Treating gynecomastia and / or breast pain

Abstract

A selective estrogen receptor modulator and / or aromatase inhibitor (A) for use in a method for preventing or treating gynecomastia and / or breast pain, wherein the method comprises administering said selective estrogen receptor modulator and / or aromatase inhibitor in combination with (B) an estrogen modulator different from said selective estrogen receptor modulator.

Description

[Technical field]

[0001] The present invention relates to a combination therapy for use in the treatment of gynecomastia and / or breast pain. More specifically, the present invention relates to a combination of (A) a selective estrogen receptor modulator and / or aromatase inhibitor and (B) an estrogen modulator for use in the treatment of gynecomastia and / or breast pain. The present invention also relates to a pharmaceutical composition comprising the compound, a method for treating or preventing gynecomastia and / or breast pain, and the use of the compound in the manufacture of a medicament for treating or preventing gynecomastia and / or breast pain. [Background technology]

[0002] Gynecomastia is a breast disorder that affects approximately 60% of men worldwide. Gynecomastia can be caused by weight gain, drug use, anabolic steroids, or other underlying medical conditions. The result can be "gyneforme breasts." Male breast enlargement can affect psychological, social, and emotional well-being.

[0003] This symptom is the reason why many men seek professional help. Fortunately, today, gynecomastia is treatable through male breast reduction surgery. Furthermore, several types of surgery are available for the treatment of gynecomastia. The surgical method varies depending on the grade of gynecomastia or the severity of breast enlargement. Various surgical procedures can provide successful and effective results.

[0004] However, not all men are ready to undergo surgery, nor are all men suitable candidates, or even willing to undergo a surgical solution. Moreover, surgical outcomes are generally poor, with up to one-third of patients not satisfied with the results. Surgical risks for gynecomastia include: anesthesia risks; bleeding (hematoma), blood clots, breast asymmetry, irregularity in breast contour and shape, changes in nipple or breast sensation, which may be temporary or permanent, damage to deep structures such as nerves, blood vessels, muscles and lungs may occur, which may be temporary or permanent, deep vein thrombosis, cardiac and pulmonary complications, fatty tissue found in the breast may die (fat necrosis), fluid accumulation (seroma), infections - inverted nipples, persistent pain, poor wound healing, possible reconstructive surgery, reactions to tapes, suture materials, adhesives, topical preparations or injectables, unacceptable scars.

[0005] Most men would prefer a medicinal solution to their breast problems. For this reason, research has been conducted to find a medical solution. Some of these studies revolve around the selective estrogen receptor modulator (SERM) tamoxifen. Many experts believe that tamoxifen is a promising option for treating gynecomastia.

[0006] Breast enlargement in patients with gynecomastia is typically due to breast tissue growth caused as a result of a hormonal imbalance between estrogen and androgen. The imbalance between hormones is often caused by increased estrogen production or abnormally high levels of estrogen. Therefore, in the treatment of gynecomastia, it is desirable to target estrogen production.

[0007] Mastalgia, also known as mastodynia, is a common breast disorder that occurs in up to 70% of women at some point in their lives, especially those aged 30-50. It is a common reason for women to seek medical attention. In men, it is commonly caused by gynecomastia, which, as mentioned above, is a breast disorder that affects approximately 60% of men worldwide. Mastalgia can be due to menstruation, weight gain, drug use, anabolic steroids, or other underlying medical conditions. Breast pain is a significant problem in the general population because it can affect quality of life, daily activities, sleep, and psychological, social, and emotional well-being (Scurr et al. 2014).

[0008] For women with breast pain, topical nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in reducing breast pain and should be considered as first-line treatment, but these treatments are not always effective.

[0009] For transgender women, hormone therapy can cause breast pain. For transgender men, breast pain can occur due to the minimal amount of breast tissue that may remain after a mastectomy.

[0010] Danazol is the only prescription drug approved by the U.S. Food and Drug Administration for the treatment of fibrocystic breasts. However, danazol carries the risk of serious side effects, including weight gain and voice changes, as well as heart and liver problems. Tamoxifen, a prescription drug for the treatment and prevention of breast cancer, can help, but the drug can have side effects that can be more bothersome than the breast pain itself.

[0011] This symptom is the reason why many men with gynecomastia seek professional help. Fortunately, today, gynecomastia-related breast pain can be treated by male breast reduction surgery. In addition, several types of surgery are available for the treatment of gynecomastia. The surgical method varies depending on the grade of breast pain or the severity of breast enlargement. Various surgical procedures can provide successful and effective results. However, as mentioned above, surgery is often not desirable or appropriate.

[0012] Most women and men would prefer a medication that would quickly resolve breast problems and have few, if any, side effects. Because of this, research has been conducted to find a medical solution. Some of these studies revolve around the selective estrogen receptor modulator (SERM) tamoxifen. Many experts believe that tamoxifen is a promising option for treating breast pain.

[0013] Breast pain is typically caused by breast tissue growth that is the result of a hormonal imbalance between estrogen and androgen. As with gynecomastia, the imbalance between hormones is often caused by increased estrogen production or abnormally high levels of estrogen. The two conditions often occur simultaneously. Therefore, in treating breast pain, it is desirable to target the production of estrogen.

[0014] Tamoxifen is the oldest and most prescribed selective estrogen receptor modulator (SERM). Tamoxifen is currently approved by the U.S. Food and Drug Administration (FDA) to treat: 1) Women and men who have been diagnosed with early-stage, hormone receptor-positive breast cancer after surgery (or sometimes chemotherapy and radiation therapy) to reduce the risk of the cancer returning (recurrence).

[0015] 2. Women and men diagnosed with advanced or metastatic hormone receptor positive disease.

[0016] 3. Reducing the risk in women who have not been diagnosed with breast cancer but are at higher than average risk for the disease.

[0017] Tamoxifen works by blocking the effects of estrogen in breast tissue. Tamoxifen is the most prescribed selective estrogen receptor modulator (SERM). Tamoxifen can block or activate the function of the female hormone estrogen. In the case of breast cells, estrogen blocks this action.

[0018] Tamoxifen is known to have two mechanisms of action in the prevention of breast cancer: (1) it competes with 17β-estradiol (E2) at receptor sites, blocking the promoting role of E2 in breast cancer; (2) it binds to DNA after metabolic activation, initiating carcinogenesis.

[0019] Tamoxifen is also used in endocrine therapy outside of oncological settings. This treatment can affect the effect of estrogen on breast cancer cells. This action reduces the risk of developing this cancer. In addition, tamoxifen is used to reduce breast density in people with dense breasts.

[0020] Tamoxifen may help prevent breast tissue from developing and is considered a promising candidate for the treatment of gynecomastia and / or breast pain (although it is not approved by regulatory authorities for the treatment of gynecomastia or breast pain).

[0021] The inventors sought alternative and / or remedial methods for preventing or treating gynecomastia and / or breast pain. The inventors have surprisingly found that the combination of (A) a SERM (such as tamoxifen) and / or an AI with (B) an estrogen modulator such as indole-3-carbinol (I3C) (different from a SERM and different from an AI) provides promising results for the treatment of gynecomastia and / or breast pain. The two components act via different biochemical pathways, thus providing a synergistic effect on the production of estrogen, resulting in a combination treatment for gynecomastia and / or breast pain.

[0022] In addition, certain SERMs or AIs may cause significant side effects. For example, the side effects of tamoxifen include headache, nausea, hot flashes, skin rashes, fatigue, sexual dysfunction, and weight and mood changes. The use of a second estrogen regulator (B) may allow the dose of SERMs (e.g., tamoxifen) and / or AIs to be reduced during the treatment of gynecomastia and / or breast pain, thereby reducing side effects.

[0023] Furthermore, reducing the dose of the SERM / AI may reduce the likelihood of SERM / AI resistance.

[0024] A combination of I3C and the anti-estrogen tamoxifen has been shown to cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone (Cover et al., 'Indole-3-Carbinol and Tamoxifen Cooperate to Arrest the Cell Cycle of MCF-7 Human Breast Cancer Cells'. J Cancer Research. 1244-1251, 59 (1999)). Some evidence suggests that I3C acts through a different mechanism than tamoxifen. For example, I3C has been shown to be unable to compete with estrogen for binding to the estrogen receptor, which notably downregulates the expression of CDK6.

[0025] These results indicate that I3C and tamoxifen act through different signaling pathways to inhibit the growth of human breast cancer cells.

[0026] Taking into account the unique features of the growth inhibitory cascade induced by I3C and tamoxifen, Cover et al. (1999) demonstrated that the combination of tamoxifen and I3C exhibited a more effective growth inhibitory response, a tighter inhibition of the specific activity of CDK2, and more endogenous Rb phosphorylation than either compound alone.

[0027] Similarly, Malejka-Giganti et al. (2007) found that treatment of rats with both tamoxifen and I3C did not attenuate the inhibition of breast cancer development by I3C, but rather enhanced the chemopreventive benefits of tamoxifen, as evidenced by a significant reduction in the average number of tumors per rat, indicating a synergistic effect of the two compounds.

[0028] However, in the only randomized placebo-controlled study of diindolylmethane, the main active metabolite resulting from the breakdown of indole-3-carbinol, on the modulation of breast cancer biomarkers in women taking tamoxifen, Thomson et al. (2017) found that the combination was associated with a decrease in tamoxifen metabolites. Therefore, DIM appears to attenuate the clinical efficacy of tamoxifen. Thomson et al. advise caution with the combination of DIM and tamoxifen, as DIM may reduce the efficacy of tamoxifen.

[0029] A surprising aspect of the present invention is the recognition that a SERM and / or an AI in combination with a different estrogen modulator represents a combination therapy for gynecomastia and / or breast pain. Summary of the Invention

[0030] In a first aspect, the present invention provides a selective estrogen receptor modulator and / or aromatase inhibitor (A) for use in a method for preventing or treating gynecomastia and / or mastalgia, comprising wherein the method comprises administering a selective estrogen receptor modulator and / or an aromatase inhibitor to a patient in need thereof, (B) The selective estrogen receptor modulator may be administered in combination with an estrogen modulator that is different from the selective estrogen receptor modulator.

[0031] In a further aspect, the present invention provides a selective estrogen receptor modulator and / or aromatase inhibitor (A) for use in a method for preventing or treating gynecomastia and / or mastalgia, comprising wherein the method comprises administering a selective estrogen receptor modulator and / or an aromatase inhibitor to a patient in need thereof, (B) in combination with a cruciferous vegetable, wild nettle root, chrysin, soy, turmeric, maca, flavonoid or grape seed supplement or extract, preferably a cruciferous vegetable supplement or extract.

[0032] In a further aspect, the present invention provides a composition comprising: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor; and (B) an estrogen modulator, the estrogen modulator being different from the selective estrogen receptor modulator, for use in the treatment or prevention of gynecomastia and / or breast pain.

[0033] In a further aspect, the present invention provides a pharmaceutical composition for combination therapy for treating gynecomastia and / or breast pain, comprising as active ingredients: (A) a first pharmaceutical ingredient comprising a selective estrogen receptor modulator and / or an aromatase inhibitor; and (B) a second pharmaceutical ingredient comprising an estrogen modulator, wherein the estrogen modulator is different from the selective estrogen receptor modulator.

[0034] In a further aspect, the present invention provides tamoxifen, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method for preventing or treating gynecomastia and / or mastalgia, wherein the method comprises administering tamoxifen in combination with (B) indole-3-carbinol (I3C) and / or 3,3'-diindolylmethane (DIM), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0035] In a further aspect, the present invention provides a combination of (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen modulator different from the selective estrogen receptor modulator, for simultaneous, separate or sequential use in the treatment of gynecomastia and / or breast pain: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0036] In a further aspect, the present invention provides a pharmaceutical product comprising (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen modulator different from the selective estrogen receptor modulator, as a pharmaceutical combination, for simultaneous, separate or sequential use in the treatment of gynecomastia and / or breast pain: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0037] In a further aspect, the present invention provides a kit comprising (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen modulator different from the selective estrogen receptor modulator, for simultaneous, separate or sequential use in the treatment of gynecomastia and / or breast pain, comprising: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0038] In a further aspect, the present invention relates to a method for treating or preventing gynecomastia and / or mastalgia, the method comprising administering to a subject in need thereof effective amounts of (A) a selective estrogen receptor modulator and / or an aromatase inhibitor and (B) an estrogen modulator other than the selective estrogen receptor modulator, either simultaneously, separately or sequentially; wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0039] In a further aspect, the present invention provides the use of (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen modulator other than the selective estrogen receptor modulator, in the manufacture of a combination pharmaceutical for the treatment of gynecomastia and / or breast pain, comprising: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0040] In a further aspect, the present invention provides a pharmaceutical composition comprising: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor; and (B) an estrogen modulator other than the selective estrogen receptor modulator: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0041] In a further aspect, the present invention provides a use of (A) a selective estrogen receptor modulator and / or an aromatase inhibitor and (B) an estrogen modulator different from the selective estrogen receptor modulator for reducing breast size and / or breast pain in a subject, comprising: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0042] In a further aspect, the invention provides a method of reducing breast size and / or breast pain in a subject, the method comprising administering (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen modulator other than the selective estrogen receptor modulator: wherein, preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharma- ceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen modulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharma- ceutically acceptable salt, solvate or hydrate thereof; wherein (A) and (B) are administered simultaneously, separately or sequentially.

[0043] The features of the aspects and / or embodiments presented in this specification can be used individually and in any combination in all technically feasible aspects and embodiments of the invention, unless otherwise indicated.

[0044] Component (A) "SERM" herein stands for selective estrogen receptor modulator. "AI" herein stands for aromatase inhibitor. SERMs and AIs are well-established classes of compounds.

[0045] SERMs are typically distinct from estrogen regulators (B). SERMs are typically distinct from AIs, which are typically distinct from estrogen regulators (B).

[0046] Wherever a component / ingredient / compound / SERM / AI is discussed, "A" is applicable to all aspects and embodiments of the present invention where technically feasible.

[0047] Selective estrogen receptor modulators (SERMs) Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER). As the name suggests, these substances differ from pure ER agonists and antagonists because their actions differ in various tissues. This results in the possibility to selectively inhibit or stimulate estrogenic actions in various tissues.

[0048] In certain embodiments, the SERM is a non-steroidal SERM.In more particular embodiments, the SERM is selected from tamoxifen, clomiphene, and raloxifene, or its pharmaceutically acceptable salt, solvate, or hydrate.The compounds discussed below (tamoxifen, clomiphene, and raloxifene, or other compounds) can be administered as their pharmaceutically acceptable salt, solvate, or hydrate.In certain embodiments, the SERM is a triphenylethylene type SERM, i.e., based on a triphenylethylene core.In other words, the SERM can include a triphenylethylene unit.

[0049] Tamoxifen has the formula:

[0050] [ka] Clomiphene has the formula:

[0051] [ka] Raloxifene has the formula:

[0052] [ka]

[0053] In certain embodiments, the SERM is a compound of the formula:

[0054] [ka] (In the formula, R 1 is selected from H, halogen (preferably Cl), or C1-C6 alkyl (preferably C1-C2 alkyl, i.e., methyl or ethyl), preferably R 1 is selected from Cl and ethyl; Each R 2 are independently selected from H, or C1-C6 alkyl (preferably C1-C2 alkyl, i.e., methyl or ethyl), preferably both R 2 The groups are the same and are either methyl or ethyl. or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0055] The SERMs tamoxifen and clomiphene are structurally similar and both have been proposed for use in gynecomastia / mastalgia. Their biochemical / physiological properties are similar.

[0056] In all aspects and embodiments of the present invention, the selective estrogen receptor modulator and / or aromatase inhibitor (A) is preferably tamoxifen, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0057] Tamoxifen Tamoxifen is an FDA-approved prescription drug used to treat hormone receptor-positive breast cancer. It is also used to reduce the development of cancer in high-risk patients. Since its approval in 1998, Tamoxifen has already improved the condition of both women and men diagnosed with breast cancer. It has also shown promising results in treating gynecomastia and breast pain.

[0058] In oncological settings, tamoxifen works by preventing the development of breast cancer: it enables treatment and prevention by interfering with the effects of estrogen on glandular tissue.

[0059] For this reason, tamoxifen is the most prescribed selective estrogen receptor modulator (SERM). It can block or activate the function of estrogen in certain breast cells. Tamoxifen blocks the action of estrogen on breast cells. Furthermore, tamoxifen attaches to proteins or hormone receptors in cancer cells. Blocking the hormone receptors effectively stops the progression of the cancer.

[0060] Tamoxifen is used in combination with other medicines undergoing hormone therapy. Tamoxifen treatment can slow the progression of cancer cells by altering the body's hormone balance.

[0061] The rapid progression of cancer is due to high levels of estrogen. Tamoxifen can lower these estrogen levels, slowing the onset of cancer and slowing tumor growth.

[0062] Tamoxifen's effectiveness is due to how it works to stop cancerous cells from developing. It can also reduce recurrent invasive breast cancer and may help reduce the chances of developing the disease in high-risk individuals.

[0063] In gynecomastia, breast tissue develops in the male chest. This tissue causes the glandular components of gynecomastia to mix with breast fat. There are several reasons why men develop gynecomastia, but it is the result of a hormone imbalance. This imbalance occurs when estrogen levels become too high and the male hormone testosterone drops. In men, breast pain, or breast pain, often occurs at the same time as gynecomastia. This is because the two symptoms can arise from the same underlying condition. In women, cyclical breast pain is also typically caused by hormone fluctuations during menstruation.

[0064] Tamoxifen has both anti-estrogenic and anti-tumor effects on glandular tissue. Researchers can use the "tamoxifen effect" to determine whether gynecomastia and / or breast pain can be treated. Tamoxifen may be beneficial in some cases, especially for gynecomastia or breast pain during puberty.

[0065] Tamoxifen has shown success in treating and preventing breast cancer, but further research is needed on anti-estrogen compounds in other settings, such as tamoxifen in gynecomastia.

[0066] Tamoxifen is typically administered as a tablet once or twice daily. However, gel formulations of tamoxifen have been shown to significantly reduce the side effects associated with oral formulations. Cationic nanoemulsions of tamoxifen containing charge inducers have been developed to improve the biopharmaceutical attributes and anticancer potential of the drug. In certain embodiments, the SERM and / or AI are administered as a topical formulation (e.g., cream, skin patch, gel, etc.) or as a cationic nanoemulsion.

[0067] Raloxifene is a sister drug to tamoxifen and, along with other SERMs such as clomiphene, may be considered as an alternative for use with this formulation.

[0068] In breast tissue, tamoxifen typically acts as an ER antagonist, resulting in inhibition of transcription of estrogen-responsive genes. The most abundant metabolites of tamoxifen in terms of circulating concentrations are N-desmethyltamoxifen, N,N-didesmethyltamoxifen, (Z)-endoxifen, and tamoxifen N-oxide.

[0069] Aromatase inhibitors Aromatase inhibitors are also a well-known class of compounds. Aromatase, also known as estrogen synthase, is a key enzyme in estrogen biosynthesis. Aromatase inhibitors, such as anastrozole and letrozole, effectively delay epiphyseal maturation in boys and improve testosterone levels in adult men. Thus, aromatase inhibitors may be used to increase adult height in boys with gonadotropin-independent precocious puberty, idiopathic short stature, constitutionally delayed puberty, and to increase gonadotropin secretion, thereby stimulating Leydig and Sertoli cell function. Aromatase inhibitors may be used to prevent or delay epiphyseal closure, thereby increasing adult height. Aromatase inhibitors may also be used to treat or prevent breast pain and / or mastalgia in women. A concern with aromatase inhibition is that it may have a detrimental effect on bone mineralization. Testolactone is considered promising as a treatment for gynecomastia and / or mastalgia. Although the long-term efficacy and safety of aromatase inhibitor use in men has yet to be established, their potential in anti-estrogen targeting is significant. It is therefore highly desirable to pursue combination therapies that could potentially reduce the dosage of aromatase inhibitors or complement their anti-estrogen properties, for example.

[0070] In certain embodiments, the aromatase inhibitor is selected from testolactone, anastrozole and letrozole, preferably testolactone, or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0071] Estrogen Regulatory Factor - Component (B) The present invention relates to a method for treating gynecomastia and / or breast pain, comprising administering to the subject a therapeutically effective amount of (A) a SERM and / or an AI; (B) In combination with an estrogen regulator.

[0072] Estrogen regulator (B) is typically a compound that has anti-estrogenic effect. It is different from selective estrogen receptor regulator (SERM) and different from aromatase inhibitor (AI). If estrogen regulator (B) can be considered as SERM and / or AI, estrogen regulator (B) is different from SERM and / or AI (A).

[0073] In certain embodiments, the estrogen regulator is an estrogen inhibitor. In certain embodiments, the estrogen regulator is an estrogen receptor antagonist. In certain embodiments, the estrogen regulator (B) is an aromatase inhibitor (AI), preferably different from any aromatase inhibitor (A). In certain embodiments, the estrogen regulator (B) is an inhibitor of the enzyme CYP19A1 (a member of the cytochrome P450 family) (Eur J Nutr (2013) 52: 1483-1492). In certain embodiments, the estrogen regulator (B) is an agent that downregulates CYP19 expression in estrogen-responsive (ER+) breast cells and / or increases CYP19 expression in estrogen-dependent (ER-) breast cells. In certain embodiments, the estrogen regulator can bind to the aryl hydrocarbon receptor (AhR). In certain embodiments, the estrogen modulator (B) affects estrogen production through a different biochemical pathway to the SERM and / or AI (A).

[0074] In certain embodiments, the estrogen modulator of (B) is the following compounds (i)-(iv):

[0075] [ka] or a pharma- ceutically acceptable salt or hydrate thereof.

[0076] Compound (i) is indole-3-carbinol (I3C); compound (ii) is 3,3'-diindolylmethane (DIM); compound (iii) is 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT); and compound (iv) is 5,11-dihydroindolo-[3,2-b]carbazole (ICZ).

[0077] In all aspects and embodiments of the present invention, preferably the estrogen modulator (B) is indole-3-carbinol (I3C) and / or 3,3'-diindolylmethane (DIM), or a pharma- ceutically acceptable salt, solvate or hydrate thereof, preferably indole-3-carbinol (I3C), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0078] Two or more estrogen regulators may be present in / as component (B) of the present invention. For example, component (B) may be or may include at least one estrogen regulator, for example at least two estrogen regulators. When multiple estrogen regulators (B) are present, they can be administered simultaneously, separately, or sequentially. As mentioned above, in this respect, the combination of I3C and DIM (or its pharma-ceutically acceptable salt, solvate, or hydrate) is particularly preferred. When multiple regulators (B) are present, they can be formulated together or separately.

[0079] In certain embodiments, the second component (B) is any of the following compounds (i') to (iv'):

[0080] [ka] (In the formula, R 1 is H, substituted or unsubstituted hydrocarbyl (e.g., alkyl or aryl), -CO-[C 1~6 alkyl], preferably R 1is selected from H, C1-C6 hydrocarbyl (preferably C1-C6 alkyl), -CO-[C1-6 alkyl], more preferably R 1 is H; In the formula, each R 2 is H, substituted or unsubstituted hydrocarbyl (e.g., alkyl or aryl), -CO-[C 1~6 alkyl], preferably R 2 is selected from H, C1-C6 hydrocarbyl (preferably C1-C6 alkyl), -CO-[C1-6 alkyl], more preferably R 2 is H ;) or a pharma- ceutically acceptable salt or hydrate thereof.

[0081] Independently selected means for and within each molecule.

[0082] In certain embodiments, the present invention provides a selective estrogen receptor modulator and / or aromatase inhibitor (A) for use in a method for treating gynecomastia and / or mastalgia, wherein the method comprises administering a selective estrogen receptor modulator and / or an aromatase inhibitor in combination with at least one of compounds (i)-(iv) or (i')-(iv') above, or a precursor (e.g., a prodrug) or a metabolite of compounds (i)-(iv) or (i')-(iv').

[0083] Indole-3-carbinol Indole-3-carbinol (I3C) is formed from a substance called glucobrassicin, which is found in cruciferous vegetables. Cruciferous vegetables typically refer to broccoli, Brussels sprouts, cabbage, collards, cauliflower, kale, mustard greens, turnips, rutabagas, and similar green leafy vegetables. I3C is formed when these vegetables are cut, chewed, or cooked. It can also be produced in the laboratory.

[0084] In the stomach, I3C molecules undergo acid-catalyzed condensation to generate several biologically active I3C oligomers, including 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and 5,6,11,12,17,18-hexahydrocyclononal[1,2-b:4,5-b':7,8-b'']triindole (CT).

[0085] Like tamoxifen and other SERMs, I3C and DIM have been shown to modulate the expression and activity of biotransformation enzymes involved in the metabolism and elimination of many biologically active compounds, such as steroid hormones, drugs, carcinogens, and toxins.

[0086] Preclinical studies suggest that the antiestrogenic activity of I3C and DIM may help reduce the risk of hormone-dependent cancers. Supplementation with I3C and DIM may alter the urinary estrogen metabolite profile in women, but the effect of I3C and DIM on breast cancer risk is unknown.

[0087] The combination of I3C with the anti-estrogen tamoxifen has been shown to cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone (Cover et al., 'Indole-3-Carbinol and Tamoxifen Cooperate to Arrest the Cell Cycle of MCF-7 Human Breast Cancer Cells'. J Cancer Research. 1244-1251, 59 (1999)). Some evidence suggests that I3C acts through a different mechanism than tamoxifen. I3C has been shown to be unable to compete with estrogen for binding to the estrogen receptor, which notably downregulates the expression of CDK6. These results indicate that I3C and tamoxifen act through different signaling pathways to suppress the growth of human breast cancer cells.

[0088] I3C can be combined with other compounds to improve bioavailability, but typically when administered orally, the active ingredient, indole-3-carbinol, is converted to diindolylmethane (see below).

[0089] The duration of activity of I3C can also be modified by the addition of other molecules that prevent its degradation in vivo.

[0090] 3,3'-Diindolylmethane Indole-3-carbinol (I3C) is converted to diindolylmethane (DIM) and other oligomers when administered orally, catalyzed by gastric acid (see Figure 1). This suggests that DIM is the primary active agent and that I3C is a precursor or "prodrug" in vivo. However, in cell culture studies performed in neutral solution, I3C appears to be fully active.

[0091] However, DIM has different biological activity and estrogen suppression from I3C. It is believed that DIM alone or in combination with I3C may also act synergistically / synergistically against SERM / AI (e.g., tamoxifen). Synergistic / synergistic effects may result from reducing toxicity, enhancing efficacy, or reducing resistance to SERM / AI (e.g., tamoxifen). Therefore, in certain embodiments, a mixture of I3C and DIM is present in component (B) of the present invention.

[0092] DIM can be combined with other compounds to improve bioavailability. For example, by administering liquid DIM (oil solution) containing cod liver oil and polysorbate, higher bioavailability is achieved compared to unformulated crystalline DIM. The duration of activity of DIM can also be modified by adding other molecules that prevent in vivo degradation. Combining DIM with d-α-tocopheryl polyethylene glycol-1000 succinate enhances intestinal absorption. Thus, in certain embodiments, DIM is administered as a liquid (oil solution), and this liquid contains cod liver oil and polysorbate. In certain embodiments, DIM is combined with d-α-tocopheryl polyethylene glycol-1000 succinate.

[0093] Food / vegetable supplements (e.g., cruciferous vegetable supplements) In certain embodiments, component (B) is a food supplement, such as a vegetable supplement, such as a cruciferous vegetable supplement.

[0094] In certain embodiments, the estrogen modulator is a glucobrassicin derivative. "Derivative" in this context typically refers to a compound formed by cutting, chewing, extracting, or cooking these cruciferous vegetables. Typically, the derivative for use in combination with a SERM and / or AI is a compound formed from the hydrolysis of glucobrassicin.

[0095] In a further aspect of the invention, the invention provides the use of glucobrassicine itself or a derivative such as 1-methoxyglucobrassicine (neoglucobrassicine), 4-hydroxyglucobrassicine, 4-methoxyglucobrassicine, 1,4-dimethoxyglucobrassicine, 1-sulfoglucobrassicine, 6'-isoferuloylglucobrassicine as component (B) in combination with a SERM and / or an AI. Thus, in a particular embodiment, the invention provides a combination of a SERM and / or an AI in combination with glucobrassicine or one of these derivatives for use in the treatment of gynecomastia and / or breast pain.

[0096] In certain embodiments, the estrogen modulator is derived from cruciferous vegetables. Cruciferous or brassica vegetables include broccoli, Brussels sprouts, cabbage, collards, cauliflower, kale, mustard greens, turnips, rutabagas, and similar green leafy vegetables.

[0097] In a particular embodiment, the present invention relates to a selective estrogen receptor modulator and / or aromatase inhibitor (A), preferably tamoxifen or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method for preventing or treating gynecomastia and / or mastalgia.

[0098] wherein the method comprises administering a selective estrogen receptor modulator and / or an aromatase inhibitor to a patient in need thereof, (B): Including administration in combination with a cruciferous vegetable supplement or extract (e.g., I3C, or I3C and DIM, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof).

[0099] By supplement or extract is meant both synthetic and naturally occurring compounds. Cruciferous vegetable supplements / extracts or Brassica vegetable supplements / extracts can include compounds found in these vegetables (both synthetic or extracted), their synthetic forms, as well as compounds that are not present in the vegetable itself but are found in the Brassica / Brassica vegetable material (i.e., after it has been chopped, cut, extracted, or processed in some way).

[0100] Although there are no clinical data proving the use of herbal supplements in gynecomastia or breast pain, certain supplements have been shown to have potential as estrogen modulating agents, typically in the context of alternative hormone therapies to treat cancer.

[0101] Other food extracts believed to have estrogen modulating effects are wild nettle root, chrysin, soy, turmeric, maca, flavonoids, grape seed extract. In certain embodiments, the present invention relates to the use of the following in the treatment or prevention of gynecomastia and / or breast pain: (A): a selective estrogen receptor modulator and / or aromatase inhibitor (preferably tamoxifen or a pharma- ceutically acceptable salt, solvate or hydrate thereof); (B) Combination of wild nettle root, chrysin, soy, turmeric, maca, flavonoids, and grape seed extract.

[0102] Synergistic / collaborative combinations Tamoxifen (TAM) is known to have two mechanisms of action: (1) competing with 17β-estradiol (E2) at receptor sites and blocking the stimulatory role of E2 in tissues, as demonstrated by experiments in estrogen receptor knockout mice, in which mammary ductal development is severely impaired;

[0103] In humans, tamoxifen is primarily used in female breast cancer, and the majority of clinical and pharmacological data are based in this context. Tamoxifen typically acts as an estrogen receptor antagonist in breast cancer cells, but in certain other cell types, tamoxifen can act as an estrogen receptor agonist. Several mechanisms have been proposed for tamoxifen's regulation of cell growth, including modulation of growth factor signaling, control of cell cycle machinery, and downregulation of oncogenes. Tamoxifen has been shown to reduce estrogen receptor activity, but has no antiproliferative effect on estrogen receptor cell lines. This is an important property for this application, as I3C (or other estrogen modulators) can inhibit cell growth regardless of estrogen receptor status.

[0104] Considering the known peculiar features of the growth-suppressive cascade induced by I3C and tamoxifen, Cover et al. (1999) demonstrated that the combination of tamoxifen and I3C exhibited a more effective growth-suppressive response, tighter inhibition of CDK2 specific activity, and more endogenous Rb phosphorylation than either compound alone. The authors recommend considering I3C and tamoxifen as a potential combination therapy for controlling estrogen-responsive breast cancer. They further suggested that combining I3C with tamoxifen may overcome some of the shortcomings of tamoxifen therapy while taking advantage of the positive effects of this proven treatment. Two of the methods that have been proposed to circumvent tamoxifen resistance are low-dose and / or pulsed administration of tamoxifen. In this regard, the authors' results showed that low doses of tamoxifen and I3C inhibited MCF-7 cell growth and CDK2 specific activity to the same extent as high doses of either agent added individually. In principle, this response could be exploited to circumvent acquired drug resistance to sustained administration of high doses of tamoxifen. Alternatively, patients could receive intermittent pulses of tamoxifen while undergoing I3C treatment. I3C has been shown to reduce both spontaneous and carcinogen-induced breast tumor formation in rodents without any apparent side effects. Human subjects receiving I3C also had no side effects.

[0105] As mentioned above, estrogen regulators (B) can affect estrogen production through different biochemical pathways to SERMs and / or AIs (A).

[0106] Indeed, tamoxifen and I3C are synergistic in their effects on gynecomastia / mastalgia because they act on the estrogen pathway via different mechanisms of action (see Table 1).

[0107] [Table 1]

[0108] Surprisingly, the inventors have found that the combination of components (A) and (B) provides favorable results in the treatment of gynecomastia and / or breast pain.

[0109] formulation The components / compounds (A) and (B) of the present invention are preferably formulated as pharma- ceutically acceptable compositions. The phrase "pharma-ceutically acceptable" as used in connection with the compositions of the present invention refers to molecular entities and other components of such compositions that are physiologically acceptable and typically do not produce undesirable reactions when administered to a mammal (e.g., human). Preferably, as used herein, the term "pharma-ceutically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in mammals, particularly humans.

[0110] It will be understood that the components / compounds (A) and (B) of the present invention can be administered in the form of salts, solvates, hydrated prodrugs or esters, particularly in the form of salts.The present invention also provides pharma-ceutically acceptable salts, esters, solvates or prodrugs of the compounds described herein, whether selective estrogen receptor modulators and / or aromatase inhibitors (A), or estrogen modulators (B), particularly their pharma-ceutically acceptable salts.The following will discuss suitable salt, solvate, prodrug or ester forms.Typically, pharma-ceutically acceptable salts can be easily prepared by using a desired acid.

[0111] The components / compounds of the present invention can be administered in the form of salts, solvates, hydrated prodrugs or esters, particularly in the form of salts. In general, pharma-ceutically acceptable salts can be easily prepared by using the desired acid. The salts can precipitate from the solution and be collected by filtration or recovered by evaporation of the solvent. For example, an aqueous solution of an acid such as hydrochloric acid can be added to an aqueous suspension of the compound, and the resulting mixture can be evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid. Alternatively, the compound of the present invention can be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and an acid can be added to the same solvent or another suitable solvent. The resulting acid addition salt can then be precipitated directly or by adding a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.

[0112] Suitable addition salts are formed from inorganic or organic acids that form non-toxic salts, examples of which are hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, trifluoroacetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, alkyl or arylsulfonate (e.g. methanesulfonate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate) and isethionate.Representative examples include trifluoroacetate and formate, such as bis or tritrifluoroacetate and monoformate or diformate, particularly tritrifluoroacetate or bistrifluoroacetate and monoformate.The particularly preferred salt of tamoxifen is its citrate. Thus, in certain embodiments, if tamoxifen is present, it is administered as tamoxifen citrate.

[0113] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with the solvents they react with or from which they precipitate or crystallize. These complexes are known as "solvates." For example, complexes with water are known as "hydrates." Solvates of the compounds of the present invention are within the scope of the present invention. The salts of compounds / components (A) and (B) may form solvates (e.g., hydrates), and the present invention includes all such solvates.

[0114] The term "prodrug" as used herein means a compound that is converted in the body, for example by hydrolysis in the blood, into an active form that has medical effects.

[0115] In certain embodiments, the present invention provides the following in the treatment of gynecomastia and / or breast pain: (A): a pharmaceutical composition comprising a selective estrogen receptor modulator and / or an aromatase inhibitor (preferably tamoxifen or a pharma- ceutically acceptable salt, solvate or hydrate thereof); (B) a pharmaceutical composition comprising an estrogen modulator, wherein the estrogen modulator is different from the selective estrogen receptor modulator; and It relates to a combination of.

[0116] While it is possible for the compounds of the invention (e.g., SERM / AI (A) or estrogen modulator (B)) to be administered as bulk substances for use in the methods of the invention, it is preferred to have the active ingredient present in a pharmaceutical formulation, e.g., the agent is mixed with a pharma- ceutically acceptable excipient or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, all discussions relating to use in the treatment or prevention of gynecomastia and / or mastalgia also apply to the formulations of the invention. Thus, in certain embodiments, the invention provides pharmaceutical compositions comprising (A) and (B) and at least one excipient for use in the treatment of gynecomastia and / or mastalgia.

[0117] In certain embodiments, the present invention provides a pharmaceutical composition (A) comprising a selective estrogen receptor modulator and / or an aromatase inhibitor for use in a method for preventing or treating gynecomastia and / or mastalgia, The method comprises combining the pharmaceutical composition (A) and (B) a pharmaceutical composition comprising an estrogen modulator, wherein the estrogen modulator is different from the selective estrogen receptor modulator.

[0118] Such considerations apply to all other compounds / compositions for the use(s), methods, etc. of the invention.

[0119] The term "excipient" refers to a diluent, carrier, and / or vehicle with which an active compound is administered. Any pharmaceutical composition discussed herein (for either component (A) or (B)) may contain a combination of multiple excipients or carriers. Such pharmaceutical excipients or carriers may be sterile liquids such as water, saline, aqueous dextrose, aqueous glycerol, and oils, such as oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, or aqueous saline, dextrose, and glycerol solutions are preferably used as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in EW's "Remington's Pharmaceutical Sciences" (EW Martin, 18th Edition). The choice of pharmaceutical carrier can be selected taking into account the intended route of administration and standard pharmaceutical practice. In addition to the excipients, the pharmaceutical compositions may contain any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s). Particularly preferred carriers for the present invention are those suitable for immediate release, i.e., release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and which allow rapid absorption of the drug.

[0120] It will be understood that the pharmaceutical compositions for use according to the present invention (whether (A) or (B)) may be in the form of oral, parenteral, transdermal, inhalation, buccal, topical, implant, nasal, or enteral dosage forms, (or other mucosally administered) suspensions, capsules or tablets, gels, liquid preparations, skin patches, injections and infusions. These may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers or excipients. Preferably, both components (A) and (B) in the present invention are administered in the form of capsules or tablets. In a further embodiment, components (A) and / or (B) are administered as topical formulations (e.g., creams, skin patches, gels, etc.).

[0121] Also contemplated are key active ingredients that have been modified to improve bioavailability, or that have a similar mode of action to estrogen but are delivered in vehicles (e.g., gel vs. tablet) that differ in bioavailability, duration, efficacy, toxicity or tolerance effects.

[0122] Depending on the different delivery systems, there may be different composition / formulation requirements. Similarly, when the composition comprises multiple active components, those components may be administered by the same or different routes.

[0123] The pharmaceutical formulations of the present invention may be liquids suitable for oral, mucosal and / or parenteral administration, e.g. drops, syrups, solutions, injectable solutions, ready-to-use or prepared by dilution of freeze-dried products, but preferably solid or semi-solid, such as tablets, capsules, granules, powders, pellets, pessaries, suppositories, creams, ointments, gels, salves, or solutions, suspensions, emulsions or other forms suitable for administration via the transdermal route or by inhalation.

[0124] Tamoxifen is available primarily in two forms: a pill taken once a day (brand name: Nolvadex) or in liquid form (brand name: Soltamox). Thus, in certain embodiments, component (A) (i.e., a SERM and / or an AI) is administered as a pill / capsule / tablet or as a liquid (i.e., a solution / suspension).

[0125] The compounds of the invention can be administered for immediate, delayed, modified, sustained, pulsed, or controlled release applications.

[0126] In one embodiment, the oral composition is a slow-release, delayed-release, or positioned-release (e.g. enteric-coated, especially colonic-release) tablet or capsule. This release profile can be achieved, without limitation, by using a coating that is resistant to conditions in the stomach but releases its contents in the colon or other parts of the digestive tract (where the site is specified), or delayed release can be achieved simply by a coating that disintegrates slowly, or the two (delayed-release and positioned-release) profiles can be combined in one formulation by selecting one or more appropriate coatings and other excipients. Such formulations constitute a further feature of the present invention.

[0127] Pharmaceutical compositions can be prepared by mixing a therapeutically effective amount of an active substance with a pharma- ceutically acceptable carrier, which may have different forms depending on the method of administration. Typically, the components of the composition include one or more of binders, fillers, lubricants, odorants, dyes, sweeteners, surfactants, preservatives, stabilizers, and antioxidants. The pharmaceutical compositions of the present invention (i.e., for (A) and (B)) may contain 0.01-99% by weight / volume of the active substance (e.g., a pharmaceutical composition containing a SERM and / or an AI can contain 0.01-99% by weight of the SERM and / or AI, and a pharmaceutical composition containing an estrogen modulator can contain 0.01-99% by weight of the estrogen modulator). The total therapeutic dose (i.e., both the SERM / AI (A) and the estrogen modulator (B) combined) is generally about 10-2000 mg / day, preferably about 30-1500 mg / day. Other ranges may be used, such as, for example, 50-500 mg / day, 50-300 mg / day, 100-200 mg / day, etc.

[0128] Administration may be once a day, twice a day, or more frequently, and may be reduced during the maintenance phase of the disease or disorder, for example, once every 2 or 3 days instead of daily or twice a day. The dose and frequency of administration will depend on the clinical signs that confirm the maintenance of the remission phase, with a reduction or absence of at least one, or more preferably two or more, clinical signs of the acute phase known to those of skill in the art.

[0129] It is within the scope of the invention to administer the compounds described herein in combination with another pharmaceutical agent, for example, another agent known to be effective against gynecomastia and / or breast pain, where "in combination" means in juxtaposition, and the other agent may be administered before, during, or after administration of the compound / formulation of the invention.

[0130] Purpose Components (A) and (B) of the present invention may be administered simultaneously, separately or sequentially in all embodiments of the present invention, i.e., the selective estrogen receptor modulator and / or aromatase inhibitor (A) may be administered simultaneously, separately or sequentially with the estrogen modulator (B).

[0131] This applies to all embodiments / aspects of the invention, whether compositions / compounds for use, kits for use, methods, uses, etc.

[0132] The components (A) and (B) of the present invention are used in combination therapy. Generally, the combination therapy utilizes two components: (A) and (B). The component (A) is or comprises a selective estrogen receptor modulator and / or an aromatase inhibitor. The component (B) is or comprises an estrogen modulator, which is different from the selective estrogen receptor modulator. "In combination" here means in juxtaposition; component (B) can be administered before, during, or after administration of component (A). Component (B) may be formulated together with component (A) or separately. In a particular embodiment, the present invention provides a method for the treatment or prevention of gynecomastia and / or breast pain, comprising administering to a subject a therapeutically effective amount of gynecomastia and / or breast pain relief agent, comprising administering to a subject a therapeutically effective amount of gynecomastia and / or breast pain relief agent, comprising administering to a subject a therapeutically effective amount of gynecomastia and / or breast pain relief agent, comprising administering to a subject a therapeutically effective amount of gynecomastia and / or breast pain relief agent, and (A) with a selective estrogen receptor modulator and / or an aromatase inhibitor; (B) an estrogen modulator, and a composition (e.g., a pharmaceutical composition / formulation) comprising the same.

[0133] The compounds of the invention may be used in combination with other compounds with known effectiveness against gynecomastia and / or breast pain.

[0134] The present invention also relates to the combination of (A) and (B) (e.g., a kit comprising (A) and (B), or a composition comprising (A) and (B)) itself. Thus, in certain embodiments, the present invention relates to a ... (A) with a selective estrogen receptor modulator and / or an aromatase inhibitor; (B) an estrogen modulator that is different from the selective estrogen receptor modulator; and

[0135] In a further embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: (A) a first composition comprising or consisting of a selective estrogen receptor modulator and / or an aromatase inhibitor; (B) a second composition comprising or consisting of an estrogen modulator, wherein the estrogen modulator is different from the selective estrogen receptor modulator.

[0136] non-therapeutic use If any use described herein is considered to be non-therapeutic, the present invention also provides the use of components (A) and (B) in reducing breast size in a subject, such as a human, such as a human male. The human, such as a human male, may be an adult or a child (i.e., under 18 years of age). The present invention also provides a method of reducing breast size in a human, such as a human male, comprising administering components (A) and (B) of the present invention. Again, such administration may be simultaneous, separate, or sequential. The use / method may be non-therapeutic and / or cosmetic.

[0137] Treating gynecomastia and / or breast pain The compounds and combinations of the present invention are proposed for use in the treatment or prevention of gynecomastia and / or breast pain. By "treat" or "treatment" is meant at least one of the following: (i) preventing or delaying the onset of clinical symptoms of a disease occurring in a mammal; (ii) inhibiting the disease, i.e., preventing, alleviating or delaying the onset or recurrence of the disease, or at least one clinical or subclinical symptom thereof; or (iii) Alleviating or alleviating one or more of the clinical or subclinical symptoms of the disease.

[0138] Typically, treating gynecomastia refers to reducing breast size in subjects who have enlarged breasts as a result of gynecomastia.Treating breast pain typically refers to reducing breast pain in patients who have enlarged breasts as a result of hormonal imbalance.

[0139] In this specification, breast pain may refer to gynecomastia-related breast pain.The compounds and combinations of the present invention can be used to prevent / treat gynecomastia, prevent / treat breast pain, or both.Typically, in the case of breast pain, the compounds or combinations of the present invention are used for treatment as opposed to prevention.

[0140] The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the patient or to the physician. Generally, one of ordinary skill in the art will understand when "treatment" occurs.

[0141] The term prevention, as used herein, is used to encompass prophylactic treatment, i.e., treating a subject at risk of developing gynecomastia and / or mastalgia.

[0142] Exercise (such as push-ups) is not known to affect gynecomastia, but may help increase muscle mass in the chest area.

[0143] The compounds or combinations of the present invention can be used in any animal subject, particularly mammals, more particularly humans or animals used as models for disease (e.g., mice, monkeys, etc.), preferably humans, preferably male humans. Humans may be females (including transgender women). Humans may be adults or children (i.e., under 18 years of age).

[0144] By "effective dose" is meant the amount of a compound that, when administered to an animal for treating a state, disorder, or condition, is sufficient to effect such treatment. An "effective dose" will vary depending on the compound, the severity of the disorder / disease, and the age, weight, physical condition, and responsiveness of the subject undergoing treatment, and will ultimately be at the discretion of the attending physician.

[0145] In all aspects or embodiments of the present invention (compounds, uses, methods of use, etc.), the following combinations of components are highly preferred: (A) tamoxifen, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; and (B) Indole-3-carbinol (I3C) and / or 3,3'-diindolylmethane (DIM), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0146] Thus, in certain embodiments, the present invention provides tamoxifen, or a pharma- ceutically acceptable salt, solvate or hydrate thereof, for use in a method for preventing or treating gynecomastia and / or breast pain, wherein the method comprises administering tamoxifen (or a pharma- ceutically acceptable salt, solvate or hydrate thereof) in combination with indole-3-carbinol (I3C) and / or 3,3'-diindolylmethane (DIM), or a pharma- ceutically acceptable salt, solvate or hydrate thereof.

[0147] Clinical trial data show that daily administration of 10 mg or 20 mg tamoxifen (TAM) shows promise for the treatment of gynecomastia and / or breast pain. These daily doses represent typical embodiments of a SERM and / or AI. Treatment duration is typically 3-9 months.

[0148] I3C is typically taken as a daily food supplement in the range of 100mg / day to 500mg / day. DIM is typically taken as a daily supplement in the range of 100mg / day to 1000mg / day. Therapeutic doses in early-stage clinical trials are 2-3 times that administered as part of a daily supplement regimen. Thus, the preferred daily dose of I3C is 100mg to 1500mg / day. Thus, the preferred dose range of DIM is 100mg to 3000mg / day.

[0149] In certain embodiments, the selective estrogen receptor modulator and / or aromatase inhibitor (A) is administered at a dosage of 1-1000 mg / day, preferably 1-100 mg / day, preferably 1-50 mg / day, preferably 5-50 mg / day, preferably 10-40 mg / day. A particularly preferred dosage range for (A) is 1-20 mg / day.

[0150] In certain embodiments, the estrogen modulator (B) is administered at a dosage of 1-5000 mg / day, preferably 1-2500 mg / day, preferably 1-1000 mg / day, preferably 50-750 mg / day, preferably 100-400 mg / day.

[0151] When more than one estrogen modulator (B) is present, the above dosages refer to the combined dosage, as well as when both a SERM and an AI are present as component (A), or when more than one SERM is present.

[0152] Thus, the following treatment protocols, taken once or twice daily, for example over a period of 1 to 12 months, for example over a period of 3, 6 or 9 months, in separate or combined tablet form, respectively, are considered to be of particular interest to the present invention, specific embodiments of which are set out below: 1) TAM 10mg + I3C 200mg, 2)TAM10mg+I3C 100mg+DIM 100mg, 3) TAM 10mg + DIM 200mg, 4) TAM 20mg + DIM 200mg, 5)TAM20mg+I3C 200mg+DIM 200mg, 6)TAM20mg+I3C 500mg+DIM 500mg, 7) TAM 20mg + DIM 1000mg, 8)TAM20mg+DIM 1000mg+I3C 500mg, 9) TAM 20mg + I3C 500mg, 10) TAM 5mg + I3C 200mg, 11) TAM 5mg + I3C 400mg, 12) TAM 5mg + I3C 500mg, 13) TAM 5mg + I3C 1000mg, 14) TAM 2mg + I3C 200mg, 15) TAM 2mg + I3C 400mg, 16) TAM 2mg + I3C 500mg, 17) TAM 2mg + I3C 1000mg, 18) TAM 1mg + I3C 200mg, 19) TAM 1mg + I3C 400mg, 20) TAM 1mg + I3C 500mg, 21) TAM 1mg + I3C 1000mg.

[0153] Treatment protocols with dosages within + / - 50% of the above values ​​are contemplated herein and form specific embodiments of the invention. A dosage of 5 mg TAM + 200 mg I3C is particularly preferred. [Brief description of the drawings]

[0154] [Figure 1] We show the acid-catalyzed condensation of indole-3-carbinol (I3C) (ii) 3,3'-diindolylmethane (DIM), (iii) 5,6,11,12,17,18-hexahydrocyclononal [1,2-b:4,5-b':7,8-b'']triindole (CT) and (iv) 5,11-dihydroindolo-[3,2-b]carbazole (ICZ) to generate biologically active I3C oligomers. [Diagram 2] The antiestrogenic effects of indole-3-carbinol (I3C) and DIM3,3'-diindolylmethane (DIM) have been demonstrated (AhR = hydrocarbon receptor; CYP = cytochrome P450; ERα = estrogen receptor alpha; ESR1 = the gene encoding ERα) [Reference 7]. [Diagram 3] Shown is a photograph of the first week of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Figure 4] Shown is a photograph of the second week of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Diagram 5] Shown is the third week of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Figure 6] Shown is the fourth week of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Figure 7] Shown is a photograph of the fifth week of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Figure 8] Shown is a photograph at 10 weeks of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Figure 9] Shown is a photograph at 11 weeks of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C. [Figure 10] Shown is a photograph at 12 weeks of treatment with tamoxifen at 5 mg per day and another tablet of 200 mg I3C.

[0155] Working Example Overview: Male subjects with gynecomastia were administered a combination of tamoxifen and I3C. The purpose of the case study was to evaluate any adverse effects and positive benefits of the combination.

[0156] method: (I) For three months, subjects took a daily dose of 5 mg tamoxifen in the morning before breakfast along with another tablet of 200 mg I3C. This regimen was continued for another three months. Subjects also increased their push-ups from 5 times a day to 30 times a day by the end of the program.

[0157] The reduction in breast size is evident from photographs taken during the experimental period. No breast pain was reported. Photographic records over a 3-month period (up to week 12) are shown in Figures 3-10. Signs of improvement in gynecomastia, as indicated by breast reduction, began after 3 weeks and increased over the course of treatment. There were no significant side effects from the treatment. In fact, tamoxifen and I3C are known to cause headaches, nausea, vomiting, weight gain, impotence, and loss of libido. Surprisingly, despite the combined treatment, the subjects experienced efficacy without any side effects associated with the trial.

[0158] (I) For three months, subjects took a daily dose of 20 mg of tamoxifen in the morning before breakfast along with another tablet of 200 mg I3C. This regimen was continued for another three months. Subjects also increased their push-ups from 5 times a day to 30 times a day by the end of the program.

[0159] References [Table 2-1] [Table 2-2]

Table 2-3

Claims

1. A selective estrogen receptor modulator and / or an aromatase inhibitor (A) for use in a method of preventing and / or treating feminized breasts and / or breast pain, wherein the method comprises administering in combination the selective estrogen receptor modulator and / or the aromatase inhibitor with (B) an estrogen regulator different from the selective estrogen receptor modulator, the selective estrogen receptor modulator and / or the aromatase inhibitor (A).

2. The method according to claim 1, wherein the method comprises administering in combination the selective estrogen receptor modulator and / or the aromatase inhibitor with (B) a supplement containing an estrogen regulator, preferably a brassica vegetable supplement, the selective estrogen receptor modulator and / or the aromatase inhibitor (A) according to claim 1.

3. The selective estrogen receptor modulator and / or the aromatase inhibitor (A) according to claim 1, wherein the selective estrogen receptor modulator and / or the aromatase inhibitor (A) is a selective estrogen receptor modulator.

4. The selective estrogen receptor modulator and / or the aromatase inhibitor (A) according to claim 1, wherein the selective estrogen receptor modulator is a triphenylethylene-type selective estrogen receptor modulator.

5. The selective estrogen receptor modulator and / or the aromatase inhibitor (A) according to claim 1, wherein the selective estrogen receptor modulator (SERM) is selected from tamoxifen, raloxifene and / or clomiphene, preferably tamoxifen, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

6. The selective estrogen receptor modulator and / or the aromatase inhibitor (A) according to claim 1, wherein the aromatase inhibitor is selected from testolactone, anastrozole and letrozole, preferably testolactone, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

7. ​ ​ ​ ​ ​ ​ The estrogen regulator (B) is indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate or hydrate thereof; preferably, indole-3-carbinol (I3C) and / or 3,3'-diindolylmethane (DIM), or a pharmaceutically acceptable salt, solvate or hydrate thereof; preferably, indole-3-carbinol (I3C), or a pharmaceutically acceptable salt, solvate or hydrate thereof, the selective estrogen receptor regulator and / or aromatase inhibitor (A) according to claim 1.

8. - The selective estrogen receptor regulator and / or the aromatase inhibitor (A) is tamoxifen or a pharmaceutically acceptable salt, solvate or hydrate thereof; - The estrogen regulator (B) is indole-3-carbinol (I3C), or a pharmaceutically acceptable salt, solvate or hydrate thereof, the selective estrogen receptor regulator and / or aromatase inhibitor (A) according to claim 1.

9. - The selective estrogen receptor regulator and / or the aromatase inhibitor (A), - The estrogen regulator (B), are administered simultaneously, separately, or sequentially, the selective estrogen receptor regulator and / or aromatase inhibitor (A) according to claim 1.

10. The selective estrogen receptor regulator and / or the aromatase inhibitor is administered at a dose of 1 to 100 mg / day, preferably 5 to 50 mg / day, preferably 10 to 40 mg / day, the selective estrogen receptor regulator and / or aromatase inhibitor (A) according to claim 1.

11. The estrogen regulator (B) is administered at a dose of 1 to 1000 mg / day, preferably 50 to 750 mg / day, preferably 100 to 400 mg / day, the selective estrogen receptor regulator and / or aromatase inhibitor (A) according to claim 1.

12. - the estrogen receptor modulator and / or aromatase inhibitor (A) and / or - the estrogen regulator (B) is preferably administered orally, parenterally, transdermally, topically or enterally, in the form of a capsule or tablet the selective estrogen receptor modulator and / or aromatase inhibitor (A) according to claim 1.

13. A selective estrogen receptor modulator and / or aromatase inhibitor (A) for use in a method of preventing or treating gynecomastia and / or breast pain, wherein the method comprises administering the selective estrogen receptor modulator and / or the aromatase inhibitor together with (B) cruciferous vegetables, wild mulberry root, chrysin, soybeans, turmeric, maca, flavonoids or grape seed supplements or extracts, preferably cruciferous vegetable supplements or extracts, including a selective estrogen receptor modulator and / or aromatase inhibitor (A).

14. A composition for use in the treatment or prevention of gynecomastia and / or breast pain, comprising: (A) a selective estrogen receptor modulator and / or aromatase inhibitor; and (B) an estrogen regulator different from the selective estrogen receptor modulator.

15. A pharmaceutical composition for combination therapy for treating gynecomastia and / or breast pain, - a first pharmaceutical component comprising a selective estrogen receptor modulator and / or aromatase inhibitor; - a second pharmaceutical component comprising an estrogen regulator, the estrogen regulator being different from the selective estrogen receptor modulator; comprising as active ingredients a pharmaceutical composition.

16. Tamoxifen, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in a method of preventing or treating gynecomastia and / or breast pain, wherein the method comprises administering the tamoxifen in combination with (B) indole-3-carbinol (I3C) and / or 3,3'-diindolylmethane (DIM), or a pharmaceutically acceptable salt, solvate or hydrate thereof, tamoxifen, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

17. For simultaneous, separate, or sequential use in the treatment of feminized breasts and / or breast pain, a combination of (A) a selective estrogen receptor modulator and / or an aromatase inhibitor and (B) an estrogen regulator different from said selective estrogen receptor modulator, wherein: Preferably, said selective estrogen receptor modulator and / or said aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; Preferably, said estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, Combination.

18. For simultaneous, separate, or sequential use in the treatment of feminized breasts and / or breast pain, a pharmaceutical combination comprising (A) a selective estrogen receptor modulator and / or an aromatase inhibitor and (B) an estrogen regulator different from said selective estrogen receptor modulator, wherein: Preferably, said selective estrogen receptor modulator and / or said aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; Preferably, said estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, Pharmaceutical.

19. A kit for simultaneous, separate, or sequential use in the treatment of feminized breasts and / or breast pain, comprising: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen regulator different from the selective estrogen receptor modulator, wherein: Preferably, the selective estrogen receptor modulator and / or the aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; Preferably, the estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; The kit.

20. A method for treating or preventing feminized breasts and / or breast pain, the method comprising administering to a subject in need thereof an effective amount of: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen regulator different from the selective estrogen receptor modulator, simultaneously, separately, or sequentially, wherein: Preferably, the selective estrogen receptor modulator and / or the aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; Preferably, the estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate, or hydrate thereof; The method.

21. In the manufacture of a combination pharmaceutical for the treatment of feminized breasts and / or breast pain, the use of: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen regulator different from the selective estrogen receptor modulator, wherein: Preferably, the selective estrogen receptor modulator and / or the aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate or hydrate thereof, Use.

22. A pharmaceutical composition comprising: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen regulator different from the selective estrogen receptor modulator, wherein: Preferably, the selective estrogen receptor modulator and / or the aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate or hydrate thereof, Pharmaceutical composition.

23. The use of: (A) a selective estrogen receptor modulator and / or an aromatase inhibitor, and (B) an estrogen regulator different from the selective estrogen receptor modulator, for reducing the breast size and / or breast pain of a subject, wherein: Preferably, the selective estrogen receptor modulator and / or aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate or hydrate thereof; Use.

24. A method for reducing the breast size and / or breast pain of a subject, the method comprising the step of administering (A) a selective estrogen receptor modulator and / or an aromatase inhibitor and (B) an estrogen regulator different from the selective estrogen receptor modulator: Preferably, the selective estrogen receptor modulator and / or the aromatase inhibitor is a selective estrogen receptor modulator selected from tamoxifen, raloxifene, and clomiphene, or a pharmaceutically acceptable salt, solvate or hydrate thereof; Preferably, the estrogen regulator is selected from indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and / or 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b'']triindole (CT), or a pharmaceutically acceptable salt, solvate or hydrate thereof; (A) and (B) are administered simultaneously, separately, or sequentially; Method.

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