Methods and devices for hormone replacement therapy

Abstract

1. A drug delivery device for use in treating one or more menopausal symptoms in a subject, comprising intravaginal insertion of an indwelling drug delivery device into the subject, wherein the drug delivery device comprises an estrogen and a progestin, and further provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 50 pg / mL.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 437,940, filed January 9, 2023, and U.S. Provisional Patent Application No. 63 / 531,469, filed August 8, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] The present invention is in the field of intravaginal rings, particularly segmented ethylene vinyl acetate (EVA) intravaginal rings, and their use to treat, alleviate, or prevent vasomotor symptoms and vulvar and vaginal atrophy (VVA) in peri-menopausal and / or menopausal women. [Background technology]

[0003] Menopause is often accompanied by vasomotor symptoms (VMS), including hot flashes and night sweats, which are the most frequently observed symptoms of menopause, although not all women experience them. Additional symptoms may include vaginal symptoms such as dryness and dyspareunia, sleep disturbances, and joint pain. Menopause is associated with the pathophysiology of urogenital symptoms caused by declining estrogen levels. Decreasing estrogen levels lead to thinning of the vaginal epithelium, decreased vaginal elasticity, and increased connective tissue, ultimately leading to fibrotic changes in some women. Decreasing estrogen levels are also associated with decreased vaginal blood flow and lubrication. These physiological changes lead to vulvovaginal atrophy (VVA), which is responsible for a range of symptoms seen in many menopausal women, including vaginal dryness, vaginal and / or vulvar irritation / itching, painful urination, vaginal pain with sexual activity, and vaginal bleeding with sexual activity.

[0004] Hormone therapy is recognized as an effective treatment for managing both VMS and symptomatic VVA, and both topical and systemic therapies are widely used. The use of estrogen for the treatment of menopausal symptoms is recommended by professional medical organizations.

[0005] Although estrogen is the most effective treatment for VMS, unopposed treatment (estrogen alone without progesterone) is associated with an increased risk of endometrial hyperplasia and carcinoma in women with an intact uterus; a meta-analysis of 30 studies showed a relative risk of 2.3 (95% CI: 2.1-2.5) between women using estrogen and those not using it. This risk is reduced by the addition of a progestogen, and the incidence of endometrial cancer under combined therapy is no different from that in untreated women. Furthermore, a Cochrane review noted that treatment with estrogen and progestogen is more effective in reducing the severity of hot flashes than estrogen alone. Summary of the Invention

[0006] The present technology generally relates to methods for treating one or more menopausal symptoms in a subject, comprising intravaginally inserting into the subject an indwelling drug delivery device, the indwelling drug delivery device comprising (and releasing) an estrogen and a progestin. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 50 pg / mL.

[0007] In an embodiment, the subject is a female subject having a uterus.

[0008] In embodiments, the one or more menopausal symptoms include vasomotor symptoms (VMS). In embodiments, the one or more menopausal symptoms include genitourinary syndrome. In embodiments, the one or more menopausal symptoms include one or more of the following: hot flashes, night sweats, vaginal pH, changes in vaginal cytology, vaginal dryness, and vaginal pain. In embodiments, the one or more menopausal symptoms are improved by at least 20%.

[0009] In embodiments, the estrogen is estradiol. In embodiments, the estrogen is an estradiol equivalent. In embodiments, the estradiol is bio-identical estradiol.

[0010] In an embodiment, the progestin is progesterone. In an embodiment, the estrogen is a progesterone equivalent. In an embodiment, the progesterone is bioidentical progesterone.

[0011] In embodiments, the indwelling drug delivery device continuously delivers estrogen and progestin over a period of time. In embodiments, this period is between 7 and 35 days. In embodiments, this period is about 28 days.

[0012] In embodiments, the indwelling drug delivery device comprises a solid ethylene vinyl acetate polymer matrix.

[0013] In an embodiment, the indwelling drug delivery device comprises an ethylene vinyl acetate (EVA) intravaginal ring (IVR), said ring comprising at least two segments / fibers, one segment containing estrogen and the second segment containing progestin.

[0014] In an embodiment, the indwelling drug delivery device comprises an inner core comprising one or more active pharmaceutical ingredients dispersed throughout a first water-insoluble polymer; an intermediate coating disposed about the inner core and comprising an acrylate polymer; and an outer coating disposed about the intermediate coating and comprising a second water-insoluble polymer.

[0015] In embodiments, the acrylate polymer is formed from one or more monomers of formula (I): [ka]

[0016] wherein R1 is selected from H, alkyl, alkenyl, alkynyl, or aryl; and R2 is selected from H or alkyl.

[0017] In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 50 μg / day to about 200 μg / day. In embodiments, the indwelling drug delivery device releases progestin at a rate of about 1 mg / day to about 15 mg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 80 μg / day and progestin at a rate of about 4 mg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 160 μg / day and progestin at a rate of about 8 mg / day.

[0018] In embodiments, the indwelling drug delivery device is removed about 20 to about 35 days after insertion. In embodiments, a second indwelling drug delivery device is inserted after removal of the indwelling drug delivery device. In embodiments, the indwelling drug delivery device is replaced every 20 to 35 days. In embodiments, the indwelling drug delivery device is replaced approximately every 28 days.

[0019] In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in a subject of about 20 pg / mL to about 30 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 1 ng / mL to about 5 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 2 ng / mL to about 4 ng / mL. [Brief explanation of the drawings]

[0020] [Figure 1] Figure 1 shows the plasma concentrations (baseline adjusted) of E2 after intravaginal administration of either 80 / 4 IVR or 160 / 8 IVR. Data are mean ± SD (n = 10 [80 / 4 IVR] or 11 [160 / 8 IVR]). [Figure 2] Figure 2 shows the plasma concentrations (baseline adjusted) of E1 after intravaginal administration of either 80 / 4 IVR or 160 / 8 IVR. Data are mean ± SD (n = 10 [80 / 4 IVR] or 11 [160 / 8 IVR]). [Figure 3] Figure 3 shows the plasma concentrations (baseline adjusted) of P4 after intravaginal administration of either 80 / 4 IVR or 160 / 8 IVR. Data are mean ± SD (n = 10 [80 / 4 IVR] or 11 [160 / 8 IVR]). [Figure 4] Figure 4 shows baseline-adjusted plasma concentrations of E2 (top panel) and E1 (bottom panel) after oral administration of Estrofem (1 mg E2) and Prometrium (100 mg P4). Data are mean ± SD (n=11). [Figure 5] Figure 5 shows plasma concentrations of P4 (baseline adjusted) after oral administration of Estrofem (1 mg E2) and Prometrium (100 mg P4). Data are mean ± SD (n=11). [Figure 6] Figure 6 shows the breakdown of subjects. [Figure 7]Figure 7 shows plasma P4 (ng / mL) on the indicated treatment days in 80 / 4 IVR. Red: 1st cycle; green: 2nd cycle; blue: 3rd cycle; EOT: end of treatment. [Figure 8] Figure 8 shows plasma P4 (ng / mL) on the indicated treatment days in 160 / 8 IVR. [Figure 9] Figure 9 shows plasma E2 (pg / mL) on the specified treatment days in 80 / 4 IVR. [Figure 10] Figure 10 shows plasma E2 (pg / mL) on the specified treatment days in 160 / 8 IVR. [Figure 11] Figure 11 shows plasma E1 (pg / mL) on the specified treatment days in 80 / 4 IVR. [Figure 12] Figure 12 shows plasma E1 (pg / mL) on the specified treatment days in 160 / 8 IVR. DETAILED DESCRIPTION OF THE INVENTION

[0021] After reading this specification, it will be apparent to those skilled in the art how to implement the present disclosure in various alternative embodiments and alternative applications. However, not all of the various embodiments of the present invention are described herein. It should be understood that the embodiments presented herein are presented by way of example only, and not by way of limitation. Therefore, this detailed description of various alternative embodiments should not be construed as limiting the scope or breadth of the present disclosure described herein.

[0022] Before the present technology is disclosed and described, it is to be understood that the embodiments described below are not limited to particular compositions, methods of preparing such compositions, or uses, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0023] The detailed description has been divided into various sections for the convenience of the reader only, and disclosure in any section may be combined with disclosure in another section. Headings or subheadings may be used throughout the specification for the convenience of the reader, but they are not intended to affect the scope of the disclosure.

[0024] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0025] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0026] "Desired" or "desirably" means that the subsequently described event or circumstance may or may not occur, and that the description encompasses both cases where the event or circumstance occurs and cases where it does not occur.

[0027] The term "about," when used before the designation of a numerical value (e.g., temperature, time, amount, concentration, and the like), including a range, indicates an approximation that may vary by ±10%, ±5%, ±1%, or any subrange or intervening value. Preferably, the term "about," when used in reference to an amount, means that the amount may vary by ±10%.

[0028] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term "consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements of essential importance in the combination for the described purpose. That is, a composition consisting essentially of the elements as defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding other ingredients beyond trace elements and substantial method steps. Embodiments defined by each of these transitional phrases are within the scope of this disclosure.

[0029] The term "estradiol equivalent" includes, but is not limited to, conjugated estrogens (e.g., Premarin, Cenestin), 17β-estradiol (e.g., Estrace), estropipate (e.g., Ogen, Ortho-Est), esterified estrogens (e.g., Menest, Estratab), Triest / Biest, or ethinyl estradiol, estradiol acetate (e.g., Femtrace).

[0030] The term "progesterone equivalent" includes, but is not limited to, medroxyprogesterone acetate (e.g., Provera), micronized progesterone (e.g., Prometrium), norethindrone acetate (e.g., Aygestin), and norethindrone (e.g., Micronor).

[0031] device Disclosed herein is an IVR that allows for the incorporation of an estrogen (e.g., E2) and a progestin (e.g., P) into a single ethylene-vinyl acetate (EVA) ring delivery system. The IVR disclosed herein can be used to treat (e.g., cure, suppress), alleviate, and / or prevent (e.g., delay or prevent the onset, recurrence, or relapse) one or more perimenopausal or menopausal symptoms, including but not limited to VMS, in women with an intact uterus, while also treating, alleviating, and / or preventing the symptoms of VVA. VMS symptoms may include one or more of the following, but are not limited to: hot flashes, hot flushes, night sweats, mood swings, anxiety, urinary incontinence, cognitive impairment (memory loss, problems concentrating, joint pain, weight gain, sexual dysfunction, vaginal complaints, sleep disorders (such as insomnia), bone loss, heart disease, atherosclerosis, and heart palpitations. VVA symptoms may include, but are not limited to, one or more of: dryness, burning, itching, vaginal discomfort, vaginal discharge, pain and burning with urination, urgency, increased urinary tract infections, urinary incontinence, dyspareunia, discomfort during intercourse, decreased vaginal lubrication during sexual activity, shortening and narrowing of the vaginal canal, and spotting during intercourse.

[0032] The IVR of the present disclosure is designed to deliver about 80 μg / day to about 160 μg / day of E2, along with a dose of P sufficient for endometrial protection, for 28 days. A previous report using an IVR comprised of a silicone elastomer matrix inner core containing E2 and P and a silicone elastomer overcoat demonstrated the efficacy of delivering 160 μg / day of E2, along with 10 mg / day or 20 mg / day of P, in 20 postmenopausal women. Results showed a significant decrease in the incidence of hot flashes and night sweats from week 2 to week 16, and ultrasound monitoring of the endometrium suggested effective protection against endometrial hyperplasia.

[0033] In some embodiments of the invention described herein, when a range of values ​​is presented, it is understood that each intervening value between the upper and lower limit of that range, to one-tenth of the lower limit unless the context clearly indicates otherwise, and any other stated or intervening value within that stated range, is also encompassed within the invention. Where a stated range contains specifically excluded limits, the upper and lower limits of these smaller ranges may independently be included within the smaller ranges and are also encompassed within the invention. Where a stated range includes one or both limits, ranges excluding either or both of those included limits are also encompassed within the invention. For example, a range of 27% to 36% would include 27% to 29%, or 27% to 33%, or 33% to 35%, etc. Such ranges also encompass individual points within that range, e.g., 28%, 29%, 30%, etc.

[0034] The IVR of the present disclosure is made by the method described in U.S. Patent Application Publication No. 20210007976, which is incorporated herein by reference in its entirety. The method involves compounding pellets, extruding fibers, and then joining the fibers by thermal welding. Mixing can be achieved using a Turbula mixer (Model T 10 B with a 17-liter stainless steel mixing vessel, Glenn Mills, Clifton, New Jersey). The resulting mixture is then compounded by hot-melt extrusion using a twin-screw extruder (Pharma 11 twin-screw extruder with a Pharma 11 gravimetric feeder), fed onto a Pharma 11 air-cooled conveyor, and then pelletized using a Pharma 11 Vericut pelletizer (Thermo Fisher Scientific, Dreieich, Germany). The pellets were formed into fibers by hot-melt extrusion using a 25 mm single-screw extruder (Dr. Collin, Ebelsberg, Germany). The resulting fibers were cut using a Dr. Collin in-line cutting station. The cut fibers (or segments) were welded using an Automationspartner single-station laboratory welder (Ramrosa, Sweden).

[0035] IVRs capable of releasing E2 (EP, Aspen Oss BV, Oss, The Netherlands) at desired rates were prepared using fibers of various lengths and drug loadings. In some embodiments, the IVRs described herein release E2 at a rate of approximately 160 μg / day and P at approximately 4 mg / day (160 / 4 IVR) or approximately 8 mg / day (160 / 8 IVR). In some embodiments, the IVRs described have an overall diameter of approximately 57 mm and a cross-sectional diameter of approximately 5 mm.

[0036] E2-loaded EVA fibers were prepared at a concentration of approximately 10 wt / w in EVA (28% vinyl acetate, Vitaldose®, Celanese Corporation, Boucherville, Canada). The length of the E2 fiber in the finished IVR was approximately 15 mm for both the 160 / 4 and 160 / 8 IVRs. IVRs releasing approximately 4 mg / day and approximately 8 mg / day of P were prepared using EVA (28% vinyl acetate, Vitaldose) to achieve a final drug loading of approximately 27% wt / w. To create the 160 / 4 IVR, the P-containing segment was approximately 74.5 mm long, and the placebo segment was approximately 74 mm long. To create the 160 / 8 IVR, the 27%-loaded EVA fiber was approximately 148.5 mm long. The 160 / 8 IVR did not contain a placebo segment.

[0037] In one aspect disclosed herein, the IVR ring described herein is used to treat VMS and / or VVA symptoms. In some embodiments of this aspect, the IVR ring includes one or more segments containing E2. In some embodiments, the IVR ring includes one or more segments containing P. In some embodiments, the IVR ring includes both P and E2, each in separate segment(s).

[0038] In some embodiments, the IVR of the present disclosure has an overall diameter of about 57 mm and a cross-sectional diameter of about 5 mm.

[0039] In some embodiments, E2-containing EVA fibers (segments) are prepared at a concentration of about 10 wt / w in EVA (28% vinyl acetate content, Vitaldose®, Celanese Corporation, Boucherville, Canada, or Polysciences, Inc., Warrington, PA) or equivalent from other vinyl acetate manufacturers. In some embodiments, the length of the E2 fiber in the finished IVR is about 15 mm.

[0040] In some embodiments, IVRs releasing about 4 mg / day and about 8 mg / day of P are prepared using EVA (28% vinyl acetate content, Vitaldose) to achieve a final drug load of about 27% w / w. In some embodiments, the length of the P-containing segment is about 74.5 mm. In some embodiments, the length of the P-containing segment is about 148.5 mm in length.

[0041] In some embodiments, the rings of the present disclosure can effectively release E2 and / or P for about 7 days or more, or about 10 days or more, or about 14 days or more, or about 20 days or more, or about 26 days, or about 27 days, or about 28 days, or about 29 days, or about 30 days, or up to 30 days, or up to 29 days, or up to 28 days.

[0042] In embodiments, the ring sustainably releases E2 and / or P over a period of time. As used herein, the terms "sustainably" or "sustained release" refer to the continuous and uninterrupted (or substantially uninterrupted) release of a drug from a formulation or device and the continuous delivery of such a drug.

[0043] method The present technology generally relates to methods for treating one or more menopausal symptoms in a subject, comprising intravaginally inserting into the subject an indwelling drug delivery device, the indwelling drug delivery device containing (and releasing) estrogen and progestin.

[0044] In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 50 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 20 pg / mL to about 30 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 40 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 30 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 20 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 20 pg / mL to about 50 pg / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 20 pg / mL to about 40 pg / mL.

[0045] In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 1 ng / mL to about 5 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 2 ng / mL to about 4 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 1 ng / mL to about 4 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 1 ng / mL to about 3 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 1 ng / mL to about 2 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in a subject of about 2 ng / mL to about 3 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in the subject of about 2 ng / mL to about 5 ng / mL.

[0046] In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 50 pg / mL and a baseline-adjusted steady-state plasma progesterone concentration in the subject of about 2 ng / mL to about 4 ng / mL. In embodiments, the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 20 pg / mL to about 30 pg / mL and a baseline-adjusted steady-state plasma progesterone concentration in the subject of about 1 ng / mL to about 5 ng / mL.

[0047] In embodiments, the subject is a female subject. In embodiments, the subject has a uterus. In embodiments, the subject is postmenopausal. In embodiments, the subject is peri-menopausal.

[0048] In embodiments, the one or more menopausal symptoms include vasomotor symptoms (VMS). In embodiments, the one or more menopausal symptoms include genitourinary syndrome. In embodiments, the one or more menopausal symptoms include one or more of the following: hot flashes, night sweats, vaginal pH, changes in vaginal cytology, vaginal dryness, and vaginal pain. In embodiments, the one or more menopausal symptoms include hot flashes. In embodiments, the one or more menopausal symptoms include night sweats. In embodiments, the one or more menopausal symptoms include abnormal vaginal pH. In embodiments, the one or more menopausal symptoms include changes in vaginal cytology. In embodiments, the one or more menopausal symptoms include vaginal dryness. In embodiments, the one or more menopausal symptoms include vaginal pain.

[0049] In an embodiment, one or more menopausal symptoms are improved by at least 20%. In an embodiment, one or more menopausal symptoms are improved by 20% to 100%. In an embodiment, one or more menopausal symptoms are improved by at least 25%. In an embodiment, one or more menopausal symptoms are improved by at least 30%. In an embodiment, one or more menopausal symptoms are improved by at least 40%. In an embodiment, one or more menopausal symptoms are improved by at least 50%. In an embodiment, one or more menopausal symptoms are improved by at least 60%. In an embodiment, one or more menopausal symptoms are improved by at least 70%. In an embodiment, one or more menopausal symptoms are improved by at least 75%. In an embodiment, one or more menopausal symptoms are improved by at least 80%. In an embodiment, one or more menopausal symptoms are improved by at least 90%. In an embodiment, one or more menopausal symptoms are improved by 20% to 90%. In an embodiment, one or more menopausal symptoms are improved by 30% to 90%. In an embodiment, one or more menopausal symptoms are improved by 40% to 90%. In an embodiment, one or more menopausal symptoms are improved by 50% to 90%.

[0050] Improvement in one or more symptoms may be measured by any suitable method. For example, the Menopausal Quality of Life (MENQOL) questionnaire may be used, which assesses not only VMS parameters but also physical, psychosocial, and sexual symptoms. Other assessment criteria include measurement of vaginal pH and cytological examination of the vaginal epithelium (vaginal maturation index).

[0051] In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 50 μg / day to about 200 μg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 70 μg / day to about 180 μg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 80 μg / day to about 160 μg / day.

[0052] In embodiments, the indwelling drug delivery device releases the progestin at a rate of about 1 mg / day to about 15 mg / day. In embodiments, the indwelling drug delivery device releases the progestin at a rate of about 2 mg / day to about 10 mg / day. In embodiments, the indwelling drug delivery device releases the progestin at a rate of about 4 mg / day to about 8 mg / day.

[0053] In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 50 μg / day to about 200 μg / day and progestin at a rate of about 1 mg / day to about 15 mg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 70 μg / day to about 180 μg / day and progestin at a rate of about 2 mg / day to about 10 mg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 80 μg / day to about 160 μg / day and progestin at a rate of about 4 mg / day to about 8 mg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 80 μg / day and progestin at a rate of about 4 mg / day. In embodiments, the indwelling drug delivery device releases estrogen at a rate of about 160 μg / day and progestin at a rate of about 8 mg / day.

[0054] In embodiments, the indwelling drug delivery device is removed about 20 to about 35 days after insertion. In embodiments, the indwelling drug delivery device is removed about 25 to about 30 days after insertion. In embodiments, the indwelling drug delivery device is removed about 25 days after insertion. In embodiments, the indwelling drug delivery device is removed about 26 days after insertion. In embodiments, the indwelling drug delivery device is removed about 27 days after insertion. In embodiments, the indwelling drug delivery device is removed about 28 days after insertion. In embodiments, the indwelling drug delivery device is removed about 29 days after insertion. In embodiments, the indwelling drug delivery device is removed about 30 days after insertion.

[0055] In embodiments, a second indwelling drug delivery device is inserted after removal of the indwelling drug delivery device.

[0056] In embodiments, the indwelling drug delivery device is replaced every 20-35 days. In embodiments, the indwelling drug delivery device is replaced every 25-30 days. In embodiments, the indwelling drug delivery device is replaced approximately every 25 days. In embodiments, the indwelling drug delivery device is replaced approximately every 26 days. In embodiments, the indwelling drug delivery device is replaced approximately every 27 days. In embodiments, the indwelling drug delivery device is replaced approximately every 28 days. In embodiments, the indwelling drug delivery device is replaced approximately every 29 days. In embodiments, the indwelling drug delivery device is replaced approximately every 30 days.

[0057] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are intended to be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. [Example]

[0058] Those skilled in the art will appreciate that the descriptions of making and using the intravaginal rings provided herein are for illustrative purposes only, and that the present disclosure is not limited by these examples.

[0059] Example 1. Phase 1 / 2 Clinical Pharmacokinetic and Safety Study: 1 Month DARE-HRT1 is an ethylene vinyl acetate (EVA) copolymer intravaginal ring (IVR) that releases bioidentical 17β-estradiol and progesterone over 28 days of use and is being developed for the following indications: 1) treatment of moderate to severe VMS associated with menopause in women with an intact uterus; and 2) reduction in the incidence of symptomatic VVA in women requiring treatment for menopausal VMS.

[0060] A Phase 1 clinical trial was conducted in Australia to understand the performance of DARE-HRT1. The primary objective of the study was to describe the pharmacokinetic (PK) parameters over 28 days for two different dose combinations: 1) 17β-estradiol (E2) with a daily release rate of 80 μg / day and progesterone (P4) with a daily release rate of 4 mg / day (80 / 4 IVR); and 2) a daily release rate of 160 μg / day E2 and 8 mg / day P4 (160 / 8 IVR). Secondary objectives of the study were to evaluate the safety and tolerability of each IVR and to compare the systemic exposure of E2 and its metabolites, estrone (E1), and P4, with those of once-daily oral Estofem® / Prometrium® over 28 days.

[0061] Materials and Methods IVRs were manufactured at QPharma (now Sever Pharma Solutions) in Malmö, Sweden. All IVRs had an overall diameter of 57 mm and a cross-sectional diameter of 5 mm. IVRs were fabricated as previously described. Briefly, IVRs were fabricated by compounding EVA (28% vinyl acetate content) with pellets of various concentrations of E2 or P, followed by hot-melt extrusion into fibers of various lengths. The fibers were joined by thermal welding to create IVRs with the desired release rates. The in vitro release rates of the 80 / 4 IVR and 160 / 8 IVR have been previously reported. Weiss H, et al. J of Pharma. Sci. 2019;108(8):2677-84.

[0062] This was a randomized, open-label, three-arm, parallel-group study conducted at two Australian centers (Keogh Institute for Medical Research, Nedlands, Western Australia, 6009, and PARC Clinical Research, Adelaide, South Australia, 5000) in approximately 30 healthy postmenopausal women with an intact uterus. The study was designed to evaluate the PK of E2, E1, and P4 from the DARE-HRT1 IVR at two dose strengths (80 / 4 IVR or 160 / 8 IVR). E2 1 mg (Estofem®) / P4 100 mg (Prometrium®) administered orally once daily for 29 days served as the active reference. Key inclusion criteria were healthy postmenopausal female subjects (defined as 12 months of spontaneous amenorrhea, or 6 months of spontaneous amenorrhea plus a serum FSH level of >40 mIU / mL, or 6 weeks after bilateral oophorectomy without hysterectomy (subjects who had undergone hysterectomy were ineligible for the study) with a body mass index of 18 kg / m² to 38 kg / m², a normal cervix and vagina, an intact uterus, up to date with all Australian screening requirements for cervical cancer, a normal mammogram within 24 months prior to screening, and no known hypersensitivity to E2 or P4 or any component of IVR.

[0063] At the screening visit, the following assessments were performed or information collected: serology (HIV, hepatitis B, and hepatitis C), follicle-stimulating hormone levels, drug / alcohol screen, transvaginal ultrasound (TVU), urine dipstick, blood samples for PK, and prior and concomitant medications. The oral treatment group had a similar visit schedule, but had one fewer visit than the IVR group.

[0064] Plasma blood samples were collected on Day 1 before administration, at -1 hour, -0.5 hours, and 0 hours (immediately; within ±5 minutes) before IVR insertion, and at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours after insertion. Subjects were discharged from the clinic after completing safety assessments on Day 3. On the mornings of Days 8, 11, 15, and 22, subjects returned to the clinic for single PK blood samples and safety assessments. Subjects returned to the clinic on Day 28 for PK blood samples, safety assessments, and confirmation of IVR placement, and began their hospital stay. On the morning of Day 29, a PK blood sample was collected. The IVR was then removed, and PK samples were collected 0.5, 1, 2, 4, 8, 12, and 24 hours after removal.

[0065] Subjects enrolled in the oral treatment group (Estofem / Prometrium) also began treatment on Day 1 and completed treatment with a final dose on Day 29. Treatment was administered at the clinic on the mornings of Days 1, 28, and 29, accompanied by a moderate-fat breakfast. Plasma samples were collected pre-dose on Day 1, at -1 hour, -0.5 hours, and 0 hours (immediately; within ±5 minutes) before oral dosing, and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after dosing. Subjects were discharged from the clinic and instructed to self-administer the medication with a meal and approximately 240 mL of water at approximately the same time in the morning from Days 2 through 27. On Days 8, 15, and 22, subjects returned to the clinic for single PK blood draws and safety assessments. Subjects were admitted back on Day 28, took the oral dose with breakfast, and PK blood sampling began on Day 29 pre-dose (0 hours) and at the following time points after oral dosing: 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours.

[0066] Plasma samples were analyzed at Agilex Biolabs Pty Ltd (Spartanburg, South Australia 5031, Australia) using two validated bioanalytical methods (one for E2 and E1, and one for P4). The lower limit of quantification (LLOQ) for E2 was 2.00 pg / mL, and for E1 it was 5.00 pg / mL. The LLOQ for P4 was 25 pg / mL.

[0067] The IVRs used in this clinical trial were returned to Sever Pharma Solutions after sterilization to determine the remaining amounts of both E2 and P4 in both IVRs. A validated assay method was used to extract and quantify the drug content in the rings. Residual drug levels were compared to the initial amount of each drug to determine the amount released during 28 days of in vivo use.

[0068] After imputing unquantifiable concentrations, concentrations were summarized if at least three subjects in a group had non-missing data for the time points being summarized. Within individual subject concentration versus time profiles, all assayed concentrations were presented, even if not summarized elsewhere, either graphically or in tabular format. For PK parameters, summaries were presented only if at least three subjects in a treatment group had non-missing data.

[0069] For each treatment group, plasma E2, E1, and P4 concentrations were summarized by descriptive statistics: n, arithmetic mean, SD, CV, median, minimum, and maximum for the PK population (defined as all subjects who received a full course of study drug and had sufficient concentration data to determine PK parameters (primary endpoint); data were analyzed according to the study drug actually administered).

[0070] The following PK parameters were determined from the plasma concentration-time profiles: time-weighted average observed plasma concentration over 24 hours (day 29 PK profile for oral administration only; Cavg), steady-state concentration (IVR administration only; Css), maximum observed plasma concentration (Cmax), concentration at the end of the dosing interval (tau) (oral administration only; Ctau), time at which Cmax was observed (tmax), area under the plasma concentration-time curve (AUC) from time 0 to 24 hours (oral administration only; AUC0-24), AUC from time 0 (day 1) to the last quantifiable concentration on day 30 (IVR administration only; AUCCD1-D30), and effective half-life (oral administration only; t1 / 2, eff). These parameters were summarized descriptively, including n, arithmetic mean, SD, CV, GM, and geometric CV, median, minimum, and maximum, for the PK-evaluable population (defined as all subjects in the PK population who completed the study and were free of significant protocol violations and / or investigational drug compliance issues that could confound PK interpretation), by treatment group. Geometric CV was calculated as the square root of the exponential SD of natural log-transformed data (SQRT[exp(sln2)-1]), where appropriate. For tmax, only n, minimum, median, and maximum are reported.

[0071] Baseline correction was performed before calculation of noncompartmental PK parameters using the mean of the three pre-dose concentrations on Day 1. Cmax (and tmax) were calculated based on each 24-hour PK profile (Day 1 and Day 29) and, for IVR administration, over the entire 28-day treatment period.

[0072] The PK-evaluable population was used for statistical analyses. The safety population (defined as all screened subjects who received active treatment, i.e., had an IVR inserted (and thus were exposed to one of the IVRs) or took at least one dose of oral comparator) was used for all tabulations. Individual sampling and subject concentration-time data for plasma concentrations of E2, E1, and P4 for the safety population were tabulated and graphed on linear and semi-log scales by treatment group. Drug concentrations were summarized descriptively in tabular and graphical form (linear and semi-log scales) by treatment group and nominal time point for the PK population.

[0073] Adverse events (AEs) and concomitant medications were assessed and recorded at each visit. Safety analyses were performed on the safety population and for all specified safety variables. All AEs were coded by major system organ class (SOC) and preferred term (PT) according to MedDRA version 24.0 or later and presented by subject in data tables. A treatment-emergent adverse event (TEAE) was defined as any AE that occurred or worsened after the first dose of study drug. A treatment-related AE was defined as any TEAE that was possibly or definitely related to the study drug.

[0074] result A total of 30 healthy postmenopausal female subjects (n=10 per group) were planned to be enrolled in the study. Overall, 34 female subjects were screened and randomized, and 31 subjects (91.2%) completed the study. All 34 screened subjects (100%) were included in the screening and randomized populations. Thirty-three subjects (97.1%) were included in the safety population, and 32 subjects (94.1%) were included in the PK and PK-evaluable populations. Table 1 lists selected demographic information, as well as some baseline information, for the subjects in this study (safety population). [Table 1]

[0075] The residual drug levels in the rings removed on day 29 are shown in Table 2. Both the 80 / 4 IVR and the 160 / 8 IVR released just over 10% of the total amount of E2 loaded into the rings, while the amount released by P4 was approximately 17% of the total amount of drug loaded into the rings. [Table 2]

[0076] The plasma concentration-time profiles of E2 from the 80 / 4 IVR and 160 / 8 IVR are shown in Figure 1. The plasma concentrations of E1 from each IVR are shown in Figure 2. The plasma concentration-time profiles of P4 from the two IVRs are shown in Figure 3. After IVR insertion on Day 1, the plasma concentrations of estradiol, estrone, and progesterone followed a similar pattern: they initially increased and peaked within 12 days of IVR insertion, then declined until approximately Day 8 (192 hours), when they were maintained until the IVR was removed on the morning of Day 29. After IVR removal, concentrations declined toward baseline levels. Estradiol, estrone, and progesterone concentrations were generally higher in the 160 / 8 IVR compared with the 80 / 4 IVR, consistent with the higher doses of both E2 and P4 in the 160 / 8 IVR, with the exception of estrone steady-state concentrations, which were very similar from day 8 to the morning of day 29 in both IVRs.

[0077] Plasma concentrations of E2, E1, and P4 in the oral dosing groups are shown in Figures 4 and 5. The oral dosing group showed the expected increases in estradiol, estrone, and progesterone concentrations on both Days 1 and 30, which returned to near baseline / pre-dose levels within 24 hours. For E2, E1, and P4, steady-state concentrations appeared to be achieved by Day 8 and were maintained throughout the 29-day dosing period. Trough concentrations of E1 were more variable than either E2 or P4, with steady-state appearing to be achieved between Days 8 and 15.

[0078] Various PK parameters of IVR treatment are shown in Table 3. For all three analytes, increased exposure was observed with the 160 / 8 IVR compared with the 80 / 4 IVR in both unadjusted and baseline-adjusted Cmax and AUCD1-D30. However, the increases were generally smaller than the two-fold increase in both E2 and P4 levels in IVR2 compared with IVR1. For both E1 and P4, Css was higher with the 160 / 8 IVR, whereas for E2, Css was similar between the 80 / 4 IVR and 160 / 8 IVR. For both E1 and P4, peak concentrations were observed within 24 hours after insertion, whereas peak E2 concentrations were observed at 48 hours after insertion.

[0079] Subdose-proportional increases were observed in both unadjusted and baseline-corrected estradiol Cmax and Css, as indicated by slope estimates (data not shown) less than 1. For unadjusted and baseline-corrected progesterone Cmax, the slope estimate was close to 1 and the 90% CI of the estimate included 1, indicating a near-dose-proportional increase in exposure after IVR treatment. Subdose-proportional increases were observed in both unadjusted and baseline-corrected P4 Css.

[0080] Various PK parameters for the oral comparator groups are shown in Table 4. On both Days 1 and 30, there was the expected increase in E2, E1, and P4 concentrations, which returned to near baseline / pre-dose levels within 24 hours. For both E2 and P4, steady-state concentrations appeared to be achieved by Day 8 and were maintained throughout the 29-day treatment period. Estrone trough concentrations were more variable than either estradiol or progesterone, with steady-state appearing to be achieved between Days 8 and 15. For both E2 and E1, unadjusted and baseline-corrected peak and overall exposures were higher on Day 29 compared with Day 1 of oral treatment. Unadjusted and baseline-corrected progesterone exposure was also higher on Day 29 compared with Day 1, although not to the same extent as for either E2 or E1. On both Days 1 and 29, peak levels of P4 occurred earlier than either E2 or E1. The estimated effective t1 / 2 for both estradiol and estrone at day 29 was much longer than the corresponding estimates for P4. [Table 3-1] [Table 3-2] [Table 4-1] [Table 4-2]

[0081] The mean baseline-adjusted Css for E2 and E1 in the 80 / 4 IVR were 20.4 pg / mL and 22.1 pg / mL, respectively, and the corresponding values ​​in the 160 / 8 IVR were 30.9 pg / mL and 25.2 pg / mL, respectively. For P4, the baseline-adjusted Css was 1.32 ng / mL and 2.08 ng / mL in the 80 / 4 IVR and 160 / 8 IVR, respectively. In comparison, mean baseline-adjusted trough concentrations of E2, E1, and P4 from days 8 to 29 after once-daily oral administration of Estrofem / Prometrium (1 mg estradiol / 100 mg progesterone) ranged from 26.8 to 58.6 pg / mL, 145 to 161 pg / mL, and 86 to 140 ng / mL, respectively. On day 29, mean baseline-adjusted Cavg values ​​for E2, E1, and P4 after once-daily oral administration of estrofem / prometrium were 35.4 pg / mL, 209 pg / mL, and 0.792 ng / mL, respectively.

[0082] No deaths or serious adverse events (SAEs) were reported. Three subjects (8.8%) discontinued the study prematurely: one (2.9%) after completing treatment with the 160 / 8 IVR due to an upper respiratory tract infection unrelated to the study drug; one (2.9%) due to subject withdrawal after 15 days of treatment with the 160 / 8 IVR; and one (2.9%) prior to treatment due to meeting the exclusion criteria for elevated ALT. Overall, 8 of 10 subjects (80.0%) reported 30 TEAEs in the 80 / 4 IVR group, 9 of 12 subjects (75.0%) reported 47 TEAEs in the 160 / 8 IVR group, and 8 of 11 subjects (72.7%) reported 17 TEAEs in the oral comparator group. Notably, 26 of the 47 TEAEs in the 160 / 8 IVR treatment group were accounted for by a single subject in the 160 / 8 IVR group. All TEAEs were mild or moderate in severity. Overall, the most commonly experienced TEAEs by SOC were reproductive and breast disorders: 6 of 10 subjects (60.0%) in the 80 / 4 IVR group experienced 14 TEAEs, 7 of 12 subjects (58.3%) in the IVR dose 2 group experienced 24 TEAEs, and 5 of 11 subjects (45.5%) in the oral comparator group experienced 6 TEAEs. Overall, the most commonly experienced TEAE by PT was vaginal bleeding: 2 of 10 subjects (20.0%) in the 80 / 4 IVR group experienced 2 TEAEs, 3 of 12 subjects (25.0%) in the 160 / 8 IVR group experienced 3 TEAEs, and 1 of 11 subjects (9.1%) in the oral comparator group experienced 1 TEAE. One TEAE, intermenstrual bleeding, occurred in the 160 / 8 IVR group.

[0083] Consideration Intravaginal rings have been evaluated for the treatment of either VMS or vaginal symptoms associated with menopause (i.e., VVA). The release rates in these studies varied widely and depended on the indication. Treatment of VMS typically requires faster E2 release rates (50 to several hundred μg / day). Most evaluated and commercially available IVRs release E2 at rates ranging from approximately 50 to 150 μg / day. Most early studies of E2 administered via multiple routes of administration reported serum concentrations. In this study, E2 (as well as E1 and P4) were measured in plasma. Comparison of serum and plasma E2 levels found them to be essentially equivalent. IVRs releasing the equivalent of 50 to 200 μg / day of E2 resulted in mean serum E2 concentrations of 38 to 126 pg / mL in postmenopausal women. This IVR is sold as Femring® (Millicent Pharma) or Menoring® (Galen Ltd), depending on the country.

[0084] One study evaluating the efficacy of a ring releasing estradiol acetate at 50 or 100 μg / day (E2 equivalent) in women under 65 years of age who experienced 20 or more hot flashes / night sweats per week found a significant reduction in hot flash / night sweat frequency from baseline in both groups at 12 and 24 weeks (p<0.001). This corresponded to an 84% and 94% reduction in the intravaginal ring group. The mean intensity of genitourinary symptoms decreased from screening to the end of treatment in both groups. The incidence of adverse events was similar in both groups. No clinically significant local effects of the intravaginal ring were observed.

[0085] The 80 / 4 IVR and 160 / 8 IVR resulted in unadjusted E2 Css of 28.6 pg / mL and 39.2 pg / mL, which are somewhat lower than those observed with FemRing / Menoring, although the 160 / 8 IVR showed E2 concentrations similar to those of the 50 μg / day FemRing (38 pg / mL).

[0086] The results of the PK and safety evaluation of two novel IVRs in postmenopausal women provide evidence that plasma concentrations of E2 over time may be sufficient to treat women suffering from menopausal VMS and genitourinary symptoms. The data also suggest that release of P4 may provide adequate endometrial protection. The results of this study support continued evaluation in women experiencing VMS.

[0087] Example 2. Phase 1 / 2 Clinical Pharmacokinetic and Safety Study: 3 Months This randomized, open-label, two-arm, parallel-group Phase 1 / 2 study was designed to evaluate the safety, PK, and preliminary efficacy of DARE-HRT1 in improving menopausal VMS and vaginal symptoms over approximately 3 months of continuous use in 21 healthy postmenopausal women with an intact uterus. The primary objective of the study was to report the safety, tolerability, and PK of two different dose combinations (DARE-HRT1 IVR1, delivering 80 μg / day E2 + 4 mg / day P4, compared with DARE-HRT1 IVR2, delivering 160 μg / day E2 + 8 mg / day P4) over 12 weeks of use. Secondary objectives of the study were to evaluate the usability, subject tolerability, and preliminary efficacy of DARE-HRT1 for both menopausal VMS and vaginal symptoms. The study was registered with ClinicalTrials.gov (NCT05367973).

[0088] method Healthy postmenopausal women who did not use tobacco products or take exogenous hormones were enrolled. Menopause was defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea plus a plasma follicle-stimulating hormone (FSH) concentration of 40 mIU / mL or higher. Subjects had a body mass index of 18 kg / m 2 More than 38kg / m 2Subjects were required to have a uterine thickness of less than 4 mm by transvaginal ultrasound (TVUS), a normal mammogram within 2 years prior to the screening visit, and a normal cervical cytology cancer screening test. Baseline laboratory values ​​had to be within the normal range or deemed clinically insignificant by the investigator and medical monitor. Subjects with an endometrial thickness of 4-6 mm on TVUS at screening were required to undergo an endometrial biopsy demonstrating benign histology (e.g., no hyperplasia, no polyps, no atypia, no carcinoma). Subjects were excluded if they had a history of postmenopausal bleeding, sexually transmitted infection (STI), endometrial hyperplasia, or significant cardiovascular, renal, pulmonary, neurological, or hepatic disease that would interfere with study compliance or affect data quality. Eligible subjects receiving exogenous HT at study enrollment were required to undergo an appropriate washout period.

[0089] Subjects used the investigational product for three 28-day cycles over 12 weeks, with a new IVR administered on Day 1 of each cycle. For each cycle, Day 1 was defined as the first day of treatment, i.e., the day the subject self-administered the IVR. Subjects were instructed to leave the IVR in place for 28 days and used a diary to record IVR insertion and removal, instances of IVR dislodgement, and any adverse events (AEs) or concomitant medication use.

[0090] In this open-label, parallel-group, randomized study, subjects who met the study entry criteria were randomly assigned in a 1:1 ratio to either DARE-HRT1 IVR1 (E2 80 μg / day + P4 4 mg / day) or DARE-HRT1 IVR2 (E2 160 μg / day + P4 8 mg / day). The randomization schedule was computer-generated using a permuted block algorithm. Study center was not a blocking factor in the randomization schedule. Randomization numbers were assigned sequentially by a member of the data management team who had no other involvement in the study.

[0091] The IVR component of DARE-HRT1 is an EVA copolymer ring. DARE-HRT1 IVR was supplied by Sever Pharma Solutions (Malmö, Sweden) as either IVR1 (E2 80 μg / day + P4 4 mg / day) or IVR2 (E2 160 μg / day + P4 8 mg / day). All investigational products were kept refrigerated (2–8°C).

[0092] Safety evaluation Safety was assessed primarily by treatment-emergent adverse events (TEAEs), which were graded for their severity and relationship to investigational product use. Vaginal or vulvar irritation, vaginal discharge, or pelvic pain, if present, were reported as AEs using Standardized Dictionary of Drug Regulatory Information (MedDRA) codes and graded for severity. Adverse drug reactions (ADRs) were defined as any untoward and unintended reaction to a drug for which there was at least a plausible possibility of a causal relationship between the drug and the AE, i.e., a causal relationship could not be ruled out. Any AE that was deemed to have a plausible causal relationship with the investigational product (IP) by either the reporting investigator or sponsor was considered an ADR. Unexpected ADRs were defined as ADRs whose nature or severity was inconsistent with the applicable product information (e.g., the Investigator's Brochure (IB) for unapproved IP).

[0093] Safety was also assessed by changes from screening in clinical laboratory assessments, vital signs, 12-lead electrocardiogram (ECG), physical examination, and endometrial thickness measurements by TVUS.

[0094] Pharmacokinetic (PK) evaluation As shown in Table 5, subjects were seen over three 28-day cycles. PK analytes measured included estrone (E1), E2, and P4. During the first IVR use cycle, baseline PK blood draws for E1, E2, and P4 were performed before the insertion of the new IVR on Day 1. These baseline values ​​for E1, E2, and P4 were added to the post-dose plasma concentrations of the analytes to adjust for each woman's endogenous hormonal status. On Day 1, plasma PK blood draws were repeated at 0.5, 1, 2, 4, and 8 hours after IVR insertion. Subjects also returned to the clinic 24 and 48 hours after the insertion of the new IVR for a single PK blood draw during each cycle. Subjects also returned on days 8, 15, and 22 of each treatment cycle for single PK blood draws and safety assessments, which included monitoring of AEs and concomitant medications, clinical laboratory findings, physical examination, vital signs, colposcopy, and TVUS (and endometrial biopsy if indicated). [Table 5]

[0095] Subjects underwent safety assessments at the end of 12 weeks of study treatment (EOT) on Day 29 of Cycle 3. PK blood sampling was performed before the removal of the last IVR and then repeated at 0.5, 1, 2, 4, 8, and 24 hours after removal.

[0096] Plasma concentrations of E1, E2, and P4 were analyzed by Agilex Biolabs (Severton, South Australia) using dual tandem liquid chromatography-mass spectrometry (LC / MS-MS). The lower limits of quantitation (LLOQ) for each analyte were as follows: E1 5 pg / mL, E2 2 pg / mL, and P4 0.025 ng / mL. For PK characterization, analyte concentrations for each IVR dose were calculated using noncompartmental analysis (NCA). Concentrations below the LLOQ (BLQ) were imputed as 0.5*LLOQ. PK parameter estimation was completed using WinNonlin (Pharsight Corporation). Actual blood collection times were used for all parameter estimation. Standard PK parameters evaluated included the area under the plasma concentration-time curve (AUC), maximum observed drug concentration (Cmax), time to maximum drug concentration (Tmax), and an index of the extent of absorption using an estimate of steady-state concentration (Css).

[0097] Sample size and statistical analysis A total of 20 healthy postmenopausal female subjects (N=10 per group) were planned to be enrolled in the study. The sample size for the study was based on feasibility and the goal of accurately assessing the safety and PK of the DARE-HRT1 IVR over a 12-week period. Therefore, the data will be primarily descriptive in nature. The defined analysis populations for the primary objective included: (1) a safety population, consisting of all enrolled subjects who received active treatment, i.e., had an IVR inserted (and therefore were exposed to at least one IVR); and (2) a PK population, for the dispensed investigational drug, which were all subjects who received a full course of investigational drug and had sufficient concentration data to determine PK parameters (primary endpoint).

[0098] Duration of exposure was calculated as the number of treatment days from the first IVR insertion to the last IVR removal. Total exposure to E2 and P4 was calculated as analyte dose * duration of exposure. Study drug compliance was calculated as 100% × (total exposed E2 [μg] / total required E2 [μg]; where total required = planned dose [μg] × 84).

[0099] Summary statistics were described for each dose cohort. Continuous variables included the number of subjects, mean, standard deviation (SD), median, minimum, and maximum. For categorical variables, the number and percentage of subjects in each category are presented. The denominator of the percentage was based on the number of subjects appropriate for the purpose of the analysis. This study was not powered to demonstrate differences in the proportion of subjects in each dose group who reported various TEAEs; therefore, comparisons of categorical variables for safety analysis were performed by Fisher's exact test. A P value of less than 0.05 was considered significant.

[0100] result As shown in Figure 6, 21 volunteers were screened and randomized to either DARE-HRT1-IVR1 (n=11) or DARE-HRT1-IVR2 (n=10). There were no screening failures. Table 6 shows the demographic data for both treatment cohorts. All subjects were considered menopausal based on 12 months of spontaneous amenorrhea. [Table 6]

[0101] Safety evaluation Table 7 shows the TEAEs, severity, and association with the investigational product. Overall, 11 of 11 subjects (100.0%) in the IVR1 group reported 35 TEAEs, and 10 of 10 subjects (100.0%) in the IVR2 group reported 62 TEAEs, with similar proportions of subjects in each treatment group reporting various categories of TEAEs (Fisher's exact test p-value = 0.39) (Table 7). All TEAEs were graded as either mild or moderate. No serious AEs (SAEs) were reported. [Table 7]

[0102] Two subjects in the IVR2 group had TEAEs (persistent breakthrough bleeding, nipple tenderness, and depressed mood) considered related to the study drug, which led to discontinuation of the study drug and withdrawal from the study.

[0103] At baseline, the mean (SD) endometrial thickness was 2.40 (1.26) and 2.11 (0.71) mm for IVR1 and IVR2, respectively. At the end of treatment, the mean (SD) endometrial thickness width was 3.03 (1.86) and 2.50 (0.98) for IVR1 and IVR2, respectively. All endometrial thickness measurements were 4.8 mm or less at the end of treatment.

[0104] Table 8 shows the most common TEAEs by treatment duration, calculated total exposure to E2 and P4, self-reported treatment adherence, and system organ class (SOC). Some compliance figures exceeded 100% because EOT occurred after day 84 due to appointment scheduling issues. [Table 8]

[0105] Pharmacokinetic evaluation Tables 9, 10, and 11, and Figures 7-12, show baseline-adjusted plasma PK parameters and mean (SD) baseline-adjusted plasma concentrations versus time for P4, E2, and E1 during each cycle of investigational product use. Table 9 and Figures 7 and 8 show that both IVRs resulted in baseline-adjusted plasma P4 concentrations greater than 1 ng / mL throughout 12 weeks of treatment. Table 10 and Figures 9 and 10 show that baseline-adjusted mean (SD) steady-state (Css) plasma E2 concentrations achieved with the 160 μg / day E2 dose IVR were at least 37.35 ± 8.96 pg / mL and ranged from 37.35 to 38.97 pg / mL over 12 weeks of treatment. The mean (SD) baseline-adjusted Css plasma E2 concentrations achieved with the low 80 μg / day E2 dose IVR across each treatment cycle ranged from 22.17 ± 4.47 pg / mL to 23.10 ± 5.27 pg / mL. [Table 9] [Table 10] [Table 11]

[0106] Consideration This 3-month study of two strengths of DARE-HRT1 demonstrated that both IVRs were safe during treatment and released plasma E2 concentrations of approximately 20-80 pg / mL, a range typical of the normal premenopausal follicular phase. Steady-state plasma P4 concentrations for both IVRs were greater than 1 ng / mL, a range typical of the normal postovulatory luteal phase, supporting the idea that in vivo release of P4 protects the endometrium from the proliferative effects of exogenous E2.

[0107] All TEAEs were mild or moderate in severity, but two subjects in the IVR2 group chose to discontinue the investigational product due to experiencing known hormone-related side effects. Product-related TEAEs and the severity of TEAEs were similar between the two treatment groups.

[0108] The levels of estradiol released from both the low-dose and high-dose formulations of DARE-HRT1 evaluated in this study achieved statistically significant improvements in menopausal VMS and urogenital symptoms, as well as vaginal pH and maturation index. Menopausal symptoms, including hot flashes and night sweats, were reduced compared to baseline in both DARE-HRT1 dose groups (p<0.01).

[0109] Subjects also demonstrated significant improvements from baseline in all indicators assessed by the Menopausal Quality of Life Questionnaire (MENQOL), which assesses not only VMS parameters but also physical, psychosocial, and sexual symptoms (p<0.01 for all domains). With DARE-HRT1, vaginal pH significantly decreased compared to baseline in all subjects (p<0.01), and vaginal epithelial cytology (vaginal maturation index) showed significant normalization (all p<0.01 for increases in superficial cells, intermediate cells, and parabasal cells from baseline). Furthermore, vaginal dryness, the most common urogenital symptom reported by 70% of subjects at baseline, significantly improved in both DARE-HRT1 groups (p<0.01). This subset also experienced a significant decrease in vaginal pain with DARE-HRT1 use (p<0.01).

[0110] The study drug was well tolerated, and the most common types of adverse events were consistent with other vaginal products. There were only two early discontinuations due to adverse events, and no serious adverse events were reported.

[0111] DARE-HRT1 demonstrated a high level of acceptability in this study, with 100% of participants reporting the IVR was comfortable to wear and no cases of the IVR falling out of the vagina during use. Furthermore, over 95% of participants stated they would be "somewhat likely" or "very likely" to use the IVR again, if necessary, for a gynecological condition or an unrelated condition.

[0112] The data from this study demonstrate that DARE-HRT1 successfully delivered estradiol and progesterone over the 12-week evaluation period. The baseline-corrected steady-state release of estradiol and progesterone from both the low-dose (IVR1) and high-dose (IVR2) versions of DARE-HRT1 evaluated in this study demonstrated steady-state release levels at month 3 of the 12-week study, as shown in Table 12 below. [Table 12]

[0113] The estradiol levels released from both the low-dose and high-dose formulations of DARE-HRT1 evaluated in this study met or exceeded the levels targeted by hormone therapy. Target estradiol levels for hormone therapy for either menopausal VMS or vaginal symptoms were established by reviewing published PK levels for FDA-approved products for the treatment of both menopausal VMS and genitourinary symptoms. Based on the estradiol PK data from the Phase 1 / 2 study of DARE-HRT1, the results support the potential of DARE-HRT1 as an effective hormone therapy for both menopausal VMS and vaginal symptoms. The progesterone levels released from both versions of DARE-HRT1 evaluated in this study achieved the goal of releasing progesterone. Progesterone is used in hormone therapy to prevent estrogen-induced endometrial hyperplasia by reducing the effects of estrogen on non-target sites, such as the endometrium.

[0114] To effectively treat VMS in postmenopausal women, who typically have serum E2 concentrations below 20 pg / mL, exogenous E2 regimens must raise serum E2 concentrations to the premenopausal range. In healthy premenopausal women, serum E2 concentrations typically range from 20 to 80 pg / mL during the early follicular phase of the menstrual cycle and rise to 150 to 500 pg / mL at ovulation. Therefore, the pharmacokinetic (PK) data for DARE-HRT1-002 demonstrate that a 160 μg / day E2 IVR placed E2 levels in all subjects within the normal premenopausal early follicular range (approximately 20 to 80 pg / mL), optimal for effectively treating menopausal VMS. In contrast, mean (SD) steady-state plasma E2 concentrations resulting from the use of an 80 μg / day E2 IVR resulted in plasma E2 levels remaining in the menopausal range (<20 pg / mL) in some IVR1 users.

[0115] The highest systemic absorption of E2 and P4 was measured during the first 2 days of the first month of DARE-HRT1 IVR use. This is likely due to the fact that this study enrolled postmenopausal women with a median age of 59 years. Although subjects were not required to meet FDA-defined criteria for VVA, baseline Vaginal Maturation Index (VMI) parameters, indicating a low number of superficial cells and a high number of parabasal cells, were consistent with VVA. It has previously been reported that menopausal women absorb vaginally applied medications more efficiently and rapidly than premenopausal women, and that after 1 month of vaginal estrogen use, vaginal absorption of topically applied medications decreases and becomes similar to that of premenopausal women (Thurman, et al. J Acquir Immune Defic Syndr. 2018;78(1):82-92). We demonstrated increased absorption during the first few days of each cycle, which was most pronounced during the first cycle.

[0116] Regarding systemic safety, the PK data for DARE-HRT1-002 also support the low-dose nature of both the 160 μg / day E2 IVR and 80 μg / day E2 IVR products. The systemic safety of exogenous E2 products is improved by the use of low-dose formulations (e.g., conjugated equine estrogens (CEE) 0.3 mg / day or 0.45 mg / day) that result in low, normal E2 plasma concentrations (20–80 pg / mL E2) during the early premenopausal follicular phase, rather than high-dose exogenous E2 products (e.g., CEE 2.5 mg / day) that result in plasma E2 concentrations above 150 pg / mL, consistent with ovulation. E2-related systemic serious AEs (e.g., pulmonary embolism, venous thromboembolism) and adverse events (e.g., nausea and breast pain) are directly related to steady-state plasma E2 concentrations and subject age.

[0117] Data also support that both DARE-HRT1 IVRs deliver P4 concentrations to the endometrium at levels expected to protect it from endometrial hyperplasia. Specifically, during menopause and anovulation (e.g., polycystic ovary syndrome), serum P4 concentrations are below 1 ng / mL (Verdonk, Vesper et al. 2019). During the normal postovulatory luteal phase of the menstrual cycle, serum P4 concentrations rise above 1 ng / mL, leading to secretory, progesterone-dominant, and atrophic changes in the endometrium (Noyes, Hertig et al. 1975). Unopposed exogenous estrogen use and chronic anovulation (e.g., PCOS) are highly associated with endometrial hyperplasia due to the lack of P4 in these clinical settings. PK data (Table 12) demonstrate that mean (SD) steady-state serum P4 concentrations achieved during the 12-week treatment period with either DARE-HRT1 IVR1 or DARE-HRT1 IVR2 were all greater than 1 ng / mL. These PK data demonstrate that both rings deliver sufficient P4 to protect the endometrium from hyperplasia by counteracting the proliferative effects of E2.

[0118] Although endometrial biopsies were not performed in this study, all TVUS endometrial thickness measurements were ≤4.8 mm at screening and end of treatment. The fact that this IVR is a combined E2 and P4 product and that steady-state plasma P4 concentrations were in the normal postovulatory range (>1 ng / mL) supports the idea that this dose of P4 counteracts the proliferative effects of E2 on the endometrium.

[0119] The strength of this study was that it achieved its primary objective of measuring the safety and systemic PK of two strengths of DARE-HRT1 in a healthy postmenopausal population. While the sample size was small, consistent with earlier PK and safety studies, the study provided systemic PK data consistent with other recently approved oral and IV VMS treatments. Subjects used the investigational product for a 12-week study period, the typical duration required to measure the efficacy of a VMS treatment in a placebo-controlled trial. DARE-HRT1 is the first vaginal combination IV VMS treatment with E2 and P4 hormones for the treatment of VMS in healthy postmenopausal women with an intact uterus. This long-acting, parenteral VMS treatment regimen is believed to fill an important gap in treatment options for this common menopause-related condition.

[0120] Example 3. Preliminary efficacy and usability evaluation of DARE-HRT1 Preliminary efficacy was assessed in the study described in Example 2 above.

[0121] Table 13 shows that use of either DARE-HRT IVR resulted in significant improvements in vaginal cytology as measured by VMI and the proportion of three vaginal cell types (all P values ​​< 0.01). Similarly, both doses of DARE-HRT1 IVR treatment significantly reduced vaginal pH (all P values ​​< 0.01).

[0122] At baseline, 14 of 21 subjects reported vaginal dryness as their MBS, 2 reported vaginal and / or vulvar pruritus as their MBS, and 3 reported vaginal pain with sexual activity (dyspareunia) as their MBS. Specifically, at baseline, subjects in the IVR1 group reported vaginal dryness (n=8 / 11), vaginal and / or vulvar pruritus (n=1 / 11), and vaginal pain with sexual activity (dyspareunia) (n=2 / 11). At baseline, subjects randomized to the IVR2 group reported the following MBS: vaginal dryness (n=6 / 10), vaginal and / or vulvar pruritus (n=1 / 10), and dyspareunia (n=1 / 10). Two subjects in the IVR1 cohort reported vaginal bleeding with sexual activity at baseline, but no subjects in either IVR group had this symptom at the end of treatment.

[0123] Among 14 subjects (8 from the IVR1 cohort and 6 from the IVR2 cohort) who reported vaginal dryness as their MBS at baseline, their median (interquartile range [IQR]) severity score was 2.0 (1, 3) at baseline and significantly decreased to a median (IQR) of 0 (0, 0) by the end of treatment with their respective IVR (P<0.01). These 14 women also experienced a significant decrease in dyspareunia, from a median (IQR) severity of 1 (0, 2) at baseline to a median (IQR) severity of 0 (0, 0) at the end of treatment (P<0.01).

[0124] Table 13 shows that when self-reported subjective severity scores (for all subjects) of all four GSM symptoms were compared as continuous variables between baseline and end of treatment, there was a significant improvement in vaginal dryness and dyspareunia in the IVR1 group (P < 0.01), but a non-significant trend toward improvement in the IVR2 group (P = 0.06). Unlike the changes in objective markers of vaginal pH and VMI (Table 1), there were no significant changes in the self-reported severity of painful urination or the severity of vulvar or vaginal pruritus in either IVR group. IVR2 users did not experience a significant change from baseline in the severity of any of the four GSM symptoms (Table 13). This is likely due to the fact that only one woman in the IVR1 cohort reported mild painful urination at baseline, whereas none of the IVR2 subjects reported the presence of this symptom at baseline. Similarly, vulvar or vaginal pruritus was an MBS for two study subjects (one in each IVR group), but the severity of vulvar or vaginal pruritus at baseline was reported as mild, moderate, or severe by two, one, and one IVR1 users, respectively.For IVR2 users, one woman reported mild vulvar or vaginal pruritus and one woman reported moderate vulvar or vaginal pruritus at baseline. [Table 13]

[0125] Preliminary systemic (VMS) PD estradiol effects The MENQOL questionnaire was used to assess the preliminary efficacy of the investigational product for treating VMS. Table 14 shows that there was a significant reduction from baseline and improvement in overall MENQOL scores and all MENQOL domains for both DARE-HRT1 IVRs. In both groups, the greatest improvement was in the sexual domain of MENQOL, which consisted of three questions regarding sexual desire, vaginal dryness, and avoidance of intimacy due to physical symptoms.

[0126] Table 15 shows the frequency of responses to questions 1–3, which are questions in the VMS domain of the MENQOL questionnaire. The most commonly reported VMS was night sweats (MENQOL question 2), which was also the most severe symptom among subjects who reported this symptom at baseline (Table 15). Use of DARE-HRT1 IVR1 significantly improved hot flashes (question 1) and night sweats (question 2) (P values ​​of 0.02 and 0.01, respectively), whereas sweating (question 3) did not change significantly (P = 0.28), because 6 of 11 IVR1 users did not report this symptom at baseline (Table 15). Among DARE-HRT1-IVR2 users, there was a significant improvement in the severity of hot flashes, night sweats, and sweating (all P values ​​< 0.03) (Table 15). [Table 14] [Table 15-1] [Table 15-2] [Table 15-3]

[0127] Usability and Acceptability Questionnaire Table 16 shows the frequency of responses by DARE-HRT1 IVR treatment group to the acceptability questionnaire at the end of treatment (Cycle 3, Day 29) or early discontinuation visit. Most women agreed or strongly agreed that the study product was comfortable to wear, easy to use, and fit into their lifestyle. Most women also reported being very likely or very likely to use IVR for the treatment of both gynecological and other health conditions. Acceptability responses were similar between the two treatment groups at the end of treatment (all P values ​​> 0.22). [Table 16]

[0128] Consideration This 3-month study of the two strengths of DARE-HRT1 demonstrated that both IVRs were tolerable and released sufficient E2 in vivo to demonstrate preliminary efficacy against both systemic menopausal symptoms (VMS) and localized menopausal symptoms (GSM).

[0129] Both 80 μg / day E2 IVR and 160 μg / day E2 IVR were found to significantly reduce vaginal pH and improve VMI. Significant improvements in vaginal dryness and dyspareunia were also observed in the IVR1 group, while a non-significant trend toward improvement was observed in the IVR2 group. Therefore, DARE-HRT1 may be an ideal product for healthy postmenopausal women with symptomatic systemic hypoestrogenism (VMS) and local hypoestrogenism (GSM) who have an intact uterus. We acknowledge that, as is the usual criteria in estrogen-based GSM treatment trials, subjects were not required to have symptomatic GSM, as defined by a vaginal pH >5.0 and less than 5% surface cells, to enroll in this study. Therefore, we interpret the preliminary GSM efficacy data with caution. However, the GSM data are consistent with what is known about local vaginal treatment with E2.

[0130] Similarly, subjects were not required to have the baseline frequency or severity of VMS, as required for placebo-controlled VMS treatment efficacy trials. Indeed, we recognize that not all women enrolled in this study had various VMS symptoms (e.g., hot flashes, night sweats, sweating) at baseline. However, among women who reported the presence of VMS symptoms at enrollment in the MENQOL questionnaire, the most severe and common systemic symptom was night sweats (MENQOL Question 2), followed by hot flashes or hot flushes (MENQOL Question 1), which are burdensome menopausal symptoms that contribute to poor overall health, in part due to chronic sleep deprivation and the sequelae of other symptoms. Users of the 80 μg / day E2 IVR (DARE-HRT1-IVR1) did not experience a significant improvement in responses to MENQOL Question 3 (P = 0.28), likely due to the fact that this symptom was reported as absent by the majority (6 / 11) of these users at baseline.

[0131] Because VMS treatment efficacy was classified as preliminary and an exploratory endpoint in this study, subjects were not asked about the frequency and severity of hot flashes at both 4 and 12 weeks of investigational product use, as required by the Food and Drug Administration (FDA) in placebo-controlled VMS treatment trials. The study was open-label, and the primary endpoint was to measure safety and PK. Due to its open-label, non-placebo-controlled design, preliminary efficacy results for VMS and GMS must be interpreted with caution. Fisher's exact test was used to compare the frequency of severity scores for the MENQOL VMS domain, which is not affected by sample size.

[0132] Although the MENQOL questionnaire was used to assess the efficacy of preliminary VMS treatment, it should be noted that the MENQOL domain for VMS does not identify the frequency of VMS events. However, the data are encouraging, as both interventions resulted in overall improvement in all four MENQOL domains. The MENQOL sexual domain showed the greatest improvement with treatment, and this domain includes a question about vaginal dryness, which was the most bothersome genitourinary symptom reported by 14 of 21 subjects at baseline.

[0133] The DARE-HRT1 IVR was acceptable and tolerable for all subjects, and there were no significant differences in acceptability survey responses based on treatment group, which is not surprising since both IVRs have the same physical characteristics.

[0134] A strength of this study was that it achieved its objective of measuring the preliminary efficacy and acceptability of a first-in-category IVR in healthy postmenopausal women. It is recognized that subjects were not required to meet FDA-defined criteria for GSM or VMS symptoms; therefore, the preliminary efficacy data must be interpreted with caution. However, the preliminary efficacy data, using surrogate measures of both systemic (VMS) and local (GSM) efficacy endpoints, are consistent with what is known about both VMS and GSM treatment regimens. Furthermore, because preliminary efficacy and acceptability were exploratory endpoints, the study was not designed to detect differences between the two IVRs in these variables. Subjects used the investigational product for the 12-week study period, which is the typical period required by the FDA to measure therapeutic efficacy for both GSM and VMS.

[0135] conclusion This investigational product is the first combined E2 and P4 IVR product for treating VMS symptoms. This parenteral VMS treatment regimen has the potential to fill an important gap in treatment options for this common menopause-related disorder in postmenopausal women with an intact uterus. By delivering E2 and P4 via a parenteral route, this product meets recommended guidance from NAMS and other international organizations for the safe and effective treatment of VMS.

Claims

1. 1. A method for treating one or more menopausal symptoms in a subject, comprising intravaginally inserting into the subject an indwelling drug delivery device comprising estrogen and a progestin, wherein the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 15 pg / mL to about 50 pg / mL.

2. 10. The method of claim 1, wherein the indwelling drug delivery device comprises a solid ethylene vinyl acetate polymer matrix.

3. 3. The method of claim 1 or 2, wherein the subject is a female subject having a uterus.

4. The method of any one of claims 1 to 3, wherein the one or more menopausal symptoms comprise vasomotor symptoms (VMS) and / or genitourinary symptoms.

5. 5. The method of any one of claims 1 to 4, wherein the one or more menopausal symptoms comprise hot flashes, night sweats, changes in vaginal pH, vaginal cytology, vaginal dryness, and vaginal pain.

6. The method of any one of claims 1 to 5, wherein the estrogen is estradiol.

7. 7. The method of claim 6, wherein the estradiol is bio-identical estradiol.

8. The method of any one of claims 1 to 6, wherein the progestin is progesterone.

9. 9. The method of claim 8, wherein the progesterone is bioidentical progesterone.

10. 10. The method of any one of claims 1 to 9, wherein the indwelling drug delivery device delivers the estrogen and the progestin continuously over a period of time.

11. 11. The method of claim 10, wherein the period is between 7 days and 35 days.

12. 11. The method of claim 10, wherein the period is about 28 days.

13. 13. The method of any one of claims 1 to 12, wherein the indwelling drug delivery device comprises an ethylene vinyl acetate (EVA) intravaginal ring (IVR), the ring comprising at least two segments / fibers, one segment containing the estrogen and a second segment containing the progestin.

14. 14. The method of any one of claims 1 to 13, wherein the indwelling drug delivery device comprises an inner core comprising one or more active pharmaceutical ingredients dispersed throughout a first water-insoluble polymer; an intermediate coating disposed about the inner core and comprising an acrylate polymer; and an outer coating disposed about the intermediate coating and comprising a second water-insoluble polymer.

15. the acrylate polymer is formed from one or more monomers of formula (I), 【Chemistry 1】 wherein R1 is selected from H, alkyl, alkenyl, alkynyl, or aryl; and R2 is selected from H or alkyl.

15. The method of claim 14.

16. 16. The method of any one of claims 1 to 15, wherein the indwelling drug delivery device releases the estrogen at a rate of about 50 μg / day to about 200 μg / day.

17. 16. The method of any one of claims 1 to 15, wherein the indwelling drug delivery device releases the progestin at a rate of about 1 mg / day to about 15 mg / day.

18. 18. The method of any one of claims 1 to 17, wherein the indwelling drug delivery device releases the estrogen at a rate of about 80 μg / day and the progestin at a rate of about 4 mg / day.

19. 18. The method of any one of claims 1-17, wherein the indwelling drug delivery device releases the estrogen at a rate of about 160 μg / day and the progestin at a rate of about 8 mg / day.

20. 20. The method of any one of claims 1 to 19, wherein the indwelling drug delivery device is removed about 20 to about 35 days after insertion.

21. 21. The method of claim 20, wherein a second indwelling drug delivery device is inserted after removal of the indwelling drug delivery device.

22. The method of any one of claims 1 to 21, wherein the indwelling drug delivery device is replaced every 20 to 35 days.

23. 23. The method of claim 22, wherein the indwelling drug delivery device is replaced approximately every 28 days.

24. 24. The method of any one of claims 1-23, wherein the indwelling drug delivery device provides a baseline-adjusted steady-state plasma estrogen concentration in the subject of about 20 pg / mL to about 30 pg / mL.

25. 25. The method of any one of claims 1-24, wherein the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in the subject of from about 1 ng / mL to about 5 ng / mL.

26. 26. The method of claim 25, wherein the indwelling drug delivery device provides a baseline-adjusted steady-state plasma progesterone concentration in the subject of about 2 ng / mL to about 4 ng / mL.

27. 27. The method of any one of claims 1 to 26, wherein the one or more menopausal symptoms are improved by at least 20%.

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