Patent Application
20080166398
The present invention relates to topical formulations useful for treating dermal diseases caused by fungi and yeasts with inflammation and/or associated with a bacterial infection. In particular the present invention relates to stable topical formulations containing an antifungal agent and an anti-inflammatory steroid. More particularly, the present invention relates to topical formulations containing sertaconazole and hydrocortisone or an antibacterial quinolone compound, or a mixture thereof.
Sertaconazole, INN of 1-[2-[(7-Chlorobenzo[b]thien-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole and CAS REG No. 99592-32-2 is a useful antifungal agent for treatment of diseases caused by fungi and yeasts in man and in animals. Sertaconazole, as well as its pharmaceutically acceptable addition salts, is disclosed in EP 0151477. The R-(−)-enantiomer of sertaconazole is disclosed in PCT application WO 03/68770 as well as its pharmaceutically acceptable addition salts.
The antibacterial agent 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (T-3912, GF-001001-00) is described in U.S. Pat. No. 6,335,447. This compound is a non-fluorinated quinolone with a wide range of activity against bacteria.
A variety of methods have been used for the treatment of fungal infections including the use of potassium iodide, Whitfield's ointment, undecylenic acid, antibiotics (e.g. nystatin and amphotericin B), griseofulvin and imidazole antifungal agents such as bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole, parconazole, sertaconazole, sulconazole and tioconazole.
Imidazole antifungal agents are the first broad-spectrum antifungal agents and are of considerable importance in clinical practice. Their broad spectrum of antifungal activity against most pathogenic fungi has provided an important advance in antifungal therapy.
A large number of suitable imidazoles have been described in the literature and are well-known to those skilled in the art. Examples of suitable imidazole antifungal agents include bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, miconazole, omoconazole, oxiconazole, parconazole, sertaconazole, sulconazole and tioconazole.
The infections caused by fungi and yeasts are commonly associated with signs of erythema and scaling and with symptoms of itching or painful burning. Clinical treatment for fungal disease requires at least two to four weeks for complete relief of symptoms. It has been found that fungal infections can be effectively treated with a combination of corticosteroids and imidazole antifungal agents. It is known that the sensitivity of fungal organisms varies with their life cycles; spores are more resistant to treatment than mycelia are. Steroids may induce fungal spores to produce mycelia, thereby making them more sensitive to treatment. Also, steroids are known to produce vasoconstriction at the site of application. This activity may delay or prevent the elimination of the antifungal agent from the application site, permitting the antifungal agent to remain in the epidermis for longer periods of time. It is therefore believed that a locally applied anti-inflammatory agent would offer direct and immediate relief for the inflammatory component of the lesion. The combination product should then provide fast relief of symptoms and eradicate the infection. Based on this concept, certain combinations of an antifungal agent and an anti-inflammatory agent have been developed for treatment of fungal diseases.
However, the antifungal and corticoid combinations are not devoid of side effects. Reported side effects for a commercially available combination, Lotricomb® cream (clotrimazole 1%/betamethasone dipropionate 0.05%), include paraesthesia, maculopapular rash, oedema and secondary infection. Common side effects reported for others commercially available combinations, Canesten® hydrocortisone (clotrimazole 1%/hydrocortisone 1%) and Lotriderm® (clotrimazole 1%/betamethasone dipropionate 0.05%) are local mild burning, irritation and hypersensitivity reactions. Moreover, such combination products sometimes fail to provide the fast relief of the inflammatory symptoms which is normally desired for the treatment of a fungal infection. Adverse effects associated with dermal antifungal/corticosteroid combinations have been reviewed by Erbagci (Am. J. Clin. Dermatol. 2004, 5, 375-384), as shown in Table 1. In Am. J. Clin. Dermatol. 2004 5(6):375-384 the author states that there are conflicting results between the studies investigating which therapy regimen, antifungal alone or antifungal plus corticosteroid, is more effective for the management of dermatophyte infections. Several references to another studies are cited, wherein combination products shows equal or lower mycologic and clinical cure rates compared with single antifungal agents in the management of dermatophytoses, as well as to adverse effects observed when the combination is used. Therefore, the combination of an antifungal agent with a corticosteroid is not always the most adequate therapy to relief the symptoms or even the combination may be inappropriate due to adverse effects.
It is known that fungal infections of the skin can be later colonized by bacteria. These bacteria contribute to the perpetuation of the injury and of the clinical symptoms.
The problem to be solved by the present invention is to provide a pharmaceutical composition useful to treat dermal diseases, caused by fungi and yeasts with inflammation and/or associated with a bacterial infection, which provides a fast relief of the symptomatology and reduces side effects. The solution is based on the fact that the applicants have found that pharmaceutical compositions, which comprise
i) sertaconazole, or its pharmaceutically acceptable salts, solvates, isomers or mixtures thereof, and
ii) hydrocortisone, or pharmaceutically acceptable esters thereof or mixtures thereof, or an antibacterial quinolone compound, or a mixture thereof,
have an improved pharmacological profile as compared to other compositions of sertaconazole alone and/or other antifungals in combination with anti-inflammatory agents and/or antibacterial agents.
Accordingly, a first aspect of the invention relates to a pharmaceutical composition comprising:
a) a therapeutically effective amount of sertaconazole, or a pharmaceutically acceptable salt, solvate, isomer thereof or mixtures thereof; and
b) a therapeutically effective amount of at least one compound selected from the group consisting of hydrocortisone, a pharmaceutically acceptable ester of hydrocortisone, an antibacterial quinolone compound or mixtures thereof; optionally in combination with at least one pharmaceutically acceptable excipient or carrier.
Accordingly, the present invention relates to a pharmaceutical composition as defined above to be used in the treatment of fungal infections, caused by fungi and yeasts with inflammation and/or associated with a bacterial infection.
According to a second aspect, the present invention relates to the use of a pharmaceutical composition as defined above, for the manufacture of a medicament for the treatment of fungal infections caused by fungi and yeasts with inflammation and/or associated with a bacterial infection in a human or animal living body, by administering an effective amount of the composition according to the invention. Preferably, the pharmaceutical composition of the invention is used in a human.
This second aspect may alternatively be formulated as a method for treatment of the diseases mentioned above in a human or animal living body, comprising administering to a human or living body in need thereof an effective amount of a pharmaceutical composition as described herein. Preferably, the method of treatment comprises administration of the pharmaceutical composition as described herein in a human.
Fungal diseases refer to fungal infections, including yeast infections, of keratinized and non-keratinized epithelial tissues, for example skin, nails, mucosa and the like. Thus, the compositions of the invention are useful to treat fungal diseases with itching and/or inflammation, such as tinea pedis, tinea capitis, tinea corporis, tinea versicolor, and tinea cruris, nail fungal diseases (onychomycosis caused by dermatophyte and yeast infection). Other indications are for yeast diseases, such as candidiasis and itertriginous dermatitis, in which the presence of pathogenic yeast organisms, causes skin disease with resultant inflammation and itching. The compositions may also be useful to treat fungal diseases associated with a bacterial infection.P
For the purposes of the present invention, the sertaconazole compound may be sertaconazole, its pharmaceutically acceptable salts, solvates and isomers. Particularly preferred is R-(−)-sertaconazole and its pharmaceutically acceptable salts and solvates. Pharmaceutically acceptable solvates may be hydrates or may comprise other solvents of crystallization such as alcohols. Representative pharmaceutically acceptable salts include hydrochloride, hydrobromide, sulphate, bisulphate, nitrate, phosphate, perchlorate, borate, acetate, tartrate, maleate, citrate, succinate, palmoate, methanesulfonate, benzoate, salicylate, and the like.
Preferably, the sertaconazole compound is selected from sertaconazole base, sertaconazole mononitrate, R-sertaconazole base and R-sertaconazole mononitrate.
For the purposes of the present invention, hydrocortisone refers to hydrocortisone base or its pharmaceutically acceptable esters. Hydrocortisone and its esters could be classified according to their potency, e.g. of low-potency hydrocortisone such as hydrocortisone base and hydrocortisone acetate and mid-potency hydrocortisone such as hydrocortisone butyrate, hydrocortisone propionate and hydrocortisone valerate.
In a preferred embodiment, the hydrocortisone is a low potency hydrocortisone. In another preferred embodiment, the hydrocortisone is a mid-potency hydrocortisone.
In a more preferred embodiment, esters of hydrocortisone are hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butylacetate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone propionate and hydrocortisone valerate.
Particularly preferred are hydrocortisone base, hydrocortisone acetate, hydrocortisone butyrate and hydrocortisone valerate.
The antibacterial quinolone compound utilized in the present invention may be generally described as being selected from the group consisting of ciprofloxacin, moxifloxacin, ofloxacin, gatifloxacin, sparfloxacin, levofloxacin, norfloxacin, enterofloxacin, GF-001001-00, trovafloxacin, lomefloxacin, enoxacin, cinoxacin, alatrofloxacin. In a preferred embodiment, the antibacterial agent is 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (GF-001001-00) or a pharmaceutically acceptable salt thereof.
The salts of GF-001001-00 include usually known salts of basic groups such as amino groups, or salts of acidic groups such as hydroxyl or carboxyl groups.
The salts of basic groups may include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and acids with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and the like.
The salts of acidic groups may include, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procain, dibenzylamine, N-benzyl-.beta.-phenethylamine, 1-ephenamine and N,N′-dibenzylethylenediamine, and the like.
Among the above salts, preferred salts of GF-001001-00 include pharmacologically acceptable salts.
The amount of the active principle ingredient utilized in the compositions of the present invention will depend on the purpose of the use, e.g., the treatment of an active infection, the prophylactic treatment of tissues to prevent an active infection from developing, or the sterilization of tissues in conjunction with a medical procedure, such as a surgical procedure. The amounts utilized will also depend on the particular tissues being treated. For example, lower concentrations will typically be utilized to treat especially sensitive tissue, while somewhat higher concentrations may be utilized to treat less sensitive tissues.
The compositions of the invention contain from 0.1% to 10% by weight of the composition of sertaconazole, or pharmaceutically acceptable salts, solvates, isomers or mixtures thereof. Preferably the amount of sertaconazole or pharmaceutically acceptable salts, solvates, isomers or mixtures thereof in the composition is from 0.2% to 8% by weight of the composition. More preferably, from 0.2% to 7% by weight of the composition. In another preferred embodiment of the invention, R-sertaconazole base and R-sertaconazole mononitrate are in an amount from 0.3% to 5% by weight of the composition. In another preferred embodiment, sertaconazole base and sertaconazole mononitrate are in an amount from 0.5% to 5% by weight of the composition.
The compositions of the invention may contain from 0.05 % to 5% by weight of the composition of hydrocortisone or a pharmaceutically acceptable ester or mixtures thereof. Preferably, from 0.1% to 2% by weight of the composition.
The compositions of the invention may contain from 0.5% to 10.0% by weight of an antibacterial quinolone compound. Preferably from 0.5% to 10.0% by weight of 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid or a pharmaceutically acceptable salt thereof.
An embodiment of the first aspect, the invention relates to pharmaceutical compositions comprising an effective amount of sertaconazole, their pharmaceutically acceptable salts, solvates and isomers and at least one hydrocortisone or their pharmaceutically acceptable esters, resulting in a synergistic effect for the treatment of fungal diseases caused by fungi or yeasts with itching and/or inflammation.
In another embodiment, the invention relates to pharmaceutical compositions comprising an effective amount of sertaconazole, its pharmaceutically acceptable salts, solvates and isomers and at least one antibacterial quinolone compound. In a more preferred embodiment, the antibacterial quinolone compound is 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (GF-001001-00) or a pharmaceutically acceptable salt thereof.
These compositions, which contain an antibacterial quinolone compound, have a synergistic effect for the treatment of bacterially infected fungal diseases, such as fungal infections caused by Gram-positive and Gram-negative organisms including drug-resistance bacteria.
In another embodiment, the invention relates to pharmaceutical compositions comprising an effective amount of sertaconazole, or its pharmaceutically acceptable salts, solvates and isomers thereof and at least one hydrocortisone or their pharmaceutically acceptable esters and at least one antibacterial quinolone compound. These compositions are endowed with a synergistic effect for the treatment of bacterially infected fungal diseases complicated by itching and/or inflammation.
According to a preferred embodiment, the invention relates to a pharmaceutical composition comprising a sertaconazole compound selected from sertaconazole base, sertaconazole mononitrate, R-sertaconazole base and R-sertaconazole mononitrate, and a hydrocortisone selected from the group consisting of hydrocortisone base, hydrocortisone valerate, hydrocortisone acetate and hydrocortisone butyrate, in combination with pharmaceutically acceptable excipients or carriers, or mixtures thereof.
According to a preferred embodiment, the invention relates to a pharmaceutical composition comprising a sertaconazole compound selected from sertaconazole base, sertaconazole mononitrate, R-sertaconazole base and R-sertaconazole mononitrate, and a antibacterial quinolone compound, in combination with pharmaceutically acceptable excipients or carriers, or mixtures thereof. Particularly preferred are those compositions wherein the antibacterial quinolone compound is 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (GF-001001-00) and pharmaceutically acceptable salts thereof.
In another preferred embodiment, the invention relates to a pharmaceutical composition comprising a sertaconazole compound selected from sertaconazole base, sertaconazole mononitrate, R-sertaconazole base and R-sertaconazole mononitrate, and a hydrocortisone selected from the group consisting of hydrocortisone base, hydrocortisone valerate, hydrocortisone acetate and hydrocortisone butyrate, and an antibacterial quinolone compound, in combination with pharmaceutically acceptable excipients or carriers, or mixtures thereof. Particularly preferred are those compositions wherein the quinolone antibacterial agent is 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (G F-001001-00) and pharmaceutically acceptable salts thereof.
The route of administration of the compositions may be ocular, nasal, otic, rectal, vaginal, intradermal, intratumoral, intralesional, intravascular, topical, transdermal, local or regional. In a preferred embodiment, the invention relates to topical compositions. In an embodiment of the invention, the composition is designed for topical administration.
The compositions of the present invention may be formulated in any dosage form such as creams, foams, pastes, ointments, emulsions, milks, pomades, powders, solutions, gels, sprays, shampoos, lotions, suspensions, microspheres, microcapsules, nanospheres, nanoparticles, lipidic vesicles, liposomes, polymeric vesicles, patches or biological inserts.
According to a preferred embodiment, the invention relates to anhydrous compositions in the form of anhydrous microemulsion or anhydrous cream.
Microemulsions are highly stable emulsions wherein the internal phase particles are extremely small, not surpassing 100 nm/diameter, a much smaller size than the visible wavelength (400-480 nm). Consequently, microemulsions are fully transparent. Active ingredients in microemulsions remain in the internal phase (oil) preserved from the aqueous phase, thus maintaining the efficacy thereof for longer periods of time than conventional compositions like emulsions and suspensions. Moreover, the very small sized particles in microemulsions increase the penetration of active ingredients across the external skin surfaces.
The formulation described herein optionally contains one or more other pharmaceutically active agents. Useful agents include any agents commonly used in dermatological formulations, which may include, but are not limited to, antibacterial agents such as those cited above, and other antiiflammatory agents.
In addition to the active pharmaceutical ingredients (APIs) mentioned above, the compositions of the invention will also include pharmaceutically acceptable excipients known in the art for pharmaceutical compounding such as for example, solvents, buffering agents, stabilizing agents, penetration enhancers, humectants and/or moisturizers, preservatives, opacifiers, fragrances, colour additives, emulsifying agents, bases, emollients, stiffening agents, solubilizing agents and the like.
In an embodiment of the process of the present invention, the present compositions may be prepared using conventional techniques, for example, by formation of solutions, gels, suspensions, etc., using well known and conventional techniques. Compositions of the present invention can also be prepared by processes known in the art, including by simple admixture, with agitation as appropriate, of the ingredients.
Generally a composition for topical use is applied once or more times per day on the area to be treated. The number of times per day that the composition is applied depends on the severity of the condition and the advice of the physician. The pharmacological profile of the compositions of the invention may be evaluated in patients suffering from fungal and yeast infections with inflammation and/or associated with a bacterial infection.
Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration and are not intended to be limiting to the present invention.
1% Sertaconazole mononitrate+0.1% hydrocortisone acetate anhydrous microemulsion
This example illustrates the present invention in the form of an anhydrous microemulsion of sertaconazole mononitrate and hydrocortisone acetate. The pharmaceutical composition of this example is given below:
Labrasol, Plurol oleic, Myritol 318 and Propylene glycol were mixed and heated to 35-40° C. Sertaconazole mononitrate and hydrocortisone acetate were added under magnetic stirring until total dissolution, after that the microemulsion was cooled and stored.
Based on the method described in Example 1, the following compositions may be prepared.
2% Sertaconazole mononitrate+0.3% hydrocortisone valerate anhydrous cream This example illustrates the present invention in the form of an anhydrous cream of sertaconazole mononitrate and hydrocortisone valerate. The pharmaceutical composition of this example is given below:
1% R-Sertaconazole+0.5% hydrocortisone valerate anhydrous cream
This example illustrates the present invention in the form of an anhydrous cream of R-sertaconazole and hydrocortisone valerate. The pharmaceutical composition of this example is given below:
2% Sertaconazole mononitrate+0.5% hydrocortisone acetate+1% GF-001001-00 anhydrous cream 35
This example illustrates the present invention in the form of an anhydrous cream of sertaconazole mononitrate, hydrocortisone acetate and GF-001001-00. The pharmaceutical composition of this example is given below:
1% R-sertaconazole+0.5% hydrocortisone acetate+1% GF-001001-00 anhydrous cream
This example illustrates the present invention in the form of an anhydrous cream of R-sertaconazole, hydrocortisone acetate and GF-001001-00. The pharmaceutical composition of this example is given below:
2% Sertaconazole mononitrate+0.3% hydrocortisone acetate+1% GF-001001-00 o/w emulsion
This example illustrates the present invention in the form of an o/w emulsion of sertaconazole mononitrate, hydrocortisone acetate and GF-001001-00. The pharmaceutical composition of this example is given below:
1% R-sertaconazole mononitrate+0.3% hydrocortisone acetate+1% GF-001001-00 o/w emulsion
This example illustrates the present invention in the form of an o/w emulsion of R-sertaconazole mononitrate, hydrocortisone acetate and GF-001001-00. The pharmaceutical composition of this example is given below:
2% Sertaconazole mononitrate+1% GF-001001-00 anhydrous cream
This example illustrates the present invention in the form of an anhydrous cream of sertaconazole mononitrate, and GF-001001-00. The pharmaceutical composition of this example is given below:
1% R-Sertaconazole mononitrate+1% GF-001001-00 anhydrous cream
This example illustrates the present invention in the form of an anhydrous cream of R-sertaconazole mononitrate, and GF-001001-00. The pharmaceutical composition of this example is given below:
A preliminary clinical trial was conducted comparing the composition of Example 1, twice daily, and a standard microemulsion composition containing 1% sertaconazole mononitrate as the only active ingredient, twice daily, in tinea pedis. The standard microemulsion composition was prepared for this experiment. Twenty-four patients, half in each group, were treated for up to 14 days. Symptoms associated with the tinea pedis lesions were scaling, maceration, and fissures most commonly in the web space between the 4th and 5th toes. Marked improvement of symptoms were assessed within 3-5 days in the group treated with the composition of Example 1, with full remission in 8-10 days. The group treated with sertaconazole mononitrate did not show marked improvement until 7-9 days and full remission at 12-14 days. The experiment demonstrates the therapeutic advantage of sertaconazole and hydrocortisone combination over sertaconazole alone.
A preliminary clinical trial was conducted comparing the composition of Example 4, twice daily, and a standard anhydrous cream containing 2% sertaconazole mononitrate and 0.5% hydrocortisone acetate, twice daily, in tinea corporis. The standard anhydrous cream was prepared for this experiment. Twenty-four patients, half in each group, were treated for up to 10 days. Marked improvement of itching and rash were assessed within 4-5 days in the group treated with the composition of Example 4, with full remission in 6-8 days. The group treated with the comparative standard anhydrous cream showed a marked improvement at 6-7 days and full remission at 9-10 days. Hence, this experiment shows the increased therapeutic efficacy of sertaconazole and hydrocortisone compositions when augmented with an antibacterial quinolone compound.
A preliminary clinical trial was conducted comparing the composition of Example 8, twice daily, and a standard anhydrous cream containing 2% sertaconazole mononitrate as the only active ingredient, twice daily, in cutaneous candidiasis. The standard anhydrous cream was prepared for this experiment. Twenty-four patients, half in each group, were treated for up to 21 days. Itchy, purple patches were the most common symptoms associated with the infection. Marked improvement of itch and a significant reduction of patches size were observed after 6-8 days in the group treated with the composition of Example 8. Cure was completed in 11-12 days. The group treated with the comparative standard anhydrous cream showed a marked improvement at 13-15 days and full remission at 17-19 days. So the addition of the antibacterial quinolone compound made the difference.
| Number | Date | Country | Kind |
|---|---|---|---|
| 05101540.2 | Mar 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/060190 | 2/22/2006 | WO | 00 | 11/30/2007 |
