Combination solid oral dosage form of a gonadotropin-releasing hormone antagonist

Abstract

The present disclosure comprises a combination solid oral dosage form comprising 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, and a hormone replacement agent. Also provided are methods for preparing and using the solid oral dosage form.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 032,469, filed May 29, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to a solid oral dosage form of a combination of a gonadotropin-releasing hormone (GnRH) antagonist and one or more hormone replacement drugs. Such dosage forms can provide non-surgical treatment of hormone-sensitive conditions while reducing or avoiding side effects such as bone mineral density loss that are typically associated with GnRH antagonists. Specifically, the present disclosure relates to N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a pharmaceutically acceptable salt thereof in a corresponding amount; and a combined oral dosage form of one or more hormone replacement drugs. In certain dosage forms, the one or more hormone replacement drugs comprise estradiol, norethindrone acetate, or both. Background Art

[0004] Hormone-sensitive diseases of the female reproductive system, such as uterine leiomyoma, endometriosis, adenomyosis, heavy menstrual bleeding or pain associated with uterine leiomyoma, endometriosis or adenomyosis, can have a significant impact on the quality of life of many women. Since these conditions are hormone-sensitive, there is concern about treatment methods that include regulating one or more hormones such as estrogen or progesterone using GnRH agonists (GnRH receptor agonists) or GnRH antagonists (GnRH receptor antagonists). It is challenging to achieve a balance between estrogen and progesterone that alleviates one or more symptoms while avoiding the serious side effects of hormone suppression. For example, if estradiol levels drop below a certain threshold, bone mineral density (BMD) loss may occur. Over time, bone mineral density loss may lead to serious negative effects such as increased fractures or osteoporosis. Suppressing progesterone without simultaneously suppressing estrogen may lead to endometrial hyperplasia, which is a risk factor for endometrial cancer. Conversely, if estrogen or progesterone levels are above the upper therapeutic limit, estrogen or progesterone-sensitive symptoms and conditions may be exacerbated. The balance of these hormonal interactions is further complicated by the sensitivity of the conditions themselves, as not all hormone-responsive gynecological conditions respond to the same levels of estrogen or progesterone.

[0005] Compound N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, also referred to herein as Compound 1, or a pharmaceutically acceptable salt thereof in a corresponding amount is described, for example, in U.S. Pat. Nos. 7,300,935, 8,058,280, and 10,350,170, and U.S. Publication No. 2020-0000730. Methods of treatment using Compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount are described, for example, in U.S. Pat. Nos. 8,735,401 and 9,346,822, and U.S. Publication No. 2019-0262346. Summary of the Invention

[0006] The present disclosure provides a fixed combination (also referred to as a fixed dose formulation or combined solid oral dosage form) oral dosage form of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea, also known as Compound 1, or a pharmaceutically acceptable salt thereof, and one or more hormone replacement drugs. Administration of such a combination of agents can reduce adverse side effects typically associated with GnRH antagonists. Examples of hormone replacement drugs include estradiol (E2) and norethindrone acetate (NETA).

[0007] In one aspect, provided herein is a combination solid oral dosage form comprising about 18% w / w to 22% w / w of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof; about 0.3% w / w to 0.7% w / w of estradiol; about 0.1% w / w to 0.4% w / w of norethindrone acetate; about 24% w / w to 28% w / w of mannitol; about 2% w / w to 6% w / w of a starch selected from the group consisting of sodium starch glycolate, pregelatinized starch, and combinations of the foregoing; about 0.5% w / w to 3% w / w of hydroxypropyl cellulose; about 0.5% w / w to 3% w / w of magnesium stearate; about 38% w / w to 42% w / w of lactose monohydrate; and about 1% w / w and 5% w / w of a film coating.

[0008] In some variations, the combination solid oral dosage form comprises about 40 mg N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof; about 1 mg estradiol; about 0.5 mg norethindrone acetate; about 51 mg mannitol; about 9 mg sodium starch glycolate; about 3 mg hydroxypropylcellulose; about 2 mg magnesium stearate; about 78 mg lactose monohydrate; and about 7 mg film coating.

[0009] In some variations, the combination solid oral dosage form includes a starch, wherein the starch is sodium starch glycolate. In other variations, the starch is a pregelatinized starch. In other variations, the starch is a combination of sodium starch glycolate and pregelatinized starch. In some variations, the combination solid oral dosage form includes approximately 9 mg of sodium starch glycolate. In some variations, the combination solid oral dosage form includes approximately 2% to 3% sodium starch glycolate and approximately 2% to 3% pregelatinized starch.

[0010] In some variations of the combined solid oral dosage form, the amount of relugolix degradant present after storage of the combined solid oral dosage form for 6 months at 60° C. and ambient relative humidity is no more than 0.5% w / w. In some variations, the amount of estradiol degradant present after storage of the combined solid oral dosage form for 6 months at 60° C. and ambient relative humidity is no more than 1.4% w / w. In certain variations, the amount of norethindrone acetate degradant present after storage of the combined solid oral dosage form for 6 months at 60° C. and ambient relative humidity is no more than 1.4% w / w.

[0011] In one aspect, a method for preparing a combination solid oral dosage form comprises: preparing a first granulation comprising one or more sub-batches, wherein each sub-batch comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, mannitol, a first fraction of starch, and hydroxypropyl cellulose; preparing a second granulation comprising estradiol, norethindrone acetate, a second fraction of starch, and lactose monohydrate; blending the first granulation and the second granulation with magnesium stearate to form a final blend; and coating the final blend with a film coating.

[0012] In some variations, a method for preparing a combination oral dosage form comprises: spraying the aqueous solution of hydroxypropylcellulose onto a fluidized mixture of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, and the first fraction of the starch to form an initial blend, wherein the initial blend is dried and milled to produce subbatches; and wherein one or more subbatches are mixed. The invention relates to a method for preparing a solid oral dosage form comprising: first blending the first granulation and the second granulation to produce the first granulation; spraying the methanolic solution of the estradiol and the norethindrone acetate onto the fluidized mixture of the first fraction of the lactose monohydrate to form an initial lactose blend, wherein the initial lactose blend is dried, milled and blended with the second fraction of the lactose monohydrate and the second fraction of the starch to produce the second granulation; blending the first granulation with the second granulation and the magnesium stearate to produce the final blend, wherein the final blend is compressed; and coating the final blend with an aqueous film coating suspension and drying the coated final blend to form the combined solid oral dosage form.

[0013] In some variations of the method for preparing the combination oral dosage form, the second granulation does not include mannitol.In certain variations, the first granulation includes two subbatches.

[0014] In some variations of the method for preparing the combined oral dosage form, the N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, and the first fraction of the starch are fluidized in a fluidized bed granulator with an inlet air flow rate of 400-500 cfm and a temperature of 75°C-80°C.

[0015] In some variations of the method for preparing a combination oral dosage form, the aqueous solution of the hydroxypropyl cellulose is sprayed at a rate of 250 g / min to 350 g / min and a target atomization pressure of 2.5 bar to 4.5 bar.

[0016] In certain variations of the process for preparing the combined oral dosage form, the initial blend is dried until the measured exhaust temperature reaches at least 37° C. and milled by a mill equipped with a 3 mm screen at an impeller speed of 930 rpm ± 100 rpm to produce the first granulation.

[0017] In some variations of the method for preparing a combination oral dosage form, the first fraction of lactose monohydrate is fluidized in a fluidized bed granulator with an inlet air flow rate of 750 cfm-1050 cfm and a temperature of 37°C-43°C.

[0018] In some variations of the method for preparing a combination oral dosage form, the methanolic solution of the estradiol and the norethindrone acetate is sprayed at a rate of 550 g / min-650 g / min and a target atomization pressure of 5 bar.

[0019] In certain variations of the process for preparing the combination oral dosage form, the initial lactose blend is dried until the measured exhaust temperature reaches at least 46° C. and milled by a mill equipped with a 0.5 mm screen at an impeller speed of 2500 rpm ± 125 rpm.

[0020] In some variations of the method for preparing a combination oral dosage form, the initial lactose blend is further blended with the second fraction of lactose monohydrate and the second fraction of starch for 180±15 revolutions.

[0021] In some variations of the method for preparing a combined oral dosage form, the first granulation and the second granulation are blended at a ratio of about 55% w / w and about 45% w / w, respectively, for 70 to 170 revolutions. In some variations, the blend of the first granulation and the second granulation is blended with magnesium stearate to produce the final blend.

[0022] In some aspects, the combination solid oral dosage form is produced by any of the methods described above.

[0023] Other objects and advantages of the present disclosure will become apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Embodiments of the present disclosure are described more fully hereinafter with reference to the accompanying drawings, in which some, but not all, embodiments of the disclosure are shown. Like numerals refer to like elements throughout.

[0025] Figure 1 Bioequivalence between combination solid oral dosage forms and co-administration of the same combination of active ingredients according to FDA guidelines was shown.

[0026] Figure 2 Bioequivalence between combination solid oral dosage forms and co-administration of the same combination of active ingredients according to EMA guidelines is shown. DETAILED DESCRIPTION

[0027] As briefly described above, when used to treat hormone-sensitive diseases of the female reproductive system, such as uterine leiomyoma, endometriosis, adenomyosis, heavy menstrual bleeding, or pain associated with uterine leiomyoma, endometriosis, or adenomyosis, it is important for the patient to combine Compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug at each administration. Effectively treating the conditions described herein is challenging. Given the hormonal sensitivity of the conditions, treatment methods include seeking methods to suppress hormone levels, particularly estrogen and progesterone levels. However, suppression of hormone levels can lead to serious side effects, including loss of bone mineral density and vasomotor symptoms, such as hot flashes and night sweats. The challenge is to find a method to treat the symptoms associated with the condition while minimizing or avoiding such side effects. The therapeutic effectiveness of GnRH antagonists without the adverse effects of a low estrogen state requires that the patient consistently and correctly ingest Compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug, without accidentally taking them separately or in the wrong ratio. Therefore, in order to ensure such optimal treatment, it is beneficial to administer a single combination formulation of Compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug.

[0028] The present disclosure provides a combination solid oral dosage form that achieves bioequivalence to a formulation of compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug for each active agent (compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug) administered alone. For example, a combination solid oral dosage form containing compound 1 or its corresponding amount of a pharmaceutically acceptable salt, estradiol, and norethindrone acetate achieves bioequivalence to a separate formulation of compound 1 or its corresponding amount of a pharmaceutically acceptable salt, estradiol / norethindrone acetate. The administration of a combination solid oral dosage form rather than a separate dosage form generally improves patient compliance with the dosing regimen and, therefore, improves outcomes in terms of efficacy and safety (e.g., minimizing bone mineral density loss and other side effects over time).

[0029] In addition, the combination solid oral dosage forms described herein maintain the stability of each active ingredient over time, thereby providing an adequate shelf life. As will be appreciated by those skilled in the art, the stability of the active ingredients in a pharmaceutical formulation over time is important for ensuring that the patient receives the correct dose of each active ingredient and for minimizing the amount of degradants. As will be appreciated by those skilled in the art, when combining active agents, it is impossible to predict whether there will be interactions between the active agents when formulated together, or whether an excipient that is acceptable for use with one active ingredient will adversely affect the stability or bioavailability of another active ingredient.

[0030] As used herein, Compound 1 is N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea. Compound 1 is also known as relugolix. Compound 1 is represented by the structure shown below.

[0031]

[0032] Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising Compound 1 can be produced by the methods described in U.S. Patent No. 7,300,935, U.S. Patent Nos. 8,058,280, 9,346,822, 9,758,528, 10,150,778, 10,544,160, 10,464,945, and 8,735,401 and U.S. Publication No. 2020-0000730.

[0033] Throughout this disclosure, the amount of Compound 1 disclosed refers to the amount of Compound 1 free form present in the formulation. As used herein, the term "corresponding amount" refers to the amount of a pharmaceutically acceptable salt of Compound 1 required to obtain the amount of Compound 1 free form described in the formulation or method. One skilled in the art will understand how to calculate the "corresponding amount" of a salt of a compound, such as the corresponding amount of a pharmaceutically acceptable salt of Compound 1, while taking into account the molecular weight difference between the free form and salt form of the compound. For example, approximately 40 mg of Compound 1 would correspond to approximately 42.3 mg of the hydrochloride salt of Compound 1.

[0034] The salt of compound 1 may be a pharmaceutically acceptable acid addition salt. Such salts include, for example, salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and salts with organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hippuric acid, etc.).

[0035] Combining Compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount and a hormone replacement drug presents several challenges that, if not successfully overcome, will reduce the viability and effectiveness of the dosage form. For example, the formulation is required to include achieving the pharmacokinetics of Compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount and the hormone replacement drug, such that when Compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount and the hormone replacement drug are administered separately, the formulation is bioequivalent, and stability of each active ingredient over time is achieved.

[0036] There are several ways to achieve the combined solid oral dosage forms of the present disclosure, and they are the subject of the present disclosure. These dosage forms and methods for their preparation are discussed below.

[0037] Combination solid oral dosage form

[0038] To ensure content uniformity of the tablets, the excipient combination and formulation type need to be carefully selected. Compound 1 is sensitive to temperature and / or moisture, so if not properly formulated, the compound can degrade. Therefore, it is necessary to combine Compound 1 or its corresponding amount of pharmaceutically acceptable salt and hormone replacement drugs in the structure of the oral dosage form to maintain stability and content uniformity therein, while achieving the desired PK parameters discussed herein and ensuring sufficient stability for shelf life. On the one hand, a combined solid oral dosage form is provided, which includes approximately 18% w / w to 22% w / w of Compound 1 or its corresponding amount of pharmaceutically acceptable salt. In some embodiments, the combined solid oral dosage form includes approximately 0.3% w / w to 0.7% w / w of estradiol. In some embodiments, the combined solid oral dosage form includes approximately 0.1% w / w to 0.4% w / w of norethindrone acetate. In some embodiments, the combined solid oral dosage form includes approximately 24% w / w to 28% w / w of mannitol. In some embodiments, the combined solid oral dosage form comprises about 2% w / w to 6% w / w starch. In some embodiments, the combined solid oral dosage form comprises about 0.5% w / w to 3% w / w hydroxypropyl cellulose. In some embodiments, the combined solid oral dosage form comprises about 0.5% w / w to 3% w / w magnesium stearate. In some embodiments, the combined solid oral dosage form comprises about 38% w / w to 42% w / w lactose monohydrate. In some embodiments, the combined solid oral dosage form comprises about 1% w / w to 5% w / w film coating.

[0039] Excipients refer to components of the solid oral dosage form that are not Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, estradiol, or norethindrone acetate. The combined solid oral dosage form can be a tablet, and the tablet can be coated with a film coating.

[0040] The mass of each excipient will vary depending on several factors, including the amount of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and the hormone replacement drug, as well as the number and amount of other excipients. In some embodiments, the excipient will be present in an amount of about 70 wt % to 80 wt %. The excipients in the dosage forms described herein include mannitol; a starch selected from sodium starch glycolate and pregelatinized starch; hydroxypropyl cellulose; magnesium stearate; and lactose monohydrate.

[0041] The weight fraction or weight percentage refers to the ratio of a substance in a mixture to the total mass of the mixture. The weight fraction or weight percentage can be expressed, for example, as w / w, %w / w or wt%.

[0042] In some embodiments, the excipient used in the composition is mannitol. In some embodiments, mannitol is added to the first granulation containing Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, mannitol is present together with other excipients.

[0043] In certain embodiments, the excipient used in the composition is lactose. As used herein, lactose comprises anhydrous lactose and lactose hydrates such as lactose monohydrate. In certain embodiments, lactose is added to the second granulation containing estradiol and norethindrone acetate. In certain embodiments, lactose exists together with other excipients. In some dosage forms of the present disclosure, compared with those dosage forms containing mannitol or those dosage forms containing a mixture of lactose and mannitol, dosage forms containing lactose as the main excipient are more stable to heat and / or moisture, wherein mannitol is most of the excipient.

[0044] In some embodiments, the combined solid oral dosage form comprises about 18% w / w to 22% w / w of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, about 0.3% w / w to 0.7% w / w of estradiol, about 0.1 w / w to 0.4% w / w of norethindrone acetate, about 24 w / w to 28% w / w of mannitol, about 2 w / w to 6% w / w of starch, about 0.5 w / w to 3% w / w of hydroxypropyl cellulose, about 0.5 w / w to 3% w / w of magnesium stearate, about 38 w / w to 42% w / w of lactose monohydrate, and about 1 w / w to 5% w / w of film coating.

[0045] In some embodiments, the combined solid oral dosage form includes about 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the combined solid oral dosage form includes about 1 mg of estradiol. In some embodiments, the combined solid oral dosage form includes about 0.5 mg of norethindrone acetate. In some embodiments, the combined solid oral dosage form includes about 51 mg of mannitol. In some embodiments, the combined solid oral dosage form includes about 9 mg of sodium starch glycolate. In some embodiments, the combined solid oral dosage form includes about 3 mg of hydroxypropyl cellulose. In some embodiments, the combined solid oral dosage form includes about 2 mg of magnesium stearate. In some embodiments, the combined solid oral dosage form includes about 78 mg of lactose monohydrate. In some embodiments, the combined solid oral dosage form includes about 7 mg of film coating.

[0046] In some embodiments, the combined solid oral dosage form comprises about 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, about 1 mg of estradiol, about 0.5 mg of norethindrone acetate, about 51 mg of mannitol, about 9 mg of sodium starch glycolate, about 3 mg of hydroxypropylcellulose, about 2 mg of magnesium stearate, about 78 mg of lactose monohydrate, and about 7 mg of film coating.

[0047] In some embodiments, the combination solid oral dosage form comprises starch. In some embodiments, the starch is sodium starch glycolate. In some embodiments, the starch is pregelatinized starch. In some embodiments, the starch is a combination of sodium starch glycolate and pregelatinized starch.

[0048] In some embodiments, the solid oral dosage form comprises about 9 mg of sodium starch glycolate. In some embodiments, the solid oral dosage form comprises a combination of sodium starch glycolate and pregelatinized starch. In some embodiments, the combined solid oral dosage form comprises about 2% to 3% sodium starch glycolate and about 2% to 3% pregelatinized starch. In some embodiments, the combined solid oral dosage form comprises about 3-6 mg of sodium starch glycolate and about 3-6 mg of pregelatinized starch.

[0049] Film coatings can be used to help reduce physical degradation during packaging and storage, increase swallowability, mitigate any unpleasant taste associated with dosage form ingredients, and add color to the tablet. Film coating ingredients include, but are not limited to, one or more film formers, colorants, pigments, or antioxidants, taste masking agents, or flavoring agents.

[0050] An example of a film forming agent is hydroxypropyl methylcellulose (HPMC). In some embodiments, HPMC is hydroxypropyl methylcellulose 2910. In some embodiments, the film coating is present in an amount of less than 5 wt% of the final combined solid oral dosage form. In some embodiments, the film coating is present in an amount of 1 wt% to 5 wt% of the final combined solid oral dosage form. In some embodiments, the film coating is present in an amount of less than 10 mg of the final combined solid oral dosage form. In some embodiments, the film coating is present in an amount of 1-10 mg of the final combined solid oral dosage form. In some embodiments, the film coating is a film forming agent such as Opadry®. Yellow and other commercial film coating systems.

[0051] In some embodiments, the combination solid oral dosage form includes a degradant. In some embodiments, the degradant is a Compound 1 (relugolix) degradant. In some embodiments, the degradant is an estradiol degradant. In some embodiments, the degradant is a norethindrone acetate degradant.

[0052] In some embodiments, the combined solid oral dosage form includes a Compound 1 degradant. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of Compound 1 degradant present is no more than 0.5% w / w after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of Compound 1 degradant present is no more than 0.4% w / w after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months.

[0053] In some embodiments, the combined solid oral dosage form includes an estradiol degradant. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of estradiol degradant present after storage of the combined solid oral dosage form for 6 months at 60° C. and ambient relative humidity is no more than 1.4% w / w. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of estradiol degradant present after storage of the combined solid oral dosage form for 6 months at 60° C. and ambient relative humidity is no more than 1.3% w / w.

[0054] In some embodiments, the combined solid oral dosage form includes a norethindrone acetate degradant. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of norethindrone acetate degradant present after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months is no more than 1.4% w / w. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of norethindrone acetate degradant present after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months is no more than 1.2% w / w. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of norethindrone acetate degradant present after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months is no more than 1.0% w / w. In some embodiments, the combined solid oral dosage form is a combined solid oral dosage form wherein the amount of norethindrone acetate degradant present after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months is no more than 0.7% w / w.

[0055] As described above, in some dosage forms of the present disclosure, dosage forms containing lactose as a majority excipient are more stable to heat and / or moisture than similar formulations containing a majority of mannitol or formulations containing a mixture of lactose and mannitol, wherein mannitol is the majority excipient. For example, when comparing similar lactose and mannitol formulations of the present disclosure, those containing a majority of lactose are more stable at 60° C. and ambient relative humidity than those containing a majority of mannitol. Methods for testing the stability of pharmaceutical formulations under these conditions are well known in the art and are described in the Examples of the present disclosure.

[0056] It should be understood that for all embodiments discussed above, the combined solid oral dosage forms of the present disclosure may include various other organic or inorganic excipients. In addition, other pharmaceutical additives may be included in the combined solid oral dosage forms of the present disclosure. Such additives include, but are not limited to, one or more preservatives, sweeteners, and effervescent excipients.

[0057] Certain embodiments of the present disclosure provide compressed film-coated tablets comprising Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, estradiol, and NETA, and excipients. The film-coated tablet may comprise from about 5% to 80% of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the compressed tablet may comprise from about 20% to 50% of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, based on the total weight of the film-coated tablet. In some embodiments, the compressed tablet may comprise from about 0.3% to 0.7% of estradiol and from 0.1% to 0.4% of NETA or a salt thereof, based on the total weight of the film-coated tablet.

[0058] Examples of excipients include mannitol, sodium starch glycolate, pregelatinized starch, hydroxypropylcellulose, magnesium stearate, lactose monohydrate.

[0059] The compressed tablets of the present disclosure are film coated. The film coating concentration can vary up to about 10% to supplement the drug content. In some embodiments, the film coating concentration is about 1% to 5%.

[0060] Sweeteners can blur, minimize, or neutralize bitter or metallic tastes. Sweeteners include, but are not limited to, natural sweeteners such as sucrose and sorbitol, and artificial sweeteners include saccharin, aspartame, sucrose, and acesulfame-K.

[0061] In some embodiments, provided are combined solid oral dosage forms produced by the methods described herein.

[0062] Pharmacokinetics

[0063] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount is formulated to achieve effective plasma levels with compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount for treatment. In some embodiments, a 40 mg formulation administered before meals as a single combination solid oral dosage form of compound 1 or a pharmaceutically acceptable salt thereof and a hormone replacement drug provides a plasma concentration of about at least 7.56 ng·h / ml 1 hour after dose administration. In some embodiments, the formulation provides a plasma concentration of about 16.2 ng·h / ml 1 hour after dose administration. In some embodiments, the formulation provides a plasma concentration of about 28 ng·h / ml 1 hour after dose administration. In some embodiments, when co-administered alone, the formulations described herein achieve the same average drug exposure in subjects as compound 1 or a pharmaceutically acceptable salt thereof in a corresponding amount and a hormone replacement drug.

[0064] In some embodiments, Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof is formulated to achieve low variability in pharmacokinetic and pharmacodynamic effects in subjects. In some embodiments, a solid oral dosage form of a combination of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, taken orally before a meal, provides pharmacokinetic and pharmacodynamic effects that are less variable across subjects, but achieves the same average drug exposure in subjects as other embodiments described herein.

[0065] In some embodiments, administration of the combination solid oral dosage form is food independent and provides desired pharmacokinetic and pharmacodynamic effects that are subject to less variability in a subject than the combination alone.

[0066] The Biopharmaceutical Classification System (BCS) classifies drug substances based on their solubility and permeability. For example, a drug substance is considered highly soluble when the highest dose strength is soluble in ≤250 ml of water over a pH range of 1-7 compared to an intravenous reference dose, and is considered highly permeable when the extent of human absorption is determined to be greater than 90% of the administered dose. BCS 1 compounds are highly soluble and highly permeable, while BCS 4 compounds are poorly soluble and have poor permeability. For BCS 4 compounds, bioavailability and pharmacokinetic (PK) profiles or parameters such as mean maximum plasma concentration (C max ), the average time to reach maximum plasma concentration (T max ) and the mean area under the plasma concentration versus time curve (AUC) can be positively or negatively affected by the formulation, the type of excipients selected, and the specific excipients. The safety and efficacy of fixed combination oral products depend on these PK parameters being within appropriate ranges. Compound 1 is a BCS4 compound, and therefore, for fixed combination oral products containing Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, the type and specificity of the excipients must be carefully selected to achieve the target pharmacokinetic parameters.

[0067] Therefore, a combination solid oral dosage form having 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug should be formulated to achieve a dissolution rate in the gastrointestinal tract and a permeability that will not adversely affect the desired PK profile of the dosage form. Thus, as disclosed herein, the combination solid oral dosage form of the present disclosure can be designed with a selected combination of excipients, formulations, and dosage form structures to derive the desired PK profile.

[0068] For example, when the combined solid oral dosage form of the present disclosure has 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug and is orally administered in a fasting state, for example, at least 2 hours after a meal and not less than 30 minutes before the next meal, the mean maximum plasma concentration or C for Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof is max In the range of 5 ng / mL to 35 ng / mL. In some embodiments, the average C max In the range of 10 ng / mL to 30 ng / mL. In some embodiments, the average C max In the range of 15 ng / mL to 25 ng / mL.

[0069] Further, when the combined solid oral dosage form of the present disclosure has 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug and is orally administered in a fasting state, for example, at least 2 hours after a meal and not less than 30 minutes before the next meal, the mean concentration under the plasma versus time curve or AUC for Compound 1 from 0 to 24 hours is 0-24 In the range of 50 to 200 ng·h / ml, or in the range of 75 to 150 ng·h / ml.

[0070] Advantageously, the combined solid oral dosage form can be taken by the patient before or after a meal, which means that a meal has minimal effect on the mean plasma AUC relative to the fasted state. In some embodiments, the ratio of the mean plasma AUC in the fed state to the mean plasma AUC in the fasted state [mean plasma AUC (fed) / mean plasma AUC (fasted)] is 0.9 to 1.1, 0.95 to 1.05, or 1 for oral administration of a 40 mg "food-independent formulation" dosage form of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. In some embodiments, the mean plasma AUC ( 进食 ) / mean plasma AUC( 禁食 ) is 0.8 to 1.25.

[0071] In some embodiments, the PK profile of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof is not affected by food intake. In other embodiments, the average C values for fed and fasted administration of a 40 mg amount of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug in an immediate release formulation are 2. max The differences from the mean plasma AUC values are shown to be clinically meaningful in human studies based on the dose-response (exposure-response) and / or pharmacokinetic-pharmacodynamic relationships of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof.

[0072] The combined solid oral dosage form having 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug containing an amount of estradiol and NETA is specifically formulated to be bioequivalent to co-administration of a first oral dose of 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof having the formulation described in Example 2 and a second separate hormone replacement oral dosage form containing the same amount of estradiol and NETA when the dosage form is administered in the fasting state.

[0073] The combined solid oral dosage form having 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof showed a mean C 0.0 ... max 60% reduction and mean plasma AUC 0-inf A 45% decrease. Further, when the dosage form is administered in the fed state, a combination solid oral dosage form having 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug containing NETA is specifically formulated to be bioequivalent to co-administering a first oral dose of 40 mg of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof having the formulation described in Example 2 and a second separate hormone replacement oral dosage form containing NETA.

[0074] As described above, a combination solid oral dosage form having Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof may be advantageous in that the combination solid oral dosage form can be administered without regard to food intake. If the 90% confidence interval for the ratio of the overall geometric means between the fed treatment and the fasted treatment based on log-transformed data is contained within the AUC 0-inf (AUC when appropriate 0-t ) and average C max The absence of a food effect on bioavailability is determined to be within the equivalence limits of 80% to 125% for both drugs, or when the clinical significance of the food effect is demonstrated to be insignificant.

[0075] Thus, in some embodiments, a solid oral dosage form of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof is provided, wherein the solid oral dosage form has a 90% confidence interval for the ratio of the overall geometric means between the fed treatment and the fasted treatment based on log-transformed data, wherein the confidence interval is within the range of the AUC of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. 0-inf or AUC 0-t between 70% and 135% of the equivalent limit or between 80% and 125% of the equivalent limit.

[0076] In some embodiments, a solid oral immediate-release dosage form of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof is provided, wherein the solid oral dosage form has a 90% confidence interval for the ratio of the overall geometric means between the fed treatment and the fasted treatment based on logarithmic transformed data, wherein the confidence interval is within the range of the mean C of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. max 70% to 135% of the equivalent limits and 80% to 125% of the equivalent limits.

[0077] In some embodiments, a combination solid oral dosage form embodiment has a 40 mg amount of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug containing estradiol and NETA in an immediate-release formulation, wherein the combination solid oral dosage form embodiment has a 90% confidence interval for the ratio of the overall geometric means between the fed treatment and the fasted treatment based on log-transformed data, wherein the confidence interval is within the range of the AUC of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. 0-inf or AUC 0-t between 70% and 135% of the equivalent limit or between 80% and 125% of the equivalent limit.

[0078] In some embodiments, a combination solid oral dosage form embodiment having a 40 mg amount of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug containing estradiol alone or in combination with NETA in an immediate release formulation has a 90% confidence interval for the ratio of the overall geometric means between the fed treatment and the fasted treatment based on log-transformed data, the confidence interval containing the mean C of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof. max between 70% and 135% of the equivalent limit or between 80% and 125% of the equivalent limit.

[0079] In some embodiments, the average C of the fed and fasted administrations of the combined solid oral dosage form embodiments max The difference in mean AUC based on the dose-response (exposure-response) and / or pharmacokinetic-pharmacodynamic relationship of Compound 1 or its corresponding amount of a pharmaceutically acceptable salt has not been shown to be clinically meaningful in human studies, wherein the combined solid oral dosage form embodiment has a 40 mg amount of Compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug containing NETA in an immediate release formulation.

[0080] For example, for Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, the mean plasma T 1 / 2Between about 37 and about 42 hours, the combined solid oral dosage form has a 40 mg amount of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof and a hormone replacement drug in an immediate release formulation and is orally administered in the fasting state, i.e., at least 2 hours after a meal and not less than 30 minutes before the next meal.

[0081] Process for preparing a combined solid oral dosage form

[0082] In another aspect, a method for preparing a combined solid oral dosage form is provided, the method comprising:

[0083] a) preparing a first granulation comprising N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, the first fraction of the starch, the hydroxypropylcellulose and optionally the first fraction of magnesium stearate;

[0084] b) preparing a second granulation comprising estradiol, norethindrone acetate, a second fraction of starch, lactose monohydrate and optionally magnesium stearate, wherein when the first fraction of magnesium stearate is added in step (a), the second fraction of magnesium stearate is added in step (b); and

[0085] c) when magnesium stearate is not added in both steps (a) and (b), blending the first granulation and the second granulation and optionally magnesium stearate to form a final blend; and

[0086] d) coating the final blend with the film coating.

[0087] In some embodiments, a method for preparing a combined solid oral dosage form comprises:

[0088] a) spraying the aqueous solution of hydroxypropylcellulose onto a fluidized mixture of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, the first fraction of starch, and optionally the first fraction of magnesium stearate to form an initial blend, wherein the initial blend is dried and milled to produce a first granulation;

[0089] b) spraying the methanolic solution of the estradiol and the norethindrone acetate onto the fluidized mixture of the first fraction of lactose monohydrate to form an initial lactose blend, wherein the initial lactose blend is dried, milled and blended with the second fraction of lactose monohydrate, the second fraction of starch and optionally magnesium stearate, wherein when the first fraction of magnesium stearate is added in step (a), the second fraction of magnesium stearate is added in step (b) to produce a second granulation;

[0090] c) when magnesium stearate is not added in both steps (a) and (b), blending the first granulation and the second granulation and optionally magnesium stearate to produce a final blend, wherein the final blend is compressed; and

[0091] d) coating the final blend with an aqueous film coating suspension and drying the resulting coated final blend to form the combined solid oral dosage form.

[0092] In some embodiments, a method for preparing a combined solid oral dosage form comprises:

[0093] a) preparing a first granulation comprising one or more sub-batches, wherein each sub-batch comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, the first fraction of starch, and the hydroxypropyl cellulose;

[0094] b) preparing a second granulation comprising the estradiol, the norethindrone acetate, the second fraction of starch and the lactose monohydrate; and

[0095] c) blending the first granulation and the second granulation with the magnesium stearate to form a final blend; and

[0096] d) coating the final blend with the film coating.

[0097] In some embodiments, a method for preparing a combined solid oral dosage form comprises:

[0098] a) spraying the aqueous solution of hydroxypropylcellulose onto a fluidized mixture of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, mannitol, and the first fraction of starch to form an initial blend, wherein the initial blend is dried and milled to produce subbatches; and wherein one or more subbatches are blended to produce the first granulation;

[0099] b) spraying the methanolic solution of the estradiol and the norethindrone acetate onto the fluidized mixture of the first fraction of lactose monohydrate to form an initial lactose blend, wherein the initial lactose blend is dried, milled and blended with the second fraction of lactose monohydrate and the second fraction of starch to produce the second granulation;

[0100] c) blending the first granulation with the second granulation and the magnesium stearate to produce the final blend, wherein the final blend is compressed; and

[0101] d) coating the final blend with an aqueous film coating suspension and drying the resulting coated final blend to form the combined solid oral dosage form.

[0102] In some embodiments, the first granulation and the second granulation are blended with the magnesium stearate to form a final blend. In some embodiments, the final blend is coated with a film coating, for example, after the final blend is compressed and dried.

[0103] In some embodiments, the first granulation comprises one or more sub-batches, wherein each sub-batch comprises Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, mannitol, a first fraction of starch, and hydroxypropyl cellulose. In some embodiments of the foregoing embodiments, the second granulation comprises estradiol, norethindrone acetate, a second fraction of starch, and lactose.

[0104] In some embodiments, a first granulation is produced by spraying an aqueous solution of hydroxypropyl cellulose onto a fluidized mixture of a first fraction of Compound 1 or a corresponding amount of a pharmaceutically acceptable salt thereof, mannitol, and starch to form an initial blend, wherein the initial blend is dried and ground to produce subbatches. In some embodiments, one or more subbatches are blended to produce the first granulation. In some embodiments, the first granulation comprises only one subbatch. In some embodiments, the first granulation comprises two subbatches.

[0105] In some embodiments, the second granulation is produced by spraying a methanolic solution of estradiol and norethindrone acetate onto a fluidized mixture of a first fraction of lactose monohydrate to form an initial lactose blend, wherein the initial lactose blend is dried, milled, and blended with a second fraction of lactose monohydrate and a second fraction of starch.

[0106] In some embodiments, the first granulation and the second granulation are blended with magnesium stearate to produce a final blend. In some embodiments, the final blend is compressed. In some embodiments, the final blend is coated with an aqueous film coating suspension, as known to those skilled in the art and described herein. In some embodiments, the coated final blend is dried to form a combined solid oral dosage form.

[0107] In some embodiments, the second granulation does not include mannitol.

[0108] In some embodiments, N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, and the first fraction of the starch are fluidized. In some embodiments of the above embodiments, N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, and the first fraction of the starch are fluidized in a fluidized bed granulator. In some of the aforementioned embodiments, N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, and the first fraction of the starch are fluidized in a fluidized bed granulator with an inlet air flow rate of 400-500 cfm and a temperature of 75°C-80°C.

[0109] In some embodiments, the aqueous solution of hydroxypropyl cellulose is sprayed. In some of the above embodiments, the aqueous solution of hydroxypropyl cellulose is sprayed at a rate of 250 g / min-350 g / min and a target atomization pressure of 2.5 bar-4.5 bar.

[0110] In some embodiments, the initial blend is dried and ground to produce a first granulation. In some embodiments of the foregoing embodiments, the initial blend is dried until the measured exhaust gas temperature reaches at least 37° C. and ground through a mill equipped with a 3 mm screen at an impeller speed of 930 rpm ± 100 rpm to produce the first granulation.

[0111] In some embodiments, the first fraction of lactose monohydrate is fluidized. In some of the above embodiments, the first fraction of lactose monohydrate is fluidized in a fluidized bed granulator. In some of the above embodiments, the first fraction of lactose monohydrate is fluidized in a fluidized bed granulator with an inlet air flow rate of 750 cfm-1050 cfm and a temperature of 37° C.-43° C.

[0112] In some embodiments, the methanolic solution of estradiol and norethindrone acetate is sprayed. In some of the above embodiments, the methanolic solution of estradiol and norethindrone acetate is sprayed at a rate of 550 g / min-650 g / min and a target atomization pressure of 5 bar.

[0113] In some embodiments, the initial lactose blend is dried and ground. In some of the above embodiments, the initial lactose blend is dried until the measured exhaust temperature reaches at least 46° C. and ground through a mill equipped with a 0.5 mm screen at an impeller speed of 2500 rpm ± 125 rpm.

[0114] In some embodiments, the initial lactose blend is further blended with the second fraction of lactose monohydrate and the second fraction of starch. In some of the foregoing embodiments, the initial lactose blend is further blended with the second fraction of lactose monohydrate and the second fraction of starch for 180±15 revolutions.

[0115] In some embodiments, the first granulation and the second granulation are blended. In some embodiments of the above embodiments, the first granulation and the second granulation are blended at a ratio of about 55% w / w and about 45% w / w, respectively, for 70 to 170 revolutions.

[0116] Granulation can be wet granulation. Wet granulation can be performed, for example, using a granulator mixer, such as a Fielder 10L high shear granulator mixer; low shear, drum or pan granulators, and fluidized bed granulators. Granulation can also be achieved by dry granulation (without fluid) using a roller compaction process. One technique for performing the granulation and drying steps according to the present disclosure is to utilize a fluidized bed granulator / dryer, such as a Glatt GPCG 2. The sizing (e.g., grinding) step can be performed, for example, using a grinder such as a Comil or Fitz grinder. The blending step can be performed in a V-blender or a box blender. The compression step to form the tablet can be performed, for example, using various presses, including a beta press, a single-station F-press, or a 6-station Korsh. Film coating can be performed, for example, in a Glatt Column coater or a smaller Hi-coater (9" x 12" pan).

[0117] For all of the above embodiments, compound 1 or its corresponding amount of pharmaceutically acceptable salt can be purposefully controlled during the crystallization step during its synthesis to produce smaller particles of compound 1. Such particles can improve the solubility and dissolution rate of compound 1 or its corresponding amount of pharmaceutically acceptable salt in the combined solid oral dosage form. Along these same routes, compound 1 or its corresponding amount of pharmaceutically acceptable salt can also be nano-milled or micronized to increase the surface area. Therefore, any of these three methods can be used alone or in combination with any of the embodiments discussed above to achieve the desired PK curve. The crystalline form of compound 1 or its corresponding amount of pharmaceutically acceptable salt is described in U.S. Application No. 62 / 913,560, U.S. Application No. 62 / 913,606 and U.S. Patent No. 10,464,945, which are incorporated herein by reference in their entirety.

[0118] How to use

[0119] The present disclosure provides a method of treating a condition comprising administering an effective amount of a combined solid oral dosage form described herein or a pharmaceutical composition comprising a combined solid oral dosage form, thereby treating the condition in a subject in need thereof.

[0120] In some embodiments of the method and purposes of the present disclosure, disease is hormone-dependent symptom.The hormone-dependent symptom can include sex hormone-dependent cancer (for example, uterine cancer, breast cancer and ovarian cancer), bone metastasis of sex hormone-dependent cancer, uterine fibroids (uterine leiomyoma), adenomyosis, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovarian syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis, heavy menstrual bleeding and the symptom related to these symptom.Such symptoms can include anemia, irregular menstrual cycle, spotting, inflammation, pain, fatigue, urinary tract obstruction, frequent urination, incontinence, constipation, anxiety, sleep disorder, quality of life decline, daily activities are difficult, female sexual dysfunction and depression.In some embodiments of the method and purposes of the present disclosure, hormone-dependent symptom is uterine cancer, breast cancer or ovarian cancer. Other conditions that Compound 1 can be used to treat are described in U.S. Patent No. 7,300,935, U.S. Patent No. 8,058,280, U.S. Patent No. 8,735,401, U.S. Patent No. 9,346,822, WO2018060501, and WO2018060463, which are incorporated herein by reference in their entireties. Phase 3 clinical trial results for Compound 1 can be found at https: / / investors.myovant.com / news-releases / news-release-details / myovant-sciences-announces-88-one-year-response-rate-positive / and https: / / investors.myovant.com / news-releases / news-release-details / myovant-sciences-announces-positive-results-phase-3-spirit-2 / .

[0121] In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is breast cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is ovarian cancer. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is pain associated with endometriosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is adenomyosis. In some embodiments of the methods and uses of the present disclosure, the hormone-dependent condition is heavy menstrual bleeding.

[0122] A "patient" or "subject" is a mammal. Examples of mammals include, but are not limited to, any member of the class Mammalia, including humans; non-human primates such as chimpanzees, monkeys, baboons, and rhesus macaques; cattle, horses, sheep, goats, and pigs; rabbits, dogs, and cats; and rodents such as rats, mice, and guinea pigs. In some embodiments, the patient or subject is a human.

[0123] When used in conjunction with one or more crystalline forms or pharmaceutical compositions of the present disclosure, the term "effective amount" or "therapeutically effective amount" can refer to an amount of the one or more crystalline forms or pharmaceutical compositions sufficient to provide a desired biological result. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses can be the amount of a pharmaceutical composition comprising one or more combined solid oral dosage forms as disclosed herein required to provide a clinically significant decrease in a condition. An appropriate "effective amount" in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0124] As used herein, the terms "treat" or "treatment" or their cognates are intended to indicate a delay in the development of a condition; and / or a reduction in the severity of such symptoms that will or are expected to occur. Thus, these terms can encompass improving existing symptoms of a condition; preventing additional symptoms; improving or preventing the underlying cause of a symptom; inhibiting a condition, e.g., halting its development; relieving a condition; causing regression of a condition; alleviating symptoms caused by a condition; or stopping or alleviating symptoms of a condition.

[0125] The terms "administered," "administration," or "administering," as used in this disclosure, may refer to administering one or more combined solid oral dosage forms or pharmaceutical compositions of the present disclosure directly to a subject.

[0126] The present disclosure provides a method of treating a condition comprising administering an effective amount of a combined solid oral dosage form, thereby treating the condition in a subject in need thereof.

[0127] The present disclosure provides a method for treating a condition, comprising administering an effective amount of one or more pharmaceutical compositions of the present disclosure, thereby treating the condition in a subject in need thereof. In some embodiments, the present disclosure provides a method for treating a condition, comprising administering an effective amount of one or more pharmaceutical compositions comprising one or more combined solid oral dosage forms disclosed herein, thereby treating the condition in a subject in need thereof. In some embodiments, the condition is a hormone-dependent condition.

[0128] The present disclosure provides one or more combined solid oral dosage forms of the present disclosure or one or more pharmaceutical compositions of the present disclosure for treating a condition in a subject in need thereof. In some embodiments, the one or more pharmaceutical compositions of the present disclosure include one or more combined solid oral dosage forms disclosed herein. In some embodiments, the condition is a hormone-dependent condition.

[0129] The present disclosure provides one or more combined solid oral dosage forms of the present disclosure for use in treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides use of a combined solid oral dosage form for treating a condition in a subject in need thereof. In some embodiments, the condition is a hormone-dependent condition.

[0130] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure for treating a condition in a subject in need thereof. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions for treating a condition in a subject in need thereof, the one or more pharmaceutical compositions comprising one or more combined solid oral dosage forms disclosed herein. In some embodiments, the condition is a hormone-dependent condition.

[0131] The present disclosure provides the use of one or more combined solid oral dosage forms of the present disclosure in the manufacture of a medicament for treating a condition. In some embodiments, the present disclosure provides the use of combined solid oral dosage forms in the manufacture of a medicament for treating a condition. In some embodiments, the condition is a hormone-dependent condition.

[0132] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure in the manufacture of a medicament for treating a condition. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions in the manufacture of a medicament for treating a condition, wherein the one or more pharmaceutical compositions include one or more combined solid oral dosage forms disclosed herein. In some embodiments, the condition is a hormone-dependent condition. In some embodiments, the present disclosure provides the use of a pharmaceutical composition in the manufacture of a medicament for treating a condition, wherein the pharmaceutical composition includes one or more combined solid oral dosage forms disclosed herein. In some embodiments, the condition is a hormone-dependent condition.

[0133] The present disclosure provides the use of one or more combined solid oral dosage forms of the present disclosure as a medicament for treating a condition. In some embodiments, the present disclosure provides the use of combined solid oral dosage forms as a medicament for treating a condition. In some embodiments, the condition is a hormone-dependent condition.

[0134] The present disclosure provides the use of one or more pharmaceutical compositions of the present disclosure as a medicine for treating a condition. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions as a medicine for treating a condition, wherein the one or more pharmaceutical compositions include one or more combined solid oral dosage forms disclosed herein. In some embodiments, the present disclosure provides the use of one or more pharmaceutical compositions as a medicine for treating a condition, wherein the one or more pharmaceutical compositions include a combined solid oral dosage form. In some embodiments, the condition is a hormone-dependent condition.

[0135] In some embodiments of the methods and uses of the present disclosure, only one pharmaceutical composition of the present disclosure is used in the method or use. In some embodiments of the methods and uses of the present disclosure, only one combined solid oral dosage form of the present disclosure is used in the method or use.

[0136] For the therapeutic uses mentioned herein, the dosage administered will of course vary with the one or more combined solid oral dosage forms or pharmaceutical compositions used, mode of administration, desired treatment, and the conditions indicated. For example, if one or more combined solid oral dosage forms or pharmaceutical compositions are administered orally, the daily dose of the one or more combined solid oral dosage forms of the present disclosure can be in the range of about 1.0 milligrams per kilogram of body weight (mg / kg) to about 10 milligrams per kilogram of body weight (mg / kg).

[0137] In some embodiments of the combined solid oral dosage form, Compound 1 or its corresponding amount of a pharmaceutically acceptable salt and a hormone replacement drug are administered orally once a day (but twice a day is possible) and formulated with pharmaceutically acceptable excipients such as those described above. The administration method is a treatment period of at least 14 days, at least 28 days, or at least 48 weeks to obtain a chronic therapy. Further, it is envisioned that the combined solid oral dosage form may include a sustained-release profile component.

[0138] This document describes embodiments of the present disclosure, wherein some, but not all, embodiments of the present disclosure are discussed. In fact, the present disclosure can be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are provided to make the present disclosure clearly meet applicable legal requirements. Throughout the text, like numbers refer to like elements.

[0139] Examples

[0140] Example I-1. A combined solid oral dosage form comprising:

[0141] about 18% w / w to 22% w / w of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof;

[0142] about 0.3% w / w to 0.7% w / w estradiol;

[0143] about 0.1% w / w to 0.4% w / w norethindrone acetate;

[0144] about 24% w / w to 28% w / w mannitol;

[0145] about 2% w / w to 6% w / w starch selected from the group consisting of sodium starch glycolate, pregelatinized starch, and combinations of the foregoing;

[0146] about 0.5% w / w to 3% w / w hydroxypropyl cellulose;

[0147] about 0.5% w / w to 3% w / w magnesium stearate;

[0148] about 38% w / w to 42% w / w lactose monohydrate; and

[0149] Approximately 1% w / w and 5% w / w film coating.

[0150] Example I-2. A combined solid oral dosage form according to Example I-1, comprising:

[0151] About 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof;

[0152] About 1mg of estradiol;

[0153] About 0.5 mg of norethindrone acetate;

[0154] About 51mg mannitol;

[0155] About 9 mg sodium starch glycolate;

[0156] About 3 mg of hydroxypropyl cellulose;

[0157] About 2 mg of magnesium stearate;

[0158] approximately 78 mg lactose monohydrate; and

[0159] Approximately 7 mg film-coated.

[0160] Embodiment I-3. The combined solid oral dosage form according to any one of embodiments I-1 to I-2, wherein the starch is sodium starch glycolate.

[0161] Embodiment 1-4. The combined solid oral dosage form of embodiment 1-3, wherein the combined solid oral dosage form comprises about 9 mg of sodium starch glycolate.

[0162] Embodiment I-5. The combined solid oral dosage form according to any one of embodiments I-1 to I-2, wherein the starch is pregelatinized starch.

[0163] Embodiment I-6. The combined solid oral dosage form according to any one of embodiments I-1 to I-2, wherein the starch is a combination of sodium starch glycolate and pregelatinized starch.

[0164] Example 1-7. A combination of a solid oral dosage form according to Example 1-6, comprising about 2% to 3% sodium starch glycolate and about 2% to 3% pregelatinized starch.

[0165] Embodiment I-8. The combined solid oral dosage form of any one of embodiments I-1 to I-7, wherein the amount of relugolix degradants present after storage of the combined solid oral dosage form for 6 months at 60°C and ambient relative humidity does not exceed 0.5% w / w.

[0166] Embodiment I-9. The combined solid oral dosage form of any one of embodiments I-1 to I-8, wherein the amount of estradiol degradants present after storage of the combined solid oral dosage form for 6 months at 60°C and ambient relative humidity does not exceed 1.4% w / w.

[0167] Embodiment I-10. The combined solid oral dosage form of any one of embodiments I-1 to I-9, wherein the amount of norethindrone acetate degradants present after storage of the combined solid oral dosage form for 6 months at 60°C and ambient relative humidity does not exceed 1.4% w / w.

[0168] Embodiment I-11. A method for preparing a combined solid oral dosage form according to any one of embodiments I-1 to I-10, comprising:

[0169] a) preparing a first granulation comprising one or more sub-batches, wherein each sub-batch comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, the first fraction of starch, and the hydroxypropyl cellulose;

[0170] b) preparing a second granulation comprising the estradiol, the norethindrone acetate, the second fraction of starch and the lactose monohydrate;

[0171] c) blending the first granulation and the second granulation with the magnesium stearate to form a final blend; and

[0172] d) coating the final blend with the film coating.

[0173] Embodiment I-12. The method according to embodiment I-11, comprising:

[0174] a) spraying the aqueous solution of hydroxypropylcellulose onto a fluidized mixture of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, mannitol, and the first fraction of starch to form an initial blend, wherein the initial blend is dried and milled to produce subbatches; and wherein one or more subbatches are blended to produce the first granulation;

[0175] b) spraying the methanolic solution of the estradiol and the norethindrone acetate onto the fluidized mixture of the first fraction of lactose monohydrate to form an initial lactose blend, wherein the initial lactose blend is dried, milled and blended with the second fraction of lactose monohydrate and the second fraction of starch to produce the second granulation;

[0176] c) blending the first granulation with the second granulation and the magnesium stearate to produce the final blend, wherein the final blend is compressed; and

[0177] d) coating the final blend with an aqueous film coating suspension and drying the resulting coated final blend to form the combined solid oral dosage form.

[0178] Embodiment I-13. The method of any one of embodiments I-11 or I-12, wherein the second granulation does not include mannitol.

[0179] Embodiment I-14. The method according to any one of embodiments I-10 to I-13, wherein the first granulation comprises two sub-batches.

[0180] Embodiment I-15. A method according to any one of embodiments I-11 to I-14, wherein the N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol and the first fraction of the starch are fluidized in a fluidized bed granulator with an inlet air flow rate of 400 cfm-500 cfm and a temperature of 75°C-80°C.

[0181] Embodiment I-16. The method of any one of embodiments I-12 to I-15, wherein the aqueous solution of hydroxypropyl cellulose is sprayed at a rate of 250 g / min-350 g / min and a target atomization pressure of 2.5 bar-4.5 bar.

[0182] Embodiment I-17. The method of any one of embodiments I-12 to I-16, wherein the initial blend is dried until the measured exhaust temperature reaches at least 37°C and ground through a mill equipped with a 3 mm screen at an impeller speed of 930 rpm ± 100 rpm to produce the first granulation.

[0183] Embodiment 1-18. The method of any one of embodiments 1-12 to 1-17, wherein the first fraction of lactose monohydrate is fluidized in a fluidized bed granulator with an inlet air flow of 750 cfm-1050 cfm and a temperature of 37°C-43°C.

[0184] Embodiment I-19. The method of any one of embodiments I-12 to I-18, wherein the methanolic solution of the estradiol and the norethindrone acetate is sprayed at a rate of 550 g / min-650 g / min and a target atomization pressure of 5 bar.

[0185] Embodiment I-20. The method of any one of embodiments I-12 to I-19, wherein the initial lactose blend is dried until the measured exhaust temperature reaches at least 46°C and ground through a mill equipped with a 0.5 mm screen at an impeller speed of 2500 rpm ± 125 rpm.

[0186] Embodiment 1-21. The method of embodiment 1-20, wherein the initial lactose blend is further blended with the second fraction of lactose monohydrate and the second fraction of starch for 180±15 revolutions.

[0187] Embodiment I-22. The method of any one of embodiments I-11 to I-21, wherein the first granulation and the second granulation are blended at a ratio of about 55% w / w and about 45% w / w, respectively, for 70 to 170 revolutions.

[0188] Embodiment 1-22a. The method of embodiment 22, wherein the blend of the first granulation and the second granulation is blended with magnesium stearate to produce the final blend.

[0189] Embodiment 1-23. A combined solid oral dosage form produced by the method according to any one of embodiments 1-11 to 1-22a.

[0190] Embodiment 1-24. A method of treating a condition in a subject in need thereof, comprising administering to the subject a combined solid oral dosage form according to any one of Embodiments 1-1 to 1-10 or 1-23.

[0191] Embodiment 1-25. The method of embodiment 1-24, wherein the disorder is a hormone-dependent condition.

[0192] Example 1-26. A method according to Example 1-25, wherein the condition is a hormone-dependent condition, which is a sex hormone-dependent cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, uterine fibroids, adenomyosis, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0193] Embodiment 1-27. The method of any one of embodiments 1-25 to 1-26, wherein the hormone-dependent condition is uterine cancer, breast cancer, or ovarian cancer.

[0194] Embodiment 1-28. The method of any one of embodiments 1-25 to 1-27, wherein the hormone-dependent condition is uterine cancer.

[0195] Embodiment 1-29. The method of any one of embodiments 1-25 to 1-27, wherein the hormone-dependent condition is breast cancer.

[0196] Embodiment 1-30. The method of any one of embodiments 1-25 to 1-27, wherein the hormone-dependent condition is ovarian cancer.

[0197] Embodiment 1-31. The method of any one of embodiments 1-25 to 1-26, wherein the hormone-dependent condition is uterine leiomyoma.

[0198] Embodiment 1-32. The method of embodiment 1-25, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0199] Embodiment 1-33. The method of embodiment 1-25, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.

[0200] Embodiment 1-34. The method of any one of embodiments 1-25 to 1-26, wherein the hormone-dependent condition is endometriosis.

[0201] Embodiment 1-35. The method of any one of embodiments 1-25 to 1-26, wherein the hormone-dependent condition is adenomyosis.

[0202] Embodiment 1-36. The method of any one of embodiments 1-25 to 1-26, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0203] Embodiment 1-37. Use of a combined solid oral dosage form according to any one of embodiments 1-1 to 1-10 or 1-23 for treating a condition in a subject in need thereof.

[0204] Embodiment 1-38. The combined solid oral dosage form for use according to embodiment 1-37, wherein the disorder is a hormone-dependent condition.

[0205] Embodiment 1-39. A combined solid oral dosage form for use according to embodiment 1-38, wherein the condition is a hormone-dependent condition is sex hormone-dependent cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, uterine fibroids, adenomyosis, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0206] Embodiment 1-40. The combined solid oral dosage form for use according to any one of Embodiments 1-38 to 1-39, wherein the hormone-dependent condition is uterine cancer, breast cancer, or ovarian cancer.

[0207] Embodiment 1-41. The combined solid oral dosage form for use of any one of Embodiments 1-37 to 1-39, wherein the hormone-dependent condition is uterine cancer.

[0208] Embodiment 1-42. The combined solid oral dosage form for use of any one of Embodiments 1-38 to 1-40, wherein the hormone-dependent condition is breast cancer.

[0209] Embodiment 1-43. The combined solid oral dosage form for use according to any one of embodiments 1-38 to 1-40, wherein the hormone-dependent condition is ovarian cancer.

[0210] Embodiment 1-44. The combined solid oral dosage form for use according to any one of embodiments 1-38 to 1-39, wherein the hormone-dependent condition is uterine leiomyoma.

[0211] Embodiment 1-45. The combined solid oral dosage form for use according to embodiment 1-38, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0212] Embodiment 1-46. The combined solid oral dosage form for use according to embodiment 1-38, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.

[0213] Embodiment 1-47. The combined solid oral dosage form for use of any one of Embodiments 1-38 to 1-39, wherein the hormone-dependent condition is endometriosis.

[0214] Embodiment 1-48. The combined solid oral dosage form for use of any one of Embodiments 1-38 to 1-39, wherein the hormone-dependent condition is adenomyosis.

[0215] Embodiment 1-49. The combined solid oral dosage form for use according to any one of embodiments 1-38 to 1-39, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0216] Embodiment I-50. Use of a combined solid oral dosage form according to any one of embodiments I-1 to I-10 or I-23 in the manufacture of a medicament for treating a condition.

[0217] Embodiment I-51. Use of a combined solid oral dosage form according to any one of embodiments I-1 to I-10 or I-23 as a medicament for treating a disorder.

[0218] Embodiment 1-52. The use according to any one of embodiments 1-50 to 1-51, wherein the disorder is a hormone-dependent condition.

[0219] Embodiment 1-53. The use according to embodiment 1-53, wherein the condition is a hormone-dependent condition, which is a sex hormone-dependent cancer, uterine cancer, breast cancer, ovarian cancer, bone metastasis of sex hormone-dependent cancer, uterine fibroids, adenomyosis, uterine fibroids, precocious puberty, menopause, premenstrual syndrome, dysmenorrhea, multifocal ovary syndrome, polycystic ovary syndrome, acne, infertility, hot flashes, endometriosis, adenomyosis or heavy menstrual bleeding.

[0220] Embodiment 1-54. The use according to any one of embodiments 1-52 to 1-53, wherein the hormone-dependent condition is uterine cancer, breast cancer, or ovarian cancer.

[0221] Embodiment 1-55. The use of any one of embodiments 1-52 to 1-54, wherein the hormone-dependent condition is uterine cancer.

[0222] Embodiment 1-56. The use of any one of embodiments 1-52 to 1-54, wherein the hormone-dependent condition is breast cancer.

[0223] Embodiment 1-57. The use of any one of embodiments 1-52 to 1-54, wherein the hormone-dependent condition is ovarian cancer.

[0224] Embodiment 1-58. The use according to any one of embodiments 1-52 to 1-53, wherein the hormone-dependent condition is uterine leiomyoma.

[0225] Embodiment 1-59. The use according to embodiment 1-52, wherein the hormone-dependent condition is heavy menstrual bleeding associated with uterine leiomyoma.

[0226] Embodiment 1-60. The use according to embodiment 1-52, wherein the hormone-dependent condition is pain or other symptoms associated with uterine leiomyoma.

[0227] Embodiment 1-61. The use of any one of embodiments 1-52 to 1-53, wherein the hormone-dependent condition is endometriosis.

[0228] Embodiment 1-62. The use of any one of embodiments 1-52 to 1-53, wherein the hormone-dependent condition is adenomyosis.

[0229] Embodiment 1-63. The use of any one of embodiments 1-52 to 1-53, wherein the hormone-dependent condition is heavy menstrual bleeding.

[0230] The following non-limiting examples are provided to illustrate aspects of the present disclosure.

[0231] Examples

[0232] Example 1

[0233] Tablets of compound 1, estradiol, and norethindrone acetate were prepared using a wet granulation process that included fluidized bed granulation, milling, blending, and lubrication, followed by tableting and film coating. The final blend for compressed tablets consisted of two fluidized bed granulations (FBG): one containing compound 1 (first granulation) and the other containing E2 and NETA (second granulation), as well as excipients.

[0234] The first granulation (Compound 1 granulation blend; Relugolix granulation blend) was prepared according to steps R1-R4 in Table 1. A degassed hydroxypropyl cellulose (HPC) binder solution was prepared according to step R1. Compound 1, mannitol, and sodium starch glycolate were then fluidized in a fluidized bed granulator and sprayed with the HPC solution, and the resulting Compound 1 granules were then dried. The granules were then ground using a rotary impeller sifter with a 3 mm screen (step R3) to produce a sub-batch. A second sub-batch of Compound 1 granules was prepared in the same manner, and the two sub-batches were then blended in a diffusion blender (step R4).

[0235] Table 1: Description of the Compound 1 (Relugolix) granulation, milling and blending process used to produce the first granulation

[0236]

[0237] The second granulation blend (estradiol / norethindrone acetate granulation blend) was prepared according to steps E1-E4 in Table 2. First, estradiol and norethindrone acetate were dissolved in methanol (step E1). Lactose monohydrate was loaded into a fluidized bed granulator. The powder bed was fluidized in the fluidized bed granulator, and the estradiol / norethindrone acetate solution from step E1 was sprayed onto the powder, and the resulting E2 / NETA granules were dried until the loss on drying (LOD) was <2% w / w. The granules were then ground using a sifter with a 0.5 mm screen (step E3) before being blended with lactose monohydrate and sodium starch glycolate in a diffusion blender (step E4).

[0238] Table 2: Description of the estradiol / norethindrone acetate granulation, milling and blending process used to produce the second granulation

[0239]

[0240] The final combined solid oral dosage form was prepared and packaged according to steps C1-C5 of Table 3. The first granulation (step R4) and the second granulation blend (step E4) were combined in a diffusion blender (step C1). Magnesium stearate was then added to the mixture at 1% w / w and blended for lubrication (step C2) to produce the final blend. This final blend was then compressed in a tablet press (step C3). The tablets were preheated in a perforated coater and a suspension of Opadry II yellow in purified water was sprayed onto the tablets until a tablet weight gain of 4% (± 1%) w / w was achieved, at which point the tablets were dried (step C4) to produce the final combined solid oral dosage form. The coated tablets were then packaged with filler and sealed using an induction seal.

[0241] Table 3: Description of the Compound 1 / E2 / NETA blending, lubricated compression, film coating, and packaging processes used to produce the combined solid oral dosage form.

[0242]

[0243]

[0244] Table 4 shows the formulation of a Compound 1 / E2 / NETA combination solid oral dosage tablet prepared according to the procedures of Example 1, with each component listed in mg / tablet. The final tablet contained approximately 100 mg of Compound 1 (first) granulation (steps R1-R4), approximately 85 mg of E2 / NETA (second) granulation (steps E1-E4), and approximately 7.4 mg of film coating (step C4).

[0245] Table 4: Formulation composition of Compound 1 / E2 / NETA combination solid oral dosage tablets

[0246]

[0247] * The % w / w in this table refers to the weight fraction of the "total core", i.e. the formulation before film coating. The total % w / w of the film-coated tablets is therefore higher than 100%.

[0248] Alternative formulations containing varying amounts of excipients in the E2 / NETA (second) granulation mixture, including but not limited to lactose and microcrystalline cellulose (MCC, pH 101 or pH 102), can be prepared by the method of Example 1 or a method analogous to that of Example 1. These formulations (Examples 2-10) contain the listed components in amounts expressed in mg per final tablet.

[0249] Alternative formulations containing varying amounts of excipients in the E2 / NETA (second) granulation mixture, including but not limited to mannitol and microcrystalline cellulose (MCC, pH 101 or pH 102), can be prepared by the method of Example 1 or a method analogous to that of Example 1. These formulations (Examples 11-19) contain the listed components in amounts expressed in mg per final tablet.

[0250] The alternative formulations shown in Examples 2-19 may contain additional excipients compared to those included in the method of Example 1.

[0251] Example 2

[0252] An alternative tablet formulation can be prepared by methods similar to Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), and hydroxypropylcellulose (3 mg / tablet).

[0253] E2 / NETA granulation included E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (78.4 mg / tablet), and pregelatinized starch (4.25 mg / tablet).

[0254] Magnesium stearate (1.85 mg / tablet) was added to the final blend.

[0255] Example 3

[0256] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0257] The E2 / NETA granulation included E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (78.4 mg / tablet), pregelatinized starch (4.25 mg / tablet), and magnesium stearate (0.85 mg / tablet).

[0258] Example 4

[0259] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0260] The E2 / NETA granulation included E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (78.4 mg / tablet), pregelatinized starch (4.25 mg / tablet), and magnesium stearate (0.85 mg / tablet).

[0261] Example 5

[0262] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0263] The E2 / NETA granulation included E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (78.4 mg / tablet), pregelatinized starch (4.25 mg / tablet), and magnesium stearate (0.85 mg / tablet).

[0264] Example 6

[0265] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0266] The E2 / NETA granulation included E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (78.4 mg / tablet), pregelatinized starch (4.25 mg / tablet), and magnesium stearate (0.85 mg / tablet).

[0267] Example 7

[0268] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0269] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (52.9 mg / tablet), MCC pH 102 (25.5 mg / tablet), pregelatinized starch (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0270] Example 8

[0271] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0272] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (69.9 mg / tablet), MCC pH 102 (8.5 mg / tablet), pregelatinized starch (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0273] Example 9

[0274] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0275] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (69.9 mg / tablet), MCC pH 101 (8.5 mg / tablet), pregelatinized starch (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0276] Example 10

[0277] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0278] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (69.9 mg / tablet), MCC pH 101 (8.5 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0279] Example 11

[0280] An alternative tablet formulation can be prepared by methods similar to Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), and hydroxypropylcellulose (3 mg / tablet).

[0281] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (78.4 mg / tablet) and sodium starch glycolate (4.25 mg / tablet).

[0282] Magnesium stearate (1.85 mg / tablet) was added to the final blend.

[0283] Example 12

[0284] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0285] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (78.4 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0286] Example 13

[0287] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0288] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (78.4 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0289] Example 14

[0290] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0291] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (78.4 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0292] Example 15

[0293] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0294] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (52.9 mg / tablet), MCC pH 102 (24.57 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (1.78 mg / tablet).

[0295] Example 16

[0296] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0297] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (68.88 mg / tablet), MCC pH 102 (8.5 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (1.78 mg / tablet).

[0298] Example 17

[0299] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0300] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (68.88 mg / tablet), MCC pH 101 (8.5 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (1.78 mg / tablet).

[0301] Example 18

[0302] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0303] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), mannitol 100SD (68.03 mg / tablet), MCC pH 101 (8.5 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (2.70 mg / tablet).

[0304] Example 19

[0305] An alternative tablet formulation can be prepared by methods similar to those of Example 1. Compound 1 (relugolix) granulation includes Compound 1 (40 mg / tablet), mannitol (51 mg / tablet), sodium starch glycolate (5 mg / tablet), hydroxypropylcellulose (3 mg / tablet), and magnesium stearate (1 mg / tablet).

[0306] E2 / NETA granulation includes E2 (1 mg / tablet), NETA (0.5 mg / tablet), lactose (8.5 mg / tablet), mannitol 100SD (68.03 mg / tablet), sodium starch glycolate (4.25 mg / tablet) and magnesium stearate (0.85 mg / tablet).

[0307] Example 20

[0308] The formulations of the present disclosure can include varying amounts of mannitol and / or lactose. Table 5 shows two such formulations. The formulation Lactose VX contains a small amount of total mannitol (27.57% w / w) and a larger amount of lactose (42.37% w / w). The formulation Mannitol VW contains only mannitol (69.94% w / w) and no lactose.

[0309] Table 5: Composition of sample formulations lactose VX and mannitol VW

[0310]

[0311] When the formulations were stored over a period of 2 weeks to 6 months, formulations that included lactose were more stable than formulations containing lactose and mannitol or formulations containing only mannitol. Table 6 shows a stability study in which lactose VX and mannitol VW formulations were stored sealed at 60°C and ambient relative humidity. The degradation of Compound 1, E2, and NETA was analyzed at different time points and reported in Table 6 as the % (w / w) impurity relative to the standard working solution of each component. For example, the value of 0.37 under the Compound 1 heading means that the total amount of degradants (impurities) was 0.37% w / w of the initial mass of Compound 1 compared to the standard working solution of Compound 1.

[0312] In order to prepare the sample solution of the formulation for analyzing compound 1, 12 tablets were weighed and transferred to a 50 mL volumetric flask, and 7 mL of DI water was added. The tablets were shaken on a mechanical shaker until all tablets were completely disintegrated. 13 mL of ethanol and 20 mL of diluent (65:35 ethanol: water) were added, and the solution was ultrasonically treated for 20 minutes, then balanced and diluted with the diluent. The solution was mixed and filtered through a 0.2 μm PVDF syringe filter, and the first 3 mL of filtrate was discarded. The filtrate was collected and analyzed by ultra-performance liquid chromatography (UPLC).

[0313] The prepared sample was run on UPLC, eluting with 100% pH 2.4 phosphate buffer: acetonitrile: tetrahydrofuran (21:2:2).Compound 1 was detected at 290 nm with a retention time of approximately 26.1 minutes.

[0314] To prepare formulation sample solutions for analysis of E2 and NETA, 10 tablets were weighed and transferred to a 250 mL volumetric flask, and diluent (0.05 M phosphate solution: acetonitrile, 4:1) was added to approximately 80% of the volume. The tablets were shaken on a mechanical shaker and sonicated until all tablets were completely disintegrated. The solution was filtered through a 0.45 μm PVDF syringe filter, and the first 3 mL of filtrate was discarded. The filtrate was collected and further diluted by transferring 6.0 mL of the filtrate to a 20 mL volumetric flask and diluting to volume with diluent. The combined sample was then analyzed by ultra-performance liquid chromatography (UPLC). The prepared sample was run on the UPLC, eluting with running solutions A (0.2% trifluoroacetic acid in water) and B (0.2% trifluoroacetic acid in acetonitrile). The gradient increased from 80% A and 20% B at time = 0 minutes to 10% A and 90% B at time = 30 minutes. NETA was detected at 240 nm with a retention time of approximately 23.2 minutes, and E2 was detected at 280 nm with a retention time of approximately 18.5 minutes.

[0315] Table 6: Comparative degradation of active ingredients in lactose and mannitol formulations at 60°C and ambient relative humidity

[0316]

[0317] As shown in Table 6, the amount of NETA degradants in mannitol VW increased to 1.25% after only 2 weeks of storage at 60°C and reached 3.3% after 6 months. In lactose VX, the amount of NETA degradants was only 0.63% after 6 months. Similarly, the relative amounts of E2 degradants in E2 of lactose VX and mannitol VW were 1.24% and 1.59%, respectively. Therefore, the thermal stability of the lactose formulation was superior to that of the mannitol formulation.

[0318] Example 21

[0319] A bioequivalence study was conducted between the combined solid oral dosage form (of Table 4) and co-administration of Compound 1 and Activella (E2 / NETA).

[0320] Norgenin is a tablet for oral administration containing 1 mg estradiol and 0.5 mg norethindrone acetate plus excipients, or 0.5 mg estradiol and 0.1 mg norethindrone acetate.

[0321] The combined solid oral dosage form bioequivalence study was an open-label, randomized, two-treatment, three-sequence, three-period crossover and partially replicated, single-dose study designed to demonstrate the bioequivalence of the combined solid oral dosage form tablet to co-administration of 40-mg relugolix tablets (T4B formulation) and norgenin (1-mg E2 / 0.5-mg NETA) in healthy postmenopausal women. The study design was based on the FDA guidance document on bioequivalence studies (FDA 2019b) and also met the recommendations in the EMA guidance on bioequivalence investigations.

[0322] Study participants were randomized to one of three treatment sequences, with a 10-day washout interval between treatment periods. Each treatment sequence consisted of a partial replicate design, in which each participant received a combined solid oral dosage form tablet and co-administered relugolix and novoglobulin twice in a crossover manner. On the first day of each treatment period, study participants received their designated study treatment with 240 mL of water after fasting for at least 10 hours overnight and continuing to fast for approximately 4 hours. Drinking water was restricted for 1 hour before and after study drug administration. Blood samples were collected for up to 168 hours after administration to determine relugolix plasma concentrations, and for up to 72 hours after administration to determine NET plasma concentrations and unconjugated E2, unconjugated E1, and total E1 serum concentrations. Triplicate blood samples (relative to -1.0, -0.5, and 0 hours of study drug administration) were collected before administration for determination of unconjugated E2 and total and unconjugated E1 serum concentrations, thereby facilitating the calculation of baseline-adjusted PK parameters. Based on estimates of pharmacokinetic variability from a previously conducted biocomparability study of a combination solid oral dosage form, ninety participants were planned and randomized (n=30 in each treatment sequence), of which 86 participants completed the study. The mean age of the study participants was 55.9 years.

[0323] For the bioequivalence evaluation between the combined solid oral dosage form tablet and co-administration of 40-mg Compound 1 (relugolix) tablets and norogensin, the AUC of Compound 1 (relugolix) 0-∞ and C max , baseline-adjusted unconjugated E2, baseline-adjusted total E1, and NET were pre-specified as primary endpoints. AUC of unadjusted unconjugated E2, unadjusted total E1, and unconjugated E1 (with and without baseline adjustment) 0-∞ and C max Secondary endpoints were provided as completeness. Log-transformed pharmacokinetic parameters were analyzed by either the ABE method or the RSABE method, depending on the within-reference treatment coefficient of variation (CV) of the parameter. WR The ABE method was used to evaluate the efficacy of the sham group with low intra-reference treatment variability (CV WR% <30%), including the AUC of unconjugated E2, total and unconjugated E1, and NET. 0-∞ and C max , where the limits of 90% CI for GMR (combination solid oral dosage form tablet / compound 1 (relugolix) and norogensin) (0.8000, 1.2500) were used as acceptance criteria. The AUCs of E2 and E1 with and without baseline adjustment were calculated. 0-∞ and C max The RSABE method was used to evaluate the efficacy of a sham group with high intra-reference treatment variability (CV WR % ≥ 30%), including the AUC of Compound 1 (relugolix) 0-∞ and C max , with the (0.8000, 1.2500) limits of GMR (combination solid oral dosage form tablet / compound 1 (relugolix) and norogensin co-administration) and the 95% upper confidence limit of the reference proportion difference less than or equal to zero as acceptance criteria.

[0324] The results of the bioequivalence study are shown in Figure 1 and Table 7. The "FDC" label corresponds to a combination solid oral dosage form.

[0325] Bioequivalence between the FDC tablet and coadministration of 40-mg relugolix tablets and E2 / NETA was established based on prespecified acceptance criteria according to the FDA (e.g., Guidance for Industry, Statistical Methods for Establishing Bioequivalence, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research [CDER], January 2001) and EMA (e.g., Guidance on Bioequivalence Investigations, 2010). All 16 primary and secondary endpoints met the bioequivalence acceptance criteria for the corresponding statistical methods.

[0326] A single dose of FDC tablets or co-administration of relugolix and E2 / NETA was generally safe and well tolerated. All 18 adverse events reported (in 15 participants) were mild or moderate in severity and transient in nature, with 12 events (in 9 participants) considered related to study drug. There were no deaths or serious adverse events in this study. One participant discontinued the study due to a non-serious adverse event (tooth abscess).

[0327] Definitions of certain abbreviations used herein include: AUC 0-∞ = area under the concentration-time curve extrapolated from time zero to infinite time; C max= maximum observed concentration; CI = confidence interval; CV = coefficient of variation; E1 = estrone; E2 = estradiol; FDA = Food and Drug Administration; FDC = fixed-dose combination; GMR = geometric mean ratio; NET = norethindrone acetate; RSABE = mean bioequivalence of the reference ratio.

[0328] Table 7: Bioequivalence study results

[0329]

[0330]

[0331]

[0332] Example 22

[0333] An attempt was unsuccessful to prepare an alternative formulation by a method similar to Example 1, in which ethanol was used instead of methanol in the second granulation blend. Referring to Table 2, ethanol was used instead of methanol in step E1. In addition, only NETA was used instead of the E2 / NETA combination. After the powder bed was fluidized and the NETA / ethanol solution was sprayed onto the powder, the resulting granules adhered to the walls of the container. After granulation and discharge, the yield was 88.3%. The material also had a lumpy consistency. The NETA content was measured by HPLC. The results showed that the amount of NETA in the entire granulated material had a high variability, with a standard deviation of 11.4%.

[0334] Figure 1 and Figure 2 Abbreviation used in: AUC 0-∞ = area under the concentration-time curve extrapolated from time zero to infinite time; C max = maximum observed concentration; CI = confidence interval; CV = coefficient of variation; E1 = estrone; E2 = estradiol; FDA = Food and Drug Administration; FDC = fixed-dose combination; GMR = geometric mean ratio; NET = norethindrone acetate; RSABE = mean bioequivalence of the reference ratio.

[0335] Figure 1 and Figure 2 Note: AUC of relugolix was estimated by RSABE method 0-∞ and C max , with the (0.800, 1.2500) limits of GMR and a 95% upper confidence limit of the reference proportion difference less than or equal to zero as acceptance criteria.

Claims

1. A combined solid oral dosage form comprising: 18% w / w to 22% w / w of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof; 0.3% w / w to 0.7% w / w estradiol; 0.1% w / w to 0.4% w / w norethindrone acetate; 24% w / w to 28% w / w mannitol; 2% w / w to 6% w / w starch selected from the group consisting of sodium starch glycolate, pregelatinized starch, and combinations of the foregoing; 0.5% w / w to 3% w / w hydroxypropyl cellulose; 0.5% w / w to 3% w / w magnesium stearate; 38% w / w to 42% w / w lactose monohydrate; as well as 1% w / w to 5% w / w film coating.

2. The combined solid oral dosage form according to claim 1, comprising: 40 mg of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof; 1mg estradiol; 0.5 mg norethindrone acetate; 51mg mannitol; 9mg sodium starch glycolate; 3mg hydroxypropyl cellulose; 2mg magnesium stearate; 78mg lactose monohydrate; and 7mg film-coated.

3. The combined solid oral dosage form according to claim 1, wherein the starch is sodium starch glycolate.

4. The combined solid oral dosage form of claim 3, wherein the combined solid oral dosage form comprises 9 mg sodium starch glycolate.

5. The combined solid oral dosage form according to claim 1, wherein the starch is pregelatinized starch.

6. The combined solid oral dosage form according to claim 1, wherein the starch is a combination of sodium starch glycolate and pregelatinized starch.

7. The combined solid oral dosage form according to claim 6, comprising 2% to 3% w / w sodium starch glycolate and 2% to 3% w / w pregelatinized starch.

8. The combination solid oral dosage form of claim 1 , wherein the amount of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea degradant present does not exceed 0.5% w / w after storage of the combination solid oral dosage form for 6 months at 60° C. and ambient relative humidity.

9. The combined solid oral dosage form of claim 1, wherein the amount of estradiol degradants present does not exceed 1.4% w / w after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months.

10. The combined solid oral dosage form of claim 1, wherein the amount of norethindrone acetate degradants present does not exceed 1.4% w / w after storage of the combined solid oral dosage form at 60°C and ambient relative humidity for 6 months.

11. The combined solid oral dosage form of claim 1 , wherein when orally administered to a subject, the mean maximum plasma concentration (C ) of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof is max ) in the range of 10 ng / mL to 30 ng / mL.

12. A method for preparing a combined solid oral dosage form according to any one of claims 1 to 11, the method comprising: a) preparing a first granulation comprising one or more sub-batches, wherein each sub-batch comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, the first fraction of starch, and the hydroxypropyl cellulose; b) preparing a second granulation comprising the estradiol, the norethindrone acetate, the second fraction of starch and the lactose monohydrate; c) blending the first granulation and the second granulation with the magnesium stearate to form a final blend; as well as d) coating the final blend with the film coating.

13. The method according to claim 12, comprising: a) spraying the aqueous solution of hydroxypropylcellulose onto a fluidized mixture of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, mannitol, and the first fraction of starch to form an initial blend, wherein the initial blend is dried and milled to produce subbatches; and wherein one or more subbatches are blended to produce the first granulation; b) spraying the methanolic solution of the estradiol and the norethindrone acetate onto the fluidized mixture of the first fraction of lactose monohydrate to form an initial lactose blend, wherein the initial lactose blend is dried, milled and blended with the second fraction of lactose monohydrate and the second fraction of starch to produce the second granulation; c) blending the first granulation with the second granulation and the magnesium stearate to produce the final blend, wherein the final blend is compressed; as well as d) coating the final blend with an aqueous film coating suspension and drying the resulting coated final blend to form the combined solid oral dosage form.

14. The method of claim 12, wherein the second granulation does not include mannitol.

15. The method of claim 12, wherein the first granulation comprises two sub-batches.

16. The method of claim 12, wherein the N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-methoxyurea or a corresponding amount of a pharmaceutically acceptable salt thereof, the mannitol, and the first fraction of the starch are fluidized in a fluidized bed granulator with an inlet air flow rate of 400-500 cfm and a temperature of 75°C-80°C.

17. The method of claim 13, wherein the aqueous solution of the hydroxypropyl cellulose is sprayed at a rate of 250 g / min to 350 g / min and a target atomization pressure of 2.5 bar to 4.5 bar.

18. The method of claim 13, wherein the initial blend is dried until the measured exhaust gas temperature reaches at least 37°C and milled by a mill equipped with a 3 mm screen at an impeller speed of 930 rpm ± 100 rpm to produce the first granulation.

19. The method of claim 13, wherein the first fraction of lactose monohydrate is fluidized in a fluidized bed granulator with an inlet air flow rate of 750 cfm to 1050 cfm and a temperature of 37°C to 43°C.

20. The method of claim 13, wherein the methanolic solution of the estradiol and the norethindrone acetate is sprayed at a rate of 550 g / min to 650 g / min and a target atomization pressure of 5 bar.

21. The method of claim 13, wherein the initial lactose blend is dried until the measured exhaust temperature reaches at least 46°C and ground by a mill equipped with a 0.5 mm screen at an impeller speed of 2500 rpm ± 125 rpm.

22. The method of claim 21, wherein the initial lactose blend is further blended with the second fraction of lactose monohydrate and the second fraction of starch for 180±15 revolutions.

23. The method of claim 12, wherein the first granulation and the second granulation are blended at a ratio of 55% w / w and 45% w / w, respectively, for 70 to 170 revolutions.

24. The method of claim 23, wherein the blend of the first granulation and the second granulation is blended with magnesium stearate to produce the final blend.

25. A combination solid oral dosage form produced by the method of claim 12.

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