JP2007501832A6 - Topical composition containing terbinafine and hydrocortisone - Google Patents

Abstract

  The present invention relates to a topical pharmaceutical composition comprising terbinafine and hydrocortisone. The composition exhibits particularly advantageous antifungal properties against dermatophytes.

Description

  The present invention relates to topical pharmaceutical compositions having antifungal activity, more particularly anti-dermatophyte activity, and anti-yeast activity.

  Dermatophytes are fungi that can cause skin, hair, and nail infections due to their ability to utilize keratin. This fungus colonizes the keratinous tissue and causes fungal infections, such as infections known as ringworm or beetles associated with infected body parts. This fungus can be in direct contact with an infected host (human or animal) or infected flakes on combs, hairbrushes, clothes, furniture, theater seats, hats, bedding, towels, hotel carpets, and locker room floors. It is transmitted by direct or indirect contact with skin or hair. Depending on the species, this fungus may be able to survive in the environment for up to 15 months. If there is a previous injury on the skin, such as a scar, burn, fatigue, high temperature, or high humidity, the susceptibility to infection increases.

  Candida species are yeast, unlike dermatophytes. These are usually present in humans and are usually only pathogenic in the case of overgrowth induced by local factors such as immunosuppression. Yeasts such as Candida are opportunistic agents and usually require cofactors to become systemic pathogenic.

  Fungal infections such as fungal diseases, in particular fungal skin diseases caused by dermatophytes, such as athlete's foot (= foot tinea), swine (= crest tinea), corn beetle or onychomycosis, and yeast The topical use of terbinafine in the treatment of treated dermatomycosis, such as sweat rashes or seborrheic dermatitis, is known in the art.

  It has now surprisingly been found that the antifungal properties are surprisingly improved by the topical use of terbinafine together with hydrocortisone. This is particularly surprising since topical hydrocortisone is known to be a corticosteroid with low efficacy. Surprisingly, the combination according to the invention is particularly advantageous in the fight against dermatophytes. As already outlined above, dermatophytes are a major cause of surface mycosis that frequently occurs in humans, such as athlete's foot, rashes, and beetles. The treatment of said surface mycosis is generally improved and more rapid healing is achieved through the use of certain combinations of the present invention. This is quite surprising in view of the fact that terbinafine is known to be quite effective in eradicating and treating dermatophytes even when used alone. In this regard, it was surprisingly found that the addition of hydrocortisone did not negatively intervene in the antifungal activity of terbinafine.

  With the combination of the present invention, healing of surface mycosis, such as athlete's foot, is generally achieved more rapidly, and more rapid relief of typical symptoms such as itching, erythema, vesicles, burns, or cracking is observed Is done.

  Accordingly, the present invention is suitable for topical administration comprising terbinafine or a locally acceptable salt thereof, and hydrocortisone or a locally acceptable ester or salt thereof together with at least one locally acceptable carrier. Relates to a pharmaceutical composition.

  Terbinafine is known and is described, for example, in The Merck Index, 12th edition, 1996. 9299. It is marketed under the trademark LAMISIL. Topically acceptable salts thereof are, for example, terbinafine hydrochloride, terbinafine lactate or terbinafine ascorbate. Terbinafine (= free base) and terbinafine hydrochloride are preferred.

  In the topical compositions of the present invention, terbinafine is typically in an amount of 0.1 to 10%, especially 0.2 to 5%, especially 0.5 to 2% of the total composition on a weight basis. Exists. All percentages given in this document are weight percent (w / w) unless otherwise indicated.

  Hydrocortisone is known and is described, for example, in The Merck Index, 12th edition, 1996. 4828. Topically acceptable esters and salts include, for example, hydrocortisone acetate, such as 21-acetate; hydrocortisone butyrate, such as 17-butyrate; hydrocortisone valerate, such as 17-valerate; hydrocotisone 21-phosphate disodium salt, or hydrocortisone 21- Sodium succinate. Hydrocortisone (= free alcohol) and hydrocortisone acetate are preferred.

  Typically, the topical pharmaceutical composition according to the invention comprises the hydrocortisone component in an amount of 0.1 to 1.5%, in particular 0.2 to 1.2%, in particular 0.25 to 1% of the total composition. Contains up to quantity.

  Widely used locally acceptable carriers depend on the type of topical composition involved (see below). These include, for example, an aqueous phase, an oil phase, or an emulsion, but on the other hand also include typical components of, for example, a dressing material, a transdermal patch environment, or a film-forming solution.

  The topical compositions of the present invention have valuable pharmacological properties. In particular, these are in the treatment of infections caused by dermatophytes, such as athlete's foot (= foot tinea), squash (= crest tinea), beetles or onychomycosis, and also infections caused by yeast. It is advantageous.

  After administration of the topical composition of the present invention, the patient is more quickly relieved of symptoms associated with surface mycosis, such as itching, erythema, follicles, burns, or cracks, and the surface mycosis is generally healed more quickly. Is done.

  The advantageous properties of the topical composition of the invention can be demonstrated, for example, in the following tests.

(1) Experimental dermatophytosis model in guinea pigs: this is [eg T. Itoyama et al., J Antibiotic Chemotherapy 40 (1997) 441-444]. In said animal model, guinea pig denatured T. pylori . Mentagrophytes infected paws are used to test terbinafine versus terbinafine plus hydrocortisone. Each group has 10 T.P. All guinea pig feet infected with mentagrophytes show typical symptoms similar to those of naturally infected foot tinea in humans. Apart from the fact that the course of infection is very effectively stopped by the topical composition of the present invention, after 4 days in groups already treated with the combination of terbinafine and hydrocortisone, prominent inflammatory symptoms and scale formation There is a decrease. The effect is clearly superior to that seen in the group treated with terbinafine alone.

  (2) A controlled double-blind comparative study involving about 480 patients with established tinea pedis, which were randomly divided into three groups of about 160 each; Each receives either terbinafine / hydrocortisone (1.0% / 0.5%), terbinafine alone (1.0%), or placebo (vehicle). Efficacy, i.e. clinical and bacteriological cure, is measured on the 5th, 7th and 6th week after the start of treatment.

  (3) A controlled double-blind comparative study involving about 640 patients with established tinea pedis, which were randomly divided into four groups of about 160 each, Either terbinafine / hydrocortisone (1.0% / 0.25%), terbinafine alone (1.0%), hydrocortisone alone (0.25% or 0.5%), or placebo (vehicle). During the entire treatment period of 7 days, after 1, 2, and 3 hours, after 24 hours, daily relief of symptoms is then measured.

  (4) A controlled double-blind comparative study involving approximately 540 patients with established tinea pedis, which were randomly divided into three groups of approximately 180 each, Treat either terbinafine / hydrocortisone acetate (1.0% / 0.25%), terbinafine alone (1.0%), or placebo (vehicle). During the entire treatment period of 7 days, after 1, 2, and 3 hours, after 24 hours, daily relief of symptoms is then measured.

  Typically, a topical pharmaceutical composition according to the present invention contains both terbinafine and hydrocortisone in a pharmacologically effective amount.

  The daily dosage of these active ingredients may depend on various factors such as the sex, age, weight, and individual condition of the patient. For example, a topical pharmaceutical composition in the form of an emulsion-gel, gel, or cream may be applied once, twice, or three times a day. However, more frequent daily applications are possible. Patches, bandages, and film-forming solutions may be used, for example, once or twice a day.

  The invention further provides terbinafine or topically for the prevention or treatment of fungal infections, in particular dermatophytoses caused by dermatophytes (for the manufacture of pharmaceutical compositions suitable for topical administration). It also relates to the use of acceptable salts, and hydrocortisone or locally acceptable esters or salts.

  Furthermore, the present invention provides a method for the treatment of fungal infections, wherein terbinafine or a locally acceptable salt thereof and hydrocortisone or a locally acceptable ester or salt thereof to a mammal in need thereof. A method comprising the topical administration of a therapeutically effective amount of the mixture.

  Pharmaceutical compositions suitable for topical administration are eg emulsion-gels, gels, foam gels, creams, lotions, solutions, microemulsions, ointments, fat ointments, shampoos, pastes, foams, tinctures, film-forming solutions, manukia (varnish) Bandages, patches, and transdermal therapeutic systems. Preferred are emulsion-gels, gels, foam gels, creams, lotions, solutions, shampoos, film-forming solutions, and manucia. The manufacture and composition of such topical pharmaceutical compositions are known in the art (see, eg, WO 98 / 00168A1, pages 8-15, or US Pat. No. 5,681,849). The concept of film-forming solutions is known in the art and is disclosed, for example, in WO 98/23291 A1. The concept of Manucia (varnish) is known in the art, for example disclosed in EP515,312A2.

  Particularly preferred is an emulsion-gel or a combination of terbinafine (free base) and hydrocortisone (free alcohol or acetate) in the gel. Likewise preferred is a combination of terbinafine hydrochloride and hydrocortisone acetate in a cream (= oil-in-water emulsion).

  The topical compositions of the present invention typically contain two active substances in dissolved or suspended form.

  The following examples are intended to illustrate the present invention.

  A gel containing 1% terbinafine hydrochloride and 0.25% hydrocortisone (free alcohol) is prepared as follows.

(I) Dissolve A and B in a mixture of E and H.
(Ii) Dissolve C, D, and G in I.
(Iii) Mix (i) and (ii) at room temperature and add F.

  An emulsion-gel containing 1% terbinafine (free base) and 0.25% hydrocortisone (free alcohol) is prepared as follows.

(I) Disperse H into a portion of K using a rotor-stator homogenizer.
(Ii) Add the solution of B, I, J, and D in C and the remaining K to this and distribute evenly.
(Iii) Melt E, G, and F together at 75 ° C. to form the fatty phase. A is added to the fat phase, then the whole fat phase is slowly added to the gel (ii) already formed and emulsified.

  An emulsion-gel containing 1% terbinafine (free base) and 0.56% hydrocortisone acetate (corresponding to 0.5% hydrocortisone) is prepared as follows.

(I) A, J, C, E, G, and H are mixed together with slight warming until all solid particles are dissolved.
(Ii) In a suitable vessel or processor containing a stirrer and homogenizer, heat about half of K to 60-70 ° C. and suspend B in it.
(Iii) Slowly add (i) to (ii) with stirring and homogenization until a homogeneous emulsion with the appropriate droplet size is obtained. The concentrated emulsion is then cooled to room temperature.
(Iv) Prepare a basic carbomer gel by dispersing carbomer F in the latter half of I and K in a separate container and neutralizing with D.

  (V) Basic emulsion (iii) is added to the basic gel and the whole is stirred at room temperature until a homogeneous emulsion gel is obtained.

  A cream containing 1% terbinafine hydrochloride and 0.56% hydrocortisone acetate is prepared as follows.

(I) Melt C, D, E, F, G, H, and I together at 75 ° C.
(Ii) A is dispersed in the majority of K and heated to 75 ° C.
(Iii) Add oil phase (i) to (ii) and emulsify.
(Iv) Adjust the pH value by adding J dissolved in a small portion of K and let the cream cool.
(V) B is suspended in a small portion of K, added to the cream and homogeneously dispersed in the cream.

Claims (9)

  A pharmaceutical composition suitable for topical administration comprising terbinafine or a locally acceptable salt thereof and hydrocortisone or a locally acceptable ester or salt thereof together with at least one locally acceptable carrier.   The composition of claim 1 comprising terbinafine or terbinafine hydrochloride.   The composition according to claim 1 or 2, comprising hydrocortisone or hydrocortisone acetate.   4. The terbinafine component is present in a weight percentage of 0.1% to 10% and the hydrocortisone is present in a weight percentage of 0.1% to 1.5% of the total composition. The composition according to claim 1.   5. A composition according to any one of claims 1 to 4 in the form of an emulsion-gel, gel, foam gel, cream, lotion or solution, shampoo, film-forming solution, or manucia.   6. A composition according to claim 5, in the form of an emulsion-gel or gel, comprising terbinafine (free base) and hydrocortisone (free alcohol or acetate) as active substances.   6. A composition according to claim 5 in the form of a cream and comprising terbinafine hydrochloride and hydrocortisone acetate as active substances.   Terbinafine or locally acceptable for use with hydrocortisone or a locally acceptable ester or salt thereof (for the manufacture of a pharmaceutical composition suitable for topical administration) for the prevention or treatment of fungal infections Use of salt.   Use according to claim 8, wherein the manufactured pharmaceutical composition is useful in the fight against dermatophytes.