CN101262848B - Antifungal composition - Google Patents
Antifungal composition Download PDFInfo
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- CN101262848B CN101262848B CN2006800333959A CN200680033395A CN101262848B CN 101262848 B CN101262848 B CN 101262848B CN 2006800333959 A CN2006800333959 A CN 2006800333959A CN 200680033395 A CN200680033395 A CN 200680033395A CN 101262848 B CN101262848 B CN 101262848B
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Abstract
The invention provides a topical liquid antifungal composition containing an antifungal agent, a film-forming agent and a solvent. The composition is applied on the infected skin area to form a film that delivers the active agent. The invention also provides a method for treating a fungal infection on the skin by applying the topical antifungal composition that forms a film on the skin.
Description
The present invention relates to have the local medicine composition of antifungal activity and the method for the treatment of fungal infection.
Dermatophytes is the fungus that can cause skin infection.These organisms reside in the keratin tissue, and cause fungal infection.For example the symptom of the cutaneous fungal infection of tinea pedis is to be feature with the infringement between toe, and this infringement also may expand to the outer surface and the vola of foot.The modal S﹠S in infected place is rubescent, pruritus and decortication, and described infection is can be contagious, and may recur.Described organism can infect by following manner: directly contact with infected host (human or animal), perhaps for example directly or indirectly contact with the skin that strips off that infects or the floor of hair, hair brush, medicated clothing, furniture, towel and cloak room on the comb.When skin has too high the prestoring during damage of causing of cicatrix (scares) for example, burn, walking (marching), temperature and humidity, will increase infectious susceptibility.
The existing at present local medicine composition that is designed for the treatment cutaneous fungal infection.These topical compositions for example can get with ointment, ointment, powder, solution and spray form commerce, and will use their every days 1 time or twice, continue 1-4 week or longer, to treat described infection.Because the therapeutic scheme of these compositionss need continue to surpass thoughtful several weeks, therefore, be very difficult according to above-mentioned therapeutic scheme with the treatment that hits pay dirk fully, the treatment premature termination is very general.
Another form of sending pharmacy activity component is the film forming liquid compositions.The nail enamel composition that liquid is dispelled the wart compositions and is used for the treatment of tinea unguium is the example of this based composition.These compositionss are applied to the infected zone repeatedly, with treatment institute chance problem.For example, this type of the treatment tinea unguium compositions must be applied to infected zone, then before said composition can be used once more with its removal.In a very long time, periodically carry out medication repeatedly and remove operation, with treatment tinea unguium.Although these film-forming compositions can not need use every day, be obedient to this therapeutic regimen and be not easy.
Extremely need to have efficient and the easy antifungal composition of therapeutic regimen, described therapeutic regimen can be obedient at an easy rate.
Summary of the invention
The invention provides the localized liquid antifungal composition, said composition comprises antifungal drug film former and solvent.Said composition is applied on the skin of infection,, and, just can obtains at least 50% mycology cure rate at the infected zone a drug with a formation skim.The present invention also provides the method for treatment cutaneous fungal infection, and this method comprises: use topical anti-fungal composition, form film on skin, and film was kept 48 hours on skin at least.More particularly, the invention provides the method for treatment cutaneous fungal infection, this method comprises that the local application film-forming composition is to form the step of a skim in the skin infection zone.Said composition comprises: antifungal drug, and this antifungal drug is selected from imidazoles, triazole type or propylamine; Film forming polymer, this film forming polymer are selected from acrylate polymer, acrylate copolymer, alkyl olefinic acid, alkyl olefinic acid ester copolymer, amide/olefinic acid, amide/olefinic acid copolymer, polyvinyl acetate, polyvinylpyrrolidone, vinyl pyrrolidone-vinyl acetate co-polymer, hydroxy alkyl cellulose and alkylcellulose; And solvent, this solvent is selected from the mixture of ethanol, isopropyl alcohol, acetone, ethyl acetate and water and one or more above-mentioned solvents.
The cutaneous fungal infection of tinea pedis, tinea corporis, tinea cruris and tinea capitis is evident in efficacy to compositions among the present invention to for example treating, and only needs 1 medication usually.Although described compositions only medication once can take effect, it repeatedly can be applied to the skin infection zone.As used herein, term " skin " refers to the health outer surface except fingernail and cornea.As used herein, term " mycology cure rate " refers to not have at test under microscope the percent of the sample of visible mycology evidence.
Detailed Description Of The Invention
The invention provides the unit-dose composition that is used for the treatment of cutaneous fungal infection, said composition can make treatment become simple.In addition, said composition is evident in efficacy curing or treating in the cutaneous fungal infection.The significant curative effect of single-dose regimen and said composition makes the treatment infectious disease become and be obedient to easily easily.Said composition contains film former, antifungal drug and solvent, with its preparation,, and kept at least 48 hours so that it can adhere on the skin, and preferably at least 60 hours, more preferably at least 72 hours, although the small part film can come off or wear and tear in the meantime.Have now found that the therapeutic effect that pharmaceutical composition a drug of the present invention obtains is equivalent to or is better than present available OTC (over-the-counter) antifungal medicine in strict accordance with the therapeutic effect in treatment 1-4 week of therapeutic regimen repeatedly.
Be applicable to that antifungal drug of the present invention comprises: imidazoles, triazole type, propylamine and composition thereof.Suitable imidazoles comprises: miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, Sertaconazole, sulconazole, thiabendazole and tioconazole (tiaconazole).Preferred miconazole, ketoconazole and clotrimazole, more preferably clotrimazole.Suitable triazole type comprises: fluconazol, itraconazole, ravuconazole and posaconazole.Suitable propylamine comprises: terbinafine, amorolfine, naftifine and butenafine.Wherein, preferably terbinafine and butenafine, and terbinafine is preferred.All above-mentioned antifungal drugs can be the form of its pharmaceutically active salt.Suitable salt form be exemplified as hydrochlorate, lactate and ascorbate forms.Particularly preferred antifungal drug is propylamine and salt thereof, and terbinafine and terbinafine HCl are preferred.Described compositions comprises 0.5%～30%w/w, preferred 0.75%～20%w/w, more preferably 0.9%～15%w/w, the antifungal drug of 1%～10%w/w most preferably.A kind of ideal especially embodiment of the present invention comprises 0.9%～1.2%w/w, preferred 0.95%～1.15%w/w, more preferably 0.97%～1.125%w/w, the terbinafine of 1%w/w most preferably.
Be applicable to that film former of the present invention comprises hydrophilic and hydrophobic film-forming polymers, when being applied in this film forming polymer on the skin, can form a skim.The film forming polymer that contains capacity in the said composition, so that it can form a skim when being applied on the skin, it can comprise the film forming polymer up to 50%w/w.Be ideally, film forming polymer forms film on skin, and this film sticks on the skin securely so that it keeps the time of one section necessity on skin, even stand conventional health also can be like this during the cleaning frequency.In a word, film former is applied on the skin with solvent, treat solvent evaporates after, film former just forms film on skin.Suitable hydrophobic polymer comprises: acrylate polymer, acrylate copolymer, alkyl olefinic acid, alkyl olefin(e) acid ester copolymer, amide/olefinic acid, amide/olefinic acid copolymer and polyvinyl acetate.Preferred hydrophobic polymer comprises octyl acrylamide, octylacrylamide acrylate copolymer, octylacrylamide acrylate copolymer, methacrylic acid aminoalkyl ester copolymer, ammonium methacrylate copolymer, polyvinyl acetate and alkyl acrylate methylmethacrylate copolymer.Suitable hydrophilic polymer comprises: polyvinylpyrrolidone, vinyl pyrrolidone-vinyl acetate co-polymer, hydroxy alkyl cellulose and alkylcellulose.Preferred hydrophilic comprises: hydroxypropyl cellulose, hydroxypropyl methyl fiber and polyvinylpyrrolidone.It is ideal not only having contained hydrophilic polymer but also contained hydrophobic polymer in compositions.As embodiment preferred, the amount of hydrophilic polymer is 0.05%～30%w/w of amount of composition, preferred 0.5%～10%w/w, more preferably 1%～5%w/w; The amount of hydrophobic polymer is 0.05～30%w/w of amount of composition, preferred 1%～10%w/w, more preferably 3%～7%w/w.Wherein, contain the octylacrylamide acrylate copolymer of 4%～6%w/w and the hydroxypropyl cellulose of 2%～3%w/w in the exemplary ideal composition.Octylacrylamide acrylate copolymer is that commerce can get, and for example commodity DERMACRYL by name, and hydroxypropyl cellulose also is that commerce can get, for example commodity KLUCEL by name.
Compositions also contains solvent in addition.Appropriate solvent can be aqueous solvent, organic solvent or their mixture.Organic solvent be those physiologically acceptable and with compositions in medicine and the compatible organic solvent of other compositions (comprising film forming polymer).Appropriate solvent comprises: ethanol, isopropyl alcohol, acetoneand ethyl acetate.Preferred solvent is the mixture of ethanol and ethanol and water.In most cases the amount of water will be lower than the amount of solvent.Typical water/solvent ratios is lower than 1: 3.But in some cases, the amount of water can surpass the amount of solvent.The ratio of the two at most can be to 2.5: 1.Solvent is used for dissolving or each composition of mixed suspension composition, and when being applied to compositions on the skin, solvent will vapor away, thereby compositions forms adherent film on skin.
Compositions among the present invention can contain other composition that improves said composition.These compositions comprise: plasticizer, film modifier, surfactant, penetration enhancers, coloring agent, antioxidant, chelating agent and UV absorbent.Suitable plasticizer comprises: bialkyl ortho phthalate (for example dibutyl phthalate), hydroxy fatty acid oils (for example Oleum Ricini), triglyceride and silicone oil.Film modifier can change over the character of membrane polymer, can improve its application feature especially, for example hardness after the solvent evaporates and the elasticity on skin.Suitable film modifier comprises: acrylate, aryl sulfonic acid amides-formaldehyde, cellulose derivative or polyamide.Suitable surfactant can help each composition solubilising.It comprises: polyethylene glycol alkyl ether (for example can get with trade name BRIJ).Suitable penetration enhancers comprises: pyrroles, dimethyl sulfoxide, unsaturated fatty alcohol, surfactant and propylene glycol.
In addition, compositions can also comprise other pharmacy activity component, comprises anti-inflammatory drug.Suitable anti-inflammatory drug comprises: steroidal class, for example hydrocortisone, cortisone, dexamethasone, fluocinolone acetonide, triamcinolone, medrysone, prednisolone, flurandrenolide (nurandrenolide), prednisone, halcinonidedcorten, methylprednisolone, flurandrenolide, prednisone, halcinonidedcorten, methylprednisolone, fludrocortisone, corticosterone, paramethasone and betamethasone; NSAID (non-steroidal anti-inflammatory drug), for example ibuprofen, diclofenac, naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen, ketoprofen, suprofen, indomethacin, sulfasalazine, piroxicam and aspirin.Particularly suitable is hydrocortisone, diclofenac, indomethacin and their salt in these anti-inflammatory agents.Add that anti-inflammatory drug can improve quickly and mycotic various symptom is followed in treatment, for example scratch where it itches, erythema, vesicle formation, burning sensation or be full of cracks.
Another embodiment of the invention is characterized as: pharmaceutical composition comprises 0.75%～20%w/w terbinafine or its pharmaceutical salts, 0.05%～30%w/w hydroxypropyl cellulose, 1%～10%w/w octyl acrylamide acrylate polymer and solvent, and described solvent is selected from ethanol, isopropyl alcohol, acetoneand ethyl acetate.Wherein especially preferred is the pharmaceutical composition that comprises plasticizer in addition, and described plasticizer is selected from bialkyl ortho phthalate, hydroxy fatty acid oils, triglyceride and silicone oil.
Compositions is applied to by the skin area of fungal infection, infects with treatment.Described compositions is evident in efficacy to the treatment cutaneous fungal infection, and above-mentioned cutaneous fungal infection comprises tinea pedis, tinea corporis, tinea cruris and tinea capitis.Compositions is applied to infected skin area, and makes the solvent evaporates of compositions.Along with the volatilization of solvent, compositions forms film on skin, closely contacts with skin, and active medicine directly is delivered to the infected zone.The mycology cure rate of described compositions single-dose treatment is at least 50%, preferably is at least 60%, more preferably is at least 70%, most preferably is at least 80%.Treatment 6 weeks of back, the skin infection zone is cultivated and microscopy, negative findings is defined as healing, and determines the mycology cure rate with this.
Further illustrate compositions of the present invention with the following examples.
Embodiment 1
96% ethanol of 1.13% (w/w) Terbinafine hydrochloride, 5% octylacrylamide acrylate copolymer (Dermacryl 79), 5% medium chain triglyceride (Miglycol 812) and 2.5% hydroxypropyl cellulose (Klucel MF) and 86.37% is mixed, and preparation comprises the fluid composition of 1% terbinafine.Content by improving terbinafine in proportion also reduces ethanol content, prepares 5% terbinafine compositions and 10% terbinafine compositions.By increasing other composition in the compositions in proportion, also can prepare the placebo that does not have active medicine.
Recruitment suffers from the patient of tinea pedis between toe, is divided into 4 groups: 1% compositions group has 107 patients, and 5% compositions group has 99 patients, and 10% compositions group has 95 patients, and placebo group has 45 patients.The fungal species of identifying in patient's culture comprises: trichophyton (T.rubrum), alpha fungus (T.mentagrophytes) and acrothesium floccosum (E.floccosum).By applying said compositions, make it cover four about 1.5 centimeters in interdigit, vola and sufficient side, each patient is carried out one-time treatment with one of above-mentioned four kinds of compositionss.The patient skin infected zone by direct examination, cultivation inspection and clinical sign and symptom, is checked during 6 weeks in the treatment back.Researcher adopts 4 minutes grading system, to comprise erythema, peel, scratch where it itches, the pus born of the same parents, vesicle forms and the symptom of incrustation is marked.With effective treatment rate in the 6th week (its by microscopy and cultivate check be negative define) as the effectiveness terminal point.Check the definition mycology healing that is negative with microscopy with cultivating.
The mycology cure rate in the 6th week is very high in all three groups with the terbinafine combination treatment, and the cure rate in the placebo group, from table 1 as seen.
Table 1
The success rate result who shows in the table 1 shows that the present composition has high healing curative effect, also has high healing curative effect even contain the compositions of low concentration antifungal activity composition.Only during a drug, the mycology cure rate of described compositions is 80%～83%.The cure rate of the present composition is similar to the cure rate that present commercially available OTC (over-the-counter) antifungal medicine reaches, but these commercial anti fungus medicines need be in strict accordance with the therapeutic regimen administration of regulation, be medication every day 1～2 time, continued for 1～4 week, just can reach above-mentioned cure rate.Present composition administration and quantitative (dosing) are simple, make infected individuality be easy to receive treatment, and impel to produce high compliance outcomes, reduce the propagation of infecting.
Embodiment 2
Described in embodiment 1, prepare 1% terbinafine liquid composition.With tinea pedis patient between fluid composition one-time treatment toe, and when the 6th week, check therapeutic effect.The existence of fungus is negative and symptom drops to bottom line (for example erythema, decortication, pruritus, pus born of the same parents, vesicle form and incrustation) and is defined as effective treatment.When the 12nd week, the patient who is effectively treated is carried out the culture method check, to carry out infection evaluation again.
Only have eighth treatment patient to be positive in the culture review in the 12nd week, this shows that they are infected again.This result with commercially available 1% terbinafine emulsifiable paste product (Lan Meishu (Lamisil
) emulsifiable paste) observed infection rate again is similar in the research of (medication every day 2 times, continue 7 days).Because in the current OTC (over-the-counter) antifungal products that gets, the therapeutic scheme that Lan Mei expresses product is the simplest, i.e. 1 administration every day, continue 7 days, therefore with its product as a comparison.The result shows that the film-forming composition of the present invention that only needs seance to use can be treated cutaneous fungal infection effectively easily.
Embodiment 3
Described in embodiment 1, prepare 5% terbinafine liquid composition.Use this compositions, form the diaphragm area that adheres to, send the terbinafine of the single dose of every square centimeter 250 μ g to every area for treatment with back the patient.The patient is divided into 3 groups.The sponge that one group of patient uses to be soaked with suds 2 hours the time after dispenser is the film used of flush away gently.Other one group, the film that flush away is used 12 hours the time after medication.To the cuticular kinetics research that absorbs the drug of patient.Pharmacokinetic study shows that about 30% terbinafine pro-arrived horny layer in 2 hours, and about 31% arrived horny layer in ensuing 2～12 hours, and about 39% arrived horny layer after 12 hours.And, in the treatment patient, just observed C in firm hour
Maximum
Embodiment 4
Described in embodiment 1, prepare 1% terbinafine liquid composition.Use this compositions, form the diaphragm area that adheres to, send the terbinafine of the single dose of every square centimeter 50 μ g to every area for treatment with back one group of patient.Another group patient is used commercially available 1% terbinafine emulsifiable paste (Lamisil
Emulsifiable paste), except this emulsifiable paste is used every day, continue 7 beyond the highest heavens, it is to use with the same way as and the concentration of described film composition employing.Treatment began in 13 days, measured the terbinafine concentration in two groups of patients' the horny layer of treatment.Pharmacokinetic analysis shows that the mean concentration of two groups of terbinafines is on similar level, and this shows that the described film composition of applied once is identical with the above-mentioned emulsifiable paste therapeutic effect of using 7 days.
The present composition is the high curative effect compositions of treatment cutaneous fungal infection.It only needs applied once usually, can treat fungal infection, and this makes the patient obey therapeutic scheme successfully to cure infection, becomes extremely convenient and easy.
Claims (5)
1. the local solvent of using liquid antifungal medicine composition, this pharmaceutical composition to comprise 0.75%～20%w/w terbinafine or its pharmaceutical salts, 0.05%～30%w/w hydroxypropyl cellulose, 1%～10%w/w octylacrylamide acrylate copolymer and be selected from ethanol, isopropyl alcohol, acetoneand ethyl acetate.
2. the part of claim 1 liquid antifungal medicine composition, this pharmaceutical composition also comprise and are selected from following plasticizer: bialkyl ortho phthalate, hydroxy fatty acid oil, triglyceride and silicone oil.
3. prepare the method for the part of claim 1 or 2 with the liquid antifungal medicine composition, described pharmaceutical composition is used for the treatment of cutaneous fungal infection and only needs a drug.
4. the method for preparing the liquid film-forming composition, said composition comprises the mixture of 0.75%～20%w/w terbinafine or its salt, 0.05%～30%w/w octylacrylamide acrylate copolymer and hydroxypropyl cellulose and the solvent that is selected from ethanol, isopropyl alcohol, acetoneand ethyl acetate, and described pharmaceutical composition is used for the treatment of cutaneous fungal infection and only needs a drug.
5. the method for preparing the liquid film-forming composition, said composition comprises the mixture of 0.75%～20%w/w terbinafine or its salt, 0.05%～30%w/w octylacrylamide acrylate copolymer and hydroxypropyl cellulose and the solvent that is selected from ethanol, isopropyl alcohol, acetoneand ethyl acetate, described pharmaceutical composition is used for the treatment of cutaneous fungal infection, comprises described compositions part is applicable to skin, makes its dry step that forms film and film was kept 48 hours at least on skin.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72262505P | 2005-09-29 | 2005-09-29 | |
| US60/722,625 | 2005-09-29 | ||
| US72316305P | 2005-10-03 | 2005-10-03 | |
| US60/723,163 | 2005-10-03 | ||
| PCT/EP2006/066816 WO2007039533A2 (en) | 2005-09-29 | 2006-09-27 | Antifungal composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101262848A CN101262848A (en) | 2008-09-10 |
| CN101262848B true CN101262848B (en) | 2011-05-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800333959A Active CN101262848B (en) | 2005-09-29 | 2006-09-27 | Antifungal composition |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101262848B (en) |
| ZA (1) | ZA200802029B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018667B (en) * | 2010-10-29 | 2012-08-08 | 杭州雷布科技有限公司 | Imidazoles antifungal skin wiping agent and preparation method thereof |
| KR101580077B1 (en) * | 2015-03-28 | 2015-12-24 | 한국콜마주식회사 | Nail lacquer composition containing a ciclopirox |
| CN112022838B (en) * | 2020-09-17 | 2022-08-19 | 澳美制药厂有限公司 | Antifungal medicine composition, preparation method thereof and film-forming gel |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0515312A2 (en) * | 1991-05-23 | 1992-11-25 | Sandoz Ltd. | Pharmaceutical composition containing terbinafine as an anti-mycotic agent |
| WO1998023291A1 (en) * | 1996-11-22 | 1998-06-04 | Soltec Research Pty. Ltd. | Percutaneous delivery system |
| US6224887B1 (en) * | 1998-02-09 | 2001-05-01 | Macrochem Corporation | Antifungal nail lacquer and method using same |
| WO2005013955A2 (en) * | 2003-08-12 | 2005-02-17 | Novartis Consumer Health S.A. | Topical composition comprising terbinafine and hydrocortisone |
-
2006
- 2006-09-27 CN CN2006800333959A patent/CN101262848B/en active Active
-
2008
- 2008-03-04 ZA ZA200802029A patent/ZA200802029B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0515312A2 (en) * | 1991-05-23 | 1992-11-25 | Sandoz Ltd. | Pharmaceutical composition containing terbinafine as an anti-mycotic agent |
| WO1998023291A1 (en) * | 1996-11-22 | 1998-06-04 | Soltec Research Pty. Ltd. | Percutaneous delivery system |
| US6224887B1 (en) * | 1998-02-09 | 2001-05-01 | Macrochem Corporation | Antifungal nail lacquer and method using same |
| WO2005013955A2 (en) * | 2003-08-12 | 2005-02-17 | Novartis Consumer Health S.A. | Topical composition comprising terbinafine and hydrocortisone |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101262848A (en) | 2008-09-10 |
| ZA200802029B (en) | 2009-08-26 |
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