Therapeutic Anti-Fungal Nail Preparation Therapeutische Antifungale Zubereitung Für Nägel Preparation Antifongique Therapeutique Pour Ongles

Europäisches Patentamt *EP001130964B1* (19) European Patent Office

Office européen des brevets (11) EP 1 130 964 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61P 31/10, A61K 31/20, of the grant of the patent: A61K 31/22, A61K 31/27, 09.11.2005 Bulletin 2005/45 A61K 31/415, A61K 31/44, (21) Application number: 99960362.4 A61K 31/47, A61K 31/495, A61K 31/505, A61K 31/71, (22) Date of filing: 15.11.1999 A61K 47/10, A61K 47/20

(86) International application number: PCT/US1999/027053

(87) International publication number: WO 2000/028821 (25.05.2000 Gazette 2000/21)

(54) THERAPEUTIC ANTI-FUNGAL NAIL PREPARATION THERAPEUTISCHE ANTIFUNGALE ZUBEREITUNG FÜR NÄGEL PREPARATION ANTIFONGIQUE THERAPEUTIQUE POUR ONGLES

(84) Designated Contracting States: (56) References cited: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU EP-A- 0 270 316 WO-A-93/11734 MC NL PT SE US-A- 5 612 324 US-A- 5 767 161 US-A- 5 814 305 (30) Priority: 16.11.1998 US 193073 • SCOTT E M ET AL: "Demonstration of synergy (43) Date of publication of application: with fluconazole and either ibuprofen, sodium 12.09.2001 Bulletin 2001/37 salicylate, or propylparaben against Candida albicans in vitro." ANTIMICROBIAL AGENTS (73) Proprietor: Astan, Inc. AND CHEMOTHERAPY, (1995 DEC) 39 (12) Birmingham, AL 35242 (US) 2610-4. , XP002196358 • TARIQ V N ET AL: "Use of decimal assay for (72) Inventor: REEVES, Stanley, Forrest additivity to demonstrate synergy in pair Demopolis, AL 36723 (US) combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro." (74) Representative: Elsy, David et al ANTIMICROBIAL AGENTS AND Withers & Rogers LLP CHEMOTHERAPY, (1995 DEC) 39 (12) 2615-9. , Goldings House, XP002196359 2 Hays Lane • SANYAL ET AL.: LETTERS IN APPLIED London SE1 2HW (GB) MICROBIOLOGY, vol. 17, 1993, pages 109-111, XP001057670 • STUETTGEN G ET AL: "BIO AVAILABILITY SKIN PENETRATION AND NAIL PENETRATION OF TOPICALLY APPLIED ANTI MYCOTICS" MYKOSEN, vol. 25, no. 2, 1982, pages 74-80, XP001068847 ISSN: 0027-5557

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 130 964 B1

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Description months) application of topical fungicidal creams and/or solutions in combination with systemic fungal treatment Technical Field drugs such as griseofulvin, terbinafine, and itraconazole. US 5814305 discloses that hydrophilic penetration [0001] The present invention relates generally to ther- 5 agents improve the penetration of antifungal agents apeutic preparations using the combination of ibuprofen through the nails. Some of the systemic treatments have and dimethyl sulfoxide ("DMSO") as a transport mech- undesirable side effects such as nausea, headache, anism to deliver active agents to infected areas. In par- photosensitivity, gastrointestinal intolerance, elevated ticular, the present invention relates to therapeutic prep- liver enzymes, and undesirable drug interactions, mak- arations using the combination of ibuprofen and DMSO 10 ing the process of eradication difficult and troublesome. to deliver anti-fungal agents to infected areas relatively [0006] It is also noted that systemic fungal treatments inaccessible to conventional therapeutic compounds. are expensive. A treatment program using terbinafine tablets (250mg) can cost over $600.00 and a therapy Background Art using itraconazole can cost between $600.00 and 15 $1200.00. Conversely, the instant invention contem- [0002] Infections on the exterior of the human body plates a non-systemic treatment program costing under are caused by a variety of micro-organisms, including $50.00. bacteria, fungi, and molds. Many micro-organisms living [0007] Part of the difficulty of quickly curing Ony- on or within the body are beneficial, but others multiply chomycosis is the inability to deliver effective anti-fungal rapidly and may form infections if left untreated. Some 20 agents to the pathogenically active areas such that all organisms such as microscopic plants or fungi can live of the pathogenic fungus is eradicated. Without full erad- on the skin and obtain nourishment from dead tissues ication, reoccurrence is likely necessitating a new cycle such as hair, nails, and outer skin layers. When fungi of combined topical and/or systemic treatments, with the growing on the body grows out of control, an infection aforementioned systemic effects. Treatment is compli- can result with detrimental effects to living tissue. In ad- 25 cated by the fact that the cutaneous nail shell is not eas- dition, fungal infections are communicable and individ- ily penetrated and treatments of infected areas often re- uals who frequent swimming pools, gyms, shower quire thinning of the nail to allow better penetration of rooms, and other humid and/or wet environments are anti-fungal agents. The nail acts as a protective barrier susceptible to being infected with various types of fungal under which fungus can grow unhindered and even acts infections as other infected individuals visit these public 30 as a vessel for spreading the disease. Current topical areas. anti-fungal ointments and solutions used to treat Ony- [0003] One class of external fungi is Onychomycosis, chomycosis do not penetrate in to nail bed easily and commonly referred to as "nail fungus." Onychomycosis tend to leave some portion of the fungus alive after treat- is an infection of the nail (i.e. unguis) and nail bed ment causing reoccurrence of the disease. Heretofore, caused by pathogenic fungi, among other micro-organ- 35 the medical industry has not produced a topical treat- isms, and while not life threatening the disease can ment having the necessary chemical properties to effec- cause chronic discomfort and embarrassment. The dis- tively pass through the hard cutaneous nail shell and ease attacks the nails and their growth centers making penetrate into the Nail bed for rapid and complete de- them appear cracked, yellow, and highly disfigured. In struction of the fungal infection. acute cases, Onychomycosis can cause the nail to be- 40 [0008] Therefore, there is a need for a topical solution come thick and yellow in color, making it vulnerable to that quickly and thoroughly penetrates the nail shell, un- easy damage and from which subungual hemorrhages derlying nail bed, and surrounding nail tissue to deliver can result. an effective anti-fungal agent that will kill the causes of [0004] Onychomycosis is caused by a variety of mi- Onychomycosis. cro-organisms such as dermatophytes, yeast, and 45 molds. However, the majority of Onychomycosis cases Disclosure of Invention are caused by fungi such as Trichophyton rubrum, Tri- chophyton mentagrophytes, Trichophyton tonsurans, [0009] It is the object of the present invention to pro- and Epidermophyton floccosum. Once these micro-or- vide a topical solution containing effective antifungal ganisms establish subcutaneous growth, eradication 50 agents that will penetrate the hard cutaneous shell to kill with current over the counter treatment is difficult and the cause of Onychomycosis. reoccurrences of the disease can be costly and time [0010] A further object of the present invention is to consuming. provide a method of making the penetrating topical so- [0005] In recent years Onychomycosis has spread to lution. a higher percentage of adults due, in part, to its conta- 55 [0011] An even further object of the present invention gious nature and the lack of effective medications that is to provide the use of the topical solution according to can quickly cure the disease once established within the the present invention for the manufacture of a medica- nail bed. Current treatments include long term (3-9 ment, for a therapeutic treatment procedure for curing

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Onychomycosis without the advent of systemic drugs. c. from 10 to 80% by volume of a polyglycol base [0012] In summary, the invention provides a combina- into which said agent and said ibuprofen are dis- tion of an anti-fungal agent with combination of ibupro- solved; and fen and DMSO in an anhydrous solution of polyglycol. d. from 10 to 80% solution DMSO mixed with said [0013] The invention provides a topical solution effec- 5 polyglycol base and in an inverse proportion by vol- tive in inhibiting the growth of micro-organisms causing ume with said polyglycol base. Onychomycosis, consisting essentially of: And: a. an antifungal agent for killing micro-organisms [0017] A topical solution according to the invention, causing Onychomycosis; 10 consisting essentially of: b. ibuprofen; c. a polyglycol base into which said agent and said a. an antifungal agent selected from Miconazole, ibuprofen are dissolved; and Clotrimazole, Tioconazole, Nystatin, Terconazole, d. a solution of DMSO mixed with said polyglycol Butoconazole Nitrate, Unecylenic Acid, Clioquinol, base. 15 Ciclopirox Olamine, Econazole Nitrate, Triacetin, Tolnaftate, Flucytosine, and Ketoconazole; [0014] The invention also provides b. ibuprofen; a pharmaceutical composition for enhancing pen- c. a polyglycol base into which said agent and said etration of a pharmaceutically active antifungal sub- ibuprofen are dissolved; and stance, comprising a topical solution according to the 20 d. a solution of DMSO mixture with said polyglycol invention, consisting essentially of: base for use in the manufacture of a medicament to treat nail fungus. a. an antifungal agent selected from Miconazol, Clotrimazole, Tioconazole, Nystatin, Terconazole, [0018] The combination of Butoconazole Nitrate, Unecylenic Acid, Clioquinol, 25 ibuprofen and DMSO acts as a delivery vehicle so Ciclopirox Olamine, Econazole Nitrate, Triacetin, that active anti-fungal agents such as Miconazole, can Tolnaftate, Flucytosine, and Ketoconazole; be delivered directly to fungal infected areas under and b. ibuprofen; around the nail. The Miconazole and ibuprofen/DMSO c. a polyglycol base into which said agent and said combination are dissolved in a viscous solution of poly- ibuprofen are dissolved; 30 glycol so that the combined ingredients may be applied And directly to the affected nails in a topical solution. The d. a solution of DMSO mixed with said polyglycol therapeutic solution is created by dissolving the Mico- base. nazole in a portion of the polyglycol until dissolution takes place, dissolving the ibuprofen in the DMSO until [0015] The invention also provides a 35 dissolution takes place, combining the two liquids, and Pharmaceutical composition for enhancing pene- adding the balance of the polyglycol until the desired tration of a therapeutic agent through unguis, compris- volume is reached. ing a topical solution according to the invention, consist- [0019] The therapeutic solution is preferably created ing essentially of: by a method comprising the steps of: 40 a. an antifungal agent for killing said micro-organ- a. heating and maintaining 40 ml of Polyglycol liquid isms causing Onychomycosis; at 45° C; b. ibuprofen for enhancing efficacy of said antifun- b. slowly stirring in 4 grams of Miconazole into said gal agent; heated Polyglycol until dissolved; c. a poly-glycol base into which said antifungal 45 c. adding 4 grams of ibuprofen to 40 ml. of 99% pure agent and said ibuprofen are dissolved; and DMSO liquid and stirring until dissolved; d. a solution of DMSO mixed with said poly-glycol d. combining the two solutions; base for enhancing penetration of said antifungal e. adding additional polyglycol to the combination agent into said unguis. solution to bring it to a total volume of 100 ml; and 50 f. allowing said solution to cool to room temperature [0016] The invention also provides a while stirring until all ingredients are uniform. composition for enhancing transdermal and tran- scutinel penetration of a pharmaceutically active sub- Repeated applications of the resulting solution on Ony- stance, comprising a topical solution according to the chomycosis infected nails over a period of 12-16 weeks invention, consisting essentially of: 55 yields an 85% to 90% satisfactory result rate without augmenting the topical treatments with systemic drugs. a. from 1 to 30% by volume of an antifungal agent; Most versions of the preferred solution may be sold b. from 1 to 40% by volume of ibuprofen; over-the-counter and should cost far less than current

3 5 EP 1 130 964 B1 6 methods of Onychomycosis eradication. talline powder with a slight odor which has for some time [0020] Other features and objects and advantages of been known as an anti-inflammatory. When ibuprofen is the present invention will become apparent from a read- compounded into a 40% by volume polyglycol solution ing of the following description. at 4% by volume amounts, delivery of anti-fungal agents 5 into a subcutinal fungus infection is faster than without Best Mode for Carrying Out the Invention ibuprofen. The exact reason for this is unknown, but the studies have shown that ibuprofen can cause ossifica- [0021] Using DMSO to assist with delivery of chemi- tion to occur in some forms of human tissue. Other anti- cals into the blood and tissue is well known. However, inflammatory agents besides ibuprofen well known in use of the combination of ibuprofen and DMSO to de- 10 the art are suspected of also improving the efficacy of liver anti-fungal agents through and under nail structure the anti-fungal agent. has been heretofore unknown. [0027] Polyglycol 300 is a viscous, mostly clear solu- [0022] In February of 1997, the inventor combined tion which is used as an anhydrous base for the inven- several therapeutic agents with DMSO and conducted tion. Polyglycol 300 is superior as a solution base be- experimental trials on human subjects to ascertain the 15 cause it is nonirritating, it has a low order of toxicity in potential for a therapeutic anti-fungal solution and treat- human tissue, it is soluble in most organic solvents, and ment for Onychomycosis. The results were surprising, is clear and non-staining. Furthermore, Polyglycol 300 with satisfactory result rates as high as 85-90% after a has viscous properties which allows better retention of twelve (12) week period of treatment, and without sys- the invention on infected areas, such as a nail when ap- temic drug therapy. In addition, anti-fungal results were 20 plied, thereby improving the dosage volume to infected seen as early as two weeks after application in some areas. subjects. [0028] Although several types of anti-fungal agents [0023] After subsequent experimental trials in which may be used in the instant invention, one agent Mico- various ingredient concentrations were tried and after nazole USP performs well to kill Onychomycosis. Mico- further variations in compounding techniques were un- 25 nazole USP (1-[2-(2,4-dichloraphenyl)-2-[(2,4-dichlora- dertaken, a topical therapeutic solution emerged that phenyl) Medthoxyl] ethyl]-1h-imidazole mononitrate; al- has the necessary penetrating characteristics to cure so known by the trade name Monistat™) is a white crys- Onychomycosis. talline powder that has been used as a primary agent in [0024] DMSO (sometimes referred to chemically as anti-fungal preparations. The inventor found that a 4% 30 CH3(SO)) is a controversial substance having well solution of Miconazole is sufficient to kill the fungi in known solvent properties. A wide range of primary phar- Onychomycosis when used in a nail penetrating bases. macological actions of DMSO have also been docu- Other anti-fungal agents effective in fighting the fungi mented in laboratory studies such as: membrane trans- causing Onychomycosis and suitable for use in the port, anti-inflammation, analgesia, bacteriostasis, non- present invention are: Clotrimazole, Tioconazole, Nys- specific enhancement of resistance to bacteria, vasodi- 35 tatin, Terconazole, Butoconazole Nitrate, Unecylenic lation, muscle relaxation, and reduction in serum cho- Acid, Clioquinol, Ciclopirox Olamine, Econazole Nitrate, lesterol. While the actual mechanism of penetration en- Triacetin, Tolnaftate, Flucytosine, and Ketoconazole. hancement is not precisely known (some studies indi- [0029] A preferred solution embodying the elements cate that increased pedicle flap circulation and hista- of the invention for producing a 100ml quantity contains mine liberation are causes), DMSO can act as a carrier 40 4 grams of ibuprofen USP, 40ml of DMSO, 4 grams of of substances into the body for non-ionized molecules Miconazole USP,and 100ml (q.s.) of polyglycol 300MW, of low molecular weight. Studies have also shown that NF liquid. To compound the preferred solution, measure DMSO increases the permeability of the stratum out (sifting is recommended) 4 grams of Miconazole and comeum by increasing its water content. warm 40ml of polyglycol in a beaker to 45°C (a temper- [0025] Some studies indicate that solutions of 90% 45 ature range of 40-50°C is satisfactory, but 45°C is opti- DMSO (by volume) are more effective as a transport mum). A magnetic stirrer should be employed to facili- carrier than solutions using less than or more than 90%. tate the mixing of ingredients and a temperature of 45°C However, clinical trials using experimental versions of should be maintained in the beaker until all ingredients the invention show that using a 40% solution of DMSO have been combined. Slowly add the Miconazole to the provides superior absorption and carrier properties for 50 polyglycol and let stir until all powder is dissolved. Meas- anti-fungal agents and anti-inflammatories. In particular, ure out 40ml of DMSO (99% pure) and 4 grams of ibu- the combination of Polyglycol 300 MW (molecular profen. Add the ibuprofen to the DMSO with stirring and weight), ibuprofen USP (U.S. Pharmacopoeia Stand- allow all of the powder to dissolve. Add the DMSO/ibu- ard), and DMSO (99% purity used at 40% volume) re- profen solution to the Miconazole/polyglycol solution sults in an effective carrier for anti-fungal agents such 55 with stirring. Add enough polyglycol to the mixture to as Miconazole and Clotrimazole. bring it to a total volume of 100ml. Allow the solution to [0026] Ibuprofen USP [(Ch3)2ChCh2Ch(Ch3COOH)], stir for 15 minutes and then remove the heat source. also known by the trade name Motrin™ is a white crys- The resultant solution will have 4% ibuprofen, 40% DM-

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SO, 4% Miconazole, by volume in the polyglycol base. topical solution contains 40% by volume DMSO. Once the solution reaches room temperature, it may be transferred into holding bottles. 6. A topical solution as recited in claim 1, wherein said [0030] To ensure the strength and the stability of the antifungal agent is between 1-30% by volume of invention solution, the above procedure should be fol- 5 said solution. lowed. For example, Miconazole is insoluble in some liquids, and hence adding it to warmed polyglycol facili- 7. A topical solution as recited in claim 1, wherein said tates the dissolution of Miconazole more quickly. Using antifungal agent is Miconazol. a different mixing procedure may prevent proper dissolution of the ingredient thereby weakening the solution. 10 8. A pharmaceutical composition for enhancing pene- Also, ibuprofen should be added to the DMSO to quick- tration of a pharmaceutically active antifungal sub- en the dissolution process. stance, consisting of a topical solution as recited in [0031] In order to kill pathogenic micro-organisms liv- claim 2. ing in an infected nail, a periodic application regime using the preferred solution is required. Nails infected with 15 9. A pharmaceutical composition for enhancing pene- Onychomycosis should be cleaned and washed, and al- tration of a therapeutic agent through unguis, com- lowed to dry. The solution is then to be applied liberally prising a topical solution as recited in claim 1, con- to the infected area and all parts of the nail, including sisting essentially of: the cuticle. The solution is left to air dry directly onto the infected nail. The application procedure should be re- 20 a. an antifungal agent for killing said micro-or- peated 3 times a day for twelve weeks, depending on ganisms causing Onychomycosis; the severity of the infection. A 12 week application of the b. ibuprofen for enhancing efficacy of said an- invention can yield up to a 85-90% satisfactory result tifungal agent; rate in most treatments. Also, the solution can be used c. a polyglycol base into which said antifungal against most types of fungi causing Onychomycosis and 25 agent and ibuprofen are dissolved; and may be purchased over the counter (according to d. a solution of DMSO mixed with said polygly- present Food and Drug Administration guidelines). col base for enhancing penetration of said antifungal agent into said unguis.

Claims 30 10. A composition for enhancing transdermal and tran- scutinel penetration of a pharmaceutically active 1. A topical solution effective in inhibiting the growth substance, comprising a topical solution as recited of micro-organisms causing Onychomycosis, con- in claim 1, consisting of: sisting essentially of: 35 a. from 1 to 30% by volume of an antifungal a. an antifungal agent for killing micro-organ- agent; isms causing Onychomycosis; b. from 1 to 40% by volume of ibuprofen; b. ibuprofen; c. from 10 to 80% by volume of a polyglycol c. a polyglycol base into which said agent and base into which said agent and said ibuprofen said ibuprofen are dissolved; 40 are dissolved; and and d. from 10 to 80% solution of DMSO mixed with d. a solution of DMSO mixed with said polygly- said polyglycol base and in an inverse propor- col base. tion by volume with said polyglycol base.

2. A topical solution as recited in claim 1, wherein said 45 11. A method of making a therapeutic solution for inhib- antifungal agent is selected from Miconazol, Clot- iting the growth of micro-organisms causing Ony- rimazole, Tioconazole, Nystatin, Tercondazole, Bu- chomycosis, comprising the steps of: toconazole Nitrate, Unecylenic Acid, Clioquinol, Ciclopirox Olamine, Econazole Nitrate, Triacetin, a. heating and maintaining 40 ml of polyglycol Tolnaftate, Flucytosine, and Ketoconazole. 50 liquid at 45° C; b. slowly stirring in 4 grams of Miconazoi into 3. A topical solution as recited in claim 2 wherein said said heated polyglycol until dissolved; ibuprofen is 4% by volume. c. adding 4 grams of ibuprofen to 40 ml of 99% pure DMSO liquid and stirring until dissolved; 4. A topical solution as recited in claim 2, wherein said 55 d. combining the two solutions; polyglycol is of the molecular weight of 300. e. adding additional polyglycol to the combination solution to bring it to a total volume of 100 5. A topical solution as recited in claim 1, wherein said ml; and

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f. allowing said solution to cool to room temper- delt. ature while stirring until all ingredients are uniform. 8. Pharmazeutische Zusammensetzung zur Verbes- serung der Penetration einer pharmazeutisch akti- 12. The method as recited in claim 11, wherein said Mi- 5 ven Substanz, bestehend aus einer topischen Lö- conazol is sifted prior to combining with said heated sung nach Anspruch 2. polyglycol base. 9. Pharmazeutische Zusammensetzung zur Verbes- 13. The method as recited in claim 11, wherein said serung der Penetration durch Unguis, enthaltend method of making a therapeutic solution includes 10 eine topische Lösung nach Anspruch 1, bestehend the additional step of filtering said solution after said im wesentlichen aus: cooling step. a. einem antimykotischen Mittel zur Abtötung 14. The method as recited in claim 11, wherein said step von Onychomykose hervorrufenden Mikroor- of stirring in Miconazol includes simultaneously 15 ganismen, adding ibuprofen to a desired level. b. Ibuprofen zur Verstärkung der Wirksamkeit des antimykotischen Mittels, 15. A topical solution as recited in claim 2 for use in the c. einer Polyglycolbasis, in der das Mittel und manufacture of a medicament to treat nail fungus. Ibuprofen gelöst werden, und 20 d. einer Lösung aus DMSO gemischt mit der Polyglycolbasis zur Verbesserung der Penetra- Patentansprüche tion des antimykotischen Mittels in Unguis.

1. Topische Lösung, wirksam zur Inhibierung des 10. Zusammensetzung zur Verbesserung transderma- Wachstums von Onychomykose hervorrufenden 25 ler und transkutaner Penetration einer pharmazeu- Mikroorganismen, im wesentlichen bestehend aus: tisch aktiven Substanz, enthaltend eine topische Lösung nach Anspruch 1, bestehend: a. einem antimykotischen Mittel zur Abtötung von Onychomykose hervorrufenden Mikroor- a. zu 1 bis 30 Vol.-% aus einem antimykoti- ganismen, 30 schen Mittel, b. Ibuprofen, b. zu 1 bis 40 Vol.-% aus Ibuprofen, c. einer Polyglycolbasis, in der das Mittel und c. zu 1 bis 80 Vol.-% aus einer Polyglycolbasis, Ibuprofen gelöst werden, und in der das Mittel und Ibuprofen gelöst werden, d. einer Lösung aus DMSO gemischt mit der und Polyglycolbasis. 35 d. zu 1 bis 80 Vol.-% aus einer Lösung aus DM- SO gemischt mit der Polyglycolbasis und im 2. Topische Lösung nach Anspruch 1, wobei das an- umgekehrten Volumenverhältnis zur Polygly- timykotische Mittel aus Miconazol, Clotrimazol, Tio- colbasis. conazol, Nystatin, Tercondazol, Butoconazol-Ni- trat, Undecylensäure, Clioquinol, Ciclopirox-Ola- 40 11. Verfahren zur Herstellung einer therapeutischen min, Econazol-Nitrat, Triacetin, Tolnaftat, Flucyto- Lösung zur Inhibierung des Wachstums von Ony- sin und Ketoconazol ausgewählt ist. chomykose hervorrufenden Mikroorganismen, be- inhaltend die Schritte: 3. TopischeLösung nach Anspruch 2, wobei Ibuprofen zu 4 Vol.-% vorliegt. 45 a. Aufheizen und Halten von 40 ml Polygly- colflüssigkeit bei 45°C, 4. Topische Lösung nach Anspruch 2, wobei Polygly- b. langsames Einrühren von 4 g Miconazol in col ein Molekulargewicht von 300 hat. das erwärmte Polyglycol bis zur Lösung, c. Zugabe von 4 g Ibuprofen in 40 ml 99%-rei- 5. Topische Lösung nach Anspruch 1, wobei die topi- 50 ner DMSO-Flüssigkeit und Rühren bis zur Lö- sche Lösung 40 Vol.-% DMSO enthält. sung, d. Vereinigen der beiden Lösungen, 6. Topische Lösung nach Anspruch 1, wobei das an- e. Zugabe von zusätzlichem Polyglycol zu der timykotische Mittel zu 1-30 Vol.-% in der Lösung vereinigten Lösung, um sie auf ein Gesamtvo- vorliegt. 55 lumen von 100 ml zu bringen, Abkühlenlassen der Lösung auf Zimmertempe- 7. Topische Lösung nach Anspruch 1, wobei es sich ratur unter Rühren, bis alle Inhaltsstoffe homo- bei dem antimykotischen Mittel um Miconazol han- gen sind.

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12. Verfahren nach Anspruch 11, wobei Miconazol vor 8. Composition pharmaceutique améliorant la péné- dem Vereinigen mit der erhitzten Polyglykolbasis tration d'une substance antifongique pharmaceuti- gesiebt wird. quement active, consistant en une solution topique selon la revendication 2. 13. Verfahren nach Anspruch 11, wobei das Verfahren 5 zur Herstellung einer therapeutischen Lösung den 9. Composition pharmaceutique pour améliorer la pé- zusätzlichen Schritt beinhaltet, die Lösung nach nétration d'un agent thérapeutique dans les ongles dem Kühlschritt zu filtrieren. comprenant une solution topique selon la revendication 1 consistant essentiellement en : 14. Verfahren nach Anspruch 11, wobei der Einrühr- 10 schritt in Miconazol die gleichzeitige Zugabe von (a) un agent antifongique pour tuer lesdits mi- Ibuprofen auf einen gewünschten Anteil beinhaltet. cro-organismes provoquant l'onychomycose ; (b) de l'ibuprofène ; 15. Topische Lösung nach Anspruch 2 zur Verwendung (c) une base de polyglycol dans laquelle ledit bei der Herstellung eines Medikamentes zur Be- 15 agent et ledit ibuprofène sont dissous ; et handlung von Nagelpilz. (d) une solution de DMSO mélangée avec ladite base de polyglycol pour améliorer la péné- tration d'un agent antifongique dans ledit ongle. Revendications 20 10. Composition pour améliorer la pénétration trans- 1. Solution topique efficace dans l'inhibition de la dermique et transcutanée d'une substance phar- croissance de micro-organismes provoquant l'ony- maceutiquement active comprenant une solution chomycose consistant essentiellement en : topique selon la revendication 1, consistant en :

(a) un agent antifongique pour tuer des micro- 25 (a) de 1 à 30 % en volume d'un agent organismes provoquant l'onychomycose ; antifongique ; (b) de l'ibuprofène ; (b) de 1 à 40 % en volume d'ibuprofène ; (c) une base de polyglycol dans laquelle ledit (c) de 10 à 80 % en volume d'une base de po- agent et ledit ibuprofène sont dissous et lyglycol dans lequel ledit agent et ledit ibupro- (d) une solution de DMSO mélangée avec une 30 fène sont dissous ; et base de polyglycol. (d) de 10 à 80 % de solution de DMSO mélan- gée avec ladite base de polyglycol et dans une 2. Solution topique selon la revendication 1, dans la- proportion inverse en volume rapport à ladite quelle l'agent antifongique est choisi parmi le mico- base de polyglycol. nazole, le clotrimazole, le tioconazole, la nystatine, 35 le tercondazole, le nitrate de butoconazole et l'acide 11. Procédé pour la préparation d'une solution théra- undécylénique, le clioquinole, l'olamine de ciclopi- peutique permettant d'inhiber la croissance des mi- rox, le nitrate d'éconazole, la triacétine, le tolnafta- cro-organismes provoquant l'onychomycose com- te, la flucytosine et le kétoconazole. prenant les étapes consistant à 40 3. Solution topique selon la revendication 2, dans la- (a) chauffer et maintenir 40 ml de liquide de po- quelle ledit ibuprofène représente 4 % en volume. lyglycol à 45°C; (b) agiter lentement 4 g de miconazol dans ledit 4. Solution topique selon la revendication 2, dans la- polyglycol jusqu'à dissolution ; quelle ledit polyglycol présente un poids moléculai- 45 (c) ajouter 4 g d'ibuprofène à 40 ml de liquide re de 300. de DMSO pur à 99 % et à agiter jusqu'à dissolution ; 5. Solution topique selon la revendication 1, dans la- (d) combiner les deux solutions ; quelle la solution topique contient 40 % en poids de (e) l'addition de polyglycol supplémentaire à DMSO. 50 une solution de combinaison pour l'amener à un total en volume de 100 ml ; et 6. Solution topique selon la revendication 1, dans la- (f) de permettre à ladite solution de refroidir à quelle l'agent antifongique s'inscrit entre 1 et 30 % température ambiante sous agitation jusqu'à en volume de ladite solution. ce que l'ensemble des ingrédients soient uni- 55 formes. 7. Solution topique selon la revendication 1, dans laquelle ledit agent fongique est le miconazole. 12. Procédé selon la revendication 11, dans lequel ledit miconazol est dérivé avant de combiner une base

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de polyglycol chauffée.

13. Procédé selon la revendication 11, dans lequel ledit procédé de préparation de la solution thérapeutique comprend l'étape supplémentaire de filtration de la- 5 dite solution après ladite étape de refroidissement.

14. Procédé selon la revendication 11, dans lequel ladite étape d'agitation dans du miconazol comprend l'ajout simultané d'ibuprofène à un niveau désiré. 10

15. Solution topique selon la revendication 2 destinée à une utilisation dans la préparation d'un médica- ment pour traiter les champignons des ongles. 15