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WO2011039175A1 - Treatment of acne vulgaris, rosacea and androgenetic alopecia and cancer protection in smokers, obesity and diabetes mellitus - Google Patents

Treatment of acne vulgaris, rosacea and androgenetic alopecia and cancer protection in smokers, obesity and diabetes mellitus Download PDF

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WO2011039175A1
WO2011039175A1 PCT/EP2010/064346 EP2010064346W WO2011039175A1 WO 2011039175 A1 WO2011039175 A1 WO 2011039175A1 EP 2010064346 W EP2010064346 W EP 2010064346W WO 2011039175 A1 WO2011039175 A1 WO 2011039175A1
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treatment
resveratrol
medicament
rosacea
acne
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Bodo Melnik
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to treatment of acne vulgaris, rosacea, androge- netic alopecia and protection of cancer, obesity and diabetes mellitus. Background of the invention
  • Acne is a chronic inflammatory disease of the pilosebaceous unit, mostly affecting the sebaceous follicles.
  • Major contributors of acne pathogenesis are abnormal follicular differentiation with increased cornification, enhanced sebaceous gland activity with hyperseborrhea, bacterial hypercolonization, inflam- mation as wells as immunological host reactions.
  • Sebaceous glands function continuously in excreting sebum to the skin surface with an average sebaceous cell transition time of 14 days. Androgens play an essential role for the stimulation of the size of sebocytes and sebum production as well as keratino- cyte proliferation in the ductus seboglandularis and the acroinfundibulum.
  • Exogeneous androgen excess or hyperandrogenism are associated with increased sebum production and the development of severe acne.
  • Acne-prone skin exhibits a higher androgen receptor density and higher 5a-reductase type-I activity than not involved skin.
  • Anti-androgens reduce the synthesis of sebaceous lipids and improve acne, whereas androgen-insensitive subjects who lack functional androgen receptors do not produce sebum and do not develop acne.
  • Rosacea is an inflammatory skin disease appearing in areas with high density of sebaceous glands.
  • the primary clinical features of rosacea include flushing, inflammatory papules, pustules, and teleangiectases.
  • Oxydative stress plays an important role in the pathophysiology of the disease.
  • mesenchymal tissue has an increased tendency of proliferation : sebaceous glands with sebaceous hyperplasia, connective tissue with fibrosis and formation of rhinophyma, and increased angiogenesis with formation of multiple teleangiectases.
  • Disturbed homeostasis of vascular and fibroblast growth factors have been implicated in the pathogenesis of rosacea.
  • Male androgenetic alopecia or male pattern hair loss is another androgen- dependent disease of the pilosebaceous unit. This most common hair loss is characterized by a progressive decline in the duration of anagen, an increase in the duration of telogen, and miniaturization of scalp follicles, indicating a final common pathway of follicular regression.
  • Interleukin-lalpha is regarded as a negative hair growth regulator and is involved in androgen-dependent gene regulation of dermal papilla cells. Multiple FGFs and FGFRs are involved in the ordered regulation of the hair cycle progression.
  • Androgen-dependent expression of dickkopfl from balding dermal papilla cells have been implicated in the apoptosis of follicular keratinocytes.
  • Androgen receptor (AR) transacti- vation is negatively controlled by FoxOl among other AR corepressors.
  • AR transcriptional activity is modulated by acetylation.
  • FoxO-1 forkhead box 0-1
  • FoxO-1 is involved in repression of several nuclear receptors like androgen receptor (AR), peroxisome proliferator-activated receptor gamma (PPARy), retinoid X receptor (RXR) and liver X receptor (LXR) and activation of the promoter of insulin-sensitive glucose transporter 4 (GLUT4).
  • AR androgen receptor
  • PPARy peroxisome proliferator-activated receptor gamma
  • RXR retinoid X receptor
  • LXR liver X receptor
  • IGF-1 insulin/insulin-like growth factor-1
  • PI3K phosphoinositide-3-kinase
  • Akt phosphorylates FoxO-1.
  • Phosphorylated FoxO-1 is translocated from the nucleus into the cytoplasm, where it is sequestered by protein 14.3.3.
  • the nuclear extrusion of FoxO-1 activates AR, PPARy, RXR/LXR heterodimers resulting in transactivation of these receptors.
  • Activation of AR is important in the pathogenesis of acne.
  • Activated AR induces sebocyte proliferation, whe- reas activated PPARY induces terminal differentiation of sebocytes with increased lipogenesis.
  • SREPBlc Sterol regulatory element binding protein lc
  • FoxO- 1 phosphorylation is further increased by FoxO- 1 acetylation .
  • FoxO- 1 is deacylated by a physiologic deacylase sirtuin 1 (SIRTl) .
  • SIRTl physiologic deacylase sirtuin 1
  • FoxO- 1 deacetylation is important to increase the concentration of nuclear FoxO- 1 which is necessary for repression of AR, PPARy, RXR/LXR and activation of GLUT4 at the promoter level . It is the major strategy of this invention to increase nuclear FoxO- 1 levels in androgen-related disorders.
  • AR transcriptional activity is modified by AR acetylation .
  • SIRTl is a corepressor of AR and deacylation of AR by SIRTl decreases AR transcriptional activity.
  • Resveratrol activates Sirtuin 1 (SIRTl) and is thus useful in the attenuation of pathological signaling in acne, rosacea, and androgenetic alopecia, especially AR-mediated growth factor signaling .
  • SIRTl Sirtuin 1
  • These treatments will also be beneficial for hypertrichosis, hirsutism, virilism and polycystic ovary syndrome.
  • One embodiment of the invention is the use of resveratrol for the preparation of a medicament for the treatment of acne, rosacea or androgenetic alopecia .
  • Resveratrol (trans-resveratrol) is trans-3,5,4 ' -trihydroxystilbene and is a natural compound especially present in red wine grapes and red wine.
  • Resveratrol derivatives are compounds of the general formulas shown in figure 4 and include cis-resveratrol and cis-resveratrol derivatives.
  • an amount of 100 to 2000 or 500 to 2000 mg resveratrol per day is preferred .
  • the use in form of capsules or liquids is especially suitable.
  • Daily dosis between 5 and 20 mg resveratrol per kg body weight are useful.
  • the application in a formulation for sublingual or buccal administration is preferred .
  • Such formulations are e.g. available from the company Terraternal .
  • Suitable sublingual preparations are e.g. chewing gums and lozenges.
  • Other useful forms for oral administration are e.g . ampoules and syrups.
  • resveratrol is combined with other hydroxystilbenes like piceatannol in comparable concentrations.
  • the medicament is in a form for topical appli- cation like a cream, a lotion, a gel, a hydrogelor a solution.
  • a suitable amount of resveratrol is 0.1 to 3% or 0.5 to 3% by weight of the topical preparation.
  • Topical application provides the possibility of topical and transdermal delivery.
  • a preferred form for topical application of resveratrol is a hydrogel .
  • a low viscosity hydrogel is preferred. Suitable preparations of hydrogels and solutions are described in Chi-Feng Hung et al., Biol. Pharm. Bull . 31 (5) 955-962 (2008).
  • topical resveratol use is the combination with other hydroxystilbenes.
  • the oral or topical treatment is combined with other topi- cal or oral treatment for the mentioned diseases.
  • the active ingredient resveratrol is combined with a further ingredient selected from
  • a preferred amount of metformin is 250 to 2000 mg per day.
  • a combination with tetracyclines, oral isotretinoin, anti- androgens like cyproterone acetate, metformin, rosiglitazone, pioglitazone and/or other related PPARy agonists (ligands) is especially preferred .
  • the substances could be combined in one pharmaceutical preparation or could be administered as overlapping treatments in separate pharmaceuticals formulations.
  • the medicament of the invention may be used in combination with topical medicaments like adapalene, erythromycin, other topical antibiotics like nadifloxacine, all-trans-retinoic acid, azelaic acid and/or benzoyl peroxide.
  • topical medicaments like adapalene, erythromycin, other topical antibiotics like nadifloxacine, all-trans-retinoic acid, azelaic acid and/or benzoyl peroxide.
  • a combination with tetracycline, oral isotre- tinoin, anti-androgens like cyproterone acetate, metformin, rosiglitazone, pioglitazone and/or other related PPARy agonists (ligands) is suitable.
  • topical metronidazol As an additional topical administration, topical metronidazol, erythromycin, azelaic acid or the like is useful.
  • a treatment with further - known oral or topical administration is useful.
  • suitable medicaments for additional systemic treatments are anti-androgens (women), finasteride (men), dutasteride (men), other 5a-reductase inhibitors, metformin, rosiglitazone, pioglitazone and/or other related PPARY agonists (ligands) .
  • the invention is directed to the use of resveratrol and/or resveratrol derivatives for the preparation of a medicament for oral preventive treatment of individuals with an increased familial risk of cancer, smokers, obese individuals, persons with pre-diabetes mellitus or with diabetes mellitus type 2.
  • a suitable dose is 100 to 2000 or 200 to 2000 mg resveratrol per day
  • the invention is directed to the use of resveratrol for the preparation of a medicament for the treatment of hypertrichosis, hirsutism, virilism and polycystic ovary syndrome.
  • FIGURES Figure 1 shows a 15 year old boy before and 4 weeks after topical 0.1% resveratrol treatment.
  • Figure 2 shows a 12-year-old boy before and 6 weeks after systemic resveratrol treatment.
  • Figure 3 shows a 15-year-old girl before and 8 weeks after systemic and topi- cal resveratrol treatment.
  • Figure 4 shows resveratrol derivatives as described in Mazue et al . , European Journal of Medicinal Chemistry 45 (2010) 2972-2980. Examples for resveratrol use in acne
  • a 15 year old boy with acne vulgaris was treated with a hydrogel comprising resveratol in a concentration of 0.1% (w/w).
  • the hydrogel was applied twice a day to the affected facial skin areas.
  • the acne improved significantly over a period of 4 weeks, see figure 1.
  • a 12-year old boy with acne vulgaris of the face was treated daily for 6 weeks with 3 x 100 mg of sublingual/buccal resveratrol tablets. Acne significantly improved after 6 weeks of systemic resveratrol treatment, see figure 2.
  • a 15-year-old girl with acne papulopustulosa was treated daily with 3 x 100 mg of sublingual/buccal resveratrol tablets as well as twice daily with a 0.1% resveratrol-containing hydrogel .
  • Acne papulopustulosa and seborrhea significantly improved after 8 weeks of systemic and topical resveratrol treatment see figure 3.

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Abstract

Use of resveratrol and/or resveratrol derivatives for the preparation of a medicament for the treatment of acne, rosacea, androgenetic alopecia or hyperproliferative skin diseases.

Description

Treatment of Acne vulgaris. Rosacea and Androqenetic Alopecia and Cancer Protection in Smokers, Obesity and Diabetes mellitus
The present invention relates to treatment of acne vulgaris, rosacea, androge- netic alopecia and protection of cancer, obesity and diabetes mellitus. Background of the invention
Acne is a chronic inflammatory disease of the pilosebaceous unit, mostly affecting the sebaceous follicles. Major contributors of acne pathogenesis are abnormal follicular differentiation with increased cornification, enhanced sebaceous gland activity with hyperseborrhea, bacterial hypercolonization, inflam- mation as wells as immunological host reactions. Sebaceous glands function continuously in excreting sebum to the skin surface with an average sebaceous cell transition time of 14 days. Androgens play an essential role for the stimulation of the size of sebocytes and sebum production as well as keratino- cyte proliferation in the ductus seboglandularis and the acroinfundibulum. Exogeneous androgen excess or hyperandrogenism are associated with increased sebum production and the development of severe acne. Acne-prone skin exhibits a higher androgen receptor density and higher 5a-reductase type-I activity than not involved skin. Anti-androgens reduce the synthesis of sebaceous lipids and improve acne, whereas androgen-insensitive subjects who lack functional androgen receptors do not produce sebum and do not develop acne.
Rosacea is an inflammatory skin disease appearing in areas with high density of sebaceous glands. The primary clinical features of rosacea include flushing, inflammatory papules, pustules, and teleangiectases. Oxydative stress plays an important role in the pathophysiology of the disease. In rosacea mesenchymal tissue has an increased tendency of proliferation : sebaceous glands with sebaceous hyperplasia, connective tissue with fibrosis and formation of rhinophyma, and increased angiogenesis with formation of multiple teleangiectases. Disturbed homeostasis of vascular and fibroblast growth factors have been implicated in the pathogenesis of rosacea. Male androgenetic alopecia or male pattern hair loss is another androgen- dependent disease of the pilosebaceous unit. This most common hair loss is characterized by a progressive decline in the duration of anagen, an increase in the duration of telogen, and miniaturization of scalp follicles, indicating a final common pathway of follicular regression. Interleukin-lalpha is regarded as a negative hair growth regulator and is involved in androgen-dependent gene regulation of dermal papilla cells. Multiple FGFs and FGFRs are involved in the ordered regulation of the hair cycle progression. Androgen-dependent expression of dickkopfl from balding dermal papilla cells have been implicated in the apoptosis of follicular keratinocytes. Androgen receptor (AR) transacti- vation is negatively controlled by FoxOl among other AR corepressors. Moreover, AR transcriptional activity is modulated by acetylation.
Although there are numbers of therapeutics for these diseases which are commonly clinically associated like acne and male pattern alopecia or rosacea there is still a need for additional ways of treating these diseases.
Summary of the invention
It has now been found that Forkhead proteins, FoxO-1 (forkhead box 0-1) in particular, play a significant role in regulating whole body energy metabolism. FoxO-1 is involved in repression of several nuclear receptors like androgen receptor (AR), peroxisome proliferator-activated receptor gamma (PPARy), retinoid X receptor (RXR) and liver X receptor (LXR) and activation of the promoter of insulin-sensitive glucose transporter 4 (GLUT4).
Growth factor signaling, in particular insulin/insulin-like growth factor-1 (IGF- 1) signaling, activate phosphoinositide-3-kinase (PI3K) and subsequently Akt, which phosphorylates FoxO-1. Phosphorylated FoxO-1 is translocated from the nucleus into the cytoplasm, where it is sequestered by protein 14.3.3. The nuclear extrusion of FoxO-1 activates AR, PPARy, RXR/LXR heterodimers resulting in transactivation of these receptors. Activation of AR is important in the pathogenesis of acne. Activated AR induces sebocyte proliferation, whe- reas activated PPARY induces terminal differentiation of sebocytes with increased lipogenesis. Sterol regulatory element binding protein lc (SREPBlc) is the key transcription factor of lipogenesis. Activation of RXR/LXR activates the promoter of SREBPlc. In acne patients, especially in puberty, transient insulin resistance is observed . Insulin resistance is caused by diminished production and secretion of the GLUT4. Diminished nuclear levels of FoxO- 1 reduce GLUT4 transcription and thus explain the insulin resistance of puberty.
FoxO- 1 phosphorylation is further increased by FoxO- 1 acetylation . FoxO- 1 is deacylated by a physiologic deacylase sirtuin 1 (SIRTl) . FoxO- 1 deacetylation is important to increase the concentration of nuclear FoxO- 1 which is necessary for repression of AR, PPARy, RXR/LXR and activation of GLUT4 at the promoter level . It is the major strategy of this invention to increase nuclear FoxO- 1 levels in androgen-related disorders. AR transcriptional activity is modified by AR acetylation . SIRTl is a corepressor of AR and deacylation of AR by SIRTl decreases AR transcriptional activity.
Resveratrol activates Sirtuin 1 (SIRTl) and is thus useful in the attenuation of pathological signaling in acne, rosacea, and androgenetic alopecia, especially AR-mediated growth factor signaling . The recognition of these new biochemical interrelationships of nuclear signaling and the identification of FoxO- 1 as the key mediator of all these signaling events, result in the formation of new treatment modalities of androgen- and sebaceous gland-related disorders like acne vulgaris, rosacea, and androgentic alopecia (AGA) . These treatments will also be beneficial for hypertrichosis, hirsutism, virilism and polycystic ovary syndrome. Detailed description of the invention
One embodiment of the invention is the use of resveratrol for the preparation of a medicament for the treatment of acne, rosacea or androgenetic alopecia .
Resveratrol (trans-resveratrol) is trans-3,5,4 ' -trihydroxystilbene and is a natural compound especially present in red wine grapes and red wine. Resveratrol derivatives are compounds of the general formulas shown in figure 4 and include cis-resveratrol and cis-resveratrol derivatives.
When used for oral treatment, an amount of 100 to 2000 or 500 to 2000 mg resveratrol per day is preferred . For oral administration the use in form of capsules or liquids is especially suitable. Daily dosis between 5 and 20 mg resveratrol per kg body weight are useful.
For oral application, the application in a formulation for sublingual or buccal administration is preferred . Such formulations are e.g. available from the company Terraternal . Suitable sublingual preparations are e.g. chewing gums and lozenges. Other useful forms for oral administration are e.g . ampoules and syrups.
In other embodiments resveratrol is combined with other hydroxystilbenes like piceatannol in comparable concentrations.
In other important embodiment, the medicament is in a form for topical appli- cation like a cream, a lotion, a gel, a hydrogelor a solution. A suitable amount of resveratrol is 0.1 to 3% or 0.5 to 3% by weight of the topical preparation.
Topical application provides the possibility of topical and transdermal delivery.
A preferred form for topical application of resveratrol is a hydrogel . A low viscosity hydrogel is preferred. Suitable preparations of hydrogels and solutions are described in Chi-Feng Hung et al., Biol. Pharm. Bull . 31 (5) 955-962 (2008).
Another preferred embodiment for topical resveratol use is the combination with other hydroxystilbenes.
In one embodiment, the oral or topical treatment is combined with other topi- cal or oral treatment for the mentioned diseases. In one embodiment, the active ingredient resveratrol is combined with a further ingredient selected from
- metformin
- phenformin
- thiazolidinediones
A preferred amount of metformin is 250 to 2000 mg per day.
In case of acne, a combination with tetracyclines, oral isotretinoin, anti- androgens like cyproterone acetate, metformin, rosiglitazone, pioglitazone and/or other related PPARy agonists (ligands) is especially preferred . The substances could be combined in one pharmaceutical preparation or could be administered as overlapping treatments in separate pharmaceuticals formulations.
In the treatment of acne, the medicament of the invention may be used in combination with topical medicaments like adapalene, erythromycin, other topical antibiotics like nadifloxacine, all-trans-retinoic acid, azelaic acid and/or benzoyl peroxide.
Also for the treatment of rosacea a combination with further oral or topical treatment can be useful .
For additional systemic treatment, a combination with tetracycline, oral isotre- tinoin, anti-androgens like cyproterone acetate, metformin, rosiglitazone, pioglitazone and/or other related PPARy agonists (ligands) is suitable.
As an additional topical administration, topical metronidazol, erythromycin, azelaic acid or the like is useful.
Also for the treatment of androgenetic alopecia a treatment with further - known oral or topical administration is useful. Suitable medicaments for additional systemic treatments are anti-androgens (women), finasteride (men), dutasteride (men), other 5a-reductase inhibitors, metformin, rosiglitazone, pioglitazone and/or other related PPARY agonists (ligands) .
For an additional topical treatment a combination like topical minoxidil and/or estradiol solutions could be used . In a further embodiment, the invention is directed to the use of resveratrol and/or resveratrol derivatives for the preparation of a medicament for oral preventive treatment of individuals with an increased familial risk of cancer, smokers, obese individuals, persons with pre-diabetes mellitus or with diabetes mellitus type 2. A suitable dose is 100 to 2000 or 200 to 2000 mg resveratrol per day
In a further embodiment, the invention is directed to the use of resveratrol for the preparation of a medicament for the treatment of hypertrichosis, hirsutism, virilism and polycystic ovary syndrome.
FIGURES Figure 1 shows a 15 year old boy before and 4 weeks after topical 0.1% resveratrol treatment.
Figure 2 shows a 12-year-old boy before and 6 weeks after systemic resveratrol treatment.
Figure 3 shows a 15-year-old girl before and 8 weeks after systemic and topi- cal resveratrol treatment.
Figure 4 shows resveratrol derivatives as described in Mazue et al . , European Journal of Medicinal Chemistry 45 (2010) 2972-2980. Examples for resveratrol use in acne
1. Topical treatment of acne vulgaris with resveratrol
A 15 year old boy with acne vulgaris was treated with a hydrogel comprising resveratol in a concentration of 0.1% (w/w). The hydrogel was applied twice a day to the affected facial skin areas. The acne improved significantly over a period of 4 weeks, see figure 1.
2. Oral treatment of acne vulgaris with resveratrol
A 12-year old boy with acne vulgaris of the face was treated daily for 6 weeks with 3 x 100 mg of sublingual/buccal resveratrol tablets. Acne significantly improved after 6 weeks of systemic resveratrol treatment, see figure 2.
3. Combination of oral and topical resveratrol treatment of acne papulopustu- losa
A 15-year-old girl with acne papulopustulosa was treated daily with 3 x 100 mg of sublingual/buccal resveratrol tablets as well as twice daily with a 0.1% resveratrol-containing hydrogel . Acne papulopustulosa and seborrhea significantly improved after 8 weeks of systemic and topical resveratrol treatment see figure 3.

Claims

Claims
Use of resveratrol and/or resveratrol derivatives for the preparation of a medicament for the treatment of acne, rosacea, androgenetic alopecia or hyperproliferative skin diseases.
The use of claim 1, wherein the medicament is in a form suitable for oral administration, preferably in form of capsules or liquids, preferably wherein the medicament is for oral treatment in an amount of 500 mg to 2000 mg resveratrol per day, preferably in a formulation for sublingual or buccal administration.
The use of claim 1, wherein the medicament is in a form for topical application, preferably a cream, lotion, gel or solution or hydrogel, preferably wherein the amount of resveratrol is 0.1 to 3% by weight.
The use of any one of claims 1 to 3 , wherein the medicament is combined with tetracyclines, oral isotretinoin, anti-androgens like cyproterone acetate, metformin, thiazolidinediones like rosiglitazone, pioglitazone and/or other related PPARy agonists (ligands).
The use of any one of claims 1 to 4 , wherein the medicament is combined with topical medicaments like adapalene, erythromycin, other topical antibiotics like nadifloxacine, metronidazol, all-trans-retinoic acid, azelaic acid and/or benzoyl peroxide.
The use of claim 1 for the treatment of androgenetic alopecia wherein the medicament is in combination with anti-androgens (women), finasteride (men), dutasteride (men), other 5a-reductase inhibitors, metformin, rosiglitazone, pioglitazone and/or other related PPARy agonists (ligands).
The use of claim 1 for the treatment of androgenetic alopecia wherein the medicament is in combination with medicaments like topical minoxidil and/or estradiol solutions.
8. Use of resveratrol for the preparation of a medicament for oral preventive treatment of individuals with an increased familial risk of cancer, smokers, obese individuals, persons with pre-diabetes mellitus or with diabetes mellitus type 2.
9. The use of claim 8, wherein the medicament is in a day dose of 100 to 2000 mg of resveratrol per day.
10. Use of resveratrol or resveratrol derivatives for the preparation of a medicament for the treatment of hypertrichosis, hirsutism, virilism and polycystic ovary syndrome.
11. The use of claim 1, wherein the hyperproliferative skin disease is selected from psoriasis or hyperproliferative skin disorders.
12. The use of any one of claims 9 to 11, wherein resveratrol is combined with metformin and/or one of the following compounds: a thiazolidinedione like rosiglitazone or pioglitazone
13. The use of an inhibitor of FOX-Ol phosphorylation or FOX-Ol acetylation for the treatment of acne, rosacea, androgenetic alopecia or hyperproliferative skin diseases or preventive treatment of individuals with an increased familial risk of cancer, smokers, obese individuals, persons with pre-diabetes mellitus or with diabetes mellitus type 2.
14. A method of screening for a compound to be used in the treatment of acne, rosacea, androgenetic alopecia, hyperproliferative skin diseases and cancer comprising the steps of
- contacting a cell with a potential compound
- measuring the amount of phosphorylated or acetylated FOX-Olor an- drogen receptor, preferably wherein measuring is in the presence of growth factors like IGF1.
15. Use of claim 1, 8, 10 or 13, wherein resveratrol is used .
16. A compound selected from the group consisting of resveratroi, resveratroi derivatives and mixtures thereof for use in the treatment of acne, rosacea, androgenetic alopecia and hyperproliferative skin diseases, hypertrichosis, hirsutism, virilism and polycystic ovary syndrome.
17. The use of claim 1 for the treatment of acne.
18. The use of claim 1 for the treatment of rosacea.
19. The use of claim 1 for the treatment of androgenetic alopecia.
20. The use of claim 1 for the treatment of hyperproliferative skin diseases.
21. The use of claim 10 for the treatment of hypertrichosis.
22. The use of claim 10 for the treatment of hirsutism.
23. The use of claim 10 for the treatment of virilism.
24. The use of claim 10 for the treatment of polycystic ovary syndrome.
PCT/EP2010/064346 2009-09-29 2010-09-28 Treatment of acne vulgaris, rosacea and androgenetic alopecia and cancer protection in smokers, obesity and diabetes mellitus Ceased WO2011039175A1 (en)

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