Pharmaceutical formulations and systems for delivery of androgenic agents and aromatase inhibitors, and methods for use

Abstract

To provide a formulation having a novel sustained release multi-phasic concentration pattern, particularly a formulation that can be used to reduce mammographic breast density and / or breast stiffness in warm-blooded animals.SOLUTION: For example, the formulation may include administration of an effective amount of an androgenic agent and an effective amount of an aromatase inhibitor to a subject, and provides a sustained release multiphasic concentration pattern in the blood of the subject over time, as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor, and particularly improves breast tissue stability and / or increases androgen receptor expression levels.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present disclosure generally relates to pharmaceutical formulations that have novel multiphasic release patterns when delivered to warm-blooded animals. and / or drug delivery systems. The disclosed compositions are organ-specific and / or or does not increase or substantially increase serum estradiol levels. androgen levels in warmer, more responsive, and more effective when organ-specific or serum androgen levels are desired. The present disclosure is also useful in animals. and organ-specific or is used in warm-blooded animals when it is desirable to increase serum androgen levels. androgenic and allotropic agents that deliver a multiphasic release pattern or pharmacokinetic profile that may be used in combination with other androgen-containing compounds. The present invention relates to providing an implant or transdermal patch containing a matase inhibitor. Methods of use are also disclosed, including methods relating to chronic autoimmune inflammatory conditions.

[0002] Related References Boyd,et al.,“Evidence that Breast Tissu e Stiffness is Associated with Risk of B reast Cancer”PLoS One 2014 Jul10;9(7):e1 00937, Cheng Q, Jabbari K, Winkelmaier G, et al.O verexpression of CD36 in mammary fibrobl asts suppresses colony growth in breast cancer cell lines.Biochem Biophys Res Co mmun 2020;526(1):41-47、 Das L,Rai A,Vaiphei K,et al.Idiopathic gigantomastia:newer mechanistic insights implicating the paracrine milieu.Endocr ine 2019;66(2):166-177、 Dawson CA,Pal B,Vaillant F,et al.Tissue -resident ductal macrophages survey the mammary epithelium and facilitate tissue remodelling.Nat Cell Biol 2020;22(5):54 6-558、 DeFilippis RA,Fordyce C,Patten K,et al. Stress signaling from human mammary epit helial cells contributes to phenotypes o f mammographic density.Cancer Res 2014;7 4(18):5032-44、 D’Orsi CJ,Sickles EA,Mendelson EB,Morri s EA et al.(2013).ACR BI-RADS(R)Atlas,Br east Imaging Reporting and Data System.R eston,VA:American College of Radiology、 Goulabchand R,Hafidi A,Van de Perre P,e t al.Mastitis in Autoimmune Diseases:Rev iew of the Literature,Diagnostic Pathway ,and Pathophysiological Key Players.J Cl in Med 2020;9(4)、 Gubbels Bupp MR,Jorgensen TN.Androgen-I nduced Immunosuppression.Front Immunol 2 018;9:794、 GuhlS,Artuc M,Zuberbier T,et al.Testost erone exerts selective anti-inflammatory effects on human skin mast cells in a c ell subset dependent manner.Exp Dermatol 2012;21(11):878-80、 Jeremy Bercoff,“Sharewave Elastography- White Paper”SuperSonic Imagine,S.A.copyr ight 2008、 Liu Y,Sun Y,Zhou Y,et al.,Sinomenine hy drochloride inhibits the progression of plasma cell mastitis by regulating IL-6 / JAK2 / STAT3 pathway.Int Immunopharmacol 2 020;81:106025、 Touraine P,Youssef N,Alyanakian MA,et a l.Breast inflammatory gigantomastia in a context of immune-mediated diseases.JC lin Endocrinol Metab 2005;90(9):5287-94. Uray IP,Liang Y,Hyder SM.Estradiol down -regulates CD36 expression in human brea st cancer cells.Cancer Lett 2004;207(1): 101-7, Walecki M, Eisel F, Klug J, et al.Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells.Molec ular Biology of the Cell 2015;10.1091 / mb c.E14-08-1323, Wang H, Franco F, Tsui YC, et al.CD36-medi ated metabolic adaptation supports regul atory T cell survival and function in tu mors.Nat Immunol 2020;21(3):298-308, U.S. Provisional Patent Application No. 62 / 067,297, filed October 22, 2014, entitled "Methods of Reducing Mammographic Breast" "Density and / or Breast Cancer Risk" U.S. Provisional Patent Application No. 62 / 324,525, filed April 19, 2016, entitled " Methods of Reducing Mammographic Breast "Density and / or Breast Cancer Risk" U.S. Patent Application No. 14 / 920,192, filed October 22, 2015, entitled "M ethos of Reducing Mammographic Breast D sensity and / or Breast Cancer Risk”, U.S. Patent Application No. 15 / 490,309, filed April 18, 2017, entitled "M ethos of Reducing Mammographic Breast D sensity and / or Breast Cancer Risk”, PCT / AU2015 / 000633, filed October 22, 2015, entitled "Me thods of Reducing Mammographic Breast De nsity and / or Breast Cancer Risk.”

[0003] These references and PCT / AU2015 / 000633, U.S. Patent Application No. 62 / Nos. 067,297, 62 / 324,525, 15 / 490,309, and No. 14 / 920,192, each of which is incorporated herein by reference in its entirety. [Background technology]

[0004] Testosterone is essential in regulating immune function in both men and women (G (Ubbels Bupp, 2018). This significantly disrupts serum estradiol levels. It simultaneously reduces estradiol levels in the same tissues without causing side effects. Increasing tissue levels of dihydrotestosterone (DHT) is desirable in some DHT is a hormone produced in tissues that is primarily derived from testosterone. The compound is delivered to the tissues in need of treatment via the circulation. Testosterone delivery is a method to increase testosterone without causing androgenic side effects. Problems arise due to the relatively small therapeutic window available for dosing.

[0005] Most tissues also contain the enzyme 5α-reductase, which converts testosterone to DHT. Therefore, it is possible to increase DHT without increasing estradiol. In desirable therapeutic situations, there is an unmet need and the present disclosure provides and 5α-reductase enzyme induction, thereby reducing DHT versus estradiol in the tissue. The present invention relates to providing a pharmaceutical formulation that affects a change in the ratio of

[0006] In both men and women, subcutaneous testosterone inhibits zero-order kinetics of testosterone. However, many physiological and disease states have been The use of testosterone alone in this condition may result in high levels of agonist activity in tissues receiving therapeutic intervention. This is an example of a woman with high mammographic breast density. They have very high levels of the aromatase enzyme in their tissues and preferentially produce testosterone. 43% of women aged 40-75 in the United States % have a mammographic breast density (MBD) classified as high, i.e., 3 and 4 (or c and d) Breast Imaging Reporting and Data System (BI-RADS (registered trademark) It is estimated that the American Cancer Foundation ation suggests that high breast density is a significant risk factor for the development of breast cancer. Traditionally, therapeutic interventions during the perimenopausal transition have consisted of low-dose combined oral contraceptives or continuous ejaculation. streptosteroid and synthetic progestin delivery systems, which are used to treat endometrial cancer risk Protects the uterus from both increased breast size and unwanted uterine bleeding. This is due to the high breast density. and / or breast hardness, and is an inappropriate treatment for women with already unstable testes. This is because it reduces steroid hormone levels and increases breast density and / or breast firmness. However, these are Menopause Society of North Am erica and the Menopause Society of Australia This is a current recommendation.

[0007] Another problem in the prior art is breast pain and its treatment. 45% of women in their 30s report that breast pain affects their quality of life It was estimated that 10% of women have experienced breast pain for at least half their lifetime. There are few treatment options available, with tamoxifen and aromatase inhibitors being the only treatments available. It has been used as an off-label medication for this condition. The aromatase inhibitors are associated with significant side effects that affect patient compliance. , as a single agent in premenopausal women due to the resulting disruption of the hypothalamic-pituitary-ovarian axis. There is a need in the art for better treatments to relieve breast pain in women. It is considered essential.

[0008] Elasticity of breast tissue is recognized as a contributing factor in the formation of breast cancer. Increased elasticity of breast cells leads to increased genome-wide mechanical signaling in cells, which leads to greater It has been demonstrated that mechanistic signals in the genome of cells can lead to malignant transformation. The composition provides a pharmaceutical formulation that reduces viral transmission and reduces the risk of malignant transformation. There is a need in the art.

[0009] A further problem in the art is the development of tissue-specific autoimmune inflammatory conditions, particularly in the breast. These conditions can be referred to as autoimmune inflammatory mastitis (AIM). The anatomical, histological, and physiological roles of salivary and mammary glands are similar, and Both belong to the effector sites of the mucosal immune system, which is relevant in that they predispose to autoimmunity. Autoimmune breast tissue has a lower level of aromatase (aromatase) compared to normal breast tissue. It has been shown that the hormone (which converts androgens into estradiol) is elevated and upregulated. IGF2, EGFR, TGF-β, PDGFR-α, and β are known to be involved in inflammation. AIM is usually associated with intensive immunosuppressive therapy and / or other factors. or treated with disfiguring surgery, and therefore improved therapies are needed. do.

[0010] How a drug composition is delivered and how it affects the body is determined by the pharmacokinetics of the drug composition. the pharmacokinetic and / or pharmacodynamic profile, the drug delivery system, and / or the drug In a broad sense, pharmacokinetics can refer to the uptake of a drug in the body, the site of delivery, and the A description of the rate and extent of distribution and / or elimination. In other words, the rate and extent of In a broad sense, pharmacodynamics is the process by which a drug acts on the body. or a description of how it affects a part of the body. For example, some drug compositions may have different pharmacokinetic and / or pharmacodynamic profiles. The kinetics and / or dynamics may be determined by the efficacy of the drug composition. and / or may have an effect on the efficacy of a particular drug composition. The role that pharmacokinetics and / or pharmacodynamics play in a particular drug delivery system may be different for a particular drug. The method may relate to a drug, a pharmaceutical composition, and / or an outcome for a subject.

[0011] Already, testosterone has been combined with aromatase inhibitors to enhance testosterone levels. Implants have been created that may result in inhibition of the conversion to tradiol. If the compound's formulation and concentration result in the active ingredient being delivered via zero-order kinetics, optimal The end result is a decrease in serum estradiol levels, which is undesirable in many situations. Possible side effects from estrogen deficiency symptoms and higher sustained levels of aromatase inhibitors The potential for medical treatment to provide a high ratio of DHT to estradiol in tissues There is a continuing need for drug formulations and / or delivery systems. Increased tissue levels of dihydrotestosterone (DHT), while simultaneously increasing serum estradiol levels. It reduces estradiol levels in the same tissues without causing significant perturbations. There is also a continuing need for alternatives to currently available treatments for diseases and conditions that would benefit from such treatment. It is considered essential. Summary of the Invention [Problem to be solved by the invention]

[0012] The present disclosure in one or more embodiments provides a method for manufacturing a semiconductor device that is compatible with conventional semiconductor devices, as will become apparent from the disclosure herein. Addressing and / or ameliorating one or more of the shortcomings of the art, or providing a useful pharmaceutical product In one or more embodiments, the present invention relates to at least providing a drug or therapeutic delivery system. The present disclosure also provides other advantages and / or improvements as discussed herein. obtain. [Means for solving the problem]

[0013] To obtain a high ratio of DHT to estradiol in tissues, the inventors performed a test A multiphasic release system for steroids and aromatase inhibitors is urgently needed. It is recognized that there is a need for one or more embodiments of the pharmaceutical formulations described herein. In this case, an early peak of serum testosterone may be provided, which is associated with high levels of aromatase. Rapidly blocked by 5α-reductase inhibitors, inhibiting the conversion of testosterone to DHT The formulation then provides a rapid reduction of the aromatase inhibitor to induce esophageal reflux. The blockade of estradiol production is not total, resulting in symptomatic reduction of serum estradiol levels. This ensures that there is no decrease in DHT in tissues where aromatase overexpression is present. The shift in the system from elevated to elevated estradiol levels takes advantage of this multiphasic release pattern. For example, if the zero-order kinetics of both components is utilized, then estradiol can be used. There is no release of hormones, which has adverse effects on women and affects their response to treatment. Undesirable long-term exposure to higher than required levels of aromatase inhibitors Brings dew.

[0014] In an embodiment of the invention, an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and and a binding agent, wherein the formulation, upon administration to a subject, inhibits vasoconstriction of the androgenic agent. Concentrations of aromatase inhibitors and serum concentrations of aromatase inhibitors are correlated over time. Provide a sustained release multiphasic concentration pattern in elephant blood and sustained release in the subject's serum or plasma. The multiphasic concentration pattern is The androgen has the first peak concentration (Tmax) in serum and inhibits aromatase. A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, The androgen will first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; Includes.

[0015] In another embodiment of the present invention, a compound comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binding agent, wherein the formulation, upon administration to a subject, over time as measured by serum concentrations for aromatase inhibitors and plasma concentrations for aromatase inhibitors. providing a sustained release multiphasic concentration pattern in the subject's blood, and The sustained release multi-phase concentration pattern is The androgen has the first peak concentration (Tmax) in serum and inhibits aromatase. A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, The androgen will first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; The androgen has a second peak concentration in serum that is less than Tmax and a third period during which the enzyme inhibitor gradually decreases in concentration in the plasma, and during the third period, a third period during which the concentration of the lomatase inhibitor is less than the concentration of the androgenic agent; The androgens have gradually decreasing serum levels, and the aromatase inhibitors have gradually decreasing serum levels. a fourth, which has a gradually decreasing concentration in the plasma, the decreasing levels of both being approximately parallel to each other; The period includes:

[0016] In another embodiment of the present invention, a compound comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binder, wherein the pharmaceutical formulation is compressed into pellets, and the pellets are Serum concentrations of androgens and aromatase inhibitors after subcutaneous administration to elephants a sustained-release multiphasic concentration pattern in the subject's blood over time as measured by plasma concentration and wherein the sustained release multiphasic concentration pattern in the serum or plasma of the subject is Androgens have the first peak concentration (Tmax) in serum, and aromatase inhibitors a first period in which the concentration is increasing in plasma but is below its Tmax concentration in plasma; , The androgen will first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; Includes.

[0017] In another embodiment of the present invention, a compound comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binder, wherein the pharmaceutical formulation is compressed into pellets, and the pellets are Serum concentrations of androgens and aromatase inhibitors after subcutaneous administration to elephants a sustained-release multiphasic concentration pattern in the subject's blood over time as measured by plasma concentration and wherein the sustained release multiphasic concentration pattern in the serum or plasma of the subject is The androgen has the first peak concentration (Tmax) in serum and inhibits aromatase. A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, The androgen will first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; The androgen has a second peak concentration in serum that is less than Tmax and a third period during which the enzyme inhibitor gradually decreases in concentration in the plasma, and during the third period, a third period during which the concentration of the lomatase inhibitor is less than the concentration of the androgenic agent; The androgens have gradually decreasing serum levels, and the aromatase inhibitors have gradually decreasing serum levels. a fourth, which has a gradually decreasing concentration in the plasma, the decreasing levels of both being approximately parallel to each other; The period includes:

[0018] In at least some embodiments, the pharmaceutical formulation comprises a test dose of 60 mg to 120 mg. steroids or their esters, 2 mg to 6 mg of an aromatase inhibitor, more preferably 4 mg to 6 mg of an aromatase inhibitor, and stearic acid, and the pharmaceutical formulation The pellets are compressed into pellets with diameters of 4.75 mm to 4.75 mm and lengths of 4 mm to 7 mm. The testosterone esters were administered subcutaneously to subjects and the serum concentrations and and aromatase inhibitors in the blood of a subject over time as measured by plasma concentrations. and providing a sustained release multi-phase concentration pattern in Testosterone or its esters have a first concentration peak (Tmax) in serum. The aromatase inhibitor is increased in plasma concentration, but not below its Tmax concentration in plasma. The first period is lower, Testosterone or its esters first decrease serum levels, then increase and aromatase inhibitors have their Tmax concentration in plasma. and a second period in which the

[0019] In at least some embodiments, the pharmaceutical formulation comprises a test dose of 60 mg to 120 mg. steroids or their esters, 2 mg to 6 mg of an aromatase inhibitor, more preferably 4 mg to 6 mg of an aromatase inhibitor, and stearic acid, and the pharmaceutical formulation The pellets are compressed into pellets with diameters of 4.75 mm to 4.75 mm and lengths of 4 mm to 7 mm. The testosterone esters were administered subcutaneously to subjects and the serum concentrations and and aromatase inhibitors in the blood of a subject over time as measured by plasma concentrations. and providing a sustained release multi-phase concentration pattern in Testosterone or its esters have a first concentration peak (Tmax) in serum. The aromatase inhibitor is increased in plasma concentration, but not below its Tmax concentration in plasma. The first period is lower, Testosterone or its esters first decrease serum levels, then increase and aromatase inhibitors have their Tmax concentration in plasma. a second period in which A second peak serum concentration of testosterone or its esters that is less than Tmax a third period in which the aromatase inhibitor is gradually reduced in concentration in the plasma; During the third period, the aromatase inhibitor increases the concentration of testosterone or its esters. The third period is when the Testosterone or its esters have gradually decreasing serum levels and aroma The enzyme inhibitor has a gradually decreasing concentration in the plasma, and both decreasing levels are approximately equal to each other. and a fourth period, which is roughly parallel to the first period.

[0020] In certain exemplary embodiments, the pharmaceutical preparation during the first period contains an aromatase inhibitor. The toxic agent does not exhibit zero-order release.

[0021] In certain exemplary embodiments, the pharmaceutical preparation during the first period contains an aromatase inhibitor. The inhibitor exhibits first-order release.

[0022] In certain exemplary embodiments, the pharmaceutical preparation during the second period contains an aromatase inhibitor. The toxic agent does not exhibit zero-order release.

[0023] In certain exemplary embodiments, in the pharmaceutical formulation during the second period, an androgenic agent (e.g., testosterone or its esters) do not exhibit zero-order release.

[0024] In certain exemplary embodiments, the medicament during the third period includes an aromatase inhibitor. The agent does not exhibit zero order release.

[0025] In certain exemplary embodiments, in the pharmaceutical formulation during the third period, an androgenic agent does not exhibit zero-order emission.

[0026] In certain exemplary embodiments, the pharmaceutical preparation during the third period contains an aromatase inhibitor. The inhibitor exhibits first-order release.

[0027] In certain exemplary embodiments, in the pharmaceutical formulation during the third period, an androgenic agent indicates first order release.

[0028] In certain exemplary embodiments, the pharmaceutical preparation during the fourth period contains an aromatase inhibitor. The toxic agent does not exhibit zero-order release.

[0029] In certain exemplary embodiments, in the pharmaceutical formulation during the fourth period, an androgenic agent does not exhibit zero-order emission.

[0030] In certain exemplary embodiments, the pharmaceutical preparation during the fourth period contains an aromatase inhibitor. The inhibitor exhibits first-order release.

[0031] In certain exemplary embodiments, in the pharmaceutical formulation during the fourth period, an androgenic agent indicates first order release.

[0032] In certain exemplary embodiments of the pharmaceutical formulation, the first period of time is The administration ends immediately after the first peak concentration (Tmax). In some embodiments, the first period ends in 5 to 14 hours. In an embodiment, the first period ends in 5.5 hours to 13 hours.

[0033] In certain exemplary embodiments of the pharmaceutical formulation, the second period of time is In certain exemplary embodiments of the pharmaceutical formulation, the second The period ends between 23 and 80 hours.

[0034] Additionally, certain embodiments include about 80 mg of testosterone or an ester thereof, about 4 mg of g of anastrozole and about 2 mg of stearic acid. The pharmaceutical preparation is a pellet having a diameter of 4.4 mm to 4.6 mm and a length of 4 mm to 7 mm. The pellets are compressed into pellets, which are then administered subcutaneously to subjects to deliver testosterone or its esters. as measured by serum concentrations for α-tocopherol and plasma concentrations for anastrozole. providing a sustained-release multiphasic concentration pattern in the subject's blood over time, testosterone or its esters have a first concentration peak (Tmax) in serum. , anastrozole is increasing in concentration in plasma, but is below its Tmax concentration in plasma. During the first period, testosterone or its esters are first released, causing serum levels to decrease. concentration, then increasing serum level concentration, so that anastrozole reaches its Tm ax concentration of testosterone or its ester less than Tmax. The anastrozole then gradually decreases in concentration in the plasma, with a second peak concentration in the serum at 0.50. a third period in which anastrozole is administered in combination with testosterone or A third period in which the concentration of testosterone or its esters is lower than that of testosterone or its esters. The drug has a gradually decreasing serum level concentration, and anastrozole has a gradually decreasing plasma concentration. and a fourth period having concentrations that decrease in both levels approximately parallel to each other. Methods of using the pharmaceutical formulations are also disclosed.

[0035] Further embodiments include a composition comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and The present invention relates to a pharmaceutical formulation comprising a binder, the pharmaceutical formulation being compressed into pellets, The serum concentration of androgens and aromatase inhibitors was measured by subcutaneous administration to subjects. A sustained-release multiphasic concentration pattern in the subject's blood over time as measured by plasma concentrations and a sustained release multiphasic concentration pattern in the subject's serum or plasma is The aromatase inhibitor has a first peak concentration (Tmax) in the serum and a second peak concentration (Tmax) in the plasma. a first period having no Tmax concentration, and a serum level concentration at which the androgenic agent declines; The aromatase inhibitor then has an increasing serum level concentration, and reaches its Tmax concentration in plasma. and a second period having a second peak in serum where the androgenic agent is less than its Tmax. and a third period in which the aromatase inhibitor has a peak concentration in the plasma and gradually decreases in concentration. and during the third period, the concentration of the aromatase inhibitor is lower than the concentration of the androgenic agent. A third period in which the serum levels of androgens are reduced and aromatase inhibitors are and a fourth period of time having a decreasing concentration in plasma.

[0036] Further embodiments include those comprising: and methods for reducing tomographic breast density in patients in need thereof. The patient is administered i) an effective amount of an androgenic agent, and ii) an effective amount of an aromatase inhibitor. The method involves administering a subcutaneous pellet containing the toxic agent.

[0037] Further embodiments of the pharmaceutical preparation in the method for reducing VBD% include administering to a patient in need thereof. The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0038] Further embodiments of the pharmaceutical preparations in methods for reducing AVBD include administering to a patient in need thereof. The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0039] Further embodiments of the pharmaceutical formulation in the method of reducing AVBD and VBD% include: The present invention relates to use in a patient in need thereof, comprising administering to the patient: i) an effective amount of androgen; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. include.

[0040] Further embodiments include those comprising: of a pharmaceutical preparation in a method for treating tomographic breast density in a patient in need thereof The present invention relates to a method for treating a patient suffering from atopic dermatitis, the method comprising administering to a patient i) an effective amount of an androgenic agent, and ii) an effective amount of an androgenic agent. The method includes administering a subcutaneous pellet containing an aromatase inhibitor.

[0041] Further embodiments of the pharmaceutical preparation in the method for reducing ABD% include administering to a patient in need thereof. The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0042] Further embodiments of the pharmaceutical preparations in the methods for reducing AABD include administering to a patient in need thereof. The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0043] Further embodiments of the pharmaceutical formulation in the method of reducing AABD and ABD% include: The present invention relates to use in a patient in need thereof, comprising administering to the patient: i) an effective amount of androgen; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. include.

[0044] Further embodiments are directed to patients with breasts having a mammographic breast density of 7.5% or greater. Use of a pharmaceutical preparation in a method for reducing mammographic breast density in wherein the patient is administered i) an effective amount of an androgenic agent, and ii) an effective amount of an aromatase inhibitor. The method includes administering a subcutaneous pellet containing the agent.

[0045] Further embodiments provide for increasing VBD% in patients with breasts with VBD% of 7.5% or greater. The present invention relates to the use of a pharmaceutical preparation in a method for reducing i) an effective amount of androgen and ii) administering to the patient a subcutaneous pellet containing an effective amount of an aromatase inhibitor. Includes.

[0046] Further embodiments provide for increasing the ABD% in patients with breasts with an ABD% of 7.5% or greater. The present invention relates to the use of a pharmaceutical preparation in a method for reducing the risk of HIV infection in a patient, comprising administering to the patient: i) an effective amount of HIV; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. Includes:

[0047] Further embodiments include 3 or 4 (or c or d) BI-RADS® ) score in a method for treating mammographic breast density in a patient with breast The present invention relates to the use of a pharmaceutical formulation, comprising administering to a patient: i) an effective amount of an androgenic agent; and ii) ) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0048] Further embodiments include 3 or 4 (or c or d) BI-RADS® In a method for reducing mammographic breast density in patients with breasts having a The present invention relates to the use of a pharmaceutical preparation comprising administering to a patient: i) an effective amount of an androgenic agent; and i) i) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0049] Further embodiments involve the pharmaceutical preparation in a method for inducing breast involution. The present invention relates to a method for treating a patient, the method comprising administering to the patient: i) an effective amount of an androgenic agent; and i) administering to the patient an effective amount of an androgenic agent; and i) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0050] Further embodiments include a method for inducing terminal cell death of proliferation in the breast of a patient. The present invention relates to the use of a pharmaceutical preparation containing the compound in a patient in need thereof, which provides the patient with: i) an effective and ii) a subcutaneous pellet containing an effective amount of an androgenic agent, and This includes giving.

[0051] Further embodiments include a method for determining the ultimate extracellular matrix development in the patient's breast. Use of pharmaceutical preparations in methods of inducing matrix degradation in patients in need thereof The present invention relates to the use of a method for treating a patient, the method comprising administering to the patient i) an effective amount of an androgenic agent, and ii) an effective amount of an anti-androgenic agent. This involves administering a subcutaneous pellet containing a lomatase inhibitor.

[0052] Further embodiments provide methods for determining breast cell counts and mammograms in peri-menopausal patients. The present invention relates to the use of a pharmaceutical preparation in a method for reversing breast density, comprising administering to a patient: i) administering to a patient an effective amount of and ii) a subcutaneous pellet containing an effective amount of an androgenic agent, and ii) an effective amount of an aromatase inhibitor. This includes administering.

[0053] Further embodiments involve the reduction of mammographic breast density and perimenopausal symptoms. The present invention relates to the use of a pharmaceutical preparation in a method for reducing the risk of heart failure in a patient suffering from heart failure. The patient is administered a therapeutic agent comprising: i) an effective amount of an androgenic agent; and ii) an effective amount of an aromatase inhibitor. This involves administering a subcutaneous pellet containing

[0054] Further embodiments provide a method for reducing the risk of breast cancer in premenopausal and / or perimenopausal women. At about the same time as reducing the hypothalamic-pituitary axis and / or other endocrine systems, e.g. Methods that may be used to avoid causing disruption to the kidney and / or ovarian glands include: This document relates to the use of pharmaceutical preparations in

[0055] Further embodiments of the pharmaceutical formulation in a method for reducing breast firmness include administering to a patient in need thereof. The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0056] Further embodiments of the pharmaceutical preparation in a method for reducing mastalgia involve The present invention relates to a method for treating a patient, the method comprising administering to the patient: i) an effective amount of an androgenic agent; and i) administering to the patient an effective amount of an androgenic agent; and i) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0057] A further embodiment of the pharmaceutical preparation in a method for reducing breast elasticity is The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0058] Further embodiments include reducing mechanotransduction in the genome of a cell to prevent malignant transformation. Use of pharmaceutical preparations in patients in need thereof in a manner that reduces the risk of transformation The present invention relates to the use of a method for treating a patient, the method comprising administering to the patient i) an effective amount of an androgenic agent, and ii) an effective amount of an anti-androgenic agent. This involves administering a subcutaneous pellet containing a lomatase inhibitor.

[0059] A further embodiment of the pharmaceutical preparation in a method for increasing the ratio of fibroglandular to adipose tissue comprises: The present invention relates to use in a patient in need thereof, comprising administering to the patient: i) an effective amount of androgen; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. include.

[0060] Further embodiments of the pharmaceutical preparations in methods for increasing CD36 include administering to a subject in need thereof. The present invention relates to use in a patient having a condition in which the patient is receiving i) an effective amount of an androgenic agent, and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0061] Further embodiments provide a method for stabilizing the level of androgen receptor expression in breast tissue of a patient. Use of a pharmaceutical preparation in a patient in need thereof in a method for enhancing and / or increasing The present invention relates to the use of a method for treating a patient, the method comprising administering to the patient i) an effective amount of an androgenic agent, and ii) an effective amount of an anti-androgenic agent. This involves administering a subcutaneous pellet containing a lomatase inhibitor.

[0062] Further embodiments of the pharmaceutical formulation in a method for reducing and / or treating macrostomia include: The present invention relates to use in a patient in need thereof, comprising administering to the patient: i) an effective amount of androgen; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. include.

[0063] Further embodiments of the pharmaceutical preparations in the methods for increasing GCDFP15 include those requiring the same. The present invention relates to use in a patient in need thereof, comprising administering to the patient: i) an effective amount of an androgenic agent; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0064] Further embodiments reduce breast pain associated with mammography images taken. The present invention relates to the use of the pharmaceutical preparation in a patient in need thereof, a subcutaneous injection containing i) an effective amount of an androgenic agent, and ii) an effective amount of an aromatase inhibitor. This involves administering pellets.

[0065] Further embodiments of the pharmaceutical formulation in a method for increasing mammography sensitivity include The present invention relates to use in a patient in need thereof, wherein the patient is administered i) an effective amount of androgen and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. nothing.

[0066] Further embodiments include the medicament in a method for reducing ABD% and / or AABD. The present invention relates to the use of a formulation in a patient in need thereof, comprising administering to the patient: i) an effective amount of and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. This includes:

[0067] Further embodiments include a pharmaceutical agent in a method for reducing BPE in an MRI image of a patient. The present invention relates to the use of a pharmaceutical preparation comprising: providing a patient with i) an effective amount of an androgenic agent; and ii) an effective amount of an androgenic agent. The method includes administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor.

[0068] Further embodiments include the use of pharmaceutical compositions in methods of reducing the size and / or volume of pustules. The present invention relates to the use of a therapeutic agent in a patient in need thereof, comprising administering to the patient: i) an effective amount of the therapeutic agent; and ii) administering a subcutaneous pellet containing an effective amount of an aromatase inhibitor. This includes:

[0069] Additionally, further embodiments involve the prevention or treatment of autoimmune inflammatory mastitis. and the prevention or treatment thereof in a patient.

[0070] In particular, in another aspect of the present invention, a subject in need of prevention or treatment of autoimmune inflammatory mastitis is A method for the prevention or treatment of a patient suffering from a steroid drug is provided, comprising administering to the patient: 1) an effective amount of a and 2) administering an effective amount of an aromatase inhibitor.

[0071] In this embodiment, the androgenic agent and aromatase inhibitor are administered to the patient under the same medical supervision. The present disclosure can be administered in a pharmaceutical formulation or in separate formulations. Covers all combination treatments for patients with inflammatory mastitis. Combination treatments include androgens and and aromatase inhibitors, together, simultaneously, or sequentially, in the same or different pathways. This means that the androgenic and aromatase inhibitors can be administered by The adverse drug reactions are those that occur in overlapping therapeutic ranges, as can be determined by the physician or attending physician. This means that each of these compounds exerts its own therapeutic effect.

[0072] Typically, at least one of the methods described herein for the treatment of autoimmune inflammatory mastitis is In some embodiments, the androgenic agent and the aromatase inhibitor are the same or It is administered in different sustained release pharmaceutical formulations.

[0073] In a particularly preferred embodiment, the sustained release pharmaceutical formulation contains an androgenic agent and an aromatase inhibitor. and for subcutaneous delivery of enzyme inhibitors to a patient, e.g., in the form of a solid dosage form, e.g., a pellet. It is a given form.

[0074] Most typically, the androgenic agent and aromatase inhibitor are administered in the same sustained-release pharmaceutical formulation. Sustained release formulations are provided that, for example, increase serum concentrations of androgens and aromatase. The sustained release multi-antibody compound is administered to the subject's blood over time as measured by plasma concentrations of the inhibitor. The pharmaceutical formulations described herein may be used to provide a phase concentration pattern.

[0075] Thus, a further embodiment provides a method for treating autoimmune inflammatory mastitis. The present invention relates to the use of a pharmaceutical preparation for a patient in need thereof, and provides the pharmaceutical preparation to the patient: i) a subcutaneous pellet comprising an effective amount of an androgenic agent, and ii) an effective amount of an aromatase inhibitor. This includes administering the compound in the form of

[0076] The autoimmune inflammatory mastitis for which patients may be treated according to the present disclosure may be, for example, idiopathic inflammatory mastitis. Selected from the group consisting of breast cancer, plasma cell mastitis, granulomatous mastitis, and combinations of the foregoing It can be done.

[0077] Thus, further embodiments of the present disclosure provide methods for treating idiopathic inflammatory hyperplasia associated with autoimmune diseases. Use of pharmaceutical preparations in a method for treating a disease in a patient in need thereof and administering to the patient a pharmaceutical formulation comprising: i) an effective amount of an androgenic agent; and ii) an effective amount of an aromatase inhibitor. This includes administering the drug in the form of a subcutaneous pellet containing a tase inhibitor.

[0078] A further embodiment of the present disclosure relates to a pharmaceutical formulation in a method of treating plasma cell mastitis, comprising: The present invention relates to a use in a patient in need thereof, comprising administering to the patient: i) an effective amount of the pharmaceutical preparation; and ii) in the form of a subcutaneous pellet containing an androgenic agent of This includes administering

[0079] Further embodiments of the present disclosure include the use of pharmaceutical formulations in methods of treating granulomatous mastitis. The present invention relates to the use of medicinal pellets in patients in need thereof, and to administering the medicinal pellets to the patient: i) effectively and ii) an effective amount of an androgenic agent, and ii) an effective amount of an aromatase inhibitor in the form of a subcutaneous pellet. This includes administering the compound in a therapeutically effective form.

[0080] The present invention further provides a method for treating autoimmune inflammatory mammary gland disease in combination with an effective amount of an aromatase inhibitor. Manufacture of a medicine for the prevention or treatment of inflammatory bowel disease in a patient in need thereof. This extends to the use of androgens in

[0081] In yet another embodiment, a method for treating autoimmune inflammation in combination with an effective amount of an androgenic agent is provided. PHARMACEUTICALS FOR PREVENTION OR TREATMENT OF SYMPTOMATIC MASTITIS IN PATIENTS IN NEED OF THE SAME - Patent application The present invention provides the use of an aromatase inhibitor in the manufacture of a product.

[0082] Typically, the autoimmune inflammatory mastitis (AIM) or AIM condition described herein androgens administered or contained in pharmaceutical formulations for use in therapy The allosterol agent is testosterone, or a pharmaceutically acceptable salt or ester thereof. The matase inhibitors may also be utilized in the form of their pharmaceutically acceptable salts or esters. .

[0083] From the above, the present disclosure provides the methods and methods for the treatment and / or purposes described herein. It will be apparent that the present invention clearly extends to methods for administering to a subject an effective amount of the pharmaceutical preparation. Additionally, in certain embodiments, the use of androgens in the manufacture of the medicaments described herein may be advantageously performed using a method of and aromatase inhibitors. The summary provided above is in accordance with the present disclosure. The illustrated embodiments are not intended to be limiting, and other embodiments may be included herein. Furthermore, the limitations of one embodiment may be combined with the limitations of other embodiments to provide additional implementations. It is possible to form an embodiment.

[0084] definition Terms used herein are those commonly used in the art unless defined below. It is the same as being The term "absolute area of ​​breast density" (AABD) refers to the area of ​​fibroglandular tissue in a subject's mammogram. It refers to the measurement of the surface area of ​​a tissue in square centimeters. For example, this means CUMUL It can be measured using US software algorithms or visual inspection of the mammogram. Several other tests can be used to measure AABD, including VOLPARA, QUANTRA, and methods that consider the surface area of ​​fibroglandular tissue in mammograms, Not limited to.

[0085] The term "androgenic agent" refers to any agent that increases the activity and / or synthesis of androgens. For example, androgenic agents have high affinity (in the pM or nM range) and and steroid hormones that bind to their intracellular mediators with specificity. The agonist receptor can stimulate cofactor incorporation, nuclear transport, and / or transactivation activity. This leads to a conformational change in the receptor that allows it to regulate the expression of target genes. Prodrugs include, for example, testosterone, methyltestosterone, and dehydroepiandrosterone. The androgen may be an androgen such as an androgen selected from the group consisting of androsterone. Combinations of these androgenic agents are also contemplated. In addition to the esters mentioned above, esters include enanthate, propionate, cypionate, and phenanthrene. Phenyl acetate, acetate, isobutyrate, bucclate, heptanoate, deca Contains decanoate, undecanoate, caprate, and / or isocaprate esters These may include, but are not limited to:

[0086] The term "breast area density percentage" (ABD%) refers to the area of ​​the breast on a mammogram. It refers to the proportion or percentage of fibroglandular (dense) tissue relative to the total surface area. For example, This was done using the CUMULUS software algorithm or visual inspection of the mammogram. Some other tests that can be used to measure ABD% include VO Considering the surface area of ​​fibroglandular tissue in LPARA, QUANTRA, and mammograms These include, but are not limited to, methods of

[0087] The term "aromatase inhibitor" refers to the enzyme that converts androgens into estrogens. Chemical compounds, hormones, or other substances that block and / or inhibit the activity of aromatase means a polypeptide. Aromatase inhibitors include, for example, anastrozole, exocytosis, The agent may be selected from the group consisting of mestan, and letrozole.

[0088] The term "autoimmune inflammatory mastitis (AIM)" refers to a non-infectious, non-lactating mastitis of breast tissue. This refers to a condition in which inflammation occurs as a result of an autoimmune response to components within breast tissue. .

[0089] The term "breast cancer" refers to a malignant proliferation of epithelial cells lining the milk ducts or lobules of the breast.

[0090] The term "breast elasticity" refers to the ability to achieve a given local deformation of the breast or a part of the breast. Elasticity is a measure of the pressure required to produce a breast. For example, elasticity = pressure / fractional change in breast radius and pressure is measured in, for example, kilopascals, and the fractional change in radius of the breast = (R 1-R2) / R1, where R1 is the radius without pressure and R2 is the radius with pressure. Another example is SuperSonic Imagine's ShearWave SuperSonic Imagine Aix™ with Elastography The breast is treated by applying shear waves through breast tissue using the plorer™. Tissue elasticity can be measured directly.

[0091] The term "breast firmness" in its broadest sense is a measure of the breast's resistance to deformation. Factors that may affect the degree of breast firmness include, but are not limited to, cellular Physical forces arising from interactions between cells and between cells and the extracellular matrix, cells The number and extent of collagen present in the breast, the degree of fluid retention in the breast, proteoglycans The degree of breast cancer expression and / or a combination thereof may be used to measure breast firmness. One example involves the use of the formula force / deformation (dN / cm), where dN is in decaNewtons and c m indicates centimeters, and the deformation is the radius of the semicircular mammography area and the volume of the semicircular mammography area. The compression force can be determined as the difference between the radii and the pressure on a mammogram, such as a digital mammogram. For example, based on Boyd et al., deformation is determined as the difference R1 - R2. where R1 is the uncompressed radius and R2 is the compressed radius (Boyd, et al., “Evidence that Breast Tissue Stif fness is Associated with Risk of Breast Cancer”PloS One 2014 Jul10;9(7):e100937)

[0092] The term "breast tissue" refers to the epithelial, interstitial, and / or intercellular tissues located within and / or adjacent to the breast. It refers to a collection of stromal cells, extracellular matrix, and / or migratory cells.

[0093] The terms "effective amount" or "pharmaceutically effective amount" of a drug or compound refer to a drug or compound that has a desired therapeutic effect. means a drug or compound in an amount sufficient to provide a beneficial effect, non-toxic, and acceptable non-toxic and / or have an acceptable side effect profile. The risk of death may vary depending on, for example, the age, the patient's general condition, the severity of the condition being treated, and the specific medication being administered. or compound, and / or a combination of one or more of these factors. An appropriate "effective amount" in any individual case will typically be determined by the relevant text. Those skilled in the art can easily identify the compounds by reference to the literature and / or by using routine experimentation. can be determined by

[0094] The term "mammographic breast density" or "MBD" refers to the total breast area (2-D measurement) Radiopacity in the breast, either for breast imaging (through 3-D determination) or volume (through 3-D determination) , or the proportion or percentage of fibroglandular ("dense") components and / or tissue Mammographic breast density (MBD) is a qualitative assessment of the amount of fibroglandular tissue (F) in the breast. This can be a qualitative or quantitative assessment of the amount of FGT (FGT). This can be the absolute amount of FGT or the amount of non-FGT. T (mainly adipose or the relative amount of FGT to the amount of fat) The absolute amount of FGT can be determined by the surface area (cm 2 ) (i.e., AABD) or Volume (cm 3 ) (i.e., AVBD). Relative volume is the assessment of the surface area of ​​FGT relative to non-FGT (i.e., percentage (ABD) %)) or by assessment of FGT volume relative to breast volume (i.e., VBD%) Alternatively, the cubic centimeters of fibroglandular tissue in the subject's breast may be measured. To determine absolute volumetric breast density (i.e., AVBD), which can be the volume measured at Mammographic breast density can be measured by, but not limited to, mammography, digital imaging, or other methods. Mammography, Magnetic Resonance Imaging (MRI), Ultrasound, Digital Breast Tomosynthesis including DBT, Virtual Touch Tissue Image Quantification (VTIQ), and their combinations. MBD can be determined by a variety of methods, including via 2D determination and / or BI- It can be qualitatively assessed using RADS® density categories, with 1 (or a) being the best. MBD is also used to measure the density of the 3D object. Qualitative and / or quantitative breast measurements, such as determining volumetric breast density using breast volume measurements or quantitatively assessed, which may involve measuring the tissue in the breast (e.g., fibroglandular (dense) tissue and The ratio of fibroglandular (dense) tissue to the total volume of the fibroglandular (cells and fat) tissue is another way of calculating the absolute volume. The objective of the present study was to determine average volumetric breast density (AVBD), which is the measurement of fibroglandular tissue in the subject's breast. The volume measured in cubic centimeters of the MBD. This may be taken into account to account for the heterogeneity of dense tissue within the breast. can be used to measure VOLPARA, QUANTRA, CUMULUS, and Volume of fibroglandular tissue (cm 3 ) are considered, but are not limited to these.

[0095] The term "patient" or "subject" refers to a subject treatable with the compositions, methods, and kits of the present disclosure. The term "patient" or "patients" means any animal, including the human species, capable of , both male and female unless gender is specifically indicated or clear from the context. The term "patient" is also intended to refer to a female-to-male transgender person. It can refer to the understudy.

[0096] The terms "perimenopause" or "menopausal transition" refer to the transition of a woman's body from permanent infertility (menopause) to Perimenopause refers to the period around menopause during which women experience a natural transition from menopause to menopause. It can begin with age, during the 40s or even as early as the mid-30s, with symptoms such as irregular menstruation. You may notice signs of progressing towards menopause. During perimenopause, estrogen levels rise unevenly. and descending, menstrual cycles may be longer or shorter, and the ovaries do not release eggs (ovulate) Menstrual cycles may begin. During perimenopause, hot flashes, sleep disturbances, and / or vaginal dryness may occur. Other menopausal-like symptoms may be experienced, including but not limited to dryness.

[0097] The term "peri-menopausal symptoms" includes, but is not limited to, menstrual irregularities, hot flashes, and sleep disturbances. Symptoms include: discomfort, mood changes, mood swings, irritability, depression, vaginal dryness, urinary tract or vaginal infections, urinary incontinence, Decreased fertility, changes in sexual arousal or desire, bone loss, brittle bones, osteoporosis, or hypocalcemia Increased high-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (H cholesterol level, such as DL) cholesterol reduction, and combinations thereof It is understood to include variations.

[0098] The term "pharmaceutically acceptable" means, within the scope of sound medical judgment, a substance that is not excessively toxic, irritating, or toxic to humans. irritation, allergic reaction, or other problems that are commensurate with a reasonable benefit and / or risk ratio. compounds, drugs, etc., which are suitable for contact with human and / or animal tissues without adverse reactions or complications; "A" refers to an agent, material, composition, excipient, and / or dosage form.

[0099] The term "pellet" refers to a compound containing an effective amount of an androgen and an effective amount of an aromatase inhibitor. The pellet or implant may be prepared in a variety of suitable Shape and size, e.g., spherical, cylindrical, rectangular, square, or a combination thereof It may have square or rounded edges. In certain embodiments, the pellet Alternatively, the implant may be compressed.

[0100] The term "pharmaceutical formulation" refers to a pharmaceutical formulation containing an effective amount of an androgen and an effective amount of an aromatase inhibitor. and when the formulation is administered to a warm-blooded subject, the formulation Over time as measured by serum concentrations and, for aromatase inhibitors, plasma concentrations provide a sustained release multiphasic concentration pattern in the subject's blood; These periods may vary depending on the formulation, delivery system, drug concentration, and formulation. individual physiological variations during the period from complete absorption to substantially complete absorption, The absorption of the formulation typically lasts for more than 3 months but not more than 5 months. In certain embodiments, the formulation may be delivered via a transdermal patch. In certain embodiments, the formulation may be delivered via a solid form, such as a subcutaneous pellet. In some embodiments, the formulation may be delivered via a solid form such as a compressed subcutaneous pellet.

[0101] The term "postmenopausal women" refers not only to older women who have gone through menopause but also to women who have undergone other means of menopause. Women who have had their ovaries removed or destroyed, or who have suppressed estrogen production for any other reason. Women with chronic conditions, such as those taking long-term corticosteroids, or Cushing's syndrome It is understood to include women who suffer from a syndrome or who have gonadal abnormalities.

[0102] The term "subject" refers to a human subject treatable with the compositions, methods, and kits of the present disclosure. The term "subject" or "subjects" is used to specifically indicate sex. Unless otherwise specified or clear from the context, it is intended to refer to both men and women. The term "subject" may also refer to a female-to-male transgender person.

[0103] As used herein, the terms "treatment" or "therapy" include preventative (e.g., prophylactic) ) treatment and / or palliative treatment, and as used herein "treating" includes preventative and / or palliative treatment. and / or refers to the act of providing palliative care.

[0104] The term "Breast Volume Density Percentage (VBD%)" refers to the total volume of tissue in the breast. It refers to the proportion or percentage of fibroglandular (dense) tissue in volume relative to the area. For example, this is achieved by using the Volpara Solution™ software algorithm. It can be measured using the Volpara Solution™ software algorithm. In rhythm, VBD% is referred to as breast density volume percentage. There are several other tests that can be used to Examples of methods include, but are not limited to, methods that take into account the volume of fibroglandular tissue. [Brief explanation of the drawings]

[0105] For a better understanding of the present disclosure and to understand how effects may be achieved in accordance with one or more embodiments thereof, To more clearly show how this can be achieved, reference is made, for example, to the accompanying drawings, in which: Serum concentrations of estosterone or its esters and plasma concentrations of aromatase inhibitors providing a sustained release concentration pattern in the subject's blood over time as measured by concentration. do.

[0106] [Figure 1] According to certain exemplary embodiments, data are presented for serum concentrations of androgens and plasma concentrations of aromatase inhibitors over an 84 day period. [Figure 2] The data from Figure 1 are expanded to further illustrate the first 42 days. [Figure 3]1 shows serum concentrations of testosterone up to 7 days post-dose in 11 subjects according to certain exemplary embodiments. [Figure 4] 1 shows serum concentrations of testosterone up to 85 days after administration in 11 subjects according to certain exemplary embodiments. [Figure 5] 1 shows the plasma concentrations of anastrozole over 336 hours post-dose in 11 subjects according to certain exemplary embodiments. [Figure 6] According to certain exemplary embodiments, plasma concentrations of anastrozole over 1680 hours post-dose in 11 subjects are shown. [Figure 7A-B] According to certain embodiments, the rate of anastrozole absorption is shown. [Figure 8A-B] According to certain embodiments, plasma anastrozole concentrations after implantation are shown. [Figure 9] 1 shows the observation frequency after implantation in Example 3. [Figure 10] 1 shows an example flow chart of the model tested in Example 3. [Figure 11] The final structural model used in Example 3 is shown below. [Figure 12A-B] 1 shows the population and individual predictions used in Example 3. [Figure 13] 1 shows plots of 11 individual observed and predicted plasma concentrations of anastrozole, according to certain embodiments. [Figure 14] 1 shows the visual predictive check (VPC) of post-implantation anastrozole concentrations used in Example 3. [Figure 15A-B] 1 shows the one-compartment model versus the two-compartment model used in Example 3. [Figure 16] 1 shows predictions for patient 10 for several different input models used in Example 3. [Figure 17] Illustrates the effect of the androgen testosterone and aromatase inhibitor (T+Ai) on breast tissue immune responses. [Figure 18]1 shows the results of Western blot analysis of CD36 protein in three explant samples of normal breast tissue obtained from three peri-menopausal women at baseline and after 24 hours of culture. [Figure 19A] Mammogram images before (left) and after (right) treatment according to the present disclosure, showing a substantial reduction in breast size and density. [Figure 19B] Volpara Soultion™ breast volume and density measurements before (left) and after (right) treatment for the patient in Figure 19A, showing breast volume reduction (58%) back to pre-disease size and fibroglandular tissue reduction (71%). [Figure 19C] Magnetic resonance images (MRI) of the breast of the patient in Figure 19 before treatment (left) and after three years of subsequent treatment, showing reversal of extreme background parenchymal enhancement on the MRI three years after treatment cessation. [Figure 20A] Mammograms of another patient before (left) and after (right) treatment according to the present disclosure, showing a substantial reduction in breast size and density. [Figure 20B] Volpara Soultion™ breast volume and density measurements before (left) and after (right) treatment for the patient in Figure 20A, showing breast volume reduction (10%) back to pre-disease size and fibroglandular volume reduction (41%). [Figure 21A] Mammograms of another patient are shown before (left) and after (right) treatment according to the present disclosure, demonstrating a substantial reduction in breast size and density. [Figure 21B] Volpara Soultion™ breast volume and density measurements before (left) and after (right) treatment for the patient in Figure 21A, showing breast volume reduction (32%) back to pre-disease size and fibroglandular tissue reduction (52%). [Figure 22A] 10A-10C are magnetic resonance images (MRI) of a further patient's breast before (left) and after (right) treatment according to the present disclosure, showing complete reversal of extreme background parenchymal enhancement on the MRI. [Figure 22B]Before (left) and after (right) mammography images of the breast of the patient in FIG. 22B, showing reduction in breast size and density. [Figure 22C] Volpara Soultion™ breast volume and density measurements before (left) and after (right) treatment for the patient in Figure 22B, showing breast volume reduction (23%) back to pre-disease size and fibroglandular volume reduction (36%). [Figure 23A] 10 shows extreme breast swelling in another patient documented by mammography prior to treatment according to the present disclosure. [Figure 23B] Magnetic resonance imaging (MRI) shows intense breast metabolic activity with little fat, as indicated by the extreme background parenchymal enhancement in the patient's breast in Figure 23A. [Figure 24A] Magnetic resonance imaging (MRI) of another patient with granuloma formation in the retroareolar space with enlarged reactive axillary lymph nodes is shown. [Figure 24B] 24B is an MRI image of the breast of the patient of FIG. 24A showing the resolution of granulomas and reduction in size of axillary lymph nodes after treatment according to the present disclosure.

[0107] In view of the following detailed description and the appended claims, various permutations and and / or modifications may be made to the present disclosure without departing from the scope of the invention as claimed. This will be apparent to those skilled in the art. DETAILED DESCRIPTION OF THE INVENTION

[0108] The following description is provided with reference to several embodiments that may share common features and characteristics. One or more features of one embodiment may be combined with one or more features of other embodiments. Furthermore, it should be understood that any single feature or combination of features in a particular embodiment may be used interchangeably. Combinations may constitute additional embodiments. Functional details should not be construed as limiting and should not be construed as limiting the scope of the disclosed embodiments and and representative examples for teaching those skilled in the art how to use various modifications of these embodiments. It should be interpreted as evidence only.

[0109] Subject headings used in the Detailed Description are included solely for the reader's ease of reference and are not intended to be limiting unless expressly stated. Should be used to limit subject matter permitted throughout the disclosure or claims Subject headings are not used in interpreting the scope of a claim or a claim limitation. It should not be.

[0110] The present disclosure is directed, at least in part, to the estrogen receptor agonist (EGTA) receptor agonist (ARR ... and into compressed pellets, which unexpectedly overcomes the problem of obtaining a high ratio of diol to Drug delivery system with a multiphasic sustained release pattern containing an agonist and an aromatase inhibitor - Patent application The desired effect is achieved rapidly with high levels of aromatase inhibitors. The early peak of serum testosterone is blocked, and the DH of testosterone This allows induction of 5α-reductase conversion to T. The rapid release of aromatase inhibitors is then There is a reduction in blood estradiol production, but no total or substantial blockage. It is desirable to ensure that there is no symptomatic decline in serum estradiol levels. High DHT levels relative to estradiol levels in tissues with overexpression of dihydrolase The shift in the system towards this is achieved by utilizing certain exemplary embodiments that exhibit this multi-phase sustained release pattern. This can be achieved.

[0111] Women and men benefit from this testosterone and aromatase inhibitor combination There are several examples of aromatase overexpression that result in disease processes that may result in Therefore, in these tissues, overexpression of the aromatase enzyme and 5α-reductase When co-expression of enzymes can occur, this enzyme combination can be pharmacologically manipulated to enhance DH These disease states may result in an orderly transition towards altered T / estradiol ratios. These include, but are not limited to, high mammographic breast density, breast pain, endometriosis, and menopausal syndrome. Gynecomastia, perimenopausal and premenstrual tissue abnormalities, autoimmune inflammatory mastitis (idiopathic inflammation) These include conditions such as uterine macromastia, plasma cell mastitis, and granulomatous mastitis.

[0112] FIG. 2 illustrates an exemplary combination of testosterone and an aromatase inhibitor. The pattern was observed in some subjects (N=11) receiving the subcutaneous pellet regime. Show the impact.

[0113] In this example, Phase I involves the evaluation of serum testosterone and plasma anastrozole levels in subjects. This increase is due to the rapid tissue induction of 5α-reductase and aromatase. High tissue levels of testosterone are rapidly converted to DHT. conversion to estradiol is completely or substantially blocked. In this example, this first phase is shown as a vertical bar separating phase 1 from phase 2. Phase 1 lasts approximately 8 days. The duration of Phase 1 depends on the specific subject biology, pellet formulation, and and / or manufacturing parameters used to create the pellets, including but not limited to may vary depending on several factors.

[0114] In an exemplary embodiment, the Phase II period lasts for approximately 14 days. The induction of 5α-reductase does not oppose the aromatase conversion of estradiol and estradiol. The duration of anastrozole continues to allow it to act without or substantially without opposition. It is desirable to rebalance the enzyme system to produce sustained high tissue levels. Rebalancing results in a reduction of serum testosterone, avoiding excess androgenic side effects, 5 This second phase avoids the continuous addition of alpha-reductase. In this example, this second phase separates phase 2 from phase 3. Phase 2 lasts for approximately 14 days, as indicated by the vertical bar separating it from the the target biology, the pellet formulation, and / or the material used to create the pellets It may vary depending on several factors, including but not limited to manufacturing parameters.

[0115] In this example, in Phase III, anastrozole levels decline rapidly and testosterone levels decrease. allowing some conversion to strradiol, e.g., observed in a zero-order release pattern. to avoid significant use and depletion symptoms that may result from persistently high levels of anastrozole. During this period, the induced 5α-reductase is released from the implant matrix and replaced. In this example, the increased testosterone continues to be converted into DHT in the target tissue until This third phase persists at least until the pellet is depleted. Phase 3 was followed for an additional 70 days. formulation, and / or manufacturing parameters used to create the pellets. This may vary depending on several factors, including but not limited to:

[0116] Certain embodiments may be used to treat extreme mammographic breast density. Serum reproductive hormone levels are determined by the inactive or active metabolism of prohormones such as testosterone. Poor correlation with tissue levels due to significant metabolism of either product. In certain disease states, such as mammographic breast density, androgens are preferred over testosterone. Testosterone is either estrogen or dihydrotestosterone, which are over 10 times more potent than estrogen. There is an overexpression of an enzyme known to convert estrogen to steroids. By altering the ratio of androgens to estrogens in breast density This may reduce its density and therefore reduce the incidence of breast cancer. The reduction also occurs in men with gynecomastia, where there is an excess of estrogen relative to androgens in the tissues. It can also be applied to situations such as puberty, which promotes a change in the ratio of androgens to estrogens. To facilitate this, the subcutaneous pellets are designed to promote a multiphasic sustained release pattern. Anastrozole and testosterone are administered in specific ways and with specific compression. When combined by compression into pellets, the resulting pharmacokinetics is due to this multi- Again, as discussed elsewhere, The minimum amount required to promote blockade or substantial blockade of aromatase in affected tissues. To achieve the maximum concentration, peak levels of testosterone should be delivered to the tissue at approximately the same time. At the same time, it is desirable to have an early increase in anastrozole. Increased testosterone promotes the conversion of testosterone to dihydrotestosterone by 5α-reduction, This initial high level of anastrozole promotes androgen excess over the stromal environment. When these drugs are administered orally, higher concentrations of aromatase inhibitors are released. either inducing hypothalamic-pituitary function or systemic aromatase inhibition as observed A significantly low level is maintained so as not to cause changes in To continue the disruption of the antigenic environment, there is induction of 5α-reductase in somatic cell lines. This unique multi-phase sustained release pattern allows for delayed delivery of testosterone to tissues that are receiving it. may result in significant physiological changes in serum reproductive hormone levels and adverse side effects. It is useful for establishing changes in tissue hormone levels without causing adverse events. do.

[0117] Certain embodiments may be used to treat one or more of high breast density and breast hardness. High breast density and / or breast hardness is not normal, but rather pathological. has been proven successful in premenopausal, perimenopausal, and / or postmenopausal women. rather than being treated as uncontrolled lifestyle modifications (e.g., diet and exercise). can be addressed by an effective amount of an androgenic agent and / or an effective amount of an aromatase inhibitor. It is something.

[0118] Certain embodiments may include measuring one or more of mammographic breast density and breast hardness separately. and pharmaceutical products that can be used in methods to provide an improved reduction in (i) determining a patient's breast size and / or breast firmness; (ii) optionally, determining the patient's free androgen index and / or the patient's free androgen index; measuring the change in the Geng index over a period of at least one month; and (iii) androgen index, taking into account the patient's weight, total body fat, MBD, age, and free androgen index. (iv) determining the adjusted dose of the agonist and aromatase inhibitor; and administering a dose to said patient. androgen index and / or changes in the patient's free androgen index for at least 1 month The measurement over a period of time involves taking blood samples and measuring the free antigen levels in the patient's serum. and measuring the amount of progesterone (or testosterone).

[0119] Certain embodiments may include individualizing one or more of VBD%, AVBD, and breast firmness. and a pharmaceutical formulation that can be used in a method for providing a reduction in blood cholesterol levels in a patient in need thereof. (i) the patient's VBD% and / or AVBD and / or breast firmness (ii) optionally determining the patient's free androgen index and / or The study measured changes in the patient's free androgen index over a period of at least one month. and (iii) the patient's weight, total body fat, VBD% and / or AVBD, age, androgen and / or aromatase, taking into account the free androgen index determining an adjusted dose of the inhibitor; and (iv) administering the adjusted dose to the patient. In certain embodiments, the patient's free androgen index and / or the patient's To measure changes in the free androgen index of subjects over a period of at least one month. This involves taking a blood sample and measuring the free androgenicity (or testosterone) in the patient's serum. and measuring the amount of steroid hormone (steroid hormone).

[0120] Certain embodiments may include individualizing one or more of ABD%, AABD, and breast firmness. and a pharmaceutical formulation that can be used in a method for providing a reduction in blood cholesterol levels in a patient in need thereof. (i) the patient's VBD% and / or AVBD and / or breast firmness (ii) optionally determining the patient's free androgen index and / or The study measured changes in the patient's free androgen index over a period of at least one month. and (iii) the patient's weight, total body fat, ABD% and / or AABD, age, androgen and / or aromatase, taking into account the free androgen index determining an adjusted dose of the inhibitor; and (iv) administering the adjusted dose to the patient. In certain embodiments, the patient's free androgen index and / or the patient's To measure changes in the free androgen index of subjects over a period of at least one month. This involves taking a blood sample and measuring the free androgenicity (or testosterone) in the patient's serum. and measuring the amount of steroid hormone (steroid hormone).

[0121] Certain embodiments reduce one or more of mammographic breast density and breast hardness. The present invention relates to a pharmaceutical preparation that can be used in patients in need thereof to , pharmaceutical preparations are used in mammography, digital mammography, magnetic resonance imaging (MRI) ), ultrasound, digital breast tomosynthesis (DBT), virtual touch tissue imaging (VTIQ) ), or a combination thereof to increase the sensitivity of breast imaging detection.

[0122] Certain embodiments reduce one or more of mammographic breast density and breast hardness. The present invention relates to a pharmaceutical preparation that can be used in patients in need thereof to The pharmaceutical preparation increases the detection of breast cancer occurring in patients.

[0123] Certain embodiments reduce one or more of VBD%, AVBD, and breast firmness. The present invention relates to a pharmaceutical preparation that can be used in patients in need thereof for the purpose of The drug formulation increases the detection of breast cancer that occurs in patients.

[0124] Certain embodiments reduce one or more of ABD%, AABD, and breast firmness. The present invention relates to a pharmaceutical preparation that can be used in patients in need thereof for the purpose of The drug formulation increases the detection of breast cancer that occurs in patients.

[0125] The pharmaceutical formulations disclosed herein reduce mammographic breast density in patients. Treating mammographic breast density and reducing breast hardness , to treat breast hardening and have breasts with mammographic breast density of 7.5% or more To reduce mammographic breast density in patients with a 3 or 4 (or c or d) Mammography in patients with breasts with a BI-RADS® score - Reducing breast density and inducing breast involution in a patient and Inducing terminal cell death in response to proliferation in the breast and the extracellular matrix in the patient's breast Inducing the ultimate extracellular matrix degradation for the development of ulcers and the role of peri-menopausal Methods for reversing breast cell count and mammographic breast density in patients Reducing mammographic breast density and perimenopausal symptoms and autoimmune inflammatory Mastitis (e.g., idiopathic inflammatory mastitis, plasma cell mastitis, granulomatous mastitis, and previously described and a combination of do.

[0126] These pharmaceutical formulations and the androgenic and aromatase inhibitor (Ai) combinations described herein ) combination therapy may be useful in premenopausal, perimenopausal, and / or postmenopausal women. obtain.

[0127] For example, high breast density in perimenopausal women is known to be a risk factor for developing breast cancer. Dense tissue in perimenopausal women is not considered normal and has pathological implications. This increase in breast density is due to high levels of estrogen in the presence of a low testosterone environment. The present inventors have investigated the effects of steroids on the development of steroid hormones, which may be due to lifetime exposure to steroid hormones and progesterone. and an effective amount of an androgenic agent such as testosterone and an effective amount of an aromatase inhibitor ( Premenopausal, perimenopausal, and and / or postmenopausal women may exhibit a decrease in breast density and / or breast firmness. The present inventors have also found that an effective amount of testosterone and an effective amount of an aromatase inhibitor Pre- and perimenopausal women receiving anti-inflammatory drugs (such as anastrozole) via multiphasic pattern preparations and / or postmenopausal women, who are more likely to experience breast involution versus proliferation and / or eventual cell death The present inventors have also discovered that administration of a multi-phase pattern formulation to a subject can induce and administering to the subject breast tissue an effective amount of an aromatase inhibitor to enhance testosterone production. stops the conversion of testosterone to estrogen, thus inducing breast cell involution We have discovered that it may be possible to do this.

[0128] Certain further embodiments relate to the prevention or treatment of autoimmune inflammatory mastitis (AIM). and the above-mentioned idiopathic inflammatory mastitis, plasma cell mastitis, and granulomatous mastitis. This includes mastitis conditions.

[0129] Breast tissue may be a target tissue in autoimmune diseases, and this process is influenced by the hormonal environment Autoimmune breast tissue is affected by the immune system, which is the same as normal breast tissue (Touraine, 2005). Elevated aromatase (which converts androgens to estradiol) compared to adenomatous tissue , and other factors related to inflammation, such as IGF2, EGFR, TGF-β, PDGF It has been shown to have R-α and R-β (Das, 2019).

[0130] The breast provides an immune-privileged environment for lactation and requires immunosuppression to avoid autoimmunity. It is unique in that it requires rapid remodeling of essential tissues after lactation (lactational involution). Central to this is the role of effector T cells in Inhibits proliferation and cytokine production, plays a major role in immune response and prevention of autoimmune diseases During T cell development, the formation of regulatory T (Treg) cells is essential for T cell development. TCR gene segments are required for immunity against invading pathogens. rearrange to generate a repertoire of autoantigens. In the case of T cells, two basic processes occur: These promote tolerance to self within the thymus (called central tolerance) before their release into the periphery. However, two processes are involved: (1) negative selection, in which autoreactive T cells are eliminated, and (2) 2) CD4 + Forkhead box P3 (Foxp3) + Regulatory T (Treg) cell viability Central to the process is the role of CD36 in facilitating the transfer of cell surface antigens and promoting homeostatic The goal of this study is to promote tolerance to host antigens during sex. The master regulator is the transcription factor Foxp3. Testosterone treatment enhances the growth of thyroid cancer in vivo and in vivo. induces a potent expansion of Treg cell populations both in vitro and in vivo (Walecki, 2015 High levels of Treg cells in breast tumors may be due to the immunosuppressive capacity of Treg cells. This reduces the ability of immunotherapy to target Treg cells. It has resulted in unacceptable autoimmune side effects that limit its use. Breast tissue immune reactivity The effects of testosterone and aromatase inhibitors on skeletal muscle are illustrated in FIG.

[0131] The manifestation of AIM is clearly demonstrated by breast MRI in affected individuals. This is associated with dense stromal replacement of breast adipose tissue (Touraine, 2005). One of the key factors in the inflammatory cascade is the cell surface protein class B scavenger. CD36 is a member of the CD36 receptor family. , monocytes, differentiated adipocytes, skeletal muscle, mammary epithelial cells, spleen cells, and some skin microorganisms a) CD36 is expressed in hormone-sensitive breast cancer cell lines. b) down-regulated by tradiol (Uray, 2004); c) fibroblasts Overexpression of CD36 in mice inhibits solid tumor formation in a subtype of breast cancer model (Cheng, 2020), and c) CD36 is associated with high mammographic breast density. Women at high risk of developing breast cancer due to breast cancer density (HMD) (i.e., low-fat breast tissue) It has been demonstrated that IL-16 is deeply suppressed in non-malignant tissues (DeFilippis, 2014). are.

[0132] Thea Tlsty's group (DeFilipis, 2014) has demonstrated that i) ii) increased basal DNA damage in epithelial cells leads to increased secretion of activin A; Cutivin A binds to its receptor in adjacent fibroblasts, activating the MAPK pathway, iii) activation of the MAPK pathway leads to PPARγ phosphorylation and inhibition, and iv) P PARγ inhibition reduced CD36 transcription and subsequently the fibrogenic-like phenotype observed in HMD tissues. This suggests a cascade that leads to the induction of the present type.

[0133] As described herein, induction of CD36 expression in breast tissue can be achieved by administering an effective amount of allogeneic steroids. androgen-releasing hormone receptor agonist (ARR) inhibitors. and the present disclosure expressly provides for such methods and patients, e.g., those in the peri-menopausal, menopausal, or or use in postmenopausal women.

[0134] Subcutaneous pellets are used to treat androgenic alopecia in the prevention or treatment of autoimmune diseases or conditions. The present invention provides a method for the preparation of a compound having a hydroxybenzoate (HQ) and a hydroxybenzoate (HQ) that can be used to promote a multiphasic sustained release pattern for varying estrogen ratios. Anastrozole and testosterone may be combined to produce a pediatric drug as described herein. The formulation can be compressed into a single tablet to provide pharmacokinetics that facilitate this multiphasic sustained release of both active ingredients. This release pattern is due to the initial high levels of testosterone being released into the bloodstream, followed by very high levels of adrenaline. associated with a dihydromatase inhibitor, thus only DHT is presented in inflamed breast tissue. This ensures that testosterone is not converted to estradiol (which is pro-inflammatory). In the second phase, testosterone levels peak, followed by the release of 5α-reductase inhibitors from the first phase. Induction of reductase ensures that high levels of DHT are maintained to exert anti-inflammatory effects. Continued high levels of anastrozole continue, while there is a more rapid decline in anastrozole. Strozole can cause adverse events due to excessive reduction of estradiol throughout the body. This risk is reduced by the rapid reduction in anastrozole delivery. The third delivery phase then involves induction of 5α-reductase in somatic cell lines. This allows for the delayed release of testosterone into tissues that continue to experience a disrupted antigenic environment. The unique multiphasic sustained release pattern prevents significant physiological changes in other serum reproductive hormone levels. and tissue hormone levels without substantially causing potential adverse side effects. Changes in breast tissue immunoreactivity as described herein can be established. The effects of the androgen testosterone and the aromatase inhibitor anastrozole , as illustrated in FIG.

[0135] The present invention relates to one or more of the disclosed compositions, delivery systems, and / or methods of use. One of the benefits of steroids is that they slow the conversion of testosterone to dihydrotestosterone in tissues. The rapid early induction and early response resets homeostatic mechanisms in a beneficial way, providing tissue This can reduce the ratio of estradiol to androgen in the may result in one or more of the following: A. Visualizing malignant tumors at an early and / or less aggressive stage by mammogram and enhanced mammographic detection due to reduced breast density allowing for B. At intervals such as those that may occur between repeated mammography screenings Reduced risk of breast cancer. These cancers are more common in breasts with high MBD. C. Reduction of breast firmness. D. Reduction of pain during mammographic breast compression. E. Achieve superior mammography compression, at least in part through pain reduction ability. F. Superior mammographic compression is achieved and the breast tissue is less dense. This reduces the amount of energy required to expose the image in a mammogram, and therefore Reduced radiation exposure to breast tissue. Reduced risk of radiation-induced breast cancer. G. The ability to improve patient compliance with regular mammography screening. H. Treating patients with concurrent hypothalamic-pituitary and / or other endocrine system disorders The ability not to wake up. I. Reduced breast pain in patients. J. Reduced breast elasticity in patients. K. Decreased expression of a gene in the genome of a cell to reduce the risk of malignant transformation in a patient Lowered mechanical signaling. L. Increased ratio of fibroglandular to adipose tissue in patients. Increased CD36 in patients with M . N. Stabilizing and / or increasing androgen receptor expression levels in the patient's breast tissue Add. O. Treatment of macromastia in patients. Increased GCDFP15 in patients with P . Q. Reduced BPE in the patient's MRI image. R. Reduction in the size and / or volume of cysts in patients. S. Reduces the risk of breast cancer. T. Autoimmune inflammatory mastitis (AIM) (e.g., idiopathic inflammatory macromastia, plasmacytic mastitis) Treatment of conditions including mastitis, mastitis, and granulomatous mastitis.

[0136] To characterize the type and / or degree of mammographic breast density in a patient's breasts There are several categories used by diagnosticians and physicians.

[0137] The diagnosing or treating physician may use one or more tests / exams to assess, characterize, or mammography, digital mammography, magnetic resonance imaging, and / or diagnostic imaging. Magnetic resonance imaging (MRI), ultrasound, digital breast tomosynthesis (DBT), virtual touch histology These include, but are not limited to, cytotoxicity assays ... The physician may also use other evidence, such as medical or family history (genetic factors related to breast density). to consider genetic predisposition), and / or qualitative assessment of MBD, e.g., "a" (breast "b" (almost entirely fatty), "b" (with scattered areas of fibroglandular density), "c" (incomplete breast "d" (the breast is extremely dense and may obscure small lumps) and "d" (the breast is extremely dense and may obscure small lumps). B uses a breast composition classification of 100% (highly dense, reducing the sensitivity of mammography) I-RADS (registered trademark) (e.g., 5th edition) (D'Orsi CJ, Si ckles EA, Mendelson EB, Morris EA et al.(2 013).ACR BI-RADS(R)Atlas,Breast Imaging Reporting and Data System.Reston,VA:Amer ican College of Radiology).

[0138] Breast pain is a significant problem in women's health. Breast pain is also associated with VBD% and / or associated with increased breast or AVBD, breast induration, breast cancer risk, or a combination of these. Certain embodiments provide a method for reducing breast pain in a patient using an androgenic agent and an anti-androgenic agent. Regarding the use of lomatase inhibitors.

[0139] Certain embodiments include a skin patch comprising an effective amount of anastrozole and an effective amount of testosterone. In an exemplary embodiment, the subject is compressed into a pellet. In pharmaceutical preparations containing 0.5 to 10 mg of anastrozole (2,2'-[5-(1H -1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methyl propylpropanenitrile) and 60 to 120 mg of testosterone. In certain embodiments, the subject receives 4 to 6 mg of the pharmaceutical formulation compressed into a pellet. Anastrozole and 60-120 mg testosterone are provided. In one embodiment, the subject receives approximately 4 mg of anastasia in a pharmaceutical formulation compressed into a pellet. The drug is administered in a dose of 100 mg of bromozole and approximately 80 mg of testosterone. Other androgens are also used. Treatment for the administration of subcutaneous pellets containing anastrozole and testosterone The duration can be 2-4 weeks, 3 months-3 years, 6 months-2 years, 3 months-5 years, 1 year-5 years, or The duration of treatment may vary from 1 to 3 years. In certain embodiments, the duration of treatment is about 2 weeks, 3 months, It can be 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years, or 3 years. The treatment period is at least 2 weeks, 3 months, 6 months, 9 months, 1 year, or 1.5 years. In certain embodiments, the treatment period is about 3 years. Treatment may include a reduction in ABD%, a reduction in AABD, and a reduction in VBD%. Reduction in AVBD, Reduction in breast pain, Reduction in breast hardness, Reduction in breast elasticity reduction in mammograms, reduction in macromastia, reduction in breast cysts, reduction in mammography diagnostic sensitivity Improvement in fibroglandular tissue and reduction in false positives, an increase in the ratio between fibroglandular tissue and adipose tissue, and and / or stabilization and / or increase in the level of androgen receptor expression. can be applied to.

[0140] Certain embodiments include a subcutaneous administration of letrozole and testosterone. In an exemplary embodiment, a patient receives 0. 5 to 20 mg of letrozole (4,4'-((1H-1,2,4-triazol-1-yl) )methylene)dibenzonitrile) and 40 to 130 mg of testosterone, subcutaneously In an exemplary embodiment, a patient receives approximately 10 pellets for subcutaneous administration. mg of letrozole (4,4'-((1H-1,2,4-triazol-1-yl)methyl) Subcutaneous pellets containing benzophenone (dibenzonitrile) and 40-130 mg testosterone are provided. Other androgenic agents may also be used, including letrozole and testosterone. The treatment duration for subcutaneous pellet administration is 2 weeks to 4 weeks, 3 months to 3 years, 6 months to 2 years, It can vary between 3 months and 5 years, between 1 year and 5 years, or between 1 year and 3 years. The treatment period is approximately 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, and 2.5 years. In certain embodiments, the treatment period may be at least 2 weeks, 3 years, or 3 years. It can be months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, or 4 years. In embodiments, the treatment period can be about 3 years. Treatment can include a reduction in ABD%, AA Reduction in BD, Reduction in VBD%, Reduction in AVBD, Reduction in breast pain , reduction in breast firmness, reduction in breast elasticity, reduction in mammary gland, reduction in breast cysts reduction in mammographic sensitivity and false positives; Increase in the ratio between androgen receptor and tissues and stabilization in the level of androgen receptor expression The present invention may be applied to one or more of the following:

[0141] Certain embodiments include a skin treatment comprising an effective amount of exemestane and an effective amount of testosterone. In an exemplary embodiment, a patient is provided with an E. coli pellet for subcutaneous administration. Xemestane, 10-75 mg of 6-methylideneandrosta-1,4-diene-3 Subcutaneous pellets containing 17-dione and 40 to 130 mg of testosterone are provided. Other androgens may also be used. The treatment period for this is 2 weeks to 4 weeks, 3 months to 3 years, 6 months to 2 years, 3 months to 5 years, 1 year, and In certain embodiments, the treatment period may vary between about 1 year and 5 years, or between 1 year and 3 years. 2 weeks, 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 2.5 years, or 3 years In certain embodiments, the treatment period is at least 2 weeks, 3 months, 6 months, 9 months, or In certain embodiments, the treatment may be for 1 year, 1.5 years, 2 years, 3 years, or 4 years. The duration can be about 3 years. Treatment includes a reduction in ABD%, a reduction in AABD, a reduction in V Reduction in BD%, reduction in AVBD, reduction in breast pain, reduction in breast firmness Reduction in breast elasticity, reduction in macromastia, reduction in breast cysts, mammogram Improvement in diagnostic sensitivity and reduction in false positives, in the ratio between fibroglandular and adipose tissue and stabilization and / or increase in the level of androgen receptor expression may be applied to one or more of:

[0142] As described herein, the preparation of esters is within the skill of those in the art of pharmaceutical chemistry and drug delivery. It will be understood that the hydroxyl and / or carboxyl groups that may be present For example, to prepare testosterone esters, the testosterone molecule The 17-hydroxyl group of the hydroxyl group is generally reacted with strong acids such as sulfuric acid and hydrochloric acid, and the reaction proceeds at reflux. a suitable organic acid under esterification conditions, with the use of a temperature sufficient to allow The ester can be reacted with, if desired, using conventional hydrogenolysis or hydrolysis procedures. It can be reconverted to the free acid by using

[0143] The effective amount of an androgenic agent may vary between androgenic agents. The effective daily amount of testosterone may also vary. In certain embodiments, the effective amount of testosterone is In certain embodiments, an effective amount of testosterone may be delivered in the form of a subcutaneous implant. For example, in certain embodiments, an effective amount of testosterone may be 40 to 200 mg. Tosterone is 40-120 mg, for example, 20 mg, 40 mg, 60 mg, 80 mg, It can be 100 mg, or 120 mg.

[0144] In certain embodiments, the effective amount of testosterone is 40-200 mg of testosterone. Ron, for example, 40-150mg, 40-100mg, 100-200mg, 50-15 0mg, 50~100mg, 40~100mg, 30~80mg, 40~90mg, 40 ~90mg, 40~80mg, 40~70mg, 40~60mg, 40~50mg, 40 ~100mg, 60-100mg, 45-75mg, or 40-45mg testosterone The compound may be delivered in the form of a subcutaneous implant, such as a subcutaneous pellet containing the compound.

[0145] The effective amount of methyltestosterone per day can vary. The effective amount of methyltestosterone is 0.1 mg to 10 mg, for example, 0.5 mg to 9 mg, 2 mg to 8 mg, 3 mg to 7 mg, or 4 mg to 5 mg. Potency doses of methyltestosterone can be 0.5 mg, 1.25 mg, or 2.5 mg. do.

[0146] An effective amount of an androgenic agent used in combination with an aromatase inhibitor is Low levels of sex hormone-binding globulin in the serum of patients may be caused by toxic drugs. Therefore, the dose may be relatively lower than the standard dose.

[0147] Sex hormone-binding globulin binds androgenic agents (e.g., testosterone) Its production is regulated by several mechanisms, the level of which is One of the effectors of bell is the amount of estrogen in the serum, and the higher the estrogen, the In other words, the sex hormone-binding globulin is high and the free androgen is low. The lower the level, the lower the sex hormone-binding globulin and the higher the free androgen. This means that estrogen has high bioavailability. When hormone levels drop, sex hormone-binding globulin levels drop, leading to decreased production of testosterone and other hormones. This free androgen increases the androgen receptors. When expressed in all cells of the body, it has multiple functions.

[0148] In certain embodiments, dosage levels below the lower end of the above range of androgenic agent are sufficient In other cases, even larger doses above the upper limit of the range may be effective. It can be used without causing any harmful side effects.

[0149] In certain embodiments, the aromatase inhibitor is, for example, a steroidal aromatase inhibitor. inhibitors, nonsteroidal aromatase inhibitors, and / or their isomers. The steroidal aromatase inhibitors developed to date are basic androstenedioic acid. The steroidal aroma is then added to the steroid core, and chemical substituents are incorporated at various positions on the steroid. Examples of enzyme inhibitors include, but are not limited to, exemestane (Aromasin®) Additional examples include hydroxylase inhibitors that mimic the substrate and are reacted with by the enzyme. Mechanism-based steroids that are converted to reactive intermediates, leading to aromatase inactivation In certain embodiments, the aromatase inhibitor is Nonsteroidal aromatase inhibitors are classified into three classes: Noglutethimide-like molecules, imidazole / triazole derivatives, and flavonoid analogues Examples of nonsteroidal aromatase inhibitors include anastrozole, In certain embodiments, aromatase inhibitors include xemestane, letrozole, or benzodiazepines. The enzyme inhibitor is either anastrozole or letrozole. In this case, the aromatase inhibitor is anastrozole.

[0150] Aromatase inhibitors are often used with anastrozole (Arimidex®). (Ferrozole), exemestane (Aromasin®), and letrozole (Fe These third-generation aromatase inhibitors include those of the Aromatase inhibitors are changing the treatment approach for patients with hormone-sensitive breast cancer. Such aromatase inhibitors virtually eliminate serum estrogen, Therefore, they are specific in their action of lowering sex hormone-binding globulin. This allows a synergistic effect to be achieved.

[0151] In certain embodiments, the aromatase inhibitor is anastrozole, exemestane In certain embodiments, the aromatase inhibitor may be selected from the group consisting of: benzodiazepine, ... The enzyme inhibitor is either anastrozole or letrozole. In the present invention, the aromatase inhibitor is anastrozole.

[0152] In certain embodiments, the patient has a BI-RAD of 3 or 4 (or c or d). Breasts with an S® score or mammographic breast density of 7.5% or greater Breasts that are dense, dense by mammography, or have as much or more fat than Breasts with tissue, breasts with more breast tissue than fat, breast cancer, or any of these A method is provided for determining whether a combination of:

[0153] In certain embodiments, the patient receives a range of 2 to 4, e.g., 2 to 3, or 3 to 4 Have or have breasts with a BI-RADS® score (1-4 scale) In certain embodiments, patients are diagnosed with a BI-RADS® score of 2 or greater. score, e.g., a BI-RADS® score of 3 or 4, or a BI- Have or be diagnosed with a RADS® score of breast.

[0154] In certain embodiments, the patient has a range of b to d, e.g., b to c, or c to d. Have or have a breast BI-RADS® score (a-d scale) In certain embodiments, the patient is diagnosed with a BI-RADS score of b or higher. a BI-RADS® score, e.g., a BI-RADS® score of c or d, have or have been diagnosed with a BI-RADS® score of d do.

[0155] In certain embodiments, the patient has a mammographic breast density of 7.5% or greater, e.g. , 10% or more, 15% or more, 20% or more, 30% or more, 50% or more, 70% or more, or have or are diagnosed with a mammographic breast density of 95% or greater .

[0156] In certain embodiments, the patient has a VBD% of 7.5% or more, e.g., 10% or more, V of 5% or more, 20% or more, 30% or more, 50% or more, 70% or more, or 95% or more Have or be diagnosed with BD% breasts.

[0157] In certain embodiments, the patient has an ABD% of 7.5% or greater, e.g., 10% or greater, e.g., 1 5% or more, 20% or more, 30% or more, 50% or more, 70% or more, or 95% or more A Have or be diagnosed with BD% breasts.

[0158] In certain embodiments, patients have a BI-RADS® score of 3 (or c). and mammographic breast density of 7.5% or more, e.g., 10% or more, 15% or more , 20% or more, 30% or more, 50% or more, 70% or more, or 95% or more of mammograms In certain embodiments, the patient has or is diagnosed with dense breasts. , patients had a BI-RADS® score of 4 (or d) and a ≥ 7.5% Mammographic breast density, e.g., ≥10%, ≥15%, ≥20%, ≥30% , 50% or more, or 95% or more mammographic breast density have or be diagnosed with breast cancer.

[0159] In certain embodiments, the patient has a VBD% in the range of 1% to 100%, for example, 1% to 24%, 5%~100%, 5%~95%, 5%~90%, 5%~80%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~25%, 5%~20 %, 10%~100%, 10%~95%, 10%~90%, 10%~80%, 10%~7 0%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 2 5%, 10%~20%, 25%~100%, 25%~75%, 25%~50%, 25%~ 49%, 30%~100%, 30%~95%, 30%~90%, 30%~80%, 30% ~70%, 30%~60%, 30%~50%, 30%~40%, 40%~100%, 40 %~95%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40 %~50%, 50%~100%, 50%~95%, 50%~90%, 50%~80%, 5 0%~75%, 50%~74%, 50%~70%, 50%~60%, 75%~100%, Have breasts with 75%-95% VBD%, or 75%-90% VBD%, or In certain embodiments, patients are diagnosed with VB in the range of 10% to 40%. Have or be diagnosed with D% breasts.

[0160] In certain embodiments, patients have an ABD% in the range of 1% to 100%, for example, 1% to 24%, 5%~100%, 5%~95%, 5%~90%, 5%~80%, 5%~70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~25%, 5%~20 %, 10%~100%, 10%~95%, 10%~90%, 10%~80%, 10%~7 0%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 2 5%, 10%~20%, 25%~100%, 25%~75%, 25%~50%, 25%~ 49%, 30%~100%, 30%~95%, 30%~90%, 30%~80%, 30% ~70%, 30%~60%, 30%~50%, 30%~40%, 40%~100%, 40 %~95%, 40%~90%, 40%~80%, 40%~70%, 40%~60%, 40 %~50%, 50%~100%, 50%~95%, 50%~90%, 50%~80%, 5 0%~75%, 50%~74%, 50%~70%, 50%~60%, 75%~100%, Have breasts with 75%-95% ABD%, or 75%-90% ABD%, or In certain embodiments, patients are diagnosed with A in the range of 50% to 100%. In certain embodiments, the patient has or is diagnosed with breast cancer. Patients should have dense breasts on mammography, i.e. breasts with almost as much or more fat as Having or being diagnosed with breast tissue.

[0161] In certain embodiments, the patient is a peri-menopausal or post-menopausal woman. In one embodiment, the patient is a peri-menopausal woman.

[0162] In certain embodiments, the pharmaceutical preparations are used to evaluate the BI-RADS® score of a patient. One or more annual interim mammography detections of cores may be reduced or decreased. For example, The pharmaceutical preparation is used to assess the patient's BI-RADS® score after one or more annual interventions. ≥ 1 point in sexual mammography detection, e.g., ≥ 1 annual interim mammogram 2 points or more, 3 points or 4 points or 4 points reduction or In certain embodiments, the pharmaceutical preparations may be used to reduce BI-RADS in a patient. (R) score is calculated as 1 point for 1 or more annual intercurrent mammogram detections, e.g. For example, a 2, 3, or 4 point reduction or In certain embodiments, the pharmaceutical preparation may reduce the patient's BI-RADS (Registered Markers of Infectious Diseases). Maintain or stabilize the target score at one or more annual interim mammogram detections.

[0163] The period of one or more annual intercurrent mammography detections ranges from 1 to 20 years, e.g., 1 year, 1 It can be 0.5 years, 2 years, 3 years, 4 years, 5 years, 6 years, 10 years, 15 years, or 20 years. The duration of annual mammography detection was 1 year, 2 years, 4 years, 5 years, 7 years, and 1 year. It can be 0, 15, or 20 years.

[0164] In certain embodiments, the pharmaceutical preparation is used to administer one or more annual interim mammograms. During detection, the mammographic breast density of the patient's breast may be reduced or decreased. In an embodiment of the present invention, the pharmaceutical preparation is used to administer one or more annual interim mammography detection During this time, the VBD% and / or AVBD of the patient's breast may be reduced or decreased. In an embodiment of the present invention, the pharmaceutical preparation is used to administer one or more annual interim mammography detection During this time, the ABD% and / or AABD of the patient's breasts may be reduced or decreased. For example, a pharmaceutical preparation may be used to measure the mammographic density of a patient's breasts at one or more annual visits. Among superficial mammography detections, the range is 1% to 99%, e.g., one or more annual intercurrent Among mammography detection, 1%-80%, 1%-50%, 1%-30%, 1%-20 %, 1%~10%, 3%~40%, 3%~20%, 5%~60%, 5%~25%, 5%~ 15%, 5% to 10%, 10% to 60%, 10% to 40%, 10% to 30%, 10% to 2 0%, 10%-15%, 20%-60%, 20%-40%, 20%-30%, 30%-6 It can be reduced or decreased by 0%, 30% to 50%, or 30% to 40%. For example, a pharmaceutical preparation may be used to administer VBD% and / or AVBD to the patient's breast one or more times. Between annual intercurrent mammography detection, the range is 1% to 99%, e.g., more than one year Among secondary mammography detection, the rates were 1%-80%, 1%-50%, 1%-30%, and 1%-40%. %~20%, 1%~10%, 3%~40%, 3%~20%, 5%~60%, 5%~25% , 5%~15%, 5%~10%, 10%~60%, 10%~40%, 10%~30%, 1 0%~20%, 10%~15%, 20%~60%, 20%~40%, 20%~30%, 3 Decrease or reduce by 0% to 60%, 30% to 50%, or 30% to 40%. For example, the ABD% and / or AABD of a patient's breast can be measured using a pharmaceutical preparation. Between one or more annual interim mammography detections, the range is 1% to 99%, e.g. Among annual intercurrent mammography detection rates, 1% to 80%, 1% to 50%, and 1% to 3% 0%, 1% to 20%, 1% to 10%, 3% to 40%, 3% to 20%, 5% to 60%, 5% ~25%, 5%~15%, 5%~10%, 10%~60%, 10%~40%, 10%~3 0%, 10% to 20%, 10% to 15%, 20% to 60%, 20% to 40%, 20% to 3 Reduce or For example, the pharmaceutical preparation may be used to reduce mammographic breast density in a patient's breasts. , at least 2% between one or more annual intercurrent mammography detections, e.g. Among annual intercurrent mammography detections, at least 5%, 10%, 20%, 30%, It may be reduced or decreased by 40%, 50%, 75%, 85%, 95%, or 99%. For example, a pharmaceutical preparation may be used to administer VBD% and / or AVBD to the patient's breast one or more times. At least 2% between annual intercurrent mammography detections, e.g., 1 or more annual intercurrent Among sexual mammography detection, at least 5%, 10%, 20%, 30%, 40%, 5 The drug may be reduced or decreased by 0%, 75%, 85%, 95%, or 99%. The formulation is used to measure the ABD% and / or AABD of the patient's breasts at one or more annual interventions. At least 2% between annual mammography detections, e.g., 1 or more annual interval mammograms Between the detection of at least 5%, 10%, 20%, 30%, 40%, 50%, 75% %, 85%, 95%, or 99% reduction or decrease. , using a pharmaceutical preparation to treat a patient's breast between one or more annual interim mammography detections. The mammographic breast density may be maintained or stabilized.

[0165] In certain embodiments, the pharmaceutical preparations are used to measure mammographic breast density of a patient's breast. Degrees over a 4 hour period, e.g., 8 hours, 24 hours, 1 day, 3 days, 1 week, 2 weeks for a period of at least 1 month, 2 months, 3 months, 6 months, 9 months, or 1 year. Both may be reduced or decreased by 2%, for example, 5%, 10%, 20%, or 30%.

[0166] In certain embodiments, the pharmaceutical preparations are used to measure mammographic breast density of a patient's breast. The degree VBD% and / or AVBD may be measured over a 4 hour period, e.g., 8 hours, 24 Hours, 1 day, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or over a one-year period, at least 2%, e.g., 5%, 10%, 20%, or 3% It can be reduced or decreased by 0%.

[0167] In certain embodiments, the pharmaceutical preparations are used to measure mammographic breast density of a patient's breast. The degree ABD% and / or AABD may be measured over a 4 hour period, e.g., 8 hours, 24 Hours, 1 day, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or over a one-year period, at least 2%, e.g., 5%, 10%, 20%, or 3% It can be reduced or decreased by 0%.

[0168] In certain embodiments, the pharmaceutical preparations are used to reduce or prevent a patient's risk of developing breast cancer. For example, in certain embodiments, the pharmaceutical preparation may be used to administer one or more Mitigate or reduce a patient's risk of developing breast cancer between annual interim mammography detections In certain embodiments, the pharmaceutical preparations may be used to reduce a patient's risk of developing breast cancer. mitigating or reducing the risk of one or more closures between one or more annual interim mammography detections Symptoms of the transperitoneal phase may be avoided, alleviated, reduced, or reversed. For example, symptoms may be alleviated or reduced. One or more perimenopause symptoms that may be alleviated or avoided include, but are not limited to, menstruation Irritability, hot flashes and sleep disturbances, mood changes, mood swings, irritability, depression, vaginal dryness, urinary tract or vaginal infections, urinary incontinence, decreased fertility, changes in sexual arousal or desire, bone loss, brittle bones , osteoporosis, or increased low-density lipoprotein (LDL) cholesterol, Changes in cholesterol levels, such as a decrease in high-density lipoprotein (HDL) cholesterol, or a combination thereof.

[0169] In certain embodiments, the pharmaceutical preparation is used to administer one or more annual interim mammograms. - detection may increase or improve the patient's fat to breast tissue ratio. The formulation is intended to be administered to a patient's fatty breast tissue between one or more annual interim mammograms. Increase or improve the ratio of fat to milk fat in treated patients to 1:19 to 19:1, for example. The ratio of breast tissue to breast tissue should be between 1:15 and 1:10 between one or more annual interim mammography detections. 19:1, 1:10~19:1, 1:5~19:1, 1:2~19:1, 2:3~19: 1, 2:1~19:1, 4:1~19:1, 6:1~19:1, 8:1~19:1, 10 :1~19:1, 1:19~10:1, 1:10~10:1, 1:4~10:1, 1:2 ~10:1, 3:2~10:1, 3:1~10:1, 5:1~10:1, 7:1~10: 1, 9:1~10:1, 15:1~10:1, 1:15~5:1, 1:5~5:1, 1: 3~5:1, 3:2~5:1, 3:1~5:1, 6:1~5:1, 8:1~5:1, 10 :1~5:1, 1:19~3:1, 1:10~3:1, 1:4~3:1, 1:2~3:1 , 2:1~3:1, 4:1~3:1, 6:1~3:1, 8:1~3:1, 10:1~3: 1, or increase or improve to 15:1 to 3:1.

[0170] In certain embodiments, the pharmaceutical preparation is used to increase the fat to breast tissue ratio of a patient. 1:19~19:1, e.g. 1:10~19:1, 1:5~19:1, 1:2~19:1 , 2:3 to 19:1, 2:1 to 19:1, over a 4-hour period, over an 8-hour period Over a 24 hour period, over a 3 day period, over a 1 week period, Over a 2-week period, over a 1-month period, over a 2-month period, over a 3-month period Over a period of time, over a 6-month period, over a 9-month period, over a 1-year period may increase or improve over a five-year period.

[0171] In certain embodiments, the pharmaceutical preparation reduces the percentage of fat in the breast of a treated patient. The stage may be increased between one or more annual interim mammography detections. The drug formulation reduces the percentage of fat in the breasts of treated patients after one or more annual interventions. Between 1% and 99% of women with mammography detection, e.g., 1 or more annual intercurrent mammograms Among the morphography detections, 1%-90%, 1%-70%, 1%-50%, 1%-30%, 1 %~20%, 1%~15%, 1%~10%, 3%~60%, 3%~20%, 5%~70% , 5%~50%, 5%~30%, 5%~20%, 5%~15%, 5%~10%, 10%~ 60%, 10%~40%, 10%~30%, 10%~20%, 10%~15%, 20%~ 50%, 20%-30%, 30%-60%, 30%-50%, or 30%-40% range Increase in the range.

[0172] In certain embodiments, the pharmaceutical preparation reduces the percentage of fat in the breast of a treated patient. The age is at least 2%, for example, at least 5%, at least 10%, at least 2 5%, at least 40%, at least 75%, at least 95%, or at least 99 %, over a 4 hour period, for example, over an 8 hour period, over a 24 hour period, Over a 3-day period, over a 1-week period, over a 2-week period, over a 1-month period over a period of 2 months, over a period of 3 months, over a period of 6 months So, over a nine-month period, over a one-year period, or over a five-year period. Add.

[0173] In certain embodiments, the pharmaceutical formulation is for use in mammographic breast visualization or detection. Breast compression may be augmented, increased, or modified between one or more annual interim mammography detections. For example, pharmaceutical preparations may improve breast compression during mammography breast visualization or detection. , among one or more annual intercurrent mammography detections, 5% to 70%, 5% to 50%, 5 %~30%, 5%~20%, 5%~15%, 5%~10%, 10%~50%, 10%~3 0%, 10% to 20%, 10% to 15%, 20% to 60%, 20% to 40%, 20% to 3 Enhancement or increase in the range of 0%, 30%-70%, 30%-50%, or 30%-40% In certain embodiments, mammographic breast visualization or detection As a result of the enhanced, increased, or improved breast compression, the pharmaceutical preparation may further For example, the pharmaceutical formulation may further be used to alleviate or reduce pain in a patient during a mammogram of the breast. Physiological findings as a result of enhanced, increased, or improved breast compression upon breast visualization or detection , patient pain during breast compression was assessed in 5% to 80%, 5% to 50%, 5% to 30%, and 5% to 2%. 0%, 5% to 15%, 5% to 10%, 10% to 80%, 10% to 60%, 10% to 40% , 10%~20%, 10%~15%, 20%~70%, 20%~50%, 20%~30% , 30% to 70%, 30% to 50%, or 30% to 40% is minimized.

[0174] In certain embodiments, the pharmaceutical preparation relieves or reduces pain in a patient during breast compression. For example, a pharmaceutical preparation may be used to alleviate a patient's pain during breast compression after one or more annual interval mammograms. Among the detection rates, 5%~80%, 5%~60%, 5%~30%, 5%~20%, 5% ~15%, 5%~10%, 10%~80%, 10%~60%, 10%~40%, 10%~ 30%, 10%-20%, 10%-15%, 20%-70%, 20%-50%, 20%- Relaxation or reduction in the range of 30%, 30%-90%, 30%-50%, or 30%-40% In certain embodiments, the patient's relief, reduction, or minimization of breast compression. As a result of the pain experienced, the pharmaceutical preparation may further include one or more annual interim mammograms. During mammographic visualization or detection of the breast, augmentation, increase, or For example, the pharmaceutical preparation may improve mammograms between one or more annual interim mammograms. Breast compression during mammographic visualization or detection should be performed on at least one annual interim mammogram. - Detection range: 5%~80%, 5%~60%, 5%~40%, 5%~30%, 5%~20 %, 5%~15%, 5%~10%, 10%~80%, 10%~60%, 10%~40%, 10%~20%, 10%~15%, 20%~80%, 20%~60%, 20%~30%, Further enhancement or increase in the range of 30% to 80%, 30% to 50%, or 30% to 40% Or improve.

[0175] In certain embodiments, the pharmaceutical formulation provides a visual analog scale (VAS) response during breast compression. ) to relieve or reduce pain in a patient. For example, the pharmaceutical preparation may be administered during breast compression. Alleviating or reducing a patient's pain according to AS, thereby allowing the patient to have one or more mammograms 50-10 at the time of mammography or at one or more annual interim mammography detections 0mm, 50~80mm, 50~70mm, 60~100mm, 70~100mm, 80 ~100mm, or between 90-100mm without experiencing significant pain.

[0176] In certain embodiments, the pharmaceutical preparation is for routine mammography visualization or detection. Patient compliance, e.g., mammograms every 6 months, every year, every 2 years, every 3 years, or every 5 years Enhance, increase, or improve compliance with radiographic visualization or detection.

[0177] In certain embodiments, the pharmaceutical preparation comprises a pharmaceutical agent necessary for visualizing or detecting the breast of a patient. The amount of radiation exposure considered to be The patient's risk of breast cancer is alleviated or reduced at the time of subsequent annual mammograms. The amount of radiation exposure required to visualize or detect the breast is determined by one or more subsequent At the time of mammography, for example at one or more subsequent annual mammograms, 5% to 9% 9%, 5%~80%, 5%~70%, 5%~50%, 5%~30%, 5%~20%, 5% ~15%, 5%~10%, 10%~80%, 10%~60%, 10%~40%, 10%~ 20%, 10%~15%, 20%~80%, 20%~60%, 20%~40%, 20%~ 30%, 30%-80%, 30%-60%, 30%-50%, or 30%-40% To mitigate or reduce to a certain extent.

[0178] In certain embodiments, the pharmaceutical preparation is administered to the patient's breast, for example, the breast of a peri-menopausal patient. Induce breast involution in

[0179] In certain embodiments, the pharmaceutical preparation is administered to the patient's breast, for example, the breast of a peri-menopausal patient. Induces breast cell involution in

[0180] In certain embodiments, the pharmaceutical preparation is administered to the patient's breast, for example, the breast of a peri-menopausal patient. Induces terminal cell death in response to proliferation in .

[0181] In certain embodiments, the pharmaceutical preparation is administered to the patient's breast, for example, the breast of a peri-menopausal patient. Reverse cell count and mammographic breast density in

[0182] In certain embodiments, the pharmaceutical preparation is administered to the patient's breast, for example, the breast of a peri-menopausal patient. For example, the pharmaceutical preparation may be Breast hardness between one or more annual interim mammography detections, 5% to 80%, 5% to 60%, 5%~40%, 5%~20%, 5%~15%, 5%~10%, 10%~80%, 10%~60%, 10%~40%, 10%~30%, 10%~20%, 10%~15%, 20%~80%, 20%~60%, 20%~40%, 20%~30%, 30%~80%, The effects are alleviated or reduced by 30% to 60%, or 30% to 40%. For example, The formulation may reduce breast firmness in the patient's breasts by at least 5% in one year, e.g., by at least 8%. %, at least 10%, at least 15%, at least 20%, or at least 30 In certain embodiments, the pharmaceutical preparation alleviates or reduces the Breast firmness may be measured over a 4 hour period, e.g., an 8 hour period, a 24 hour period, a 3 day period, or Period, 1 week period, 2 weeks period, 1 month period, 2 months period, 3 months period, 6 months At least 5% over a one-month period, a nine-month period, a one-year period, or a five-year period , e.g., at least 8%, at least 10%, at least 15%, at least 20%, Or at least 30% mitigation or reduction.

[0183] In certain embodiments, the pharmaceutical preparation is administered to the patient's breast, for example, the breast of a peri-menopausal patient. Enhance, increase, or improve mammographic visualization or detection of, e.g., pharmaceutical preparations The mammographic visualization or detection of a patient's breast is determined by one or more annual interim mammograms. Among the detection rates, 5%~80%, 5%~50%, 5%~30%, 5%~20%, 5% ~15%, 5%~10%, 10%~80%, 10%~60%, 10%~30%, 10%~ 20%, 10%~15%, 20%~80%, 20%~60%, 20%~30%, 30%~ Enhancement, increase, or improvement in the range of 80%, 30%-60%, or 30%-40% In certain embodiments, the pharmaceutical preparation is administered after mammographic visualization or imaging of the patient's breast. Detection can be performed over a 4 hour period, or 8 hours, 24 hours, 3 days, 1 week, 2 weeks, or 1 month. , 2 months, 3 months, 6 months, 9 months, 1 year, or 5 years. At least 5%, for example, at least 10%, at least 15%, at least 25%, at least at least 40%, at least 50%, or at least 75% enhancement, increase, or improvement do.

[0184] In certain embodiments, the pharmaceutical preparation reduces mammographic breast density and virilizes Avoid inducing androgenic side effects or inducing a hyperandrogenic state For example, virilizing androgenic side effects include male pattern hair loss, hirsutism, or unwanted side effects. These may include increased hair growth in areas, thinning of the skin, acne, or a combination thereof. In an embodiment, the pharmaceutical preparation reduces mammographic breast density and inhibits virilization and Inducing androgenic side effects or inducing a hyperandrogenic state. In an embodiment, the pharmaceutical preparation reduces mammographic breast density and inhibits virilization and Minimize the induction of androgenic side effects or the induction of a hyperandrogenic state.

[0185] In certain embodiments, the pharmaceutical preparation is effective in treating a patient's central nervous system, sexual desire, musculoskeletal system, cardiovascular the risk of developing an autoimmune disease, the severity of symptoms associated with an autoimmune disease, or substantially improves the patient's physical function, including the physical function associated with any combination of these; or For example, in relation to the patient's central nervous system, the pharmaceutical preparation may improve symptoms including depression, anxiety, and memory. may reduce common cognitive impairment, including dementia and Parkinson's disease, or may reduce the risk of For example, in relation to a patient's sexual desire, the pharmaceutical preparation may reduce the rate and intensity of sexual arousal. It may provide a significant improvement in overall sexual desire, including the ability to achieve orgasm. With respect to the musculoskeletal system, the pharmaceutical preparations are useful for reducing inflammatory and degenerative arthritis, improving bone mineral density, For example, the patient may experience improved muscle tone or muscle strength. The formulation is effective in reducing foamy macrophage deposition in the arterial wall, reducing atherosclerosis, and preventing cholecystolytic damage. Increased high density lipoprotein or high density lipoprotein ratio leading to improved sterol For example, in relation to a patient's risk of developing an autoimmune disease, the pharmaceutical formulation may provide Treated patients with autoimmune diseases such as Sjögren's syndrome, lupus, and rheumatoid arthritis For example, the patient may have an autoimmune disease. In relation to the severity of symptoms associated with autoimmune diseases in treated patients, e.g. For example, it can substantially reduce the severity of symptoms associated with Sjögren's syndrome, lupus, and rheumatoid arthritis. In certain embodiments, the pharmaceutical preparation may reduce or decrease cognitive function, cognitive reduction of degenerative CNS diseases including rheumatoid arthritis or Parkinsonism, muscle strength, libido, energy, monoatheca and the reduction of anxiety and depression, or a combination thereof, induced by steroid hormone. substantially improve or improve the physical function of a person.

[0186] In certain embodiments, the pharmaceutical formulation further comprises: i) reducing mammographic breast density; or ii) in the patient's breast without converting testosterone to estrogen. or iii) increase the involution effect, or iii) substantially reduce or alleviate perimenopausal symptoms. or iv) improve or reverse cognitive function, including dementia or Parkinsonism. Reduction of symptoms associated with degenerative CNS diseases, including muscle strength, libido, energy, and monoamine oxidase and improving the patient's physical function, including reducing anxiety and depression, or a combination thereof. Improves or substantially improves one or more of the following: In the method, the pharmaceutical preparation further comprises: i) reducing mammographic breast density; or ii) It is not affected by hormones, including breast cancer, without converting hormones into estrogen. iii) increase the involutional effect on the end organs involved in the treatment of fluctuating estrogen levels; substantially reduce, reduce, or reverse associated perimenopausal symptoms, or iv) associated with cognitive function, dementia, or degenerative CNS disease, including Parkinsonism Reduction of symptoms, muscle strength, libido, energy, monoamine oxidase-induced anxiety and depression or a combination thereof, substantially improving the patient's physical function; improves, or provides one or more of the following.

[0187] In certain embodiments, the patient is treated with an androgenic agent and an aromatase inhibitor. Within 4 hours of the onset of breast cancer, high free androgen index levels, e.g., 30%, In certain embodiments, the patient is receiving an androgenic agent and an aromatase inhibitor. Within 4 hours of administration of the toxin, the breast showed supraphysiological free androgen index levels. It has.

[0188] In certain embodiments, an androgenic agent and an aromatase inhibitor described herein Treatment with a pharmaceutical formulation or combination treatment of the present invention may be performed by: a) collecting a sample from the patient at least one month after treatment; The free androgen index level and / or allogeneic androgen levels in serum isolated from the blood samples were measured. b) measuring the level of an androgenic agent and and c) administering to the patient a subsequent dose comprising an effective amount of an aromatase inhibitor. and administering the dose.

[0189] In certain embodiments, an androgenic agent and an aromatase inhibitor described herein Treatment with a pharmaceutical formulation or combination treatment of the present invention may be performed by: a) collecting a sample from the patient at least one month after treatment; The free androgen index level and / or allogeneic androgen levels in serum isolated from the blood samples were measured. 2. Measuring the matase inhibitor level by centrifuging the patient's blood sample and extracting the serum. and b) measuring a subsequent effective amount of an androgenic agent and a subsequent effective amount of an androgenic agent. c) administering to the patient a subsequent dose comprising an effective amount of an aromatase inhibitor; and and administering

[0190] In certain embodiments, the free androgen level measured after one month of treatment in a treated patient is The number serum levels are 10-25%, e.g., 10-20%, 10-15%, 15-25%, It can be 15-20%, 12-18%, 8-15%, or 11-14%.

[0191] In certain embodiments, the free androgen levels measured after 3 months in treated patients are The number serum levels can be 2-10%, e.g., 2-8%, 2-6%, 2-5%, 2-4%, 4- 10%, 5-8%, 3-7%, 4-6%, 3-6%, 4-7%, 5-10%, or 2- It could be 5%.

[0192] In certain embodiments, administration of an aromatase inhibitor to the subcutaneous fat of the treated patient. Reduces the aromatization of testosterone to estrogen in the For example, the aromatase inhibitor administered reduces breast cancer in patients by 95% or 100%. the subcutaneous fat of the patient's pelvis, the subcutaneous fat of the patient's buttocks, the subcutaneous fat of the patient's abdomen, or or combinations thereof, reducing the aromatization of testosterone to estrogen; For example, aromatization may be reduced by 80-95% or even 100%.

[0193] In certain embodiments, administration of an aromatase inhibitor to the subcutaneous fat of the treated patient. Reduces the aromatization of adrenal androgens, such as androstenedione, to estrogens in the For example, aromatization is reduced by 80-95% or 100%. The thromatase inhibitor is administered to the subcutaneous fat of the patient's breasts, the subcutaneous fat of the patient's pelvis, and the subcutaneous fat of the patient's buttocks. Testosterone levels in the fat, subcutaneous fat in the patient's abdomen, or a combination of both Reduce aromatization to strogens, e.g., reduce aromatization by 80-95% or 100%. obtain.

[0194] Annual mammography screening for density and fibroglandular tissue volume as a percentage of total breast volume Breast density is measured as a percentage (MBD) using an appropriate mammography algorithm. The goal is to determine the MBD as a function of the average of both breast densities. The goal is to achieve a reduction in breast density of less than 10% over a period of at least 1 year. If 2% is not achieved in the first year, the annual increase factor (V1(N) above) should be , 10% of the medication can be introduced into TD and AD. This annual increase factor is usually It will only be introduced on an annual basis if the AI ​​increases by less than 10%.

[0195] Annual mammography screening for density and fibroglandular tissue volume relative to total breast volume Using an appropriate mammography algorithm, the percentage of VBD (VBD%) is measured. The goal is to determine the VBD% as a function of the average of both breast densities. The goal is to achieve less than 10% of breast density reduction (VBD%) at 1 year. If 2% is not achieved in the first year, the annual increase factor ( The above V1(N) can be introduced into TD and AD at 10% of the dose. This annual increase coefficient is usually only observed if the androgenic index (AI) increases by less than 10% on an annual basis. It will be introduced in.

[0196] In certain embodiments, administration of an aromatase inhibitor in combination with testosterone , improving the bioavailability of dihydrotestosterone by 25% to 75% and 35% to 65% In certain embodiments, the amount of dihydrotestosterone is The increase in bioavailability may be greater than 25%, greater than 35%, greater than 45%, or greater than 55%.

[0197] The androgenic agent used in the pharmaceutical formulations or combination treatments described herein can be, for example, , testosterone, methyltestosterone, and / or dehydroepiandrosterone In certain embodiments, the androgenic agent may be selected from the group consisting of about 40 mg It can be testosterone undecanoate, such as testosterone undecanoate 100 mg. Tase inhibitors include, for example, anastrozole, exemestane, or letrozole. In certain embodiments, the aromatase inhibitor may be selected from the group consisting of about 1 mg of anabolic acid. It may be anastrozole, such as astrozole.

[0198] In certain embodiments, the pharmaceutical agent may be a hydroxyl group or a hydroxyl group containing an aromatase inhibitor, such as an ester bond. androgenic agents linked via an androgen-binding protein or an androgen / aromatase inhibitor complex The conjugate may be prepared by methods known in the art. will be done.

[0199] In a preferred embodiment, an androgenic agent (e.g., testosterone, methyltestosterone) is used. steroids, and / or dehydroepiandrosterone), and aromatase inhibitors (e.g., anastrozole, exemestane, or letrozole) are both administered subcutaneously. For example, it may be administered as an implant, such as a pellet.

[0200] In certain embodiments, androgenic agents (e.g., testosterone, methyltestosterone) terone, and / or dehydroepiandrosterone), and aromatase inhibitors ( For example, anastrozole, exemestane, or letrozole) are administered subcutaneously. For example, testosterone and anastrozole are administered as pellets. It may be administered subcutaneously.

[0201] Androgens, aromatase inhibitors, or androgens and aromatase inhibitors The appropriate dosing regimen utilizing a pharmaceutical formulation containing the agent, the amount of each dose administered, and the compound The interval between doses of the compounds may depend on various factors, for example, the specific compounds used in combination. the type of pharmaceutical preparation used, the physiological condition being treated, type of medical condition, characteristics of the subject being treated (e.g., species, age, weight, sex, medical condition) , fed / fasted), route of administration, and the severity of the disorder being treated, or a combination thereof. A normally trained physician or diagnostician may prescribe a drug to prevent or treat a particular physiological condition. androgenic agent, aromatase inhibitor, or pharmaceutical formulation in an effective amount for treating can be determined and prescribed.

[0202] The pharmaceutical preparation or formulation to be administered contains an amount of the compound effective to treat the condition of the subject being treated. The compound may contain two different compounds or a pharmaceutically acceptable salt or ester thereof. Since the compounds may be used together in combination therapy, the efficacy of each of the compounds and the effectiveness of combining them together will be discussed. The interaction effects achieved by combining these factors are also usually considered. For the purpose of determining the therapeutically or prophylactically effective dose required to improve side effects, Therefore, it is well within the scope of a normally skilled clinician.

[0203] Pharmaceutical formulations containing an androgenic agent and an aromatase inhibitor, or a combination thereof Administration of the drug to a subject may be by self-administration or by another person (e.g., a doctor, nurse, healthcare professional, friend, etc.). This includes both administration to a subject by injection (e.g., by steroid injection).

[0204] In certain embodiments, the pharmaceutical preparation may be formulated in a manner consistent with the desired outcome. Pharmaceutical formulations may be administered in convenient formulations. The following formulation examples are for illustrative purposes only. nor is it intended to limit the scope of the disclosure.

[0205] In certain embodiments, the pharmaceutical formulation is an implant or capsule formulated by direct compression. For example, pellet formulations contain not only the active ingredient but also the diluent. Exemplary diluents include, for example, various sorbents, binders, lubricants, and disintegrants. Various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate Powdered cellulose derivatives include inorganic salts such as cellulose acetate, sodium chloride, and powdered sugar. Natural and synthetic gums are also advantageous, including acacia, alginates, and methicone. Polyethylene glycol, methylcellulose, and / or polyvinylpyrrolidine. Pell, ethyl cellulose, and waxes can also serve as binders. The pellet formulation requires a lubricant to prevent the pellets and punches from sticking to the die. Lubricants include talc, magnesium stearate and calcium stearate, may be selected from slippery solids such as stearic acid, and / or hydrogenated vegetable oils Typically, the implant or pellet will have a weight of about 6 kg / N to about 10 kg / N, preferably Preferably, the implant weight ranges from about 7 kg / N to about 9 kg / N, most preferably about 8 kg / N. or pellet hardness, and all such dosage forms within this range are expressly provided herein. It is served.

[0206] Compressing the formulation into a solid dosage form, such as an implant in the form of a pellet for subcutaneous administration By shrinking the concentration of the compound, it is possible to obtain the sustained release multi-phase concentration pattern described herein. Such a release pattern of the androgenic agent and aromatase inhibitor can be obtained. In view of the disclosure provided herein, one of skill in the art will be familiar with the various possibilities of using the formulations. different components may be utilized to provide such pharmaceutical formulations in accordance with the present disclosure. .

[0207] In certain embodiments, the implant or pellet is administered to the subject's subcutaneous fat in the pelvis, versus Subcutaneous fat from the udder of an elephant, subcutaneous fat from the buttocks of a subject, subcutaneous fat from the abdomen of a subject, or a combination thereof In certain embodiments, the implant or pellet may be inserted into a In certain embodiments, the implant or pen may be inserted into the subcutaneous fat of the elephant's lower abdominal wall. The insert may be inserted into the subcutaneous fat in the upper gluteal area of ​​the subject.

[0208] As will be appreciated, the androgenic agent and aromatase inhibitor may be administered in combination as described herein. For use in therapeutic treatment, they are administered subcutaneously either together in the same formulation or in separate formulations. The present invention may be provided in pharmaceutical formulations other than those described above, such formulations being suitable for administration by any other desired route. and / or to achieve a desired release pattern of the active agent (e.g., a sustained multiphasic release pattern). Suitable fillers, lubricants, binders, disintegrants, and and / or a pharmaceutically acceptable carrier or excipient.

[0209] In certain embodiments, an androgenic agent, an aromatase inhibitor, or a combination thereof The pharmaceutical formulation containing the combination may be provided in the form of an article of manufacture, such as a kit, and packaged for distribution. The kit comprises the active ingredient(s) therein, or in a suitable pharmaceutical formulation. may further include instructions for using the kit components in one or more of the methods described. The instructions may include instructions for carrying out one or more of the disclosed methods. Thus, for example, the kit may include an anti-inflammatory agent in a pharmaceutical formulation in a container, pack, or dispenser. a prophylactic or aromatase inhibitor together with instructions for administration to a human subject. The instructions may further include indications of satisfactory clinical endpoints or any adverse events that may occur. adverse symptoms, or any additional conditions required by the Food and Drug Administration for use in humans. It may contain information.

[0210] The instructions may be in "printed material," such as on paper or cardboard within the kit, or The label may be on a label affixed to the kit or packaging material, or may be on a label affixed to a component of the kit. The instructions may be attached to a vial or tube. , e.g., disks (floppy disks or hard disks), optical CDs, e.g., CD- or DVD-ROM / RAM, magnetic tape, electronic storage media, e.g. RAM and and ROM, as well as hybrids thereof, e.g., magnetic / optical storage media. .

[0211] To facilitate a better understanding of the present disclosure, the present disclosure provides certain exemplary embodiments. Although the present invention has been described with reference to various preferred embodiments, various modifications may be made without departing from the principles disclosed herein. It is to be understood that modifications may be made to the present invention, and therefore it is intended that the present invention include such modifications within its scope. It should be understood that [Example]

[0212] Example 1: A study in women to evaluate the pharmacokinetics of testosterone and anastrozole Subcutaneous testosterone and anastrozole implant, 80mg / 4mg (T+ Single-dose clinical trial of Ai Pharmacokinetic analysis was performed in 11 healthy volunteers with high mammographic breast density. The study was performed with subcutaneous testosterone 80g and anastrozole 4mg implants. This study evaluated patterns for both anastrozole and testosterone, Locations known to have excessive aromatase activity, i.e., high mammograms To demonstrate the pattern and end-organ pharmacodynamic response in tissues of women with dense breasts This allowed for modeling of the pharmacokinetics of this exemplary implant. It is assessed by direct measurement of breast tissue elasticity in relation to radiographic breast density.

[0213] Ultrasound assessment of pellet dissolution was performed, and a comprehensive analysis of reproductive hormone input dissolution was performed. How this is done will be examined to assess potential effects on hypothalamic-pituitary function. I testified.

[0214] Primary Objective: Pharmacokinetic characteristics of testosterone after a single dose of T+Ai by subcutaneous implantation To evaluate gender.

[0215] Pharmacokinetics of anastrozole after a single dose of T+Ai by subcutaneous implantation To evaluate characteristics.

[0216] Second Objective Exploring potential effects on breast tissue elasticity assessed by shear wave ultrasound .

[0217] Implant preparation: Testosterone-anastrozole pellets Pellets for subcutaneous insertion are prepared containing sterile non-micronized testosterone, anastrozole, and stearic acid in a ratio of 80:4:2 in a cylindrical die with a diameter of 5 mm. The pellet was placed in a sterile 5 ml amber vial covered with sterile cotton wool. Transfer to a vial and seal with a crimped rubber stopper and aluminum lip seal. The al is sterilized by gamma irradiation at 25 KGy. USP-grade anastrozole is available from Azelis (Brookvale, NSW) NF quality stearic acid was obtained from Medisca (Mascot, NSW). The steps for making these pellets are outlined below. 1. Testosterone (non-micronized), anastrozole, and stearic acid titrate The ration is mixed by mechanical means for 2 hours. 2. Mix the titration thoroughly. The pellets are compressed in a press resulting in a pellet hardness of 3.8 Kg / N. 4. Store the pellet in a 5 ml amber glass vial and cover the pellet with sterile cotton. Protect with wool. 5. Gamma sterilize the stored pellets at 25KyG. 6. Properly label the pellets. 7. Store in a cool, dry place (room temperature: 20-25°C, 66-78°F).

[0218] methodology Premenopausal women with high mammographic breast density (MBD) were selected for the study After a successful screening, participants were referred to Wellend Clinic So I came to Australia to avoid the rapidly changing hormonal environment of the follicular phase. Participants were to receive the injection during the luteal phase of their menstrual cycle. PK blood sampling was performed over a 3-month period. Briefly, samples were collected on the day of administration. , daily for the first week, weekly for the next 4 weeks, and every 2 weeks for the final 8 weeks, for a total of 3 months of sampling Repeated sampling was performed over the ring period. Evaluation was completed on day 85, the last day of evaluation. After that, the trial was terminated.

[0219] The selected pharmacokinetic (PK) sampling plan will determine the serum / plasma concentration duration profile of T+Ai. After day 29, blood samples were collected to determine whether the sample provided sufficient information about the file. Samples were collected from the first two participants and analyzed for testosterone, dihydrotestosterone, and The sampling plan was one blood sample (6 hours post-dose) ) was added and revised, and the timing of existing time points was not adjusted. The sampling period was extended. It wasn't long.

[0220] Briefly, following dosing on Day 1, blood samples were collected pre-dose (within 1 hour of dosing) and Participants were asked to take samples at 1, 2, 4, 6, 8, and 12 hours after the initial sampling. Patients returned for blood draws at 9:00 AM on days 5, 22, 29, 43, 57, 71, and 85. Ta.

[0221] A total of 11 subjects were dosed and included in the safety analysis set. 11 subjects were included in the PK analysis set. Women were included in the study. They were aged 35-55 years and had a body mass index (BMI) of 20-30 kg / m 2 The demographics of the participants are shown in Table 1. [Table 1]

[0222] PK result A summary of PK parameters for plasma anastrozole and serum testosterone is shown in Table 2 and illustrated in Figs. [Table 2]

[0223] Regarding pharmacokinetics, the median T of plasma anastrozole max 2 days after administration (range 1- 3 days), and the average C max = 5.30 ng / mL, with a mean terminal half-life of 14 days. Concentrations were below the limit of quantification (0.1 ng / mL) in most participants after 12 weeks. The observed half-life of 14 days from T+Ai is consistent with that stated for oral anastrozole. This was significantly longer than the 2-day half-life observed, demonstrating that the T+Ai product acted as a sustained-release formulation. The purpose of this therapy is to This is because it reduces the aromatization of T in the subcutaneous fat and other tissues where aromatase is high. For the treatment of breast cancer, where systemic aromatase inhibition is required to maximize antitumor efficacy, In comparison, the lowest effective dose is given. The IC50 of anastrozole in the guinea pig and JEG3 human choriocarcinoma cell lines was are 3.62 and 5.66 nM, respectively. Therefore, C max=5.3ng / mL(1 8.07nM) is due to the initial higher C max =4.1ng / mL T, a decrease in T levels The pellets are therefore covered by sustained low levels of anastrozole. The use of 4 mg of anastrozole during pregnancy inhibits the aromatase enzyme in target tissues. The concentration required for a sufficient aromatase IC50 was achieved. In contrast, the 2 mg dose appears not to have been enough.

[0224] For serum testosterone, the median T max 8 hours (range 6-12 hours) after administration mean C compared with a baseline mean of 0.2 ng / mL max =4.1ng / m There was a second low peak at 2-3 weeks. Compared to baseline testosterone levels, The increase compared to baseline was maintained at 12 weeks in participants with a mean blood concentration of 0.8 ng / mL. Serum dihydrotestosterone was not measurable in most samples, and the maximum measurable value was In participants with T max This example shows the pellet after subcutaneous insertion. indicates that the pattern was represented.

[0225] Example 2: Combination of Testosterone and Anastrozole for Reducing MBD in Women Therapy This example illustrates the use of a steroid for mammographic breast density (MBD) reduction in women. This study provides an analysis of the effects of testosterone and anastrozole combination therapy on llend Clinic(Burnside War Memorial Hospi) The study was conducted in Adelaide, South Australia. The main indications for are one or more of the following: perimenopausal hormone dysfunction, high MBD, It is thought to be a factor that reduces breast cancer (BC) risk.

[0226] All 652 patients were female, with a mean age at the time of first T+Ai implant of 18.5 years. The patient was 52 years old (range 23-79).

[0227] MBD / BC risk reduction was the primary indication for treatment in 89 patients (14%); In 334 patients (51%), hormone dysfunction was secondary, and in 177 patients (27%) ) for both indications. The primary indication was not offered to 52 patients.

[0228] A history of BC was reported in 90 patients (14% of patients had a non-eliminating response in their BC history). The type of BC was observed in 20 patients, 14 of whom had non-invasive BC, Six patients had invasive BC.

[0229] Use of estrogen-based concomitant medications was observed in 222 patients (34%), the majority of whom was in the form of a topical medication (n=192).

[0230] As of data cut in July 2017, 365 patients (56%) were receiving T+Ai therapy. One patient had no treatment information recorded, and the remaining 286 had T+ The most common reason for discontinuing T+Ai therapy was the lack of follow-up The inability to continue therapy (n=123) was followed by a decision to discontinue therapy (n=46), Cost (n=30), subjects who felt that T+Ai therapy was not effective (n=28), and cost The patient was advised by their family doctor that T+Ai therapy had been completed (n=25).

[0231] Efficacy Measurement Continuous variable measurements obtained from mammograms (including %VBD and AVBD measurements of MBD) Summary statistics for mammograms were not planned for specific time points, so A visit window system was applied to the data to provide specific data values ​​for the selection The window was as follows: 6 months (180 days + / - 60 days after first T+Ai implant) 1 year (365 days + / - 180 days after first T+AI implant) 2 years (730 days + / - 180 days after first T+AI implant) 3 years (1095 days + / - 180 days after first T+AI implant) 4 years (1460 days + / - 180 days after first T+AI implant)

[0232] Relationship between drug dose and %VBD response To examine the effect of T+Ai intervention on MBD measured by %VBD, We considered a subset of patients who had mammograms both before and after treatment initiation. For a subset of patients (n=142), the change from baseline MBD was assessed using SAS ( Used as an outcome measure in mixed model analyses using PROC MIXED® This procedure was performed after the initiation of T+Ai treatment (repeated measures analysis) and after multiple maneuvers for individual patients. to consider the different covariance patterns among the data, as well as the possible contributions to the phenomenon. Make it possible.

[0233] From the dataset provided for analysis, the following independent (explanatory) variables were used to estimate M Their influence on the changes in BD was investigated. i. Days since first implant ii. Baseline % VBD MBD measurement (closest to first T+Ai implant) (but not later than iii.) iii. Cumulative testosterone dose (mg) throughout the study (<500mg, 500mg) stratified into g~<700mg, and 700mg+). iv. Cumulative anastrozole dose (mg) throughout the study (as a continuous covariate) v. Age at first implant vi. Equipment type (GE or Hologic equipment) vii. Radiation Dose in Mammograms viii. Mammogram compression pressure ix. History of breast cancer (yes or no) x. Use of concomitant estrogen medications (yes or no) xi. Interaction period between days since first implant and cumulative dose of testosterone layer between

[0234] The last interaction term listed above fits different slopes to each of the testosterone dose strata. This allows you to see if there are any potential differences across layers.

[0235] To fit the model, the following syntax was used in SAS: proc mixed data=mmg3; class TESTO_GP SUBJIDC MMG_MACH_N BCA_H IST_N E2_USED_N; model CHANGE_MMG_RESULT=MMG_DAY BASE_MM G_RESULT TESTO_GP MMG_MACH_N BCA_HIST_N E2_USED_N SUM_ANAST MMG_RAD_DOSE_N MMG_C OMP_PRES_N MMG_DAY*TESTO_GP / ddfm=kr cl s; random INT MMG_DAY / subject=SUBJIDC ty pe=un; lsmeans TESTO_GP / at MMG_DAY=365 cl; lsmeans TESTO_GP / at MMG_DAY=730 cl; lsmeans TESTO_GP / at MMG_DAY=1095 cl; lsmestimate TESTO_GP 'Across all dose l evels at 1 yr' 1 1 1 / divisor=3 at MMG_ DAY=365 cl; lsmestimate TESTO_GP 'Across all dose l evels at 2 yr' 1 1 1 / divisor=3 at MMG_ DAY=730 cl; lsmestimate TESTO_GP 'Across all dose l evels at 3 yr' 1 1 1 / divisor=3 at MMG_ DAY=1095 cl; format TESTO_GP testo.BCA_HIST_N E2_USE D_N yes no.MMG_MACH_N machine; run.

[0236] Each term in the model statement represents an item in the previous bulleted list. Statements are used to account for repeated measurements made over time in each patient. The structured covariance structure is defined as the compound symmetry (CS) and It was used because it provided a slightly better fit compared to the autoregressive (AR1) option. Use the LSMEANS and LSMESTIMATE statements to Changes from baseline in MBD by steroid dose strata will be assessed at 1, 2, and 3 years. Table 3 shows the parameter estimates obtained from the model.

[0237] Days since first T+Ai implant and days since first T+Ai implant A statistically significant interaction between number and cumulative testosterone tier was observed. Specifically, patients receiving >500 mg testosterone compared with patients receiving <500 mg A greater reduction in MBD was observed over time in patients with cumulative doses. The strozole dose also approached the significance level of 0.05 (p=0.06), and the estimates were also higher. The lower the cumulative anastrozole dose, the greater the reduction in MBD. BD was also statistically significant, with higher baseline scores associated with greater observed change. (reduction in %VBD). [Table 3]

[0238] Change from baseline in %VBD measures of MBD by cumulative testosterone stratum The least squares means of were estimated at 1, 2, and 3 years. Table 4 below shows the results from the model. Highlighted rows indicate estimated gains from baseline that are statistically significantly different from zero. Changes from baseline in %VBD least squares mean are shown (p<0.05). The analysis of the change is estimated at 1, 2, and 3 years. [Table 4]

[0239] Efficacy of T+Ai in reducing MBD measured by AVBD In addition to analyses conducted using %VBD MBD measurements, baseline was used as the dependent variable. The same model described previously in this example was used to measure the change from absolute volumetric breast density (AVBD). Complementary analyses were performed using the The only other change to the list of dependent variables used was The baseline %VBD was replaced with baseline AVBD. The least squares mean estimates from the variance are shown below in Table 5. Again, statistically significant values ​​are highlighted. Significant values ​​are shown in the rows marked with a sig- nificantly at 2 and 3 years after the first T+Ai implant. Only the 700mg+ cumulative testosterone group had values ​​from baseline AVBD estimates. The change was -22 cm in 2 and 3 years, respectively. 3 and -60cm 3 It was. [Table 5]

[0240] Efficacy conclusions 142 patients with mammograms taken both before and after starting T+Ai therapy Using mammogram information from patients, %VBD after intervention with T+Ai therapy was calculated. There were statistically significant changes from baseline MBD measurements for both and AVBD.

[0241] When MBD was measured as %VBD, patients receiving cumulative testosterone doses of 700 mg or more , the estimated change one year after starting therapy was -1.87, the estimated change two years after starting therapy was -2.34, The estimated change in 3 years after starting the regimen was -2.82. For patients receiving 00 mg, the estimated change at 1 year after starting therapy was -1.12 (p=0.09); The estimated change 2 years after starting therapy was -1.69, and the estimated change 3 years after starting therapy was -2.26.

[0242] When MBD was measured by AVBD, significant values ​​were obtained after the first T+Ai implant. The results were in the 700mg + cumulative testosterone group at 2 and 3 years. The change from the AVBD estimate was -22 cm in 2 and 3 years, respectively. 3 and -60c m 3 It was.

[0243] Most women in Example 2 received 2 mg of anastrozole per implant. This dose was kept as low as possible to avoid side effects. This administration was effective, but Example 2 showed no change in MBD. indicates that cumulative anastrozole dose is a variable of interest when assessing p=0.06). Higher cumulative anastrozole dose was associated with a higher baseline MBD. Surprisingly, and unexpectedly, the results were associated with a large change from baseline (decrease from baseline). Unfortunately, the PK and PD of anastrozole shown in Example 1 are not consistent with those of the high dose anastrozole. strozole (4 mg per implant) was used to achieve efficacy and The side effects associated with the disclosed aromatase inhibitors may be avoided or minimized. Indicates that.

[0244] Example 3: Pharmacokinetic profile of anastrozole using a modeling approach This example uses a modeling approach to assess optimal input functions. The present invention provides an analysis of the pharmacokinetic profile of anastrozole in the clinical trial shown in Example 1. Table 6 shows the sampling plan for anastrozole and testosterone. At least 8 mL of blood samples were collected by venipuncture at each time point specified in Table 6. Serum testosterone / DHT and plasma anastrozole were collected. Figures 7A-B , and the anastrozole absorption rate are shown. Data in these figures are expressed as mean + / - standard deviation. 7A shows the Y-axis on a logarithmic scale. FIG. 7B shows the Y-axis on a linear scale. was generated using the pellet absorption data summarized in Table 2 of Example 1. The rate of change was calculated for the mean volume and plotted over time in months. (Figure 8A) Figure 8A-B plots plasma anastrozole concentrations after implantation. In Figure 8B, data on the X-axis are plotted as time (hours) after implantation. The X-axis is a logarithmic scale. In Figures 8A-B, open circles represent the observed data, and closed circles represent the observed data. The line is equal to the median of the PK profile, and the dark gray dashed line is the lower limit of quantification (0.1 ng / mL ) Figure 9 shows the frequency of observations after implantation. Approximately 15% of the data are The BLQ concentrations were below the lower limit of quantification (BLQ). This was observed either after 1000 hours of treatment. [Table 6]

[0245] In this example, a population modeling approach is used to characterize the PK of anastrozole. One- and two-compartment models were fitted to the data. Several absorption models were tested, including first and zero order, mixed order, and The choice of model is based on statistical criteria (objective function) and This was based on visual inspection of the diagnostic plots. Figure 10 shows the flow chart of the models tested. The final structural model used in this example is shown in Figure 11. The best fit model is a two-compartment model with absorption explained by dual inputs. The inter-subject variability (BSV) was the apparent clearance. (CL / F), apparent volume of distribution in the central compartment (Vc / F), and first-order absorption The rate constant (KA) was included. Residual unexplained variability (RUV) was calculated using a proportional error model. explained.

[0246] Table 7 below provides parameter estimates for anastrozole. The parameters are Vc The estimation was performed with good accuracy (RSE<30%) by excluding the target variable in / F. The intercompartmental clearance (Q / F) of the compound is acceptable given the available data. The model estimated CL / F was 1.77 L / hr, which is consistent with Table 1 of Example 1. This is comparable to the estimate from the NCA of 1.88 L / h shown in 2. [Table 7]

[0247] Figures 12A-B show population and individual predictions. Figure 12A shows population predictions. B shows individual predictions. The light grey line represents the identity line, and the dark grey line represents the data. The tailing in the trend line in Figure 12B is due to the BLQ data. Overall, the model predicts the data with minimal bias. Population predicted concentrations are representative of a typical patient. Individual predicted concentrations are Posterior Bayesian / individualized prediction. Figure 13 (ID: 1-11) shows the observations of anastrozole. Separate plots of predicted plasma concentrations are shown. Data are plotted at nominal time. The black dashed line corresponds to the ensemble model prediction, the grey solid line corresponds to the individual model prediction, and the circles correspond to the individual The final model was used to simulate 1000 replicates of the data set. The model simulation characteristics were verified by averaging the data. 95% CI around the median and predicted intervals for the 10th and 90th percentiles The median, 10th percentile, and 90th percentile of the observed data were then calculated. The model was validated by overlaying the images onto the simulation data.

[0248] Figure 14 shows a visual predictive check of post-implant anastrozole concentrations (V VPC indicates the degree to which observed data is better matched with simulated data from a model. The X and Y axes are logarithmic scales. Black dashed line = observed 1 0th and 90th percentiles, solid black line = observed median, grey shaded area Area = 80% prediction interval, light grey dashed line = lower limit of quantification.

[0249] Figures 15A-B show the one-compartment model versus the two-compartment model. Figure 15A represents a one-compartment configuration with a primary. Figure 15B represents a one-compartment configuration with a dual input. This represents a two-compartment configuration. The distribution of conditional weighted residuals (CWRES) for the intervals indicates that there was misspecification at the exclusion stage. In contrast, the two-compartment model (Figure 15B) shows the CWRES distribution over time. This indicates that the fabric is evenly distributed.

[0250] Figure 16 shows predictions from different input models for patient 10, with a single primary input. input (Model 9), first- and zero-order simultaneous input (Model 10), single zero First-order inputs (Model 11), and dual first-order inputs (Model 15). From the results, it was found that models other than the dual-first-order input model could not adequately capture the early stages of absorption. It was clear that

[0251] overview This analysis demonstrates that anastrozole PK follows a two-compartment disposition profile. The absorption profile of anastrozole was well described by dual input. Other input models failed to adequately capture the absorption step.

[0252] Example 4: Breast tissue elasticity This example demonstrates the efficacy of shear wave ultrasound for subjects participating in the clinical trial described in Example 1. This study examines the potential impact on breast tissue elasticity, which is assessed using shear wave ultrasound. Elastic and adipose tissue were measured by wave measurements on days 1, 29, 57, and 85. Four measurements of elasticity were taken for each breast. A total of eight measurements were taken for each tissue type. The calculated mean was the value used in the breast elasticity summary and analysis. A summary of the severity and change from baseline is shown in Table 8. Table 8 shows a gradual decline over time. Decreased breast tissue elasticity: 28% from baseline in glandular tissue and 32% in adipose tissue This was accompanied by a reduction in [Table 8]

[0253] Example 6: Expression of CD36 Breast tissue from women with autoimmune inflammatory mastitis (AIM) contains elevated levels of aromatase and enzymes. Women with AIM have high strradiol levels and therefore a significant suppression of Treg expression. Induction of CD36 in adult breast tissue results in tissue-specific immunosuppression without systemic immunosuppression. This example demonstrates that CD36 may contribute to aromatase inhibition as described herein. that can be expressed in normal breast tissue by treatment with androgen agents in combination with Shows.

[0254] Normal breast tissue was excised from three perimenopausal women and collected during surgery. The specimens were transported to the laboratory on ice with a maximum of 1 hour between excision and tissue processing. 5 ml of 200 mM glutamine (SAFC biosciences, Kansas , USA), 5 ml of 100x antibiotic / antimycotic (Sigma, St. Louis, MO) O, USA), 10 μg / ml insulin (Sigma, St Louis, MO, USA), SA), and 10 μg / ml hydrocortisone (Sigma, St Louis, MO). O, USA) supplemented with medium (phenol red-free RPMI, SAFC biosciences, The tube was washed with a syringe (Frances, Kansas, USA) to remove excess blood.

[0255] A representative piece of each tissue sample was immediately placed in 4% hormonal fluid in phosphate-buffered saline (PBS). The tissue was fixed overnight in marine at 4°C and then processed in an automated tissue processor (Sakura Tiss The tissue was dehydrated using a Tube-Tek VIP (USA) and embedded in paraffin wax. Histopathology was assessed using hematoxylin and eosin (H&E) stained sections. of fresh tissue was cut into small (approximately 3 x 3 x 1 mm) pieces and separated into 1 cm 3 Gelatin sponge ( Spongostan, Johnson&Johnson, Skipton, UK) on The cells were placed in triplicate in a 24-well tissue culture plate (BD Bioscience 10% dextran-coated charcoal-stripped calf in situ (Salt Lake City, NJ, USA) Fetal serum (DCC-FCS) (SAFC biosciences, Kansas, US The tissue samples were pre-soaked and then half-submerged in treatment medium containing 0.1% ethanol. Nol, 5 nM testosterone, and 25 ng / ml anastrazole vehicle The mixture was cultured for 24 hours.

[0256] Lysis buffer (1% Triton X-100, 50 mM KCl, 25 mM HEPE) S, pH 7.8, 10 mg / mL leupeptin, 20 mg / mL aprotinin, 12 5 mM dithiothreitol, and 1 mM phenylmethylsulfonyl fluoride) Western blotting of whole cell lysates and controls by sonication at 48°C Adipose tissue was prepared and analyzed on the same Western blot. 50 mg of total protein samples were with 50 ml of sodium dodecyl sulfate (SDS)-mercaptoethanol sample buffer. After mixing and boiling for 10 min, proteins were separated on a 7.5% SDS gel and purified using polyfluoride. The membrane was then transferred to a vinylidene membrane. Block using 5% non-fat milk in physiological saline (PBS) for 1 h at room temperature, then resuspend in PBS. Diluted antibody against human CD36 and horseradish peas diluted in PBS peroxidase-conjugated secondary antibodies (Jackson Immunoresearch) Immunoblotting was performed, followed by chemiluminescence reagent (Amersham Bioscience, B The band density was measured using Image e Master VDS and Image Quant Analysis Software ware(Amersham Pharmacia Biotech, Hong Kong g) was measured by densitometry. Relative protein levels of CD36 and β-actin in protein lysates were obtained. D36 protein expression was normalized to β-actin protein expression. The antibody was generated using a synthetic peptide derived from the sequence of human CD36, and the peptide affinity was determined. The explants were purified by affinity chromatography and validated using a control peptide. The results of Western blot analysis of CD36 protein in the samples are shown in Figure 17. Cell lysates were immunoblotted with an antibody against CD36. The experiment was performed twice with similar results. Data are presented relative to actin. A two-tailed Student's t-test showed significance at p=0.00757. The results are presented below. Shown in Table 9 below. [Table 9]

[0257] Increased CD36 increases the conversion of fibroblasts into adipocytes (fat). Fat is semi-fluid and therefore has greater elasticity. Normal breast milk production after treatment with the drug testosterone in combination with the aromatase inhibitor anastrozole The increased CD36 expression was associated with a decrease in breast firmness. As described herein, certain embodiments of the present disclosure are directed to androgenic and Combination therapy with aromatase inhibitors increases CD36 and reduces breast firmness It relates to.

[0258] The above shows that the combination of testosterone and aromatase inhibitors induces CD36. It has been shown in normal breast tissue that CD36 is highly effective in detecting breast cancer cells. Western blot analysis demonstrated that the α-amyloid β-amyloid complex was significantly induced by treatment of explant-grown normal breast tissue. This has been demonstrated by protein blot.

[0259] Example 7: Idiopathic inflammatory macromastia Four patients with mild to moderate idiopathic inflammatory mastitis associated with macromastia were reported below. As discussed, treatment was performed according to the present disclosure.

[0260] Patient 1:42.03416971 Symptoms A 38-year-old chiropractor with rapid breast enlargement (doubling in size) and periaorolar inflammation The patient's condition persisted for two months and was unresponsive to over-the-counter pain medications and NSAIDs, affecting the patient's ability to work. I have severe, constant pain for a long time.

[0261] Bra cup size before the onset of the disease The patient had a bra cup size of 32A and was unable to wear a bra after the onset of the disease. It was.

[0262] Medical history Patients with severe premenstrual anxiety disorder that is partially controlled by oral contraceptives The patients included those who had stopped taking oral contraceptives 2 years before the onset of symptoms and had had two pregnancies and two She had a regular 28-day cycle with a live birth. Severe postpartum arthritis - undiagnosed - 1 year later Stable and no abnormal blood parameters were observed.

[0263] Pre-onset VAS pain scale: 95 mm treatment 80 mg testosterone and 4 mg anastrozole as described in Example 1 The subcutaneous implant pellets were placed for 3 months, and then repeated twice for another 3 months.

[0264] result i. VAS pain scale 10mm at 4 weeks ii. No detectable inflammation at 4 weeks iii. 71% reduction in fibroglandular tissue iv. Breast volume reduction 58% to return to pre-disease size v. After cessation of therapy, continued MRI over the next 3 years showed no significant background parenchymal enhancement. Complete reversal vi.No SAE vii. No change in BMI

[0265] Mammograms of the patient's breasts before and after treatment are shown in Figure 19A, and the results are shown for the following three years before and after treatment. MRI images are shown in Figure 19C. Breast volume and density measurements are shown in Figure 19B.

[0266] Patient 2:42.09761311 Symptoms A 42-year-old nurse with rapid breast enlargement - "very hard", diffuse inflammation, was treated with over-the-counter Not responding to painkillers and NSAIDs, affecting work and family life - unable to ride horses She has had severe, constant pain for 4 months affecting her left breast. Her left breast is much larger than her right. It was.

[0267] Bra cup size: before the onset of the disease The patient had a bra cup size of 36C and was unable to wear a bra after the onset of the disease. She wore the sports bra all day, even to bed.

[0268] Medical history Regular 28-day cycles, two pregnancies with severe preeclampsia and two live births, No postpartum depression or abnormalities in blood parameters were observed, including in the hospital.

[0269] Pre-onset VAS pain scale: 100 mm treatment Subcutaneous implant pellet containing 80 mg testosterone and 4 mg anastrozole The study was conducted for three months, and then repeated twice for three months.

[0270] result i. VAS pain scale 15mm at 4 weeks ii. No detectable inflammation at 4 weeks iii. 41% reduction in fibroglandular tissue iv. Breast volume reduction 10% to return to pre-disease size v. No SAE vi. No change in BMI vii. No mammoplasty

[0271] Mammograms of the patient's breasts before and after treatment are shown in Figure 20A. Breast volume and density The measured values ​​are shown in FIG. 20B.

[0272] Patient 3:42.09761311 Symptoms A 37-year-old lawyer with rapid breast enlargement, especially inflammation around the nipples, was treated with over-the-counter painkillers and A 2-month-long severe episode of bronchitis that was unresponsive to steroids and NSAIDs and affected work and home life There is a certain amount of pain.

[0273] Bra cup size Before the onset of the disease, my temperature was 34C, but after the onset of the disease, I was unable to wear a bra and had to wear a sports bra all day at work. I wore it until I went to bed.

[0274] Medical history Regular 28-day cycle without pregnancy, moderate endometriosis, no abnormalities in blood parameters I couldn't.

[0275] Pre-onset VAS pain scale: 100 mm treatment 80 mg testosterone and 4 mg anastrozole as described in Example 1 The subcutaneous implant pellets were administered for 3 months, and then repeated twice for another 3 months.

[0276] result i. VAS pain scale 0mm at 4 weeks ii. No detectable inflammation at 4 weeks iii. 52% reduction in fibroglandular tissue iv. Breast volume reduction 32% to return to pre-disease size v. No SAE vi. No change in BMI vii. No mammoplasty

[0277] Mammograms of the patient's breasts before and after treatment are shown in Figure 21A. Breast volume and density The measured values ​​are shown in FIG. 21B.

[0278] Patient 4:42.83593371 Symptoms A 41-year-old police officer presented with rapid breast enlargement - "very hard", diffuse inflammation, and was prescribed over-the-counter Painkillers and NSAID unresponsive patients' work and home life - Kevlar protective kit - I have severe constant pain for a month that affects my ability to wear a mask.

[0279] Bra cup size Before the onset of the disease, her bust was 36B, but after the onset of the disease, she was unable to wear a bra and had to sleep in a sports bra all day. I wore it until.

[0280] Medical history She had a regular 28-day cycle without pregnancy, severe endometriosis with multiple surgeries, and blood parameters No abnormalities were observed in the data.

[0281] Pre-onset VAS pain scale: 100 mm treatment 80 mg testosterone and 4 mg anastrozole as described in Example 1 Subcutaneous implant pellets for 3 months, then repeated twice for another 3 months, breast augmentation, and two more post-operative treatments over the same three-month period.

[0282] result i. VAS pain scale 0mm at 4 weeks ii. No detectable inflammation at 4 weeks iii. 36% reduction in fibroglandular tissue iv. Breast volume reduction of 23% to return to pre-onset size v. Complete reversal of extreme background parenchymal enhancement on MRI vi.No SAE vii. No change in BMI

[0283] MRI images of the patient's breast before and after treatment are shown in Figure 22A. Mammography images are shown in Figure 22B. Breast volume and density measurements are shown in Figure 22C. .

[0284] Example 8: Treatment of autoimmune inflammatory mastitis Patient:42.04033771 Symptoms A 24-year-old physiotherapist presented with rapid breast enlargement - "very painful", diffuse inflammation and 4 months Severe constant pain for months - unable to work and unresponsive to: i. Over-the-counter pain relievers and NSAIDs ii.OCP iii. Oral progesterone iv. Danazol v. LhRh agonists

[0285] Bra cup size The 36B before the onset of the disease expanded to 36EE.

[0286] Medical history Obstetric / gynecological history included irregular 28-day cycles with Zoladex - amenorrhea. There were no pregnancies. No abnormalities were observed in blood parameters.

[0287] Pre-onset VAS pain scale: 100 mm treatment Subcutaneous injection of 100 mg testosterone and 3 mg anastrozole for 3 months Lantpellet, breast reduction surgery was performed, followed by two more post-operative treatments over the above three months.

[0288] result i. VAS pain scale 50mm at 4 weeks ii. Inflammation was significantly reduced at 4 weeks iii. Mammogram high density and MRI extreme background breast enhancement were reversed. iv. No SAE v. No change in BMI vi. He was later diagnosed with myasthenia gravis.

[0289] A mammogram of the patient's breast before treatment is shown in Figure 23A. A post-treatment MRI image is shown. Shown in Figure 23B.

[0290] Example 9: Treatment of plasma cell mastitis Plasma cell mastitis is an autoimmune inflammatory destructive process of the subareolar ducts, resulting in multiple fistulas. This condition inevitably leads to disfiguring surgery and carries a high risk of recurrence. There is no known treatment for plasma cell mastitis other than surgery, which has significant limitations. , exemplified by the intrusion of the ductal system with inflammatory cells secreting pro-inflammatory cytokines. Recently, it has been shown that the IL-6 inflammatory pathway is important in this inflammatory process, and that plasmacytic mammary glands demonstrated to be targeted as a potential mechanism for the treatment of inflammation. (Liu, 2020). Women's breasts have been shown to be a testosterone-lowering agent in reducing IL-6 levels. demonstrated that the cells were highly responsive (53% reduction) to treatment with telone. (Guhl, 2012).

[0291] A 43-year-old fit and healthy woman had a complex that had not responded to antibiotic therapy at the initial stage. She presented with multiple fistulas around the right nipple area and was subsequently treated with high doses of corticosteroids and external steroids. Total duct resection as a medical treatment only provided short-term relief. There was a lesion around the right nipple-areola complex with four fistulas at the 4 o'clock position on the edge of the annulus. 0-10c The patient had significant pain measured at 8 on the visual analog pain scale. The patient was started on a subcutaneous implant containing 80 mg of testosterone and 4 mg of anastrozole. Within 3 weeks, the visual analog pain scale had dropped to 3 and some of the periareolar redness had subsided. After 11 months of inserting three implants of the same strength, there was no sign of fistula formation. There was complete resolution and no associated pain. At 12-month follow-up, the disease There was no evidence of recurrence.

[0292] Example 10: Granulomatous Mastitis Granulomatous mastitis is also known as granulomatous lobular mastitis because the inflammation occurs around the breast lobules. It is known that it is a manifestation of autoimmune inflammatory mastitis in breast tissue, resulting in granulomatous formation. There is no known cure for the condition, and women frequently They often undergo multiple surgeries and / or receive immunosuppressive treatments.

[0293] A 32-year-old woman presented with a second mastectomy 6 months after treatment for histologically proven granulomatous mastitis. She was given antibiotics, corticosteroids, and methotrexate. All of these patients had undergone surgery to remove the fistula. MRI taken on July 23, 2017 showing multiple areas of granulomatous formation with nodes So as evidenced, it failed.

[0294] Between the first MRI and the second MRI taken on May 23, 2018, Example 1 Three doses of testosterone 80 mg and anastrozole 4 mg as described in The implant was inserted. The inflammation rapidly decreased, and the remaining fistula healed over a period of 3 months. The tenderness and discomfort in the breasts lasted for 5 months and then slowly subsided. May 2018 A clinical examination on the 23rd of the month revealed only slight scarring on the breast from previous surgery. No other abnormalities were noted. She was disease-free when reviewed in February 2020. continued.

[0295] A mammogram of the patient's breast before treatment is shown in Figure 24A. MRI images obtained after treatment are shown. The I image is shown in Figure 23B.

[0296] Other exemplary non-limiting embodiments.

[0297] A further advantage of the claimed subject matter is that the invention is described in detail in conjunction with certain embodiments of the claimed subject matter. This will become clear from the following example.

[0298] A Example 1A. A pharmaceutical composition comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binding agent. An agent comprising: The pharmaceutical preparation was administered subcutaneously to a subject, and the serum concentrations of androgens and aromatase were measured. The sustained release multi-antibody compound is administered to the subject's blood over time as measured by plasma concentrations of the inhibitor. providing a phase concentration pattern; a sustained-release multiphasic concentration pattern in the subject's serum or plasma; Androgens have the first peak concentration (Tmax) in serum and aromatase inhibitors A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, Androgens first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; 10. A pharmaceutical formulation comprising:

[0299] 2A. A pharmaceutical composition comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binding agent. An agent comprising: The pharmaceutical formulation is compressed into pellets; The pellets were administered subcutaneously to subjects, and serum concentrations of androgens and aromatase were measured. The inhibitor is released into the blood of the subject over time as measured by plasma concentration. providing a multiphase concentration pattern; a sustained-release multiphasic concentration pattern in the subject's serum or plasma; Androgens have the first peak concentration (Tmax) in serum and aromatase inhibitors A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, Androgens first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; 10. A pharmaceutical formulation comprising:

[0300] 3A. A pharmaceutical composition comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binding agent. An agent comprising: The formulation was administered subcutaneously to subjects and measured serum concentrations of androgens and aromatase inhibitors. A sustained release multi-phase concentration of the agent is produced in the subject's blood over time as measured by plasma concentration. Provides degree patterns, a sustained-release multiphasic concentration pattern in the subject's serum or plasma; Androgens have the first peak concentration (Tmax) in serum and aromatase inhibitors A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, Androgens first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; The androgen has a second peak concentration in serum that is less than Tmax and a third period during which the enzyme inhibitor gradually decreases in concentration in the plasma, and during the third period, a third period during which the concentration of the lomatase inhibitor is less than the concentration of the androgenic agent; Androgens have gradually declining serum levels, and aromatase inhibitors a fourth, which has a gradually decreasing concentration in the plasma, the decreasing levels of both being approximately parallel to each other; A pharmaceutical preparation comprising:

[0301] 4A. A pharmaceutical composition comprising an effective amount of an androgenic agent, an effective amount of an aromatase inhibitor, and a binding agent. An agent comprising: The pharmaceutical formulation is compressed into pellets; The pellets were administered subcutaneously to subjects, and serum concentrations of androgens and aromatase were measured. The inhibitor is released into the blood of the subject over time as measured by plasma concentration. providing a multiphase concentration pattern; a sustained-release multiphasic concentration pattern in the subject's serum or plasma; Androgens have the first peak concentration (Tmax) in serum and aromatase inhibitors A first period during which the agent is increasing in concentration in plasma but is below its Tmax concentration in plasma. and, Androgens first cause a decrease in serum levels, then an increase in serum levels. a second period during which the aromatase inhibitor has its T concentration in the plasma; The androgen has a second peak concentration in serum that is less than Tmax and a third period during which the enzyme inhibitor gradually decreases in concentration in the plasma, and during the third period, a third period during which the concentration of the lomatase inhibitor is less than the concentration of the androgenic agent; Androgens have gradually declining serum levels, and aromatase inhibitors a fourth, which has a gradually decreasing concentration in the plasma, the decreasing levels of both being approximately parallel to each other; A pharmaceutical preparation comprising:

[0302] 5A. 60mg to 120mg of testosterone or its esters, 4mg to 6mg of allo 1. A pharmaceutical formulation comprising a matase inhibitor and stearic acid, The pharmaceutical preparation has a diameter of 4.25 mm to 4.75 mm and a length of 4 mm to 7 mm. compressed into pellets, The pellets were administered subcutaneously to subjects, and serum concentrations of testosterone or its esters were and for aromatase inhibitors, as measured by plasma concentrations over time. providing a sustained-release multiphasic concentration pattern in elephant blood; A sustained release multi-phase concentration pattern Testosterone or its esters have a first concentration peak (Tmax) in serum. However, aromatase inhibitors are increasing in plasma concentration, but their Tmax concentration in plasma a lower, first period; Testosterone or its esters first induces a decrease in serum levels, then The aromatase inhibitor has an increased serum level concentration and has its Tmax concentration in plasma. and a second period of time during which the pharmaceutical formulation

[0303] 6A. 60mg to 120mg of testosterone or its esters, 4mg to 6mg of allo 1. A pharmaceutical formulation comprising a matase inhibitor and stearic acid, The pharmaceutical preparation has a diameter of 4.25 mm to 4.75 mm and a length of 4 mm to 7 mm. compressed into pellets, The pellets were administered subcutaneously to subjects, and serum concentrations of testosterone or its esters were and for aromatase inhibitors, as measured by plasma concentrations over time. providing a sustained-release multiphasic concentration pattern in elephant blood; A sustained release multi-phase concentration pattern Testosterone or its esters have a first concentration peak (Tmax) in serum. However, aromatase inhibitors are increasing in plasma concentration, but their Tmax concentration in plasma a lower, first period; Testosterone or its esters first induces a decrease in serum levels, then The aromatase inhibitor has an increased serum level concentration and has its Tmax concentration in plasma. a second period in which A second peak concentration of testosterone or its esters in serum that is less than Tmax a third period during which the aromatase inhibitor gradually decreases in concentration in the plasma; During the third period, the aromatase inhibitor increases the concentration of testosterone or its esters. The third period is when the Testosterone or its esters have gradually decreasing serum levels and are allotropic. The matase inhibitor has a gradually decreasing concentration in plasma, and both decreasing levels are and a fourth period substantially parallel thereto.

[0304] 7A. Sustained release multi-phase concentration pattern A second peak concentration of testosterone or its esters in serum that is less than Tmax a third period during which the aromatase inhibitor gradually decreases in concentration in the plasma; During the third period, the aromatase inhibitor increases the concentration of testosterone or its esters. The third period is when the Testosterone or its esters have gradually decreasing serum levels and are allotropic. The matase inhibitor has a gradually decreasing concentration in plasma, and both decreasing levels are and a substantially parallel fourth period. Agent.

[0305] 8A. Any of Examples 1A-7A, wherein the aromatase inhibitor exhibits first order release during a first period of time. One or more of the pharmaceutical preparations described above.

[0306] 9A. Any of Examples 1A-8A, wherein the aromatase inhibitor does not exhibit zero-order release during the first period. One or more of the pharmaceutical preparations described above.

[0307] 10A. Examples 1A-9A, wherein the aromatase inhibitor does not exhibit zero-order release during the second period. 10. The pharmaceutical formulation according to claim 9, wherein the pharmaceutical

[0308] 11A. During the second period, testosterone or its ester does not exhibit zero-order release. , a pharmaceutical formulation according to one or more of Examples 1A to 10A.

[0309] 12A. Examples 1A-11, wherein the aromatase inhibitor does not exhibit zero-order release during the third period. A pharmaceutical formulation according to one or more of A.

[0310] 13A. During the third period, testosterone or its esters do not exhibit zero-order release. , a pharmaceutical formulation according to one or more of Examples 1A to 12A.

[0311] 14A. The cysts of Examples 1A-13A, wherein the aromatase inhibitor exhibits first-order release during the third period. The pharmaceutical preparation according to any one of the preceding claims.

[0312] 15A. Example 1, wherein testosterone or its ester exhibits first-order release during the third period. A pharmaceutical formulation according to one or more of A to 14A.

[0313] 16A. Examples 1A-15, wherein the aromatase inhibitor does not exhibit zero-order release during the fourth period. A pharmaceutical formulation according to one or more of A.

[0314] 17A. During the fourth period, testosterone or its esters do not exhibit zero-order release. , a pharmaceutical formulation according to one or more of Examples 1A to 16A.

[0315] 18A. The cysts of Examples 1A-17A, wherein the aromatase inhibitor exhibits first-order release during the fourth period. The pharmaceutical preparation according to any one of the preceding claims.

[0316] 19A. Example 1, wherein testosterone or its ester exhibits first-order release during the fourth period. A pharmaceutical formulation according to one or more of A to 18A.

[0317] 20A. The first period is when androgen has its first peak concentration (Tmax) in serum. The pharmaceutical formulation according to one or more of Examples 1A to 19A, which is terminated immediately thereafter.

[0318] 21A. One or more of Examples 1A-20A, wherein the first period ends between 5 hours and 14 hours. The pharmaceutical formulation described in

[0319] 22A. One of Examples 1A-21A, in which the first period ends between 5.5 hours and 13 hours. The pharmaceutical formulation described above.

[0320] 23A. The second period ends shortly after the aromatase inhibitor has its Tmax, e.g. 1A to 22A. A pharmaceutical formulation according to one or more of 1A to 22A.

[0321] 24A. One or more of Examples 1A-23A, where the second period ends between 23 hours and 80 hours. The pharmaceutical formulation described above.

[0322] 25A. The pharmaceutical preparation of any one of Examples 1A to 24A, wherein the pharmaceutical preparation is an implant. Drug formulations.

[0323] 26A. One or more of Examples 1A-25A, wherein the implant is a compressed pellet. The pharmaceutical formulation described in

[0324] 27A. The pharmaceutical preparation according to one or more of Examples 1A to 24A, wherein the pharmaceutical preparation is a transdermal patch. formulation.

[0325] 28A. One of Examples 1A to 25A, wherein the implant is administered subcutaneously to the subject. The pharmaceutical formulation described above.

[0326] 28A. Of Examples 1A-26A, wherein the compressed pellet is administered subcutaneously to the subject. 10. The pharmaceutical formulation according to claim 1, wherein the

[0327] B example 1B. Approximately 80 mg of testosterone or its ester, approximately 4 mg of anastrozole, and and about 2 mg of stearic acid, The pharmaceutical preparation is formed into pellets having a diameter of 4.4 mm to 4.6 mm and a length of 4 mm to 7 mm. compressed into a The pellets were administered subcutaneously to subjects to measure serum concentrations of testosterone or its esters. and the blood of the subject over time as measured by plasma concentrations of anastrozole. providing a sustained release multi-phase concentration pattern in the solution; A sustained release multi-phase concentration pattern Testosterone or its esters have a first concentration peak (Tmax) in serum. However, anastrozole is increasing in plasma concentration, but not at its Tmax concentration in plasma. The first period is lower, Testosterone or its esters first induces a decrease in serum levels, then The Tmax concentration of anastrozole in plasma is increased by 200 mg / kg of acetaminophen. a second period in which A second peak concentration of testosterone or its esters in serum that is less than Tmax a third period in which the anastrozole is gradually reduced in concentration in the plasma; During the third period, anastrozole reduces the concentration of testosterone or its esters. The third period, Testosterone or its esters have gradually decreasing serum levels and The strozole has a gradually decreasing concentration in the plasma, and both decreasing levels are approximately equal to each other. and a fourth period approximately parallel thereto.

[0328] Although specific embodiments are shown and described herein, such embodiments are provided by way of example only. It will be apparent to those skilled in the art that the following claims define the scope of the present invention. Methods and structures within the scope of these claims and their equivalents are defined as It is intended to be covered by

[0329] In the foregoing descriptions of specific embodiments, specific terminology is employed for the sake of clarity. However, the present disclosure is not limited to the particular terms so selected. Each specific term is intended to be used interchangeably with other technical equivalents that operate in a similar manner to achieve a similar technical purpose. "Left" and "right", "front" and "back", "top" and "bottom" should be understood to include equivalents. Terms such as "under" and "under" are used as terms of convenience to provide a point of reference and are not intended to limit should not be construed as a general term.

[0330] As used herein, the word "comprising" means that "open" "open" meaning, i.e., "including" should, and therefore its "closed" meaning, i.e., "only from It is not limited to the meaning of "consisting only of." The meaning is that when they occur, they are used in conjunction with the corresponding words "comprise" and "contain" "comprises" and "comprises."

[0331] Additionally, the above describes only some embodiments of the present invention, and variations, modifications, additions, and the like may be made thereto. , and / or substitutions may be made without departing from the scope and spirit of the disclosed embodiments. The embodiments are illustrative and not restrictive.

[0332] The invention is not limited to the disclosed embodiments, but rather is within the spirit and scope of the invention. It is understood that the present invention is intended to cover various modifications and equivalent arrangements included within the scope of the present invention. In addition, the various embodiments described above may be implemented in conjunction with other embodiments, for example, Aspects of one embodiment may be combined with aspects of another embodiment to achieve yet another embodiment. Furthermore, each independent feature or component of any given assembly may be combined. The elements may constitute additional embodiments.

Claims

1. 1. A pharmaceutical formulation comprising an effective amount of an androgenic agent, an aromatase inhibitor in an amount effective to block and / or inhibit the conversion of said androgenic agent to estrogen by the aromatase enzyme, and a binder, the pharmaceutical formulation is compressed into pellets; wherein the pellet, upon subcutaneous administration to a subject, provides a sustained-release multiphasic concentration pattern in the blood of the subject over time as measured by serum concentrations for the androgenic agent and plasma concentrations for the aromatase inhibitor; the androgenic agent is testosterone or a pharmaceutically acceptable salt or ester thereof that releases testosterone into the serum or plasma of the subject; the aromatase inhibitor is anastrozole or letrozole; the sustained-release multiphasic concentration pattern in the serum or plasma of the subject is a first period of time during which the androgenic agent has a first concentration peak (Tmax) in the serum and the aromatase inhibitor is increasing in concentration in the plasma but is below its Tmax concentration in the plasma; a second period during which the androgenic agent has an initial decreasing serum level concentration, then an increasing serum level concentration, and the aromatase inhibitor has its Tmax concentration in the plasma.

2. 10. The pharmaceutical formulation of claim 1, wherein during the first period, the aromatase inhibitor exhibits first-order release.

3. 10. The pharmaceutical formulation of claim 1, wherein the aromatase inhibitor does not exhibit zero-order release during the first period of time.

4. 10. The pharmaceutical formulation of claim 1, wherein during the second period, the aromatase inhibitor does not exhibit zero-order release.

5. 10. The pharmaceutical formulation of claim 1, wherein during the second period of time, the androgenic agent does not exhibit zero-order release.

6. The sustained-release multi-phasic concentration pattern in the serum or plasma of the subject further comprising: a third period during which the androgenic agent has a second peak concentration in the serum that is less than the Tmax and the aromatase inhibitor gradually decreases in concentration in the plasma, wherein the aromatase inhibitor becomes less than the concentration of testosterone or an ester thereof during the third period; and a fourth period during which the androgenic agent has a gradually decreasing serum level concentration and the aromatase inhibitor has a gradually decreasing concentration in the plasma, both decreasing levels being approximately parallel to each other.

7. 7. The pharmaceutical formulation of claim 6, wherein during the third period, the aromatase inhibitor does not exhibit zero-order release.

8. 7. The pharmaceutical formulation of claim 6, wherein during the third period of time, the androgenic agent does not exhibit zero-order release.

9. 7. The pharmaceutical formulation of claim 6, wherein during the third period, the aromatase inhibitor exhibits first-order release.

10. 7. The pharmaceutical formulation of claim 6, wherein during the third period, the androgenic agent exhibits first-order release.

11. 7. The pharmaceutical formulation of claim 6, wherein during the fourth period, the aromatase inhibitor does not exhibit zero-order release.

12. 7. The pharmaceutical formulation of claim 6, wherein during the fourth period of time, the androgenic agent does not exhibit zero-order release.

13. 7. The pharmaceutical formulation of claim 6, wherein during the fourth period, the aromatase inhibitor exhibits first-order release.

14. 7. The pharmaceutical formulation of claim 6, wherein during the fourth period, the androgenic agent exhibits first-order release.

15. 2. The pharmaceutical formulation of claim 1, wherein the first period of time ends shortly after the androgenic agent has a first peak concentration (Tmax) in the serum.

16. 2. The pharmaceutical formulation of claim 1, wherein the second period ends shortly after the aromatase inhibitor has its Tmax.

17. 2. The pharmaceutical formulation of claim 1, wherein the first period of time ends between 5 hours and 14 hours and / or the second period of time ends between 23 hours and 80 hours.

18. 2. The pharmaceutical formulation of claim 1, wherein the androgenic agent is selected from the group consisting of testosterone, methyltestosterone, dehydroepiandrosterone, and testosterone undecanoate.

19. 10. The pharmaceutical formulation of claim 1, for subcutaneous delivery of the androgenic agent and the aromatase inhibitor.

20. The pharmaceutical formulation of claim 1, wherein the pellets have a diameter of 4.25 mm to 4.75 mm.

21. The pharmaceutical formulation of claim 1, wherein the pellet has a length of 4 mm to 7 mm.

22. The pharmaceutical formulation of claim 1, wherein the pellets have a hardness of 7 kg / N to 9 kg / N.

23. 1. A pharmaceutical formulation comprising 60 mg to 120 mg of testosterone or an ester thereof, 2 mg to 6 mg of an aromatase inhibitor, and stearic acid; the aromatase inhibitor is anastrozole or letrozole; the pharmaceutical formulation is compressed into pellets having a diameter of 4.25 mm to 4.75 mm and a length of 4 mm to 7 mm; wherein the pellet, upon subcutaneous administration to a subject, provides a sustained-release multiphasic concentration pattern in the blood of the subject over time as measured by serum concentrations of the testosterone or ester thereof and plasma concentrations of the aromatase inhibitor; The sustained release multi-phasic concentration pattern comprises: a first period of time during which the testosterone or ester thereof has a first concentration peak (Tmax) in the serum and the aromatase inhibitor is increasing in concentration in the plasma but is below its Tmax concentration in the plasma; a second period during which the testosterone or ester thereof has an initial decreasing and then increasing serum level concentration and the aromatase inhibitor has its Tmax concentration in the plasma.

24. The sustained release multiphasic concentration pattern further comprises: a third period during which the testosterone or ester thereof has a second peak concentration in the serum that is less than the Tmax and the aromatase inhibitor gradually decreases in concentration in the plasma, wherein the aromatase inhibitor becomes lower than the concentration of the testosterone or ester thereof during the third period; and a fourth period during which the testosterone or ester thereof has a gradually decreasing serum level concentration and the aromatase inhibitor has a gradually decreasing concentration in the plasma, the decreasing levels of both being approximately parallel to each other.

25. 2. The pharmaceutical formulation of claim 1, wherein the aromatase inhibitor is anastrozole.

26. 24. The pharmaceutical formulation of claim 23, wherein the aromatase inhibitor is anastrozole.

27. 27. The pharmaceutical formulation of any one of claims 1 to 26 for use in the prevention or treatment of a subject with a condition selected from the group consisting of high mammographic breast density, breast pain, breast induration, macromastia, endometriosis, mammary inflammation, gynecomastia in men, and autoimmune inflammatory mastitis, and breast cysts.

28. The pharmaceutical preparation of any one of claims 1 to 26 for use in the prevention or treatment of autoimmune inflammatory mastitis in a subject in need thereof.

29. 29. The pharmaceutical preparation of claim 28, wherein the autoimmune inflammatory mastitis is selected from the group consisting of idiopathic inflammatory mastitis, plasma cell mastitis, granulomatous mastitis, and combinations of the foregoing.

30. 10. The pharmaceutical formulation of claim 1, wherein the subject is selected from the group consisting of a peri-menopausal woman, a menopausal woman, or a postmenopausal woman.

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