IL133760A

IL133760A - Composition for the treatment of dandruff

Info

Publication number: IL133760A
Application number: IL133760A
Authority: IL
Original assignee: Pharmaskin Ltd
Priority date: 1999-12-28
Filing date: 1999-12-28
Publication date: 2007-10-31
Also published as: AU2021601A; IL133760A0; WO2001047481A1

Description

Composition For The Treatment Of Dandruff Avi Dascalu, M.D., Ph.D Yoram Oron, Ph.D The present invention relates to a composition for the treatment of seborrheic dermatitis of the scalp (dandruff). Dandruff is a common disease involving a large amount of the population.

Organ function is totally dependent on an incessant proliferation process accompanied by a metabolic build-up and final apoptosis. The proliferation of cells is a continuous mitotic event, regulated by genetically derived forces and by environmental cellular inputs. More specifically, the cells respond to a myriad of inputs by selected biochemical transduction pathways. Therefore, a final common pathway exists in response to external hormones, cytokines, electrolytes, mechanical stimuli or specific chemicals, etc.

An imbalance of the cell multiplication process causes diseases. Especially, the skin may be affected by such imbalances, due to its unique structure and activity, which involve total cell turnover about every 50 days in the epidermis and a layer which matures without a direct vascular supply (Greaves and Shuster, eds. Springer Verlag 1989, Chapter 1 , pp. 14-21). The skin multiplication rate is controlled by its unique feeding on a fibroblast layer of cells in the dermis. An imbalance of this process, i.e. an accelerated cell turnover more than the normal rate, generates in skin an incomplete cell maturation process, and results in a thick stratum corneum which causes excessive cellular shedding, known in every day life as squames. Squames may be generated by hyperproliferative diseases, such as dandruff, which implies an increase of proliferation rate of cells (x 2-3). The exact pathophysiology of rapid multiplication of cells is unknown.

Innumerous medications have been tried for the remedy of dandruff.

A general postulation in the literature claimes that a colonization by a yeast, Pityrosporum Ovale, is responsible for the disease (Shuster, Blachford, R. Soc. Med. Publ. London, 1 1 1 :235-42, 1988). Antifungals such as ketoconazole, econazole, etc. have been used with limited success. A more recent view involves additional etiologies in the disease and suggests more therapeutic drug classes (Baran, Maibach, eds Martin Dunitz, 1994, pp 1 17-132). Keratolytics such as salicylic acid, resorcinol, alpha-hydroxy acids or selenium were used to dissolve the squames (scales), again with limited results. Similarly, antiproliferative agents, such as coal tar or zinc pirythione were used for the treatment of dandruff with a temporary relief, only.

Additional approaches have been tried, such as treatment by lithium succinate. Combination therapies have been used, i.e. the treatment with a combination of e.g. a keratolytic (selenium) and a cytotoxic (zinc pyrithione or coal tar) and an antifungal (ketoconazole) (PCT WO 9629045); or a keratolytic (salycilic acid) and an antifungal.

Zinc pyrithione: empirical formula: CioHi0N2O2S2Zn, name: bis(1 -hydroxy-2(1 H)-pyridinethionato) zinc or zinc, bis(2-pyridylthio)-N-oxide) and its derivatives are known as antiproliferative/cytotoxic agents, as described in USP Dl Volume I, Drug Information for the Health Care Professional, DE400, (Revised: 08/13/98); and piroctone olamine, empirical formula: C14H23 O2 · C^HyNO, name: 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-(1 H)pyridinone, 2-aminoethanol salt, or its derivatives, such as piroctone monoethanolamine, are cytotoxic, as well and were formerly used as preservatives and biocides.

It has thus been desirable to design a method and composition which can directly inhibit proliferation of the dermal layer, which is the real skin proliferation controller, to a greater extent than existing treatments. Such composition should cause the recovery of cells from their pathological hyperproliferative state and restore a normal multiplication rate. Since seborrheic dermatitis is also an inflammatory process, an additional cytotoxic agent, which possesses also anti-inflammatory attributes should be part of the composition.

It is known that bisabolol or its derivatives: Racemate, Levomenol, alpha-bisabolol, anymol, epi-form, etc. - empirical formula: Ci5H260, name: (R*.R*)-. alpha., 4-dimethyl-.alpha.-(4-methyl-3-pentenyl)-3-cyclohexene-1 -methanol, (synonym: 6-methyl-2-(4-methyl-3-cyclohexen-1-yl)-5-hepten-2-ol; 1-methyl-4-(1 ,5-dimethyl-1-hydroxyhex-4(5)-enyl) cyclohexen-1), an active ingredient of Chamomile extract, is an anti-inflammatory, anti-irritant ingredient and a hair lighter (D. Andre et al., Int. J. Cosmet. Sci. 13:137, 1991). It has been known that the addition of bisabolol to cells does not affect their proliferation. Unexpectedly it has beend discovered that the addition of bisabolol to cytotoxic agents converts the bisabolol into a cytotoxic agent. This has been shown by the inhibition of the fibroblast (dermal) layer in a proliferative assay. Thus, we found agents active on fibroblast layer which control proliferation and can further control immature keratinization and diminish squame generation. The final result should be regeneration of normal functioning to skin, slowing down of replication and transition to normal proliferation, which is desirable in the treatment of dandruff. 3A It is known from XP00216447 cosmetic hair preparations containing Piroctone olamine and water-soluble sulfur and/or UV absorber. More particularly said document describes use of Piroctone and Bisabolol in a formula which is common.

It is known from EP Patent Application No. 0158481 hair care compositions more specifically it describes use of Piroctone olamine and Zinc pyrithione inside formula which is common.

In both documents, no synergestic effect is shown of 3 other materials as in the present invention Piroctone olamine + Bisabolol + Zinc pyrithione . 4 The present invention thus consists in a composition for the treatment of seborrheic dermatitis of scalp (dandruff) comprising a mixture of bisabolol, one of its derivatives with zinc pyrithione and piroctone olamine and/or their derivatives. The bisabolol may be part of a Chamomile extract.

The composition according to the present invention comprises : 1. Bisabolol (either pure or racemic) , from 0.001-25 % (all percentages are indicated herein in w/w), preferably between 0.01-10 % and advantageously between 0.05-1.0 % by weight; or a chamomile extract, from 0.001-75 %, preferably between 0.01-25 % and advantageously between 0.1-5 % by weight; 2. Zinc pyrithione in a concentration from 0.001-20.0 %, preferably between 0.1-5 % and advantageously between 0.5-2% by weight; and 3. Piroctone olamine in a concentration from 0.001-20.0 %, preferably between 0.05-5 % and advantageously between 0.2-2% by weight.

The composition according to the present invention may be topically applied as such or internally ingested within a suitable carrier, solvent, emulgent, extract, a solution e.g. water, alcohol, an oil, a suspension; microemulsions, microcapsules, vesicles, etc.

The active agents may be formulated into various compositions, e.g. a lotion, a conditioner, a hair tonic, a shampoo, a lotion with conditioner, a gel, a styling gel, a mousse, a styling wax, a mask, an aerosol, a moisturizer, a powder, a perfume, a brilliantine, a pomade, a dye, a cream, an ointment, etc.

The composition according to the present invention might be formulated, e. g. as an internally ingested tablet, capsule, drops or suspension.

The above composition can be used alone or in conjunction with a pharmaceutical effective compound selected among: 1. Keratolytic agents such as salicylic acid, sulphur, resorcinol, selenium, alpha hydroxy-carboxylic acids, etc.; 2. Anti proliferatives, e.g. coal tar, selenium, etc.; 3. Antifungals, e.g. ciclopyroxolamine, azoles (such as ketoconazole, bifonazole), metronidazole, undecylenic acid and derivatives of the said compounds, etc.; 4. Antimicrobials, e.g. aluminium chloride, chlorothymol, hexamine, zinc salycilate, zinc sulphide, triclorocarban, triclosan, etc.; . Germicides, such as phenols, hydroxyquinolones, undecenoic acids, etc.; 6. Anti irritancy agents, such as triterpenes, poiyciclic polyenes or saponins, etc.; 7. Anti-inflammatory agents, e.g. cyclo-oxygenase inhibitors, panthenol, comilower extract, guaiazulene, etc.; 8. Sterols, e.g. medicated low (hydrocortisone), intermediate (mometasone) to high (betamethasone, dexamethasone); potency steroids, of plant origin, e.g. phytosterols such as glycyrrhizic acid and derivatives, etc.; 9. Hair nourishment agents, such as vitamins, e.g. tocopherol (Vitamin E) and its derivatives, Vitamin B6, vitamin C, biotin, pantothenic acid, Vitamin D and its derivatives; amino acids e.g. arginine, citrulline, ornithine, serine and methionine; organic acids, e.g. lactate or malate, minerals and metals, e.g. zinc and its derivatives, magnesium, aluminum, death sea minerals; eugenol, polyamines and antioxidants, etc.; 133760/2 6 . Lipid derivatives, e.g. mineral oil, vegetable oil, animal and synthetic oil, fatty alcohol, saturated and unsaturated fatty acids, waxes, squalene, etc.; 11. Refrigerants, e.g. menthols, camphor; 12. Herbal extracts which restore the skin natural protective factor ability, such as aloe vera, rosemary, tea tree oil or thyme, etc.; 13. Vasodilating compounds or nitric oxide donors, e.g. of natural source (arginine) or medicated (nitroprusside, sodium nitrite), etc.; and 14. Hair stimulating and /or hair invigorating agents, e.g. saw palmetto, diazoxide, glycirrhizic acid or 5 alpha reductase inhibitors, etc.

The amounts of said derivatives may be varied in accordance with the specific requirements.

The composition according to the present invention may be prepared by conventional methods, as becomes apparent from the Experiments given hereinafter.

The composition according to the present invention is suitably applied in portions of about 1 - 10 ml/daily from 1-7 times weekly, advantageously 5 ml/daily each other day.

The present invention consists also in the use of a composition according to the present invention for the treatment of humans and animals against seborrheic dermatitis. 7 Example 1 Fibroblast cells, the feeding layer of the skin, were exposed to the addition of bisabolol, piroctone olamine and zinc pyrithione. Bisabolol alone was not antiproliferative. Whenever bisabolol was added to cells previously treated with piroctone olamine and zinc pyrithione, the unexpected conversion of bisabolol into an antiproliferative agent was observed. a. Methodology Tetrazolium salt assay The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) colorimetric reaction is based on the uptake of tetrazolium salt exclusively by live cells and its reduction to a soluble violet (formazan) compound. The absorbance of formazan is proportional to the amount of active mitochondrial enzyme succinate-dehydrogenase of the cells and cell viability. Fibroblast 3T3 cells were seeded at 30000 cells/well in 96-well microtiter wells (Corning) and grown until confluence. The absorbance spectrum of MTT was determined by a diode array spectrophotometer (Hewlett Packard, 8452A). MTT exhibited peak absorbance at 560 nm and minimal readings beyond 620 nm, as previously shown. A microplate reader (Thermomax, Molecular Devices) was used to read absorbance at 550 nm with background subtraction at a reference absorbance of 650 nm at 25 EC (Methodology in Dascalu A, Peer A, Academic Radiology, 1 :140-145, 1994). 8 b. Experiment The experiments employed confluent cells which were loaded with 0.15 pg/ml of MTT and dark incubated at 37 0 C. Four hours later the media was removed by plate flipping and 100 μΙ of DMSO were added to each well in order to solubilize the formazan crystals. Results were expressed as compared to control values of untreated cells and each result consisted of three to six repeated measurements in at least two different experiments. Fibroblast cells were exposed to active ingredients at the indicated concentrations for about 4 hours prior to optical density readings. c. Results Both zinc pyrithione and piroctone olamine may cause antiproliferative and cytotoxic effects. First of all, the minimal concentration of these compounds, which does not cause a cytotoxic effect, has to be determined. Figure 1a demonstrates that addition of 0.2 pg/ml - 0.4 g pg/ml piroctone olamine doesn't cause any effects on cellular viability (a threefold concentration of 1.2 pg/ml caused a 10% decrease of cell viability, data not shown). Zinc pyrithione did not cause any cytotoxic effect at 0.2 Mg/ml, but at 0.4 pg/ml a 10 % decrease of viability was observed (Fig. 1b). Therefore, we employed a concentration of 0.2 pg/ml zinc pyrithione and 0.2 pg/rnl of piroctone olamine, which did not affect fibroblast viability (Fig. 1 c).

Addition of bisabolol at 1.0 % (Fig. 2) resulted in a small decrease of cellular viability which did not achieve any statistical significance [One Way Analysis of Variance, Multiple Comparison test (Student-Newman-Keuls)]. The same concentration of bisabolol was added to fibroblasts already treated with zinc pyrithione 0.2 g/ml and piroctone olamine 0.2 pg/ml (concentrations which do not 9 affect cell viability, as shown in Fig. 2). Surprisingly, a distinct cytotoxic effect on cells was observed (Fig. 2). It is shown that bisabolol addition decreased significantly the cell viability as compared to control untreated cells or cells treated by bisabolol solely (p<0.05, One Way Analysis of Variance, Multiple Comparison test of Student-Newman-Keuls).

It has thus been shown that bisabolol, a compound without a known cytotoxic effect, can reduce cellular viability of fibroblasts, provided the cells have been treated with additional agents. In order to prove this activity, one has to use innocent low concentrations of cytotoxic agents, which by themselves do not decrease cell viability.

In order to further consolidate this unexpected finding, a dose-response curve was performed. Figure 3 demonstrates that at a concentration of 0.05% Bisabolol, no effects on cell viability can be seen. However, above this concentration, at 0.1 , 0.4 and 1.0 %, an increased damage to cellular viability is observed (Figure 3, p<0.05).

The present invention will be illustrated by the following Examples without being restricted by them. Said Examples use composition being active in the field of dandruff treatment.

EXAMPLE II Exemplary formula for topical formulation of a composition according to the present invention in a shampoo based formula.

Ingredient % by Weight Zinc pyrithione ( 48% Dispersion) 1.50 Piroctone olamine 0.60 Bisabolol 0.25 Magnesium aluminium silicate 1.20 Tetrasodium pyrophosphate 0.06 Deionized water 51.39 Sodium laureth sulfate 40.00 Myristamide DEA 5.00 Citric Acid ( for pH adjustment to 6-7 ) q.s.

Preservative; Color ; Fragrance q.s. 11 EXAMPLE III Exemplary formula for topical formulation of a composition according to the present invention in a creamy based formula.

EXAMPLE IV Exemplary formula of a composition according to the topical formulation according to the present invention in a shampoo formula with a hair invigorating compound: Example V Antidandruff cream-shampoo formula of a composition according to the present invention for normal and dry-hair dispensed by pump hair lotion. 12 Example VI Antidandruff lotion-shampoo formula of a composition according to the present invention for normal and dry-hair dispensed by pump hair lotion.

INGREDIENT % FUNCTION w/w Part 1 PEG-5-cethet-10 phosphate (crodafos SG) 2.00 Anionic surfactant Perfume 0.50 Fragrance Sodium lauryl ether sulfate 28% 30.00 Anionic surfactant Bisaboloi 0.50 Active ingredient Triclosan 0.50 Preservative Part II Aqua 50.00 Solvent.vehicle Cocoamidopropyl betaine 12.00 Amphoteric surfactant Piroctone-olamine 1.00 Active ingredient Part III Zinc pyrithione 48% dispersion 2.10 Active ingredient Citric Acid q.s. pH-adjustment Aqua q.s. to 100 13 Example VII Antidandruff cream-shampoo formula of a composition according to the present invention for normal and oily-hair dispensed by pump hair lotion INGREDIENT % FUNCTION w/w PART 1 Acrylate/steareth 20 metacrylate copolimer 3.00 Anionic polymer, Thickener Triethanolamine lauryl sulfate 40% 24.25 Anionic surfactant Sodium lauroyl sarcosinate 30% 10.00 High-foaming anionic surfactant C12-15 alkyl lactate 1.00 Foam booster, thickening agent Piroctone-olamine 1.00 Active ingredient Aqua 50.00 Solvent, Carrier PART II Bisabolol 0.75 Active ingredient Tocopheryl acetate 0.10 Antioxidant Triclosan 0.50 Preservative Zinc pyrithione 48% dispersion 2.10 Active ingredient Perfume 0.50 Fragrance Citric Acid q.s. pH-adjustment Sodium chloride q.s. Thickener Aqua Up to Solvent, Carrier 100 14 Example VIII Antidandruff cream for scalp and hair-care mask formula of a composition according to the present invention for oily and damaged-hair, dispensed by pump hair lotion.

INGREDIENT % FUNCTION w/w Part 1 Aqua q.s. Solvent, vehicle up to 100 Propylene glycol 2.00 Cosolvent Part INVENTIVE IMPROVEMENT Isostearyl neopentanoate 4.00 Non greasy emollient Polyquaternium - 2 1.00 Conditioner, hair protector Isodecyl isononanoate 1.50 Non greasy emollient Cetearyl alcohol (and) ceteareth-20 4.00 Emulgator Cetearyl alcohol 6.00 Fatty alcohol Lactate myristyl 1.00 Emulgator Piroctone-olamine 1.00 Active ingredient Part III Hydrolysed keratin 0.50 Hair protector Part IV Bisabolol 0.50 Active ingredient Zinc pyrithione 48% dispersion 2.10 Active ingredient Triethanolamine 99% q.s. pH - controler Propylene glycol (and) diazolidinyl urea (and) 0.3 Preservative Methyl paraben (and) propyl paraben Perfume 0.50 Fragrance Example IX Antidandruff cream for scalp mask formula of a composition according to the present invention for dry and damaged-hair, dispensed by pump hair lotion.

INGREDIENT % FUNCTION w/w Part 1 Glyceryl stearate (and) PEG-100 stearate 7.00 Emulsifier Cetearyl alcohol 6.00 Fatty alcohol Wheat(triticum vulgare)germ oil 4.00 Natural vegetal triglyceride Coconut(cocos nucifera) oil 5.00 Natural vegetal triglyceride Mineral oil 7.00 Emollient Piroctone-olamine 1.00 Active ingredient Part INVENTIVE IMPROVEMENT Aqua q.s.u Solvent, vehicle p to 100 Part III Dimethicone (and) laureth-8 (and) 4.00 Hair protector succinoglycan Hydroxypropyltrimonium hydrolyzed wheat 0.50 Conditioner protein Propylene glycol (and) diazolidinyl urea (and) 0.20 Preservative methyl paraben (and) propyl paraben Zinc pyrithione 48% dispersed 2.10 Active ingredient Bisabolol 0.50 Active ingredient Citric Acid 50 % solution q.s. pH-controler Perfume 0.50 Fragrance

Claims

133760/2

1. A composition for the treatment of seborrheic dermatis of scalp (dandruff) comprising a mixture of bisabolol, one of its derivatives with zinc pyrithione and piroctone olamine and/or their derivatives;

2. A composition according to Claim 1 , which comprises 0.001 - 20% of zinc pyrithione;

3. A composition according to Claim 1 or 2, which comprises 0.02 - 20% of piroctone olamine;

4. A composition according to any of Claims 1 to 3, which comprises 0.001 - 25% of bisabolol;

5. A composition according to Claim 4 wherein the bisabolol is part of a chamomile extract;

6. A composition according to any of claims 1 to 5 which comprises one or more pharmaceutical effective compounds;

7. A composition according to claim 6 whereis said pharmaceutical compound is selected among keratolytic agents; anti proliferatives; antifungals; antimicrobials; germicides; anti irritancy agents; anti-inflammatory agents; sterols; hair nourishment agents; lipid derivatives; refrigerants; herbal extracts; vasodilating compounds; nitric oxide donors and hair stimulating and/or hair invigorating agents. 17

8. A composition according to claims 6 or 7 wherein the keratolytic agents are selected among salicylic acid, sulphur, resorcinol, selenium and alpha hydroxy-carboxylic acid;

9. A composition according any of claims 6 to 8 wherein the anti proliferative is selected among coal tar and selenium;

10. A composition according any of claims 6 to 9 wherein the antifungal is selected among cyclopyroxolamine, azoles (e.g. ketoconazole, bifonazole), metronidazole, undecylenic acid and derivatives of the said compounds;

1. A composition according any of claims 6 to 10 wherein the antimicrobial is selected among aluminium chloride, chlorothymol, hexamine, zinc salycilate, zinc sulfide, trichlorocarban and triclosan;

12. A composition according any of claims 6 to 11 wherein the germicide is selected among phenols, hydroxyquinolones and undecenoic acids;

13. A composition according any of claims 6 to 12 whereas the irritancy agent is selected among triterpenes, polyciclic polyenes and saponins;

14. A composition according any of claims 6 to 13 whereas the anti-inflammatory agent is selected among cyclo-oxygenase inhibitors; panthenol; cumilar extract and guaiazulene.

15. A composition according any of claims 6 to 14 whereas the sterol is selected among medicated low (hydrocortisone), intermediate (mometasone) to high (betamethasone, dexamethasone) potency steroids, and potency steroids of plant origin, e.g. phytosterols such as glycyrrhizic acid and derivatives; 133760/2 18

16. A composition according to any of claims 6 to 15 whereas the hair nourishment agent is selected among vitamins, e.g. tocopherol (Vitamin E) and its derivatives, Vitamin B6, vitamin C, biotin, pantothenic acid, Vitamin D and its derivatives; amino acids e.g. arginine, citrulline, ornithine, serine and methionine; organic acids, e.g. lactate or malate, minerals and metals, e.g. zinc and its derivatives, magnesium, aluminum, death sea minerals; eugenol, polyamines and antioxidants;

17. A composition according to any of claims 6 to 16 whereas the lipid derivative is selected among mineral oil, vegetable oil, animal and synthetic oil, fatty alcohol, saturated and unsaturated fatty acids, waxes and squalene;

18. A composition according to any of claims 6 to 17 wherein the refrigerant is selected among menthols and camphor;

19. A composition according to any of claims 6 to 18 wherein the herbal extract is selected among aloe vera, rosemary, tea tree oil and thyme;

20. A composition according to any of claims 6 to 19 wherein vasodilating compounds and nitric oxide donors are selected among natural source (arginine) or medicated (nitroprusside, sodium nitrite);

21. A composition according to any of claims 6 to 20 wherein hair stimulating and hair invigorating agents are selected among saw palmetto, diazoxide, glycirrhizic acid or 5 alpha reductase inhibitors. FOR T! j A PP LICANT