PHARMACEUTICAL USE

Abstract

The invention relates to the use of a pharmaceutical medication comprising an aromatase inhibitor, preferably a steroidal aromatase inactivator and an antioxidant as effective ingredients for the treatment of sex hormone-dependent diseases. Furthermore, the invention relates to a composition comprising an aromatase inhibitor/—inactivator and a-lipoic acid and/or extract of green tea containing polyphenols. The combination of an aromatase inhibitor and—inactivator and a-lipoic acid and/or extract of green tea containing polyphenols is particularly suitable for the treatment of sex hormone-dependent diseases as well as for the treatment of benign tumors such as e.g. lipomatoses as occurring in Madelung's disease.

Claims

1. A method for treating a sex-hormone dependent disease in a subject diagnosed with the sex-hormone dependent disease, wherein said sex-hormone disease is breast cancer, the method comprising topically administering to the subject a treatment effective amount of a pharmaceutical medication comprising as active ingredients a steroidal aromatase-inhibitor and an antioxidant that is different from the aromatase-inhibitor.

2. The method according to claim 1, wherein the treatment is effective only in a peripheral, intracrine target tissue.

3. The method of claim 1, wherein the pharmaceutical medication is a topical dosage form.

4. The method according to claim 1, wherein the treatment is an adjuvant or neoadjuvant therapy of breast cancer.

5. The method according to claim 1, wherein the treatment is continued or resumed after an initial treatment of breast cancer.

6. The method according to claim 1, wherein the steroidal aromatase inhibitor is a steroidal aromatase inactivator selected from the group consisting of 4-hydroxyandrostenedione, exemestane, 4-acetoxyandrostenedione, 5-alpha-androst-3-ene-17-one, and 3-alpha,4-alpha-epoxy-5-alpha-androstane-17-one.

7. The method according to claim 1, wherein the antioxidant is selected from the group consisting of flavonoids, vitamins, carotenoids, minerals, hormones, steroids, ubichinones, N-acetylcysteine, alpha-lipoic acid, extract of green tea containing polyphenols; glutathione, glutathionperoxidase; superoxid dismutase, and catalase.

8. The method according to claim 1, wherein the aromatase inhibitor is selected from the group consisting of 4-hydroxyandrostenedione, exemestane, 4-acetoxyandrostenedione, 5-alpha-androst-3-ene-17-one, and 3-alpha,4-alpha-epoxy-5-alpha-androstane-17-one, and the antioxidant is alpha-lipoic acid.

9. The method according to claim 1, wherein the aromatase-inhibitor is exemestane or 4-hydroxyandrostenedione, and wherein the antioxidans is alpha-lipoic acid.

10. The method according to claim 1, wherein the amount of antioxidant is at least 0.05 wt.-%, at least 0.1 wt.-%, or at least 0.5 wt.-% of the total pharmaceutical medication.

11. The method according to claim 5, wherein the treatment that is continued or resumed after initial treatment of the breast cancer comprises topical administration of 0.5-4 g of the pharmaceutical medication onto the diseased breast, wherein the pharmaceutical medication comprises 0.05-5 wt.-% of antioxidant, and 0.1-5 wt.-% steroidal aromatase inhibitor, in a suitable base cream.

12. The method according to claim 10, wherein the antioxidant is alpha lipoic acid, and the steroidal aromatase inhibitor is selected from the group consisting of 4-hydroxyandrostenedione, exemestane, 4-acetoxyandrostenedione, 5-alpha-androst-3-ene-17-one, and 3-alpha,4-alpha-epoxy-5-alpha-androstane-17-one.

13. The method according to claim 1, wherein the breast cancer is estrogen-receptor positive breast cancer.

14. The method according to claim 1, wherein the subject is a woman.

15. The method according to claim 1, wherein the pharmaceutical medication further comprises hyaluronic acid.

16. A method for treating a sex-hormone dependent disease in a subject diagnosed with the sex-hormone-dependent disease, wherein said sex-hormone disease is breast cancer, the method comprising topically administering to the subject a treatment effective amount of a pharmaceutical composition, consisting essentially of: a steroidal aromatase-inactivator, wherein the steroidal aromatase-inactivator is 4-hydroxyandrostenedione, exemestane, or 4-acetoxyandrostenedione, wherein the steroidal aromatase-inactivator is from 1 wt. % to 3 wt. % of the total composition; an antioxidant, wherein the antioxidant is α-lipoic acid, wherein the antioxidant is from 0.5 wt.-% to 2 wt. % of the total composition; hyaluronic acid, wherein the hyaluronic acid is from 0.2 wt.-% to 0.3 wt. % of the total composition; optionally, one or more carriers, wherein the one or more carriers are selected from the group consisting of glycerol monostearate, cetyl alcohol, medium chain triglycerides, white petrolatum, macrogol-20-glycerolmonostearate, propylene glycol, and purified water; and optionally, one or more additional additives selected from the group consisting of amino acids, mineral nutrients (trace elements) and polysaccharides; wherein said topical pharmaceutical composition is formulated as a cream, a gel, an ointment or an emulsion.

17. The method according to claim 16, wherein the steroidal aromatase-inactivator, wherein the steroidal aromatase-inactivator is 4-hydroxyandrostenedione or exemestane, wherein the steroidal aromatase-inactivator is from 1 wt. % to 3 wt. % of the total composition; the antioxidant is α-lipoic acid, wherein the antioxidant is from 0.5 wt.-% to 2 wt. % of the total composition; hyaluronic acid, wherein the hyaluronic acid is from 0.2 wt.-% to 0.3 wt. % of the total composition; glycerol monostearate, cetyl alcohol, medium chain triglycerides, white petrolatum, macrogol-20-glycerolmonostearate, propylene glycol, and purified water as carriers; and optionally, one or more additional additives selected from the group consisting of amino acids, mineral nutrients (trace elements) and polysaccharides.

18. The method according to claim 16, wherein the carrier is a combination of glycerol monostearate, cetyl alcohol, medium chain triglycerides, white petrolatum, macrogol-20-glycerolmonostearate, propylene glycol, and purified water.

19. A method for treating a sex-hormone dependent disease in a subject diagnosed with the sex-hormone dependent disease, wherein said sex-hormone dependent disease is breast cancer, the method comprising topically administering to the subject a treatment effective amount of a pharmaceutical medication comprising as active ingredients a steroidal aromatase-inhibitor and an antioxidant that is different from the aromatase-inhibitor, wherein the treatment is continued or resumed after an initial treatment of breast cancer.

20. The method according to claim 19, wherein the steroidal aromatase inhibitor is a steroidal aromatase inactivator selected from the group consisting of 4-hydroxyandrostenedione, exemestane, 4-acetoxyandrostenedione, 5-alpha-androst-3-ene-17-one, and 3-alpha,4-alpha-epoxy-5-alpha-androstane-17-one; and wherein the antioxidant is selected from the group consisting of flavonoids, vitamins, carotenoids, minerals, hormones, steroids, ubichinones, N-acetylcysteine, alpha-lipoic acid, extract of green tea containing polyphenols; glutathione, glutathionperoxidase; superoxid dismutase, and catalase.

Description

EXAMPLE 1

[0067] An ER-positive tumor has been diagnosed in the right breast of a 59-year-old female patient. Prior to the start of the treatment, the tumor has been measured mammographically (FIG. 1A). In the following 29 days, α-lipoic acid 0.5% and 4-hydroxyandrostenedione 1.5% (integrated in the basic cream DAC) have been administered topically onto each breast twice per day, 2 g each. Subsequently, the tumor has been measured again (FIG. 1A) and the tumor volume before and after the treatment has been shown graphically in a diagram (FIG. 1B). The tumor volume has been reduced by 78.5% over the course of the 29 days of treatment.

EXAMPLE 2

[0068] A 69-year-old female patient has been diagnosed with an ER-positive tumor in the left breast. A treatment of the breasts was carried out for 14 days by topical administration of α-lipoic acid 0.5% and 4-hydroxyandrostenedione 1.5% (integrated into the basic cream DAC) twice per day, 2 g each. The tumor volume has been determined before and after the treatment as described under Example 1 (FIG. 2A). The tumor volume after treatment was reduced by 61.8%.

EXAMPLE 3

[0069] An ER-positive tumor has been diagnosed in the right breast of a 53-year-old female patient. Prior to the start of the treatment, the tumor was measured mammographically. In the following 24 days α-lipoic acid 0.5% and 4-hydroxyandrostenedione 1.5% (integrated into the basic cream DAC) have been administered topically onto each breast twice per day, 2 g each. Subsequently, the tumor has been measured again and the tumor volume has been compared. The tumor volume has been reduced by 76% over the course of the 24 days of treatment.

EXAMPLE 4

[0070] An ER-positive tumor has been diagnosed in the left breast of a 62-year-old female patient. A treatment was carried out by topical application using the composition according to the invention. In the following 14 days, α-lipoic acid 0.5% and 4-hydroxyandrostenedione 1.5% (integrated into the basic cream DAC) have been applied topically onto each breast twice per day, 2 g each. The tumor volume before and after the treatment has been determined as described under Example 1. The volume of the tumor has been reduced by 64.5% after the treatment.

EXAMPLE 5

[0071] A 47-year-old female patient suffered from an ER-positive tumor in the right breast. For 28 days treatment as described under Example 1 and 2 has been carried out and the tumor volume at the beginning and at the end of the treatment, respectively, has been determined. A reduction by 60.5% has been found.

EXAMPLE 6

[0072] Inventive use of the medication in mastopathy.

[0073] S.H.C., female, 49 years.

[0074] The following combination was selected for the use:

[0075] As active ingredients

[0076] OM24® 0.4%

[0077] Exemistane 1.0%

[0078] As additive (facilitator of absorption and distribution) hyaluronic acid 0.3%.

[0079] Anamnesis and Therapy:

[0080] A fibrocystic mastopathy grade II has been diagnosed in the patient. At the request of the patient, in order to avoid the risk of breast cancer, a therapeutic trial has been carried out by using the above combination, once per day, 2 g onto each breast. The mastopathy (mastopathia fibrosa cystica) has been degenerated completely after 11 months of application. The breast tissue exhibited an ordered structure without any micro-calcification.

[0081] Examples 7 and 8: Use of the Medication According to the Invention in Mastodynia:

[0082] The following combination was selected for the use:

[0083] As active ingredients:

[0084] α-lipoic acid 0.5%,

[0085] 4-acetoxyandrostenedione 1.0%, hyaluronic acid 0.2% (merely as a facilitator of absorption and distribution).

EXAMPLE 7

[0086] I.H., female, 21 years.

[0087] Anamnesis: Menstrual pain occurring monthly since age 13, becoming so strong during the preparation of High School exams (at age 18), that her gynaecologist carried out a mammography, which however merely revealed as a result a slight mastopathy in the upper quadrants. Previous prescription: Voltaren gel applied multiple times per day as needed.

[0088] Present situation: Pain occurring in both breasts 3-5 days prior to each menstruation together with a strong sensation of tension, from the upper quadrants in a seemingly bundled manner shooting towards the nipples. Further continuing under Voltaren gel, during the whole menstrual cycle, afterwards slowly decreasing pain, feeling of tension and dragging until about the 12.sup.th day after beginning of the menstruation.

[0089] Individual Trial Application Using the Medication According to the Invention:

[0090] 4 g once per day, namely 2 g applied onto each breast and massaged in with caution. The individual trial application started about 2 weeks before the beginning of the menstruation.

[0091] Result of the Individual Trial Application:

[0092] The next menstruation proceeded with significantly reduced tension pain in the breast. Overall symptoms: less limiting and ceasing faster. Already 5 days after the beginning of the menstruation the patient was free of any pain. Continuation of the trial application with daily application.

[0093] Result after the second following menstruation: absence of pain

[0094] Continuation of the trial with the medication according to the invention without any undesired side effects.

EXAMPLE 8

[0095] S.P., female, 32 years, married;

[0096] Anamnesis: Pre-menstrual syndrome with symptoms of strong pain in both breasts since puberty. Dynamic increase of the symptoms since age 27 with extremely strong tactile sensitivity, strong sensation of swelling and tension with pain symptoms diffusely radiating into the chest and the arms, which becomes virtually unbearable until the beginning of the menstruation. Unable to work because of these conditions for 2-4 days per month since 3 years. Intimate touching not possible for 14 days per month due to the pathologic tactile hyper-sensitivity. Fading-away of the symptoms only 7-10 days after the beginning of the menstruation.

[0097] Mammography 6 months ago without finding. Writing a pain-diary since 1 year in order to document the pre-menstrual syndrome.

[0098] Previous prescription: Testosterone gel and/or Voltaren gel for years basically without any effect.

[0099] The same applies to temporary therapeutic attempts with Bromocriptin or Danazol. Only administration of Tamoxifen 20 mg led to a considerable alleviation of the symptoms, leading, however, to equally substantial side-effects, mainly in the cardiovascular field (uncontrolled increase of blood pressure). This led to quitting the therapy and already after two menstruation cycles the symptoms showed again their original intensity.

[0100] Individual trial application with the medication according to the invention: 4 g, twice per day (in the mornings and in the evenings), namely 2 g applied onto each breast and massaged in cautiously. The trial application started 2 weeks prior to the beginning of the menstruation.

[0101] Result of the Trial Application:

[0102] The next menstruation proceeded with considerably reduced tension pain in the breast. Overall symptoms develop in a less limiting way and cease faster. Already 5 days after the beginning of the menstruation, the patient was free of any pain.

[0103] Continuation of the Trial with Daily Application:

[0104] Subsequent period: considerably reduced symptoms of swelling and tension, noticeably reduced pain symptoms, mainly in the breasts, less radiating, no incapacity to work.

[0105] Continuation of the Trial Application:

[0106] 3. menstruation: further decrease of the sensation of swelling and tension, reduced pain, remaining only in the breasts, substantially reduced tactile sensitivity, no incapacity to work.

[0107] Further periods of application: almost no remaining sensations of swelling and tension, almost no remaining tactile sensitivity, practically free of pain, no incapacity to work due to mastodynia. No undesired side-effects during the whole treatment period.

[0108] Examples 9 and 10: Use of the medication according to the invention in benign tumors (fat tumors).

[0109] For this application, the following combination was selected: as active ingredients α-lipoic acid 1.0%, 4-hydroxyandrostenedione 1.5%, hyaluronic acid 0.2% (as a local delivery system) integrated into a basic cream (DAC).

EXAMPLE 9

[0110] Patient: E.M.S., 56 years, female: the patient suffers from a very rare, extreme disorder in fat distribution (incidence: 1:25.000 in men and 1:300.000 in women) caused by a Madelung's diseases since almost 15 years, which has led, on the one hand, to a grotesque redistribution of fatty tissue with substantial shrinkage of the breasts and the posterior and to a symmetric lipomatosis focused on the upper trunk and, on the other hand, to impaired motility due to the disturbing fat tumors. In addition, Ms. S. suffers from considerable pain in the fat tumors on the neck, on the back, at the throat, at the lateral thoracic wall, the sides above the shoulder and at the upper arms. This corresponds to the typical image of a Madelung's disease with Lipomatosis dolorosa. The patient had multiple surgeries carried out in cycles from the years 1995 to date. For the last series of surgeries (back and neck, each of those semi-laterally in separate surgeries, likewise upper arms and sides) in the year 2008, six appointments for surgery were required in total. Until December 2010: recurrence in all localizations; further increased growth of the spread-out fat tumors.

[0111] The grotesque transformation of the physical appearance and the considerable pain symptoms together with the difficulties in carrying adequate cloth, have led to a restriction of the life quality, which is difficult to tolerate. The situation is further aggravated by the fact that the patient avoids any intimate contact with her partner since years due to a sense of shame and due to the pain. The patient's condition at the beginning of the trial therapy with the medication according to the invention was worse than at the beginning of the last cycle of surgeries in the year 2008.

[0112] The patient naturally fears a new surgical intervention as obviously also in that case again multiple recurrences are to be expected.

[0113] Start of the individual trial cure on Dec. 14, 2010; the composition according to the invention is massaged into all the fat tumors twice per day. Weekly measurements are carried out of the following regions: neck, breast, left and right upper arms, hip and throat.

[0114] Result: not only could the excessive growth be stopped, but the following results have been achieved: during the course of a therapy, which lasted for 6 weeks so far, the circumferences decreased as follows:

TABLE-US-00001 neck from 36 cm to 31.5 cm, breast from 116 cm to 111.5 cm, upper arm left from 42 cm to 34 cm, upper arm right from 36 cm to 33 cm, hip from 104 cm to 101 cm, throat circumference from 42 cm to 38.5 cm (see Table 1)

TABLE-US-00002 TABLE 1 Results of the measurements in cm (Example 8) THROAT DATE NECK BREAST ARM le ARM ri HIP CIRCUMFERENCE 14 Dec. 2010 36 116 42 42 21 Dec. 2010 35 114 37 103 41 21 Dec. 2010 34 114 36 33 102 40 5 Jan. 2011 33 114 35 33 101 40 12 Jan. 2011 32 112 34 33 101 39 19 Jan. 2011 32 112 34 33 101 39 26 Jan. 2011 31.5 111.5 34 33 101 38.5

[0115] On average, the patient consumed about 100 g per week of the composition according to the invention, which means, in an application twice per day, a concentration of the active ingredients of

[0116] 140 mg α-lipoic acid and

[0117] about 214 mg 4-hydroxyandrostenedione.

[0118] Under the present treatment no undesired effects whatsoever; the trial cure is continued.

EXAMPLE 10

[0119] The 71-year-old male patient E.H.S. over the course of 1 year developed a lipoma above the left shoulder joint, which in the beginning was of the size of a pigeon egg. Until the beginning of the trial cure with the composition according to the invention, the lipoma enlarged to an egg-shaped structure of about 12 cm longitudinal section, 8 cm latitudinal section, and 2.5 cm in height. Besides the cosmetic aspect, the lipoma influences the up-and-down movements of the left arm and the shoulder joint by causing pain, since the lipoma apparently triggers substantial pain during movement by exerting pressure on the supraspinal ligament in the shoulder joint. The patient was willing to undergo surgical treatment.

[0120] However, the patient now decided in October 2010 to use the composition according to the invention.

[0121] Application: twice per day about 2 g massaged into the entire region of the lipoma.

[0122] Result: after 10 weeks of treatment:

TABLE-US-00003 The lipoma shrank in the longitudinal section from 12 cm to 7 cm, in the latitudinal section from 8 cm to 4 cm, in height from 2.5 cm to 1 cm.

[0123] The pain due to pressure and movement is considerably reduced, so that the left arm can again be moved almost freely.

[0124] As the application of the composition according to the invention is not only highly effective, but also mediates a pleasant skin sensation, the trial cure is continued.

[0125] Goal: complete dissolution of the lipoma.