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(11) EP 2 292 226 A2

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 09.03.2011 Bulletin 2011/10 A61K 31/353 (2006.01) A61P 17/00 (2006.01) A61P 17/02 (2006.01) A61P 35/00 (2006.01) (21) Application number: 10012395.9

(22) Date of filing: 08.10.2004

(84) Designated Contracting States: (72) Inventor: Stockfleth, Eggert AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 25767 Albersdorf (DE) HU IE IT LI LU MC NL PL PT RO SE SI SK TR (74) Representative: Bösl, Raphael Konrad (30) Priority: 09.10.2003 US 510101 P Isenbruck Bösl Hörschler LLP Patentanwälte (62) Document number(s) of the earlier application(s) in Prinzregentenstrasse 68 accordance with Art. 76 EPC: 81675 München (DE) 04790231.7 / 1 684 780 Remarks: (71) Applicant: MediGene AG This application was filed on 30-09-2010 as a 82152 Martinsried (DE) divisional application to the application mentioned under INID code 62.

(54) The use of a for the treatment of a cancerous or pre-cancerous lesion of the skin

(57) The present invention refers to a method for cancerous or pre-cancerous lesions of the skin by ad- treating cancerous or pre-cancerous lesions of the skin ministering a pharmaceutically effective amount of a by administering a pharmaceutically effective amount of polyphenol to a patient as well as to the production of a a polyphenol to a patient as well as to the production of medicament thereto. a medicament thereto. The present invention refers to a method for treating EP 2 292 226 A2

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 292 226 A2 2

Description that comprise most of the upper layers of skin. Squamous cell cancers may occur on all areas of the body including [0001] The present invention refers to a method for the mucous membranes, but are most common in areas treating cancerous or pre-cancerous lesions of the skin exposed to the sun. Although squamous cell carcinomas by administering a pharmaceutically effective amount of 5 usually remain confined to the epidermis for some time, a polyphenol to a patient as well as to the production of they eventually penetrate the underlying tissues if not a medicament thereto. treated. In a small percentage of cases they spread (me- [0002] Skin cancer is a disease in which malignant tastasize) to distant tissues and organs which can be (cancer) cells are formed in the tissues of the skin. The fatal for the person afflicted. Metastasing squamous cell skin is the body’s largest organ. It protects against heat, 10 carcinomas most often arise on sites of chronic inflam- sunlight, injury, and infection, helps to control the body matory skin conditions or on the mucous membranes or temperature and stores water, fat, and vitamin D. The lips. Chronic exposure to sunlight causes most cases of skin has several layers, but the two main layers are the squamous cell carcinoma because tumors appear most epidermis (upper or outer layer) and the dermis (lower frequently on sun-exposed parts of the body. The rim of or inner layer). Skin cancer usually starts growing in the 15 the ear and the lower lip are especially vulnerable to the epidermis, which is made up of three kinds of cells. The development of these cancers. Squamous cell carcino- squamous cells are thin, flat cells that form the top layer mas may also occur where skin has suffered certain kinds of the epidermis. The basal cells are round cells below of injury such as burns, scars, long- standing sores, sites the squamous cells and melanocytes are found in the previously exposed to X-rays and/or certain chemicals lower part of the epidermis. These cells produce melanin, 20 such as arsenic and petroleum byproducts. In addition, the pigment that is responsible for the natural color of the chronic skin inflammation or medical conditions that sup- skin. When skin is exposed to the sun, melanocytes are press the immune system over an extended period of induced to produce more pigment causing the skin to tan time may encourage development of squamous cell car- or darken. cinoma. Occasionally, squamous cell carcinoma arises [0003] Skin cancer can occur anywhere but it is most 25 spontaneously on what appears to be normal, healthy or common in skin that has been exposed to sunlight, such undamaged skin. Some researchers believe that a ten- as the face, ears, neck, bald scalp, hands, shoulders, dency to develop this cancer may be inherited. arms and/or the back. There are several types of cancer [0006] Certain precursor conditions, some of which re- that start in the skin. The most common types are basal sult from extensive sun damage, are sometimes associ- cell carcinoma and squamous cell carcinoma which are 30 ated with the later development of squamous cell carci- non melanoma skin cancers. Actinic keratosis is a skin noma. They include actinic keratoses, actinic cheilitis, condition that sometimes develops into squamous cell leukoplakia and Bowen’s disease. carcinoma. [0007] Actinic keratosis (AK), also known as a solar [0004] Basal cell carcinoma or basalioma is the most keratosis, arises on the skin surface. AK appears as common form of skin cancer affecting 800,000 Ameri- 35 rough, scaly crusty and/or slightly raised growths that cans each year. In fact, it is the most common of all can- range in color from brown to red and may be up to one cers. One out of every three new cancers is a skin cancer inch in diameter. It appears most often in older people. and the vast majority are basal cell carcinomas often re- The base may be light or dark, tan, pink, red or a com- ferred to by the abbreviation, BCC. These cancers arise bination of these or has the same color as the skin itself. in the basal cells which are at the bottom of the epidermis 40 The scale or crust is homy, dry and rough and is often (outer skin layer). Until recently, those people which were recognized by touch rather than sight. Occasionally, it most often affected, were older people, particularly men itches or produces a pricking or tender sensation. It can who had worked outdoors. Although the number of new also become inflamed and surrounded by redness. In cases has increased sharply each year in the last few rare instances, actinic keratoses can even bleed. The decades, the average age of onset of the disease has 45 skin abnormality or lesion develops slowly and generally steadily decreased. More women are getting BCC than reaches a size from an eighth to a quarter of an inch. in the past. Nonetheless, men still outnumber them great- Early on, it may disappear only to reappear later. Several ly. Chronic exposure to sunlight is the cause of almost Aks can often been seen at a time and are most likely to all basal cell carcinomas which occur most frequently on appear on the parts of the body most often exposed to exposed parts of the body. Rarely, however, tumors de- 50 sunshine. The growths may be flat and pink or raised and velop on non- exposed areas. In a few cases, contact with rough. AK can be the first step in the development of skin arsenic, exposure to radiation and complications of cancer. It is thus a precursor of cancer or a precancer. If bums, scars, vaccinations or even tattoos are contribut- treated early, almost all AKs can be eliminated without ing factors. becoming skin cancers. But untreated, about two to five [0005] Squamous cell carcinoma (SCC), the second 55 percent of these lesions may progress to squamous cell most common skin cancer after basal cell carcinoma, carcinomas. In fact, some scientists now believe that AK afflicts more than 200,000 Americans each year. It arises is the earliest form of Squamous Cell Carcinoma (SCC). from the epidermis and resembles the squamous cells These cancers are usually not life-threatening, provided

2 3 EP 2 292 226 A2 4 they are detected and treated in the early stages. How- is a non-virally induced lesion, in particular a lesion not ever, if this is not done, they can grow large and invade caused by a papilloma virus, preferably not a lesion se- the surrounding tissues and, on rare occasions, metas- lected from hyperplasia, Condyloma acuminata, warts, tasize or spread to the internal organs. including without limitation common warts and/or plantar [0008] Actinic cheilitis is another form of actinic kera- 5 warts, and/or cervical intra-epithelial neoplasia. tosis which occurrs on the lips and causes them to be- [0017] According to the present invention, the term come dry, cracked, scaly and pale or white. It mainly af- "non-virally induced cancerous lesion" means a cancer- fects the lower lip, which typically receives more sun ex- ous and/or pre-cancerous condition of the skin which is posure than the upper lip, and may evolve into a type of not caused or induced by viruses which can infect the SCC that can spread rapidly to other parts of the body. 10 skin, such as papilloma viruses, in particular human pap- [0009] Chronic sun exposure is the cause of almost all illoma viruses, e.g. HPV 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, AKs. Sun damage to the skin accumulates over time, so 14, 15, 16, 17, 18, 19-29, 31, 32, 34, 36-38, 46-50 and/or that even a brief exposure adds to the lifetime total. The 56-58, and/or herpes viruses, such as herpes simplex likelihood of developing AK is highest in regions near the virus 1, herpes simplex virus 2, varicella zoster virus equator. However, regardless of climate, everyone is ex- 15 and/or human herpes virus, such as HHV 1, 2, 3, 4, 7 posed to the sun. About 80 percent of solar UV rays can and/or 8. Examples of diseases caused or induced by pass through clouds. These rays can also bounce off viruses are verrucae plantares, verrucae vulgares, ver- sand, snow and other reflective surfaces giving you extra rucae planae juveniles, epidermodysplasia verruci- exposure. AKs can also appear on skin that has been formis, Condylomata acuminata, Condylomata plana, frequently exposed to artificial sources of UV light, such 20 bowenoid papulosis, papillomas on the larynx and oral as tanning devices. More rarely, they may be caused by mucosa, focal epithelial hyperplasia, herpes labialis, Ka- extensive exposure to X- rays or specific industrial chem- posi’s sarcoma, varicella and shingles. icals. Individuals whose immune systems are weakened [0018] The term "pharmaceutically effective amount" as a result of cancer chemotherapy, AIDS or organ trans- means an amount of at least one polyphenol which caus- plantation are also at higher risk. AK is the most common 25 es a positive effect on the lesion of the skin of the patient, type of precancerous skin lesion. Older people are more e.g. causes a reduction or disappearance of the lesion, likely than younger ones to develop these lesions be- in particular with the aim to improve or cure the disease cause cumulative sun exposure increases with the years. of the patient. Pharmaceutically effective amounts are Some experts believe that the majority of people who live e.g. formulations, preferably ointments, containing about to the age of 80 will have AK. 30 2% (w/w) to about 50% (w/w), especially about 5% (w/w) [0010] Leukoplakia, another precursor condition, are to about 20% (w/w), in particular about 10% (w/w) to white patches on the tongue or inside of the mouth having about 15% (w/w) and most preferred about 10% (w/w) the potential to develop into squamous cell carcinoma. or about 15% (w/w) of at least one polyphenol or of a [0011] Bowen’s disease is generally considered to be mixture of several (different) . These a superficial squamous cell cancer that has not yet35 amounts can be applied once or several times, e.g. 3 to spread. It appears as a persistent red- brown, scaly patch 5 times a week for 6 to 12 weeks, until the positive effect which may resemble psoriasis or eczema. If untreated, on the lesion of the skin of the patient occurs. it may invade deeper structures. [0019] The term "about" means according to the inven- [0012] The standard therapies used in pre-cancerous tion a general error range of +/- 20%, especially +/- 10%, or cancerous lesions of the skin might not be applicable 40 in particular +/- 5%. in all patients, e.g. surgery in patients with severe con- [0020] Polyphenols are naturally accurring phenolic comitant diseases, or have severe side- effects and may compounds, preferably with 1, 2 or 3 aromatic rings, in result in skin breakdown, discoloration, irritation, damage particular with 2 aromatic rings, carrying at least two hy- to surrounding normal skin, swelling and/or scars. droxyl groups, such as catechols, flavons, [0013] Consequently, the problem underlying the45 and/or , e.g. pelargonidin, cyanidin, del- present invention resides in providing an alternative ther- phinidin, paonidin, petunidin, malvidin and/or hirsutidin, apy for pre-cancerous or cancerous lesions of the skin whereas catechols are naturally occurring polyphenols for at least most of the group of patients. usually found in resins and/or lignins. Alternative names [0014] Surprisingly, it has been found that the treat- used in the literature for catechols are , pyro- ment of the skin with at least one polyphenol, in particular 50 catechols or 1,2-dihydroxybenzenes. with at least one elicits a positive effect on pre- [0021] The polyphenols, in particular the catechols cancerous or cancerous lesions of the skin. employed in the present invention may be obtained either [0015] One subject-matter of the present invention is, synthetically or fromnatural sources. Thenatural sources therefore, a method for treating a cancerous, including which may especially be mentioned are tea plants, in pre-cancerous, lesion of the skin by administering a phar- 55 particular . In this context, the natural constitu- maceutically effective amount of a polyphenol or a mix- ents may be present in differing concentrations depend- ture of polyphenols to a patient, in particular to a human. ing on the species and variety. In this connection, the [0016] In a preferred embodiment the lesion of the skin polyphenols,in particular the catechols which are em-

3 5 EP 2 292 226 A2 6 ployed are preferably isolated or extracted from Camellia in which sinensis, Camellia asamica, Camellia bohea, Camellia R8 is -H or -OH, and chinensis and/or Camellia oleosa. All the components of R9 is -H or a group of the formula (III) tea plants, in particular the leaves, can be used for iso- lating or extracting the polyphenols, in particular the cat- 5 echols. The polyphenols, in particular the catechols which are employed are preferably isolated from a tea extract, in particular from a green tea extract or easily extracted from a tea, in particular from a green tea. Suit- able methods for the isolation or extraction of polyphe- 10 nols, in particular catechols are described e.g. in U.S. 4,613,672, U.S. 4,673,530, U.S. 4,913,909, U.S. 6,096,359 or U.S. 4,248,789. [0022] Generally, the polyphenols have the formula (I) 15

Examples of polyphenols are: [0023] Polyphenol derivatives of with the formu- la (IV): 20

25

in which 30 R1, R2 and R6 are independently from each other -H or [0024] Polyphenol derivatives of flavan-3-ol with the -OH, formula (V): R3 is -H or =O, R4 is independently from each other -H, -OH or a group of the formula (III) 35

40

[0025] Polyphenol derivatives of flavanon with the for- 45 R5 and R 7 are independently from each other -H, -OH or mula (VI): -OCH3, and ---- optionally represents a bond, and the catechols have the formula (II)

50

55

[0026] Polyphenol derivatives of flavon with the formu-

4 7 EP 2 292 226 A2 8 la (VII): chol, catechol gallate, epicatechol, epicatechol gallate, epigallocatechol, epigallocatechol gallate, and/or gallocatecholgallate and in particular from (+)-cat- echol, (-)-catechol, (+)-catechol gallate, (-)-catechol gal- 5 late, (+)-epicatechol, (-)-epicatechol, (+)-epicatechol gal- late, (-)-epicatechol gallate, (+)-epigallocatechol, (-)-ep- igallocatechol, (+)-epigallocatechol gallate, (-)-epigallo- catechol gallate, (+)-gallocatechol, (-)-gallocatechol, (+)-gallocatechol gallate and (-)-gallocatechol gallate. 10 [0030] The structural formula of the most preferred cat- echols are: [0031] For (-)-epigallocatechol gallate (-)-EGCG: [0027] Polyphenol derivatives of flavonol with the for- mula (VIII): 15

20

25 [0032] For (-)-epigallocatechol (-)-EGC: [0028] Polyphenol derivatives of chalcon with the for- mula (IX):

30

35

[0033] For (-)-epicatechol gallate (-)-ECG: and anthocyanidins with the formula (X): 40

45

50

[0034] For (-)-epicatechol (-)-EC:

55 with R5 and R7 are independently from each other -H, -OH or -OCH3, as e.g. in pelargonidin, cyanidin, delphi- nidin, paonidin, petunidin, malvidin or hirsutidin. [0029] Preferably, the catechol is selected from cate-

5 9 EP 2 292 226 A2 10

5

10 [0035] For (+)-epicatechol (+)-EC:

[0039] For (-)-catechol gallate (-)-CG: 15

20

[0036] For (+)-catechol (+)-C:

25

[0040] For (+)-gallocatechol (+)-GC:

30

[0037] For (-) catechol (-)-C: 35

40 [0041] For (-)-gallocatechol (-)-GC:

45

[0038] For (-)-gallocatechol gallate (-)-GCG:

50

[0042] In another particularly preferred embodiment of the present invention the polyphenols, in particular the catechols, are present in the form of a mixture of polyphe- 55 nols, in particular catechols, especially containing cate- chol, catechol gallate, epicatechol, epicatechol gallate, epigallocatechol, epigallocatechol gallate, gallocatechol and/or gallocatechol gallate, preferably in the stereo-

6 11 EP 2 292 226 A2 12 chemistry as defined above. The preferred catechols are ing these pharmaceuticals in the application according in particular the gallates of catechol, epicatechol, epigal- to the invention. For this, the active compounds are locatechol or of gallocatechol, as they are generally more worked up, together with one or more suitable, pharma- active as the catechols. In particular, the present inven- ceutically acceptable additives, if necessary, into the me- tion is directed to mixtures of the particular gallates con- 5 dicinal forms which are suitable for the different indica- taining more than about 40% (w/w), preferably more than tions and sites of administration. In this context, the phar- about 50% (w/w), especially more than about 60% (w/w) maceuticals can be prepared such that the rate of release and in particular more than 65% (w/w) of the particular in each case desired, for example a rapid accumulation gallates. These gallates may be (-) or (+) stereoisomers and/or a delayed-release or depot effect, is achieved. wherein the (-) stereoisomers are preferred. 10 [0047] Consequently, another embodiment of the [0043] Preferred catechols employed in the present in- present invention is directed to the use of a pharmaceu- vention are (-)-epicatechol, (-)-epicatechol gallate, tical effective amount of a polyphenol, in particular a cat- (-)-epigallocatechol, (-)-epigallocatechol gallate, (+)-gal- echol or a mixture of (different) polyphenols, in particular locatechol and/or (-)-gallocatechol gallate, in particular catechols, as specified above, for the production of a in form of a mixture containing about 2-20% (w/w) epi- 15 medicament for the treatment of cancerous, including catechol, about 2-20% (w/w), epicatechol gallate, about pre-cancerous, lesions of the skin, preferably a non-vi- 1-25% (w/w) epigallocatechol, about 40-75% (w/w) epi- rally induced lesion, in particular a lesion not caused by gallocatechol gallate, about 0.05-5% (w/w) gallocatechol a papilloma virus, preferably not a lesion selected from and/or about 0.5-20% (w/w) gallocatechol gallate, espe- hyperplasia, Condyloma acuminata, warts, including cially a mixture containing about 10.8% (w/w) of epicate- 20 without limitation common warts and/or plantar warts, chol, about 6.5% (w/w) of epicatechol gallate, about 9.2% and/or cervical intra-epithelial neoplasia, as explained (w/w) of epigallocatechol, about 54.8% (w/w) of epigal- therein, preferably for the topical administration of the locatechol gallate and/or about 4.0% (w/w) of gallocate- polyphenol, in particular catechol, or polyphenol, in par- chol gallate, all of them preferably in the stereochemistry ticular catechol mixture. as defined above, in particular in form of a mixture con- 25 [0048] Examples of suitable additives are sodium al- taining about 10.8% (w/w) of (-)-epicatechol, about 6.5% ginate, as a gelatinizing agent for preparing a suitable (w/w) of (-)-epicatechol gallate, about 9.2% (w/w) of base, or cellulose derivatives, such as guar or xanthan (-)-epigallocatechol, about 54.8% (w/w) of (-)-epigallo- gum, inorganic gelatinizing agents, such as aluminum catechol gallate and/or about 4.0% (w/w) of (-)-gallocate- hydroxide or bentonites (what are termed thixotropic gel- chol gallate. 30 formers), polyacrylic acid derivatives, such as Car- [0044] Alternatively, the mixture of catechols contains bopol®, polyvinylpyrrolidone, microcrystalline cellulose about 2-12% (w/w), preferably about 5-8% (w/w) epicate- and carboxymethylcellulose. Amphiphilic low molecular chol, about 4-15% (w/w), preferably about 5-7% (w/w), weight and higher molecular weight compounds, and al- in particular about 5-6% (w/w) epicatechol gallate, about so phospholipids, are also suitable. The gels can be 1-8% (w/w), preferably about 2-3% (w/w), in particular 35 present either as water- based hydrogels or as hydropho- about 6-8% (w/w) epigallocatechol, about 60-68% (w/w), bic organogels, for example based on mixtures of low preferably about 61-65% (w/w) epigallocatechol gallate, and high molecular weight paraffin hydrocarbons and about 0.05-1% (w/w) gallocatechol and about 1-7% vaseline. The hydrophilic organogels can be prepared, (w/w), preferably about 2-4% (w/w) gallocatechol gallate. for example, on the basis of high molecular weight poly- [0045] Consequently, the catechols can be used both 40 glycols. These gelatinous forms are washable. individually and in the form of mixtures having different However, the organogels which are preferred are the hy- compositions as specified above. For example, a com- drophobic organogels. Particular preference is given to position known under the tradename Polyphenon® 100 hydrophobic additives, such as petroleum jelly, wax, oleyl is composed of about 5.9% (w/w) of (-)-epicatechol, , propylene glycol monostearateand/or propylene about 12.6% (w/w) of (-)-epicatechol gallate, about45 glycol monopalmitostearate, in particular isopropyl myr- 17.6% (w/w) of (-)-epigallocatechol, about 53.9% (w/w) istate. It is, of course, likewise possible to add skin-se- of (-)-epigallocatechol gallate and/or about 1.4% (w/w) dating and/or inflammation-inhibiting additives which are of (-)-gallocatechol. As another example, a composition known to the skilled person, such as synthetically pre- known under the tradename Polyphenon® E is com- pared active compounds and/or extracts and/or active posed of about 10.8% (w/w) of (-)-epicatechol, about50 compounds from medicinal plants, in particular bisobolol 6.5% (w/w) of (-)-epicatechol gallate, about 9.2% (w/w) and panthenol.It is furthermorealso possible to adddyes, of (-)-epigallocatechol, about 54.8% (w/w) of (-)-epigal- for example yellow and/or red iron oxide and/or titanium locatechol gallate and/or about 4.0% (w/w) of (-)-gallo- dioxide for the purpose of matching as regards color. catechol gallate. [0049] Generally, the polyphenol, in particular the cat- [0046] The familiar methods of pharmaceutical tech- 55 echol or mixture of polyphenols, in particular catechols, nology are used, in a customary manner, for preparing is contained in a carrier, e.g. in the form of an emulsion, pharmaceuticals which comprise one or more com- a gel, a cream or an ointment. pounds according to the present invention and/or for us- [0050] Customary emulsions, gels, creams and oint-

7 13 EP 2 292 226 A2 14 ments of the mixed-phase or amphiphilic emulsion sys- [0057] An alternative embodiment of the present in- tems (oil/water-water/oil mixed phase), and also lipo- vention is directed to a combination therapy. somes and transfersomes or plasters, preferably oint- [0058] Therefore, the present invention also encom- ments and creams, particularly preferably an ointment, passes a method for treating a cancerous, including pre- may be mentioned for conventional application to the 5 cancerous, lesion of the skin, preferably a non- virally in- skin. The catechol is preferably applied locally in the re- duced lesion, in particular a lesion not caused by a pap- gion in which there is a cancerous or pre- cancerous skin illoma virus, preferably not a lesion selected from hyper- lesion. plasia, Condyloma acuminata, warts, including without [0051] Emulsifiers which can be employed are anionic, limitation common warts and/or plantar warts, and/or cer- cationic or neutral surfactants, for example alkali metal 10 vical infra-epithelial neoplasia, as explained therein, by soaps, metal soaps, amine soaps, sulphurated and sul- administering a pharmaceutically effective amount of a phonated compounds, invert soaps, higher fatty alco- catechol or a mixture of catechols, as specified above, hols, partial fatty acid esters of sorbitan and polyoxyeth- in combination with a different anticancer treatment and ylene sorbitan, e.g. lanette types, wool wax, lanolin or the preparation of a corresponding medicament. The ad- other synthetic products for preparing the oil/ water and/or 15 ministration of the different anticancer agent can be si- water/oil emulsions. multaneous with, prior to or after the administration of [0052] Itis possible to use vaseline, natural or synthetic the polyphenol, in particular catechol or the mixture of waxes, fatty acids, fatty , fatty acid esters, for polyphenols, in particular catechols. example as monoglycerides, or triglycer- [0059] According to the present invention the term "dif- ides, paraffin oil or vegetable oils, hydrogenated castor 20 ferent anticancer treatment" refers preferably to surgery, oil or coconut oil, hog fat, synthetic fats, for example electrodessication, curettage, excision, Mohs micro- based on, caprylic acid, capric acid, lauric acid or stearic graphic surgery, radiation, proton therapy, chemothera- acid, such as Softisan®, or triglyceride mixtures, such as py, photodynamic therapy, cryosurgery, laser, immuno- Miglyol®, can be used as lipids, in the form of fatty and/or therapy, vaccine therapy and/or biologic therapy. Pre- oleaginous and/or waxy components for preparing the 25 ferred chemotherapeutic treatments encompass the use ointments, creams or emulsions. of podophyllin, 5- fluorouracil, bleomycin, interferon or im- [0053] It is possible to use, for example, osmotically iquimod, and mixtures thereof. A preferred radiotherapy active acids and alkaline solutions, for example hydro- is X-ray radiation and/or γ-radiation. chloric acid, citric acid, sodium hydroxide solution, po- [0060] The skin lesions referred to in the present in- tassium hydroxide solution, sodium hydrogen carbonate, 30 vention are preferably skin cancer or cutaneous carcino- and, in addition, buffer systems, such as citrate, phos- ma, basal cell carcinoma, squamous cell carcinoma, ac- phate, tris buffer or triethanolamine, for adjusting the pH. tinic or solar keratosis, epithelioma or epithelial tumors, It is possible to add preservatives as well, such as methyl skin neoplasm, Bowen’s disease, acanthoma, cancroid, benzoate or propyl benzoate (parabens) or sorbic acid, cutaneous horn, hyperkeratosis, keratosis, molluscum for increasing the stability. 35 contagiosum, lid tumors, xanthelasma, xanthoma, fibro- [0054] Pastes, powders and solutions may be men- ma, verucca senilis, seborrheic keratosis, cheilocarcino- tioned as additional forms which can be applied topically. ma, papillomatosis, penis carcinoma, radiodermatitis, As consistency-imparting bases, the pastes frequently sailor’s skin, tar cancer, vaginal carcinoma, vulvar can- contain hydrophobic and hydrophilic auxiliary substanc- cer, erythroplasia queyrat and/or carcinoma of the es, preferably, however, hydrophobic auxiliary substanc- 40 tongue. In particular, the skin lesions are actinic or solar es containing a very high proportion of solids. In order to keratosis and/or basal cell carcinoma. increase dispersity, and also flowability and slipperiness, [0061] Taken together, one of the most preferred em- and also to prevent agglomerates, the powders or topi- bodiments of the present invention is the use of a phar- cally applicable powders can, for example, contain starch maceutical formulation containing a mixture of different species, such as wheat or rice starch, flame-dispersed 45 polyphenols as disclosed above in an amount of about silicon dioxide or siliceous earth, which also serve as 10% (w/w) to about 15% (w/w) in the pharmaceutical for- diluent. mulation for the treatment of actinic keratosis, solar kera- [0055] The medicinal forms which are in each case tosis and/or basal cell carcinoma. The mixture of different suitable can be produced on the basis of pharmaceutico- polyphenols contains in particular more than 60% (w/w), physical principles in conformity with formulation guide- 50 especially more than 65% (w/w) gallates of catechol, ep- lines and methods known to a skilled person. icatechol, epigallocatechol or of gallocatechol. Preferred [0056] As a further example, the pharmaceutical em- mixtures of different polyphenols are Polyphenon® 100 ployed in the present invention preferably comprises or Polyphenon ® E as specified above. Finally, a preferred about 35% (w/w) of isopropyl myristate, about 15% (w/w) pharmaceutical formulation comprises about 35% (w/w) of at least one catechol, about 24.5% (w/w) of petroleum 55 of isopropyl myristate, about 15% (w/w) of at least a mix- jelly, about 20% (w/w) of wax, about 5% (w/w) of propyl- ture of different polyphenols as specified in this para- ene glycol monostearate or propylene glycol monopalmi- graph, in particular Polyphenon ® 100 or Polyphenon ® E, tostearate and about 0.5% (w/w) of oleyl alcohol. about 24.5% (w/w) of petroleum jelly, about 20% (w/w)

8 15 EP 2 292 226 A2 16 of wax, about 5% (w/w) of propylene glycol monostearate of Example 1) or propylene glycol monopalmitostearate and about V after 12 weeks of treatment only single actinic 0.5% (w/w) of oleyl alcohol which can be used in the keratoses have been left and after 16 weeks of treatment of actinic keratosis, solar keratosis and/or ba- treatment actinic keratoses have disappeared sal cell carcinoma. 5 completely [0062] The following examples are intended to clarify the invention without restricting it. Skilled persons can [0067] The following pages 22 to 27 contain specific modify the invention appropriately, within the bounds of embodiments. customary ability, without departing from the protective scope. 10 1. Use of a pharmaceutically effective amount of a polyphenol for the preparation of a medicament for Example 1: the treatment of a cancerous lesion of the skin of a patient. [0063] Patient: 65 years old, male with actinic kera- toses known since 10 years; 15 2. The use according to 1, wherein the cancerous [0064] The patient was treated with Polyphenon® E lesion is a pre-cancerous lesion. (15% ointment containing 35% (w/w) isopropyl myristate, 15% (w/w) catechol extract, 24.5% (w/w) petroleum jelly, 3. The use according to 1, wherein the lesion of the 20% (w/w) wax, 5% (w/w) propylene glycol monostearate skin is a non-virally induced lesion. and 0.5% (w/w) oleyl alcohol): 20 4. The use according to 3, wherein the lesion is a Treated area: about 5 cm2 on the forehead lesion not caused by papilloma virus.

Treatment schedule: 5 times a week (each with 10 5. The use according to 4, wherein the lesion is not hours) 25 a lesion selected from the group consisting of hyper- plasia, Condyloma acuminata, warts and cervical in- Treatment period: 6 weeks tra-epithelial neoplasia.

Treatment progression: 6. The use according to 1, wherein the patient is a 30 human. Vafter about 13 days of treatment skin irritation of the treated area (more precisely treated areas 7. The use according to 1, wherein the cancerous afflicted by actinic keratoses) occurred lesion of the skin is an advanced tumor. V also an up-regulation of subclinical lesions occurred 35 8. The use according to 1, wherein the polyphenol V skin irritation ameliorated during further treat- is isolated from tea. ment V after 12 weeks of treatment actinic keratoses 9. The use according to 1, wherein the polyphenol have disappeared completely is extracted from a tea. 40 Example 2: 10. The use according to 9, wherein the tea is a green tea. [0065] Patient: 73 years old, male with actinic kera- toses known since about 15 years, multiply pre-treated; 11. The use according to 1, wherein the polyphenol [0066] The patient was treated with Polyphenon® E 45 is isolated from a tea extract. (15% ointment containing 35% (w/w) isopropyl myristate, 15% (w/w) catechol extract, 24.5% (w/w) petroleum jelly, 12. The use according to 1, wherein the polyphenol 20% (w/w) wax, 5% (w/w) propylene glycol monostearate is selected from the group consisting of catechol, and 0.5% (w/w) oleyl alcohol): catechol gallate, epicatechol, epicatechol gallate, 50 epigallocatechol, epigallocatechol gallate, gallo- Treated area: about 5 cm2 on the head catechol and/or gallocatechol gallate. Treatment schedule: 3 times a week Treatment period: 12 weeks 13. The use according to 1, wherein the polyphenol Treatment progression: has the general formula (I) 55 V after 3.5 weeks of treatment skin irritation of the treated area afflicted by actinic keratoses occurred (but less intense than that of the patient

9 17 EP 2 292 226 A2 18

5

10 15. The use according to 12, wherein the catechol is selected from the group consisting of of (+)-cate- chol, (-)-catechol, (+)-catechol gallate, (-)-catechol in which gallate, (+)-epicatechol, (-)-epicatechol, (+)-epicate- 15 R1, R2 and R 6 are independently from each other -H chol gallate, (-)-epicatechol gallate, (+)-epigallocate- or -OH, chol, (-)-epigallocatechol, (+)-epigallocatechol gal- R3 is -H or =O and late, (-)-epigallocatechol gallate, (+)-gallocatechol, R4 is independently from each other -H, -OH or a (-)-gallocatechol, (+)-gallocatechol gallate and/or group of the formula (III) (-)-gallocatechol gallate. 20 16. The use according to 1, wherein the polyphenol is present in the form of a mixture of polyphenols, in particular catechols, especially containing catechol, catechol gallate, epicatechol, epicatechol gallate, 25 epigallocatechol, epigallocatechol gallate, gallo- catechol and/or gallocatechol gallate, whereas the gallates of catechol, epicatechol, epigallocatechol or of gallocatechol are most preferred in the mixture of polyphenols. 30

R5 and R7 are independently from each other -H, 17. The use according to 16, wherein the mixture of -OH or -OCH3, and polyphenols is a tea extract. ----- optionally represents a bond 18. The use according to 17, wherein the tea extract 14. The method according to 12, wherein the cate- 35 is a green tea extract. chol has the general formula (II) 19. The use according to 17, wherein the mixture of polyphenols is selected from the group consisting of catechol, catechol gallate, epicatechol, epicatechol 40 gallate, epigallocatechol, epigallocatechol gallate, gallocatechol and/or gallocatechol gallate.

20. The use according to 19, wherein the catechols are selected from the group consisting of (-)-epicate- 45 chol, (-)-epicatechol gallate, (-)-epigallocatechol, (-)-epigallocatechol gallate, (+)-gallocatechol and/or in which (-)-gallocatechol gallate. R8 is -H or -OH, and R9 is -H or a group of the formula (III) 21. The use according to 19, wherein the catechols 50 are selected from the group consisting of about 2-20% (w/w) epicatechol, about 2-20% (w/w) epi- catechol gallate, about 1-25% (w/w) epigallocate- chol, about 40-75% (w/w) epigallocatechol gallate, about 0.05-5% (w/w) gallocatechol and/or about 55 0.5-20% (w/w) gallocatechol gallate.

22. The use according to 19, wherein the catechols are selected from the group consisting of about

10 19 EP 2 292 226 A2 20

10.8% (w/w) of epicatechol, about 6.5% (w/w) of ep- cision, Mohs micrographic surgery, radiation, proton icatechol gallate, about 9.2% (w/w) of epigallocate- therapy, chemotherapy, photodynamic therapy, cry- chol, about 54.8% (w/w) of epigallocatechol gallate osurgery, laser, immunotherapy, vaccine therapy and/or about 4.0% (w/w) of gallocatechol gallate. and/or biologic therapy. 5 23. The use according to 19, wherein the mixture 33. The use according to 32, wherein the chemo- contains about 10.8% (w/w) of (-)-epicatechol, about therapy is carried out with an agent selected from 6.5% (w/w) of (-)-epicatechol gallate, about 9.2% the group consisting of podophyllin, 5-fluorouracil, (w/w) of (-)-epigallocatechol, about 54.8% (w/w) of bleomycin, interferon, imiquimod, and mixtures (-)-epigallocatechol gallate and about 4.0% (w/w) of 10 thereof. (-)-gallocatechol gallate. 34. The use according to 32, wherein the radiation 24. The use according to 19, wherein the catechols is selected from the group consisting of X-ray radi- are selected from the group consisting of about ation and γ-radiation. 2-12% (w/w) epicatechol, about 4-15% (w/w) epi- 15 catechol gallate, about 1-8% (w/w) epigallocatechol, 35. The use according to 1 or 2, wherein the lesion about 60-68% (w/w) epigallocatechol gallate, about of the skin is selected from the group consisting of 0.05-1% (w/w) gallocatechol and/or about 1-7% skin cancer, cutaneous carcinoma, basal cell carci- (w/w) gallocatechol gallate. noma, squamous cell carcinoma, actinic keratosis, 20 solar keratosis, epithelioma, epithelial tumors, skin 25. The use according to 19, wherein the catechols neoplasm, Bowen’s disease, acanthoma, cancroid, are selected from the group consisting of about 5-8% cutaneous horn, hyperkeratosis, keratosis, mollus- (w/w) epicatechol,about 5-7% (w/w) epicatechol gal- cum contagiosum, lid tumors, xanthelasma, xantho- late, about 2-3% (w/w) epigallocatechol, about ma, fibroma, verucca senilis, seborrheic keratosis, 61-65% (w/w) epigallocatechol gallate and/or about 25 cheilocarcinoma, papillomatosis, penis carcinoma, 2-4% (w/w) of gallocatechol gallate. radiodermatitis, sailor’s skin, tar cancer, vaginal car- cinoma, vulvar cancer, erythroplasia queyrat and/or 26. The use according to 19, wherein the catechols carcinoma of the tongue, in particular actinic or solar are selected from the group consisting of about 5-8% keratosis and/or basal cell carcinoma. (w/w) epicatechol,about 5-6% (w/w) epicatechol gal- 30 late, about 6-8% (w/w) epigallocatechol, about 61-65% (w/w) epigallocatechol gallate and/or about Claims 2-4% (w/w) of gallocatechol gallate. 1. A pharmaceutically effective amount of a polyphenol 27. The use according to 1, wherein the polyphenol 35 for the treatment of a cancerous lesion of the skin of is combined with an additive. a patient.

28. The use according to 27, wherein the additive is 2. Polyphenol according to claim 1, wherein the can- selected from the group consisting of petroleum jelly, cerous lesion is a pre-cancerous lesion. wax, oleyl alcohol, propylene glycol monostearate, 40 propylene glycol monopalmitostearate and/or iso- 3. The polyphenol according to claim 1, wherein the propyl myristate. polyphenol is extracted from a green tea.

29. The use according to 1, wherein the polyphenol 4. The polyphenol according to claim 1, wherein the is administered topically. 45 polyphenol is selected from the group consisting of catechol, catechol gallate, epicatechol, epicatechol 30. The use according to 1, wherein the polyphenol gallate, epigallocatechol, epigallocatechol gallate, is contained in a carrier selected from the group con- gallocatechol and/or gallocatechol gallate. sisting of an emulsion, a gel, a cream and/or an oint- ment. 50 5. The polyphenol according to claim 1, wherein the polyphenol has the general formula (I) 31. The use according to 1, wherein the treatment of said lesions is combined with a different anticancer treatment. 55 32. The use according to 31, wherein the different anticancer treatment is selected from the group con- sisting of surgery, electrodessication, curettage, ex-

11 21 EP 2 292 226 A2 22

5

10

7. The polyphenol according to claim 4, wherein the catechol is selected from the group consisting of of in which 15 (+)-catechol, (-)-catechol, (+)-catechol gallate, R1, R2 and R 6 are independently from each other -H (-)-catechol gallate, (+)-epicatechol, (-)-epicatechol, or -OH, (+)-epicatechol gallate, (-)-epicatechol gallate, R3 is -H or =O and (+)-epigallocatechol, (-)-epigallocatechol, (+)-epi- R4 is independently from each other -H, -OH or a gallocatechol gallate, (-)-epigallocatechol gallate, group of the formula (III) 20 (+)-gallocatechol, (-)-gallocatechol, (+)-gallocate- chol gallate and/or (-)-gallocatechol gallate.

8. The polyphenol according to claim 1, wherein the polyphenol is present in the form of a mixture of 25 polyphenols, in particular catechols, especially con- taining catechol, catechol gallate, epicatechol, epi- catechol gallate, epigallocatechol, epigallocatechol gallate, gallocatechol and/or gallocatechol gallate, whereas the gallates of catechol, epicatechol, epi- 30 gallocatechol or of gallocatechol are most preferred in the mixture of polyphenols.

R5 and R7 are independently from each other -H, 9. The polyphenol according to claim 8, wherein the -OH or -OCH3, and mixture of polyphenols is selected from the group ----- optionally represents a bond 35 consisting of catechol, catechol gallate, epicatechol, epicatechol gallate, epigallocatechol, epigallocate- 6. The polyphenol according to claim 4, wherein the chol gallate, gallocatechol and/or gallocatechol gal- catechol has the general formula (II) late.

40 10. The polyphenol according to claim 9, wherein the catechols are selected from the group consisting of (-)-epicatechol, (-)-epicatechol gallate, (-)-epigallo- catechol, (-)-epigallocatechol gallate, (+)-gallocate- chol and/or (-)-gallocatechol gallate. 45 11. The polyphenol according to claim 9, wherein the catechols are selected from the group consisting of about 2-20% (w/w) epicatechol, about 2-20% (w/w) epicatechol gallate, about 1-25% (w/w) epigallocate- in which 50 chol, about 40-75% (w/w) epigallocatechol gallate, R8 is -H or -OH, and about 0.05-5% (w/w) gallocatechol and/or about R9 is -H or a group of the formula (III) 0.5-20% (w/w) gallocatechol gallate.

12. The polyphenol according to claim 1, wherein the 55 polyphenol is combined with an additive.

13. The polyphenol according to claim 12, wherein the additive is selected from the group consisting of pe-

12 23 EP 2 292 226 A2 24

troleum jelly, wax, oleyl alcohol, propylene glycol monostearate, propylene glycol monopalmitostear- ate and/or isopropyl myristate.

14. The polyphenol according to claim 1, wherein the 5 polyphenol is administered topically.

15. The polyphenol according to claims 1 to 14, wherein the lesion of the skin is selected from the group con- sisting of skin cancer, cutaneous carcinoma, basal 10 cell carcinoma, squamous cell carcinoma, actinic keratosis, solar keratosis, epithelioma, epithelial tu- mors, skin neoplasm, Bowen’s disease, acanthoma, cancroid, cutaneous horn, hyperkeratosis, kerato- sis, molluscum contagiosum, lid tumors, xanthelas- 15 ma, xanthoma, fibroma, verucca senilis, seborrheic keratosis, cheilocarcinoma, papillomatosis, penis carcinoma, radiodermatitis, sailor’s skin, tar cancer, vaginal carcinoma, vulvar cancer, erythroplasia queyrat and/or carcinoma of the tongue, in particular 20 actinic or solar keratosis and/or basal cell carcinoma.

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13 EP 2 292 226 A2

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 4613672 A [0021] • US 6096359 A [0021] • US 4673530 A [0021] • US 4248789 A [0021] • US 4913909 A [0021]

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