.5 mL of SSA2 and 2.5 mL of SSB2 with methanol to 50.0 mL. S2: Dilute 5.0 mL of S5 with methanol to 50.0 mL S1: Dilute 5.0 mL of S3 with methanol to 50.0 mL NES Area Rejection Stock Solution: Dilute 2.5 mL of SSA1 with methanol to 50.0 mL (R1). ·EE Area Rejection Stock Solution: Dilute 2.5 mL of SSB1 with methanol to 50.0 mL (R2). NES / EE area rejection solution: 1.0 mL of R1 + 5.0 mL of R2 diluted to 100.0 mL with methanol. Rejection peak area at 254 nm: NES area. Rejection peak area at 280 nm: EE area. System compatibility solutions: SST1: Dissolve 15.0 mg of 17β-estradiol and dilute to 50.0 mL with methanol. SST2: Dissolve 15.0 mg of estrone and dilute to 50.0 mL with methanol. SST3: Dissolve 15.0 mg of Δ6-Nestrone and dilute to 10.0 mL with methanol. SST4: Dissolve 15.0 mg of NES ST-alcohol and dilute to 10.0 mL with methanol. · ST solution: 2.5 mL SSA2 + 5.0 mL SSB2 + 5.0 mL SST1 + 5.0 mL SST2 + 2.5 mL SST3 + 2.5 mL SST4 diluted to 50.0 mL with methanol. Extraction procedure The ring was cut into 8 pieces, each of which was split lengthwise and transferred to an Erlenmeyer flask. 70 mL of acetone was added (weight before and after was recorded) and the Erlenmeyer flask was capped. Shake at 180 rpm for 24 hours (weight after extraction was recorded). 10.0 mL of the extraction medium was transferred to a test tube and evaporated to dryness. Dissolved in 1.0 mL of methanol. Once a clear supernatant was obtained, it was transferred to an LC vial (test solution). Liquid chromatography column Analytical column: SUNFIRE™ C18, 5 μm, 250 × 4.6 mm (Waters) Precolumn: SUNFIRE™ C18, 5 μm, 20 × 4.6 mm (Waters) Stationary phase: End-capped reversed-phase C18, 100Å (5μm), USP L1 ·Temperature: 35℃ Mobile phase A: acetonitrile, B: water [Table 6] ·Flow rate: 1mL / min Detection (UV): NES 254nm, EE 280nm Detection (PDA): Scanning 220~310nm ·Injection: 10μL Sample temperature: 2 to 8°C Runtime: 85 minutes System suitability: SST solution ·Separation power Between 17β-estradiol and NES ST-alcohol ≥ 2.0 at 280 nm EE and estrone ≥ 1.5 at 280 nm Δ6-Nestrone and NES ≥ 4.0 at 254 nm Peak tailing (T): 0.8≦T≦1.5 Area precision (n=5): RSD (%) ≤ 3.0 for NES peak at 254 nm, ≤ 3.0 for EE peak at 280 nm [Table 7]

[0219] It is understood that the "Detailed Description" section, and not the "Summary" and "Abstract" sections, are intended to be used to interpret the claims. The "Summary" and "Abstract" sections may set forth one or more, but not all, exemplary embodiments of the disclosure as contemplated by the inventors, but are in no way intended to limit the scope of the disclosure and the appended claims.

[0220] The present disclosure has been described above using functional building blocks that illustrate the implementation of certain functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of description. Alternative boundaries can be defined as long as the specified functions and relationships thereof are appropriately performed.

[0221] The foregoing description of specific embodiments will enable others, by applying their knowledge, to readily modify and / or adapt such specific embodiments to various uses and to make fully apparent the general nature of the present disclosure without undue experimentation and without departing from the general concepts of the present disclosure. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description and not of limitation; consequently, the terminology or terminology used herein should be interpreted by those skilled in the art in the light of the teaching and guidance.

[0222] The breadth and scope of the present disclosure should not be limited by either the ease with which such specific embodiments may be modified and / or adapted for various uses without undue experimentation without departing from the general concepts of the disclosure. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description and not of limitation; consequently, the terminology or terminology used herein should be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0223] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. 1. A reusable vaginal system for preventing pregnancy, the system comprising a silicone elastomer ring body having a platinum concentration of about 3 ppm to about 10 ppm and a hydride / vinyl ratio before curing of about 1:1 to about 1.3:1, the silicone elastomer ring body comprising two cores, each core comprising a condensation cure silicone elastomer and dibutyltin dilaurate, the cores containing a total of about 103 mg segesterone acetate and about 17.4 mg ethinyl estradiol; the system is configured to release an average of about 0.15 mg / day of segesterone acetate and an average of about 0.013 mg / day of ethinyl estradiol for up to thirteen 21-day cycles, A vaginal system, wherein about 80% to about 90% of the ethinyl estradiol is recoverable from the system after about 18 months of storage at 25° C. and 60% relative humidity.

2. 2. The vaginal system of claim 1, wherein one of the two cores contains segesterone acetate and the other contains segesterone acetate and ethinyl estradiol.

3. 3. The vaginal system of claim 2, wherein the core containing segesterone acetate and ethinyl estradiol is cured at a temperature of about 60°C to about 90°C.

4. 4. The vaginal system of claim 3, wherein the core containing segesterone acetate and ethinyl estradiol is cured at a relative humidity of about 1% to about 2%.

5. 3. The vaginal system of claim 2, wherein the core containing segesterone acetate and ethinyl estradiol is aged for at least 30 days before being assembled into the ring body.

6. 10. The vaginal system of claim 1, wherein the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm.

7. 10. The vaginal system of claim 1, wherein the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

8. 1. A multi-component 13-cycle vaginal system for preventing pregnancy, said system comprising: a) a silicone elastomer ring body adapted to receive first and second drug-containing cores, said ring body comprising a silicone elastomer having a platinum concentration of about 3 ppm to about 10 ppm and a hydride / vinyl ratio of about 1:1 to about 1.3:1 before curing; b) a first core and a second core comprising a total of about 103 mg of segesterone acetate and about 17.4 mg of ethinyl estradiol, each core further comprising one or more condensation cure silicone elastomers and dibutyltin dilaurate; the system is configured to release an average of about 0.15 mg / day of segesterone acetate and an average of about 0.013 mg / day of ethinyl estradiol for each of up to thirteen 21-day cycles; A vaginal system, wherein about 80% to about 90% of the ethinyl estradiol is recoverable from the system after about 18 months of storage at 25° C. and 60% relative humidity.

9. 9. The vaginal system of claim 8, wherein the silicone elastomer ring body has a platinum concentration of about 4 ppm to about 9 ppm.

10. 9. The vaginal system of claim 8, wherein the silicone elastomer ring body has a platinum concentration of about 5 ppm to about 8 ppm.

11. 9. The vaginal system of claim 8, wherein one of the two cores contains segesterone acetate and the other contains segesterone acetate and ethinyl estradiol.

12. 12. The vaginal system of claim 11, wherein the core containing segesterone acetate and ethinyl estradiol is cured at a temperature of about 60°C to about 90°C.

13. 13. The vaginal system of claim 12, wherein the core containing segesterone acetate and ethinyl estradiol is cured at a relative humidity of about 1% to about 2%.

14. 12. The vaginal system of claim 11, wherein the core containing segesterone acetate and ethinyl estradiol is aged for at least 30 days before being assembled into the ring body.

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