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(11) EP 2 481 747 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 01.08.2012 Bulletin 2012/31 C07K 1/00 (2006.01) A61K 31/498 (2006.01) A61P 5/24 (2006.01) A61K 9/00 (2006.01) (21) Application number: 12165603.7

(22) Date of filing: 21.07.2004

(84) Designated Contracting States: (72) Inventor: Scherer, Warren J. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Naples, FL 34119 (US) HU IE IT LI LU MC NL PL PT RO SE SI SK TR (74) Representative: Jansen, Cornelis Marinus (30) Priority: 23.07.2003 US 626037 Vereenigde Johan de Wittlaan 7 (62) Document number(s) of the earlier application(s) in 2517 JR Den Haag (NL) accordance with Art. 76 EPC: 04778941.7 / 1 789 433 Remarks: This application was filed on 26-04-2012 as a (71) Applicant: Galderma Pharma S.A. divisional application to the application mentioned 1000 Lausanne 30 Grey (CH) under INID code 62.

(54) Methods of treating cutaneous flushing using selective alpha-2-

(57) A composition comprising: at least one selective carrier, α2 adrenergic receptor selected from the group for use in treating cutaneous flushing in an individual, consisting of , , alpha-methyl wherein the composition is to be administered to said DOPA (methydopamine), amphetamine, methylpheni- individual via topical dermatological application in an date, , moxonidine, dexmedetomidine, mivaz- amount sufficient to prevent, reduce, ameliorate or inhib- erol, and (2-imidazolin-2-ylamino) quinoxaline deriva- it, cutaneous flushing. tives, which derivates are formed with an acidic group other than tartrate; and a dermatologically acceptable EP 2 481 747 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 481 747 A1 2

Description treatments that stabilize the contractile state of cutane- ous blood vessels would have a beneficial effect on this Cross Reference to Related Application symptom. Improvement and stabilization of vascular tone via a vasoconstrictive mechanism is the approach taken [0001] This application is a continuation of U.S. Appli- 5 by the instant disclosure. It appears that there are only cation Serial No. 10/626,037, filed July 23, 2003, which two prior art patent methods of influencing vascular tone is hereby incorporated by reference in its entirety, includ- and reducing facial flushing. These include topical appli- ing all formulae and references. cation of phytosphingosine (U.S. Published Application No. 2003/0068343) and nitric oxide synthetase inhibitors Field of the Invention 10 (WO 98/36730). Mechanistically, these differ greatly from the instantdisclosure. Sphingosines are lipids thatinduce [0002] The present invention relates to a method of in certain tissues via activity of specific treating, reducing, inhibiting, preventing and/or reversing cellular sphingosine receptors. Nitric oxide is a potent cutaneous facial flushing caused by abnormal, endog- regulatory vasodilator that is produced by vascular en- enously-induced vasomotor instability associated with, 15 dothelial cells. Inhibition of the enzyme that produces ni- but not limited to acne rosacea, menopause-associated tric oxide would therefore be expected to result in base- hot flashes, hot flashes resulting from orchiectomy or in- line vasoconstriction. However, the safety and tolerability gestion of substances capable of inducing a cutaneous of these compounds have not been established. Attempt- facial flushing reaction (e.g., alcohol, chocolate, spices) ed treatment methods for facial flushing that have been by topical dermatological application of an effective dose 20 published in the peer-reviewed medical literature have of a composition comprising at least one α2 adrenergic been limited to oral administration of the antihypertensive receptor agonist (such as a (2- imidazolin-2-ylamino) qui- medication, (Guarreraet al., 1982; Wilkin, noxaline derivative such as brimonidine tartrate) and a 1983). suitable carrier. [0006] Clonidine is an alpha α( ) adrenergic receptor 25 agonist that crosses the blood-brain barrier and acts di- Background of the Invention rectly on the central nervous system. The chemical name of clonidine is N-(2,6-dichlorophenyl)-4,5-dihydro-1H- [0003] Facial flushing is a symptom observed in med- imidazol-2-amine. Clonidine has affinity for both theα 1 ical conditions associated with vasomotor instability. Cu- and α2 subtypes of alpha adrenergic receptors. Tradi- taneous vasomotor instability is the term commonly used 30 tionally, clonidine has been used to treat uncontrolled in the medical arts to refer to involuntary dilatation and hypertension. Clonidine stimulates alpha adrenergic re- reactivity of subcutaneous blood vessels. The mecha- ceptors in the brainstem, resulting in reduced sympathet- nism of facial flushing involves involuntary dilation of sub- ic outflow that decreases renal vascular resistance, cutaneous arteries. The etiology underlying the initiation rate and . Because clonidine acts directly of facial flushing is unknown. There are essentially four 35 on the central nervous system, its use is associated with commonmedical conditions addressed by the instant dis- multiple systemic side effects, such as , heart closure in which facial flushing occurs. These include: block, hypotension, dizziness, dry mouth and depres- 1.) acne rosacea, 2.) postmenopausal hot flashes, 3.) sion. Some of the side effects may be life threatening. patients who are status post surgical orchiectomy, and [0007] For the purpose of patient convenience and de- 4.) flushing secondary to ingestion of food substances. 40 sire to maintain adequate blood levels of the drug to con- [0004] Acne rosacea is a chronic dermatological dis- trol hypertension, clonidine has been administered via ease of unknown cause characterized by facial flushing, transdermal patch (U.S. Patent No. 4,201,211). Howev- erythema, recurrent papules and pustules, superficial te- er, this transdermal delivery system for clonidine is simply langiectasias (dilations of previously existing small blood an alternate route of administration and does not alter its vessels) and rhinophymia (hypertrophy of the nose with 45 ability to affect the central nervous system or its mixed follicular dilation). The disorder is found mainly in fair- α1 and α2 adrenergic receptor kinetics. Topical clonidine skinned patients between 30 and 50 years of age. Wom- has also been proposed to aid in alleviating neuropathic en are more commonly affected than men and acne ro- pain syndromes such as diabetic neuropathy and post- sacea is a common disorder. Because these clinical herpetic neuralgia (U.S. Patent No. 6,534,048). Howev- signs, rosacea was originally thought to resemble the 50 er, the mechanism of this analgesic action may be sec- acne (acne vulgaris) typically encountered in teenagers, ondary to the release of endogenous enkephalin-like however, rosacea is now known to represent a separate substances by the central nervous system (Nakamura et and distinct dermatological condition, It is estimated that al., 1988). approximately 13 million Americans have acne rosacea. [0008] Research has shown that vasoconstriction of Alcohol, stress, spicy foods and temperature extremes 55 small, distal subcutaneous resistance arteries depends may exacerbate the condition. entirely on α2 adrenergic receptor stimulation (Chotani [0005] Facial flushing associated with rosacea is due et al., 2000; Nielson et al., 1989). Unfortunately, because to vasomotor instability of unknown etiology. Therefore, of its mixed α1 and α2 activity, oral dosages of clonidine

2 3 EP 2 481 747 A1 4 sufficient to produce peripheral cutaneous vasoconstric- agonist, such as the (2-imidazolin-2-ylamino) quinoxa- tion via α2 adrenergic receptor stimulation would also line derivative brimonidine tartrate, which is a highly ef- result in intolerable systemic side effects. Hot flashes are fective treatment for cutaneous facial flushing caused by sudden sensations of flushing andheat that some women vasomotor instability. experience when they are going through menopause. 5 [0012] One objective of the present invention involves Although their etiology is not completely understood, it local cutaneous application of an effective amount of at is thought that a decrease in the female hormone estro- least one α2 adrenergic receptor agonist with an ability gen leads to vasomotor instability. Symptoms include to act locally and inability to cross the blood- brain barrier redness and warmth of the skin of the face, neck and to treat facial flushing reactions caused by vasomotor 10 shoulders, pounding heartbeat and sweating. Hot flashes instability. In certain preferred embodiments, theα2 last from a few minutes to a half hour. Approximately 20% adrenergic receptor agonist is bromonidine tartrate. of women seek medical treatment for postmenopausal [0013] Thus, the instant disclosure describes a method symptoms associated with vasomotor instability. Similar of safely treating facial flushing in humans. This method symptoms are experienced by men with prostate cancer comprises administering a composition comprising an ef- 15 who undergo orchiectomy (surgical removal of the tes- fective amount of at least oneα 2 adrenergic receptor tes). Treatment of hot flashes requires oral estrogen re- agonist, for example, brimonidine tartrate, wherein the placement therapy which is thought to raise the core body α2 adrenergic receptor agonist is admixed with a derma- temperature sweating threshold (Freedman et al., 2002). tologically acceptable carrier or a pharmaceutically ac- However, many patients have relative or absolute con- ceptable carrier. This compound, due to its properties as 20 traindications to estrogen replacement therapy ( e.g., his- a highly specific, locally-acting α2 adrenergic receptor tory of breast cancer). These patients would benefit from agonist, acts to reduce cutaneous flushing via vasocon- a safe, locally-acting compound that alleviates facial striction of subcutaneous arteries. flushing. Although the exact etiology of hot flashes is un- known, the underlying physiological mechanism of facial Detailed Disclosure of the Invention flushing (dilation of subcutaneous arteries) is similar to 25 that observed with rosacea in that there is endogenously- [0014] The subject invention provides methods for the induced vasomotor instability. Treatment of the reactive treatment of flushing in an individual comprising the ad- cutaneous vascular bed with the (2-imidazolin-2-ylami- ministration of a composition comprising at least one se- no) quinoxaline derivative brimonidine tartrate would lective α2 adrenergic receptor agonist and a carrier in an 30 stimulate α2 adrenergic receptors, thus restoring vascu- amount sufficient to prevent, reduce, ameliorate, or in- lar tone and reversing or preventing the cutaneous flush- hibit facial flushing. In a preferred embodiment, brimoni- ing reaction. dine tartrate is an α2 adrenergic receptor agonist used [0009] It is known that patients with vasomotor insta- in the formulation of the compositions used in the subject bility are also susceptible to facial flushing following the invention. In various aspects of the subject invention, the ingestion of certain foods such as alcohol, chocolate, caf- 35 individual is a human. In other embodiments, the subject feine or spices. Flushing associated with ingested sub- invention treats facial flushing in individuals or humans. stances is primarily limited to the "blush area" of the mid [0015] Selective α2 adrenergic receptor agomsts suit- face (Wilkin, 1988). able for use in the subject invention include, and are not [0010] Topical brimonidine tartrate eye drops have limited to, guanabenz, guaniacine, alpha-methyl DOPA been FDA approved for the treatment of elevated intraoc- 40 (methydopamine), amphetamine, metllylphenidate, ular pressure. In addition to treating elevated intraocular loflexidine, moxonidine, dexmedetomidine, mivazerol, pressure, brimonidine tartrate eye drops have also been (2-imidazolin-2-ylamino) quinoxaline derivatives (includ- patented for treating neural injury secondary to glauco- ing, but not limited to, brimonidine tartrate). Brimonidine ma, retinitis pigmentosa and age related macular degen- tartrate is a quinoxaline derivative and quinoxaline deriv- 45 eration (U.S. Patent No. 6,194,415). Brimonidine tatrate atives having α2 receptor agonist activity were originally is known to have 10 fold moreα 2 adrenergic receptor suggested as therapeutic agents by U.S. Patent No. activity than clonidine (Burke et al., 1996) and because 4,029,792 which is hereby incorporated by reference in of its hydrophilic composition, is capable of acting locally its entirety. and is unable to cross the blood- brain barrier and there- [0016] The phrase "selective α2 adrenergic receptor fore, unable to directly influence the central nervous sys- 50 agonist(s)" is intended to convey an agonist (or agonists) tem (Chien et al., 1990). Toxicity studies have proven that are more selective for the α2 adrenergic receptor as brimonidine tartrate to be nontoxic and to have no onco- compared to the α1 adrenergic receptor. In certain em- genic or teratogenic activity (Walters, 1996). bodiments of the invention, "selective α2 adrenergic re- ceptor agonist(s)" are at least ten (10) to 1000-fold (or 55 Brief Summary of the Invention higher) more selective for the α2 adrenergic receptor than the α1 receptor. Other embodiments provide for "selec- [0011] The instant invention involves topical cutane- tive α2 adrenergic receptor agonist(s)" that are at least ous application of at least oneα 2 adrenergic receptor two-fold to 50-fold (or higher) more selective for the α2

3 5 EP 2 481 747 A1 6 adrenergic receptor as compared to clonidine (for exam- treatment of acne rosacea in addition to one or more α2 ple, brimonidine is 7-12 fold more selective for theα 2 adrenergic receptor agonists, such as the (2-imidazolin- adrenergic receptor than is clonidine). 2-ylamino) quinoxaline derivative brimonidine tartrate. [0017] For the treatment of facial flushing in humans, These additional compounds include, and are not limited one embodiment of the subject invention provides a (2- 5 to, antibacterial agents, anthelmintic agents, antiangio- imidazolin-2-ylamino) quinoxaline derivative, such as bri- genesis agents, steroidal anti-inflammatory agents, non- monidine tartrate admixed with a dermatologically ac- steroidal anti-inflammatory agents, antioxidants or deriv- ceptable carrier which is then administered topically in atives of retinoic acid, as well as halogens. Compositions accordance with the present invention to skin. Any suit- according to the subject invention can also further com- able, conventional, dermatologically acceptable carrier 10 prise aloe for skin protection a compound known to act may be employed. A carrier is dermatologically accept- as a sunscreen in addition to those components dis- able if it does not inhibit the effectiveness of the active cussed herein. As would be apparent to the skilled arti- compound(s) and it has substantially no long term or per- san, compositions used in the practice of the subject in- manent detrimental effect on the skin to which it is ad- vention, can have any combination of the components ministered. In various preferred embodiments, composi- 15 discussed herein. tions of the subject invention are topically administered [0022] While the present invention has been described to facial skin. in terms of various preferred embodiments, those of or- [0018] The compositions encompassed by this inven- dinary skill in the art will appreciate that various modifi- tion include formulations for topical application to the hu- cations, substitutions, omissions, and changes may be 20 man skin. For topical application, one or more α2 adren- made without departed from the spirit of the invention. ergic receptor agonists, such as (2- imidazolin-2-ylwnino) Accordingly, it is intended that the scope of the present quinoxaline derivatives (a non- Iimitmg example of which invention not be limited solely by the instant disclosure is brimonidine tartrate), may be formulated into any phar- and the scope of the following claims, including equiva- maceutical form normalcy employed for such an appli- lents thereof. cation, in particular in the form of aqueous, aqueous/al- 25 coholic or oily solutions, dispersions of lotion or serum Features of Parent Application type, aqueous anhydrous or lipophilic gels, emulsions of liquid or semi- liquid consistency of the milk type, obtained [0023] by dispersion of a fatty phase in an aqueous phase or conversely an aqueous phase in a fatty phase, or sus- 30 1. A method of treatingcutaneous flushing in humans pensions or emulsions of semi- sofid or solid consistency caused by abnormal, endogenously-induced vaso- of the cream or gel type, soaps or detergents, or alter- motor instability comprising administering, to said natively microemulsions, microcapsules, microparticles, human via topical dermatological application, a com- or vesicle dispersions of and/or non-ionic type. Among position comprising at least one selective α2 adren- additional alternative means for topical application of35 ergic receptor agonist admixed with a dermatologi- compositions accordingto the subject inventionare spray cally acceptable carrier, in an amount effective to pumps, aerosol dispersions, impregnated cosmeticfacial reduce, inhibit, reverse or prevent cutaneous facial masks, and impregnated cosmetic facial cloths or spong- flushing. es. These formulations may be produced by conventional techniques. 40 2. The method of feature 1, wherein the composition [0019] Preparation of the compositions comprising contains at least one (2-imidazolin-2-ylamino) qui- one or more α2 adrenergic receptor agonists, such as noxaline derivative. the (2-imidazolin-2-ylamino) quinoxaline derivative bri- monidine tartrate, admixed with dermatologically accept- 3. The method of feature 1, wherein the cutaneous ed carriers would also include standard acids, bases and 45 flushing is facial flushing and the flushing reaction is buffers including, but not limited to substances such as caused by acne rosacea. sodium hydroxide and lactic acid to adjust and optimize pH between approximately 6.0 and 8.5. 4. The method of feature 2, wherein the cutaneous [0020] Compositions of the subject invention can also flushing is facial flushing and the flushing reaction is further comprise standard dermatological preservatives 50 caused by acne rosacea. to prevent the growth of microorganisms. Such standard preservatives include substances such as benzoic acid, 5. The method of feature 1, wherein the cutaneous benzyl alcohol, phenoxyethanol and parabens. Appro- flushing is facial flushing and the flushing reaction is priate binding agents or other substances may be includ- caused by menopause-associated hot flashes. ed to alter the viscosity or color of the final preparation. 55 [0021] Compositions provided by the subject invention 6. The method of feature 2, wherein the cutaneous can also contain, in addition to the components dis- flushing is facial flushing and the flushing reaction is cussed supra, compounds known to be beneficial to the caused by menopause-associated hot flashes.

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7. The method of feature 1, wherein the cutaneous tion further comprises an agent, or combination of flushing is facial flushing and the flushing reaction is agents, selected from the group consisting of anti- the result of hot flashes following orchiectomy. bacterial agents, anthelmintic agents, antioxidant agents, steroidal anti-inflammatory agents, non- 8. The method of feature 2, wherein the cutaneous 5 steroidal anti-inflammatory agents, antiangiogenic flushing is facial flushing and the flushing reaction is agents, and derivatives of retinoic acid. the result of hot flashes following orchiectomy. 19. The method of feature 18, wherein the compo- 9. The method of feature 1, wherein the cutaneous sition further comprises: aloe; compounds that act flushing is facial flushing and the flushing reaction is 10 as sunscreens; or a combination of aloe and com- caused by ingestion of a substance capable of in- pounds that act as sunscreens. ducing cutaneous facial flushing selected from the group consisting of alcohol, chocolate, spice, flavor- 20. The method of feature 19, wherein the compo- enhancing additives and mono-sodium glutamate. sition further comprises a preservative. 15 10. The method of feature 2, wherein the cutaneous 21. The method of feature 20, wherein the compo- flushing is facial flushing and the flushing reaction is sition further comprises a halogen. caused by ingestion of a substance capable of in- ducing cutaneous facial flushing selected from the 22. A composition comprising at least one selective 20 group consisting of alcohol, chocolate, spice, flavor- α2 adrenergic receptor agonist admixed with a der- enhancing additives and mono-sodium glutamate. matologically acceptable carrier and one or more agents selected from the group consisting of anti- 11. The method of feature 2, wherein the composi- bacterial agents, anthelmintic agents, antioxidant tion further comprises an agent, or combination of agents, steroidal anti-inflammatory agents, non- agents, selected from the group consisting of anti- 25 steroidal anti-inflammatory agents, antiangiogenic bacterial agents, anthelmintic agents, antioxidant agents, derivatives of retinoic acid, aloe, compounds agents, steroidal anti-inflammatory agents, non- that act as sunscreens, a combination of aloe and steroidal anti-inflammatory agents, antiangiogenic compounds that act as sunscreens, preservatives, agents, and derivatives of retinoic acid. halogens and combinations of said agents. 30 12. The method of feature 1, wherein the composi- 23. The composition according to feature 22, where- tion further comprises an agent, or combination of in the selective α adrenergic receptor agonist is a agents, selected from the group consisting of anti- (2-imidazolin-2-ylamino) quinoxaline derivative. bacterial agents, anthelmintic agents, antioxidant agents, steroidal anti-inflammatory agents, non- 35 24. The composition according to feature 23, where- steroidal anti-inflammatory agents, antiangiogenic in said (2-imidazolin-2-ylamino) quinoxaline deriva- agents, and derivatives of retinoic acid,. tive is brimonidine tartrate.

13. The method according to feature 2, wherein said 25. The composition according to feature 23, where- at least one (2- imidazolin-2-ylamino) quinoxaline de- 40 in said at least one selective adrenergic receptor ag- rivative is brimonidine tartrate. onist is selected from the group consisting of gua- nabenz, guanfacine, alpha-methyl DOPA (methy- 14. The method of feature 2, wherein the composi- dopamine), amphetamine, methylphenidate, lofexi- tion further comprises: aloe; compounds that act as dine, moxonidine, dexmedetomidine, mivazerol, (2- sunscreens; or a combination of aloe and com-45 imidazolin-2-ylamino) quinoxaline derivatives, bri- pounds that act as sunscreens. monidine, and combinations thereof.

15. The method of feature 2, wherein the composi- 26. A method for the treatment of flushing in an in- tion further comprises a preservative. dividual comprising the administration of a compo- 50 sition comprising at least one selective α2 adrenergic 16. The method of feature 2, wherein the composi- receptor agonist and a carrier in an amount sufficient tion further comprises a halogen. to prevent, reduce, ameliorate, or inhibit facial flush- ing. 17. The method of feature 2, wherein the (2-imida- zolin-2-ylamino) quinoxaline derivative is combined 55 27. The method of feature 26, wherein said at least with an acidic group other than tartrate. one selective adrenergic receptor agonist is selected from the group consisting of guanabenz, guanfacine, 18. The method of feature 1, wherein the composi- alpha-methyl DOPA (methydopamine), ampheta-

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mine, methylphenidate, lofexidine, moxonidine, flushing reaction is caused by acne rosacea. dexmedetomidine, mivazerol, (2-imidazolin-2- ylamino) quinoxaline derivatives, brimonidine, and 4. The use or composition of claim 1 or claim 2, wherein combinations thereof. the cutaneous flushing is facial flushing and the 5 flushing reaction is caused by menopause- associat- 28. The method of feature 1, wherein said at least ed hot flashes. one selective adrenergic receptor agonist is selected from the group consisting of guanabenz, guanfacine, 5. The use or composition of claim 1 or claim 2, wherein alpha-methyl DOPA (methydopamine), ampheta- the cutaneous flushing is facial flushing and the mine, methylphenidate, lofexidine, moxonidine,10 flushing reaction is the result of hot flashes following dexmedetomidine, mivazerol, (2-imidazolin-2- orchiectomy. ylamino) quinoxaline derivatives, brimonidine, and combinations thereof. 6. The use or composition of claim 1 or claim 2, wherein the cutaneous flushing is facial flushing and the 15 flushing reaction is caused by ingestion of a sub- Claims stance capable of inducing cutaneous facial flushing selected from the group consisting of alcohol, choc- 1. Use of a composition comprising: olate, spice, flavor-enhancing additives and mono- sodium glutamate. 20 at least one selective α2 adrenergic receptor ag- onist selected from the group consisting of gua- 7. The use or composition for use according to claim 1 nabenz, guanfacine, alpha-methyl DOPA or claim 2, wherein the composition further compris- (methydopamine), amphetamine, methylpheni- es an agent, or combination of agents, selected from date, lofexidine, moxonidine, dexmedetomi- the group consisting of antibacterial agents, an- dine, mivazerol, and (2-imidazolin-2-ylamino) 25 thelmintic agents, antioxidant agents, steroidal anti- quinoxaline derivatives, which derivates are inflammatory agents, non- steroidal anti-inflammato- formed with an acidic group other than tartrate, ry agents, antiangiogenic agents, and derivatives of admixed with a dermatologically acceptable car- retinoic acid. rier for the manufacture of a medicament for treating 30 8. The use or composition for use according to claim cutaneous flushing in humans caused by abnor- 1, claim 2, or claim 7,wherein the composition further mal, endogenously-induced vasomotor instabil- comprises: aloe; compounds that act as suncreens; ity, whereby the composition is administered to or a combination of aloe and compounds that act as said human via topical dermatological applica- sunscreens. tion in an amount effective to reduce, inhibit, re- 35 verse or prevent cutaneous flushing. 9. The use or composition for use according to claim 1, claim 2, or claim 7, wherein the composition further 2. A composition comprising: comprises a preservative.

40 at least one selective α2 adrenergic receptor ag- 10. The use or composition for use according to claim onist selected from the group consisting of gua- 1, claim 2, or claim 7, wherein the composition further nabenz, guanfacine, alpha-methyl DOPA comprises a halogen. (methydopamine), amphetamine, methylpheni- date, lofexidine, moxonidine, dexmedetomi- 11. A composition comprising: dine, mivazerol, and (2-imidazolin-2-ylamino) 45 quinoxaline derivatives, which derivates are at least one selective α2 adrenergic receptor ag- formed with an acidic group other than tartrate, onist selected from the group consisting of gua- and nabenz, guanfacine, alpha-methyl DOPA a dermatologically acceptable carrier (methydopamine), amphetamine, methylpheni- for use in treating cutaneous flushing in an indi- 50 date, lofexidine, moxonidine, dexmedetomi- vidual, wherein the composition is to be admin- dine, mivazerol, and (2-imidazolin-2-ylamino) istered to said individual via topical dermatolog- quinoxaline derivatives, which derivates are ical application in an amount sufficient to pre- formed with an acidic group other than tartrate, vent, reduce, ameliorate or inhibit, cutaneous admixed with a dermatologically acceptable car- flushing. 55 rier and one or more agents selected from the group consisting of antibacterial agents, an- 3. The use or composition of claim 1 or claim 2, wherein thelmintic agents, antioxidant agents, steroidal the cutaneous flushing is facial flushing and the anti-inflammatory agents, non-steroidal anti-in-

6 11 EP 2 481 747 A1 12 flammatory agents, antiangiogenic agents, derivatives of retinoic acid, aloe, compounds that act as sunscreens, a combination of aloe and compounds that act as sunscreens, pre- servatives, and halogens. 5

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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 62603703 A [0001] • US 6534048 B [0007] • US 20030068343 A [0005] • US 6194415 B [0010] • WO 9836730 A [0005] • US 4029792 A [0015] • US 4201211 A [0007]

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