WO2008115413A1

WO2008115413A1 - Aromatase inhibitors for the treatment of mastalgia

Info

Publication number: WO2008115413A1
Application number: PCT/US2008/003384
Authority: WO
Inventors: James Symons
Original assignee: Meditrina Pharmaceuticals, Inc.
Priority date: 2007-03-16
Filing date: 2008-03-14
Publication date: 2008-09-25

Abstract

The present invention relates to a method for treating, preventing or moderating mastalgia in a patient, which includes administering to the patient in need thereof a pharmaceutically effective amount of an aromatase inhibitor. The aromatase inhibitor, preferably letrozole, anastrozole or exemestane, may be used alone or in combination with danazol.

Description

AROMATASE INHIBITORS FOR THE TREATMENT OF MASTALGIA

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Serial No. 60/918,387, filed March 16, 2007, and United States Serial No. 60/922,902, filed April 11, 2007. The entire content of the aforementioned applications is incorporated herein.

BACKGROUND OF THE INVENTION

[0002] Mastalgia (also known as mastodynia or mammalgia) is breast pain and generally classified as either cyclical (associated with menstrual periods) or noncyclic. It is also found in men, e.g., those with liver cirrhosis (see, e.g., Am. J. Gastroenterol., 2000, 95 (4): 1051- 1055). Noncyclic pain may come from the breast or may come from somewhere else, such as nearby muscles or joints, and may be felt in the breast. Pain can range from minor discomfort to severely incapacitating pain in some cases. It has been reported that nearly two-thirds of women experience significant breast pain (see, e.g., Leirster, SJ. et al., Br. J. Surg., 1987, 74: 220-227; Ader, D.N. et al., Am. J. Obstet. Gynecol, 1997, 177: 126-132) and that in 10% of women with breast pain treatment is sought (see, e.g., Mansel, R.E. et al., Lancet, 1990; 35: 190-193).

[0003] In addition, cyclical mastalgia, while being a common complaint in premenopausal women, may also represent an independent risk factor for breast cancer with increasing relative risk of breast cancer with increasing duration of cyclical mastalgia (see, e.g., PIu- Bureau, Le, Sitruk-Ware, Thalabard 2006).

[0004] The cause of premenstrual mastalgia is not known; however, a number of candidate mechanisms have been postulated including estrogen dominance, enhanced response to prolactin, lipoprotein imbalance and vitamins B6 and E deficiency. Various therapeutics have been investigated to test these hypotheses without achieving marked success. For example, Kaleli et al., Fertil. Steril. 2001, 75: 718-723, reported that women with cyclical mastalgia treated with daily lisuride maleate (0.2 mg), a dopamine agonist that also reduces prolactin levels, had reduced breast pain compared to placebo. While this effect reached statistical significance, it was ascertained whether this was a clinically meaningful effect for the patients. Homeopathic remedies such as primrose oil and fish oil have been proposed as therapeutics but well controlled studies conclude that there is no beneficial effect on severe chronic mastalgia compared to placebo controls (Bloomers, J. et al., Am. J. Obstet. Gynecol., 2002, 187: 1389-1394).

[0005] Danazol is the only approved hormonal treatment. Acting like an androgenmimetic, danazol suppresses pituitary gonadotropins that lead to production of estrogen. However, due to its adverse event profile it is best used cyclically to limits these effects. Specifically, adverse effects include dizziness, headache, fatigue, appetite changes, nausea, bloating, anxiety, hot flashes, sleep disturbances, sexual dysfunction, muscle cramps and fluid retention; it may also decrease HDL-c levels. In addition, regular liver function tests are recommended. Thus, the only approved therapeutic available currently reduces endogenous production of estrogen, but has limited utility due to its adverse event profile. [0006] Identification of therapeutics that alleviate chronic moderate to severe mastalgia, while not producing adverse effects that compromise their benefit, would be an important advance for women's health. Given danazol's limited benefit to risk profile, other therapeutics that mechanistically have scientific logic for treatment of mastalgia would provide an alternative treatment modality that is not available presently provided they have a benign adverse effect profile.

[0007] Women with mastalgia also report increased anxiety due to a fear of breast cancer that they feel may be associated with the breast pain (Olawaiye, et al., J. Reprod. Med., 2005, 50: 933-939). Therefore, there clearly is a need for a therapeutic that can address chronic premenstrual mastalgia while reducing the breast cancer anxiety. To the degree that these effects are due to estrogen mediated processes, a therapeutic that can directly modulate the estrogen levels has the potential to be effective in reducing breast pain. Given the approved indications of treatment and prevention of breast cancer in postmenopausal women common to certain third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) and their mechanism of action, i.e. inhibition of catalysis of androgens to estrogens via aromatiziation, this class of drugs may be useful for treatment and prevention of moderate to severe mastalgia and also may alleviate the anxiety of breast cancer often associated with syndrome due to its anti-breast cancer indication. To the extent that cyclical mastalgia is associated with increased risk of breast cancer, use of an aromatase inhibitor to control cyclical mastalgia may also decrease the risk of future breast cancer cases. In addition, if chronic cyclical mastalgia is due to multiple factors, combination therapy may provide additional benefit beyond that obtained with a single agent. SUMMARY OF THE INVENTION

[0008] The present invention relates to a method for treating, preventing or moderating mastalgia in a patient, which includes administering to the patient in need thereof a pharmaceutically effective amount of an aromatase inhibitor. [0009] In some embodiments, the patient is a premenopausal woman. [0010] In some other embodiments, the aromatase inhibitor is administered during the luteal phase of the menstrual cycle to premenopausal woman.

[0011] In some other embodiments, the aromatase inhibitor is administered continuously for at least 3 days.

[0012] In some other embodiments, the aromatase inhibitor is administered continuously for at least 7 days (e.g., 7 to 14 days).

[0013] In some embodiments, the aromatase inhibitor is administered at least once a day (e.g., once or twice a day).

[0014] In some embodiments, the aromatase is letrozole, anastrozole, or exemestane. [0015] In some other embodiments, the daily dosage of the aromatase is from about 0.5 mg to about 250.0 mg. For instance, the daily dosage is from about 0.5 mg to about 60 mg, from about 1.0 mg to about 60.0 mg, from about 2.5 mg to about 60 mg, or from about 10 mg to about 200 mg, from about 25 mg to about 200 mg.

[0016] In some embodiments, the aromatase inhibitor is administered orally. [0017] In some other embodiments, the method further includes administering danazol to the woman, either together with the aromatase inhibitor or separately. For instance, danazol can be administered once a day and concurrently with the aromatase inhibitor. [0018] In some embodiments, the daily dosage of danazol is from about 20.0 mg to about 150.0 mg (e.g., from about 50.0 mg to about 100.0 mg). In some other embodiments, the combination of the aromatase inhibitor and danazol is administered daily during the luteal phase of the menstrual cycle of a premenopausal woman for 7 to 14 days. [0019] In some embodiments, danazol is administered daily, twice a day, to the patient. In some other embodiments, the danazol dosage is about 50.0 mg to about 100.0 mg per dose. [0020] In some embodiments, the patient is a man with liver cirrhosis. [0021] In some other embodiments, the aromatase inhibitor is administered orally. [0022] Also within the scope of this invention is a composition for treating, preventing, or moderating mastalgia. The composition includes an aromatase inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention relates to a method for treating, preventing, or moderating mastalgia or symptoms thereof in a patient, comprising administering to the patient a pharmaceutically effective amount of an aromatase inhibitor.

[0024] As used herein, an "effective amount" is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).

[0025] As used herein, the term "aromatase inhibitors" refers to substances that inhibit the enzyme aromatase (also known as estrogen synthase), which is responsible for converting androgens to estrogens, by that means lowers the level of the estrogen estradiol. Aromatase inhibitors may have a non-steroidal or a steroidal chemical structure. According to the present invention, both non-steroidal aromatase inhibitors and steroidal aromatase inhibitors can be used.

[0026] The aromatase inhibitors that can be used for the method of this invention generally have an in vitro inhibition activities exhibiting IC₅0 values of 10^"2 M or lower, e.g., 10^"3 M or lower, 10 M or lower, 10^* M or lower, 10^" M or lower, or 10^"7 M or lower. The in vitro inhibition of aromatase activity of a substance can be demonstrated, for example, by using the methods described in J. Biol. Chem., 1974, 249: 5364, or in J. Enzyme Inhib., 1990, 4: 169. In addition, the IC₅₀ values for aromatase inhibition can be obtained, for example, in vitro by a direct product isolation method relating to inhibition of the conversion of 4-4 C- androstenedione to 4-4 C-estrone in human placental microsomes. [0027] The in vivo aromatase inhibition activity of a substance can be determined, for example, by the method as described in J. Enzyme Inhib., 1990, 4: 79. Specifically, androstenedione (30 mg/kg subcutaneously) is administered on its own or together with an aromatase inhibitor (orally or subcutaneously) to sexually immature female rats for a period of 4 days. After the fourth administration, the rats are sacrificed and the uteri are isolated and weighed. The aromatase inhibition is determined by the extent to which the hypertrophy of the uterus induced by the administration of androstenedione alone is suppressed or reduced by the simultaneous administration of the aromatase inhibitor.

[0028] The aromatase inhibitors that are suitable for this invention can be any aromatase inhibitor, including but are not listed to those listed in the PCT Publications WO 2006/041941 A2 and WO 2006/041939 A2, both of which are incorporated herein by reference in their entireties. These aromatase inhibitors are either commercially available or can be readily made by methods known in the art or described in the literature. Specific examples of suitable aromatase include anastrozole (as in Arimidex^®), exemestane (as in Aromasin^®), letrozole (as in Femara^®), aminoglutethimide, and 4-androstene-3,6,17-trione. [0029] The aromatase inhibitors suitable for this invention include their pharmaceutically acceptable salts, which include, for example, pharmaceutically acceptable acid addition salts or pharmaceutically acceptable metal or ammonium salts. Pharmaceutically acceptable acid addition salts are especially those with suitable inorganic or organic acids, e.g., strong mineral acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, especially aliphatic or aromatic carboxylic or sulfonic acids (e.g., formic, acetic, propionic, succinic, glycolic, lactic, hydroxysuccinic, tartaric, citric, maleic, fumaric, hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4- aminosalicylic, pamoic, gluconic, nicotinic, methanesulfonic, ethanesulfonic, halobenzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid); or with other acidic organic substances (e.g., ascorbic acid). Pharmaceutically acceptable salts may also be formed, for example, with amino acids, such as arginine or lysine. Compounds containing acid groups, e.g., a free carboxy or sulfo group, can also form pharmaceutically acceptable metal or ammonium salts, such as alkali metal or alkaline earth metal salts (e.g., sodium, potassium, magnesium or calcium salts), or ammonium salts derived from ammonia or suitable organic amines. Also under consideration are especially aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or poly amines, such as lower alkylamines (e.g., di- or tri- ethylamine), (hydroxyalkyl)amines (e.g., 2-hydroxyethylamine, bis(2-hydroxyethyl)amine or tris(2-hydroxyethyl)amine), basic aliphatic esters or carboxylic acids (e.g., 4-aminobenzoic acid 2-diethylaminoethyl ester), lower alkylene amines (e.g., 1-ethylpiperidine), cycloalkylamines (e.g., dicyclohexylamine), benzylamines (e.g., N,N'- dibenzylethylenediamine), heterocyclic bases, for example of the pyndine type (e.g., pyridine, collidine, or quinoline). If several acidic or basic groups are present, mono- or poly-salts can be formed. Compounds according to the invention having an acidic and a basic group may also be in the form of internal salts, e.g., in the form of zwitterions and another part of the molecule in the form of a normal salt. Use of such salts is also within the scope of this invention as long as they can be formed.

[0030] The aromatase inhibitors can also in the free form and in the form of hydrates, co- crystals, which may include, for example, the solvent used for crystallization. The present invention relates also to all those forms.

[0031] Most of the aromatase inhibitors suitable for this invention contain at least one asymmetric carbon atom. They can, therefore, occur in the form of R- or S-enantiomers and as enantiomeric mixtures thereof, for example in the form of a racemate. Accordingly, use of all these enantiomers, and their combinations, are within the scope of this invention. Also included are, for example, all geometric isomers, for example cis- and trans- isomers, that can occur when the compounds contain one or more double bonds. [0032] The invention also relates to pharmaceutical compositions that contain at least one aromatase inhibitor (or its pharmaceutically acceptable salt) and a pharmaceutical carrier (and/or a filler or excipient), and can be used to treat, prevent or moderate mastalgia. These pharmaceutical compositions may be administered to a patient via oral administration, enteral (peroral or rectal) administration, transdermal or sublingual administration, parenteral (e.g., intravenous, subcutaneous and intramuscular) administration.

[0033] The proportion of active ingredient in such pharmaceutical compositions is generally from approximately 0.001% to approximately 90%, e.g., from approximately 0.1% to approximately 80%, from approximately 5.0% to approximately 60%, or from approximately 10.0% to approximately 45%.

[0034] Suitable excipients for pharmaceutical compositions for oral administration are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate), and binders, such as starches (e.g., corn, wheat, rice or potato starch), gelatin, tragacanth, methylcellulose and/or hydroxypropylcellulose, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, and/or cellulose, for example in the form of crystals, especially in the form of microcrystals, and/or flow regulators and lubricants, for example, silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, cellulose and/or polyethylene glycol. [0035] Dragee cores can be provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate.

[0036] Other orally administrable pharmaceutical compositions are dry-filled capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, e.g., in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers and/or anti-bacterial agents may also be added. There may also be used capsules that are easily bitten through, in order to achieve by means of the sublingual ingestion of the active ingredient that takes place as rapid an action as possible.

[0037] Suitable rectally or transvaginally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. [0038] There may also be used gelatin rectal capsules, which contain a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons. Suitable formulations for transdermal administration comprise the active ingredient together with a carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents that serve to facilitate the passage through the skin of the host. Transdermal systems are usually in the form of a bandage that comprises a support, a supply container containing the active ingredient, if necessary together with carriers, optionally a separating device that releases the active ingredient onto the skin of the host at a controlled and established rate over a relatively long period of time, and means for securing the system to the skin.

[0039] Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, and also suspensions of active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or aqueous injection suspensions that comprise viscosity- increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilizers. [0040] Dyes or pigments may be added to the pharmaceutical compositions, especially to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.

[0041] The pharmaceutical compositions of the present invention can be prepared in a 3 0 manner known per se, e.g., by means of conventional mixing, granulating, confectioning, dissolving or lyophilizing processes. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to form tablets or dragee cores. [0042] The effectiveness of an aromatase inhibitor for the method of this invention can be determined by methods known in the art, e.g., by the patient's feel of the severity or existence of his or her breast pain. Additionally, as breast cancer patients usually also suffer mastalgia, symptoms related to breast cancer can also be used to determine the effectiveness of the aromatase inhibitor when used for the method of this invention. Details of these methods to determine the effectiveness have been described in detail in scientific literature that describe treatment of mastalgia with other types of therapeutics. See, e.g., Mansel, R. et al., Breast Cancer Res Treat, 2007 Mar 10 issue; Halbreich, U. et al., CNS Drugs, 2006, 20 (7): 523-47; Greydanus, D.E. et al., Prim. Care, 2006, 33(2): 455-502; Martin, T.A. et al., J Cell Biochem. 2006, 98 (5): 1308-1319; Olawaiye, A. et al., J Reprod Med., 2005, 50 (12): 933-939; Gong, C. et al., Arch. Surg., 2006, 41(1): 43-7; Liu, J.H., Am. J. Med., 2005, 118 (Suppl. 12B): 88- 92; and Mahady, G.B., Treat Endocrinol, 2005, 4(3), 177-184.

[0043] The contents of all of the references cited herein are incorporated herein by reference in their entireties.

[0044] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating, preventing, or moderating mastalgia in a patient, comprising administering to the patient a pharmaceutically effective amount of an aromatase inhibitor.

2. The method of claim 1 , wherein the patient is a premenopausal woman.

3. The method of claim 2, wherein the aromatase inhibitors is administered during the luteal phase of the menstrual cycle to premenopausal woman.

4. The method of claim 1, wherein the aromatase inhibitor is administered continuously for at least 3 days.

5. The method of claim 4, wherein the aromatase inhibitor is administered continuously for at least 7 days.

6. The method of claim 5, wherein the aromatase inhibitor is administered continuously for 7 to 14 days.

7. The method of claim 1, wherein the aromatase inhibitor is administered at least once a day.

8. The method of claim 7, wherein the aromatase inhibitor is administered once or twice a day.

9. The method of claim 8, wherein the aromatase inhibitor is administered once a day.

10. The method of claim 1, wherein the aromatase is letrozole, anastrozole, or exemestane.

11. The method of claim 1 , wherein the daily dosage of the aromatase is from about 0.5 mg to about 250.0 mg.

12. The method of claim 11, wherein the aromatase inhibitor is administered once a day.

13. The method of claim 11, wherein the daily dosage of the aromatase inhibitor is from about 1.0 mg to about 60 mg.

14. The method of claim 13, wherein the aromatase inhibitor is letrozole.

15. The method of claim 14, wherein the aromatase inhibitor is administered continuously for 7 to 14 days during the luteal phase of the menstrual cycle of a premenopausal woman.

16. The method of claim 11, wherein the daily dosage of the aromatase inhibitor is from about 0.5 mg to about 60.0 mg.

17. The method of claim 16, wherein the aromatase inhibitor is anastrozole.

18. The method of claim 17, wherein the aromatase inhibitor is administered continuously for 7 to 14 days during the luteal phase of the menstrual cycle of a premenopausal woman.

19. The method of claim 11, wherein the daily dosage of the aromatase inhibitor is from about 10 mg to about 200 mg.

20. The method of claim 19, wherein the aromatase inhibitor is exemestane.

21. The method of claim 20, wherein the aromatase inhibitor is administered orally.

22. The method of claim 21 , wherein the aromatase inhibitor is administered continuously for 7 to 14 days during the luteal phase of the menstrual cycle of a premenopausal woman.

23. The method of claim 1, further comprising administering to the woman with danazol.

24. The method of claim 23, wherein danazol is administered daily and concurrently with the aromatase inhibitor.

25. The method of claim 24, wherein the daily dosage of danazol is from about 10.0 mg to about 200.0 mg.

26. The method of claim 25, wherein the daily dosage of danazol is from about 25.0 mg to about 100.0 mg.

27. The method of claim 24, wherein the combination of the aromatase inhibitor and danazol is administered daily during the luteal phase of the menstrual cycle of a premenopausal woman for 7 to 14 days.

28. The method of claim 23, wherein danazol is administered daily, twice a day.

29. The method of claim 28, wherein the danazol dosage is about 10.0 mg to about 100.0 mg per dose.

30. The method of claim 1 , wherein the patient is a man with liver cirrhosis.

31. The method of claim 1 , wherein the aromatase inhibitor is administered orally.

32. A composition for treating, preventing, or moderating mastalgia, comprising an aromatase inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.