EP1718295A2

EP1718295A2 - Use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous inflammation

Info

Publication number: EP1718295A2
Application number: EP05729170A
Authority: EP
Inventors: Fabrizio Dolfi; Irina Safonova
Original assignee: Galderma Research and Development SNC
Current assignee: Galderma Research and Development SNC
Priority date: 2004-02-20
Filing date: 2005-02-17
Publication date: 2006-11-08
Also published as: JP2007523134A; FR2866570B1; FR2866570A1; WO2005089751A3; KR20060124706A; CN1921851A; US20070281984A1; RU2006133546A; CA2553933A1; WO2005089751A2; AU2005224124A1; BRPI0506551A

Abstract

The invention relates to the use of metronidazole for preparing a pharmaceutical composition for treating a cutaneous inflammation and preferably an inflammatory component in a rosacea.

Description

USE OF METRONIDAZOLE FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SKIN INFLAMMATION

The present invention relates to the field of the treatment of skin inflammations, and more particularly the treatment of skin inflammations in rosacea. The invention aims to provide new pharmaceutical compositions, more particularly dermatological compositions, useful for the treatment of skin inflammations, and more particularly the treatment of skin inflammations in rosacea and comprising as active agent metronidazole.

Rosacea is a common chronic and progressive inflammatory dermatosis linked to vascular relaxation. It mainly affects the central part of the face and is characterized by flushing of the face or hot flushes, facial erythema, papules, pustules, and telangiectasia. In severe cases, especially in humans, the soft tissue in the nose can swell and produce a bulbous swelling called rhinophyma.

Rosacea usually occurs between the ages of 25 and 70, and is much more common in fair skinned people. It affects more particularly women, although this condition is generally more severe in men. Rosacea is chronic and persists for years with periods of exacerbation and remission.

Rosacea was originally called "acne rosacea" because its papules (slight raised skin) and inflammatory pustules (scabs of pus) are very similar to those of acne vulgaris. Unlike acne vulgaris, the etiology of which is based on both abnormal keratinization, increased sebum production and bacterial inflammation, inflammation of rosacea is vascular in nature and poorly understood. It results from this facial vascular anomaly, a permanent edema of the dermis which could accompany an increased colonization by Demodex folliculorum, mite which is usually found in the follicles of the face. According to various studies, Demodex folliculorum has an etiological role in rosacea (Erbagi et al., 1998, Int J Dermatol, vol.37, pages 421-425; Purcell et al, 1986, J Am Acad Dermatol, vol.15, pages 1159-1162; Sibenge et al., 1992, J Am Acad Dermatol, vol. 26, pages 590-593). It seems that Demodex folliculorum causes or worsens inflammatory reactions, resulting in papules and pustules, by blocking the pilosebaceous follicles of the face (Roihu et al., 1998, J Cutan Pathol, vol.25, pages 550-552 ). This parasite would also trigger a humoral immune response (Nunzi et al., 1980, Br J Dermatol, vol 103, pages 543-551; Manna et al., 1982, Br J Dermatol, vol 107, pages 203-208).

The pathogenesis of rosacea is poorly understood. Many factors can be involved without necessarily inducing this condition. These are for example psychological factors, gastrointestinal disorders, environmental factors (exposure to the sun, temperature, humidity) and emotional factors (stress), food (alcohol, spices), hormonal, vascular, or even infection with Helicobacter pilori.

Rosacea develops in 4 stages, but passing through all stages is not compulsory:

- stage 1 of vascular relaxations (around 20 years). Patients have sudden onset of paroxysmal redness of the face and neck, with a feeling of warmth, but without systemic signs. After the attacks, the facial skin becomes normal again. These "flushes" are triggered by changes in temperature (sometimes leading to thermophobia), the absorption of hot drinks or alcohol.

- stage 2 erythematato-telangiectatic (around 30 years). The malar areas are diffusely red. We observe dilated capillaries constituting the classic rosacea. Unlike stage 1, the redness is permanent. In addition to the cheeks, the chin and the middle part of the forehead can be affected. - stage 3 of papulo-pustules (around 40 years). On a background of erythema develop papules and pustules a few millimeters in diameter, without associated comedones. This dermatosis can be very widespread, sometimes to the glabrous part of the scalp in men, but respects the periphery of the mouth and the eyes. Patients complain of sensitive skin, with subjective intolerance to most oily topicals and cosmetics.

- stage 4 of rhinophyma (around 50 years or later). This late phase mainly affects men, unlike the other stages. The nose is enlarged, diffusely red and the follicular orifices are dilated. The skin gradually thickens. Minor forms of rosacea can be treated with active ingredients such as anti-seborrheics and anti-infectives, for example benzoyl peroxide, retinoic acid. As for the most diffuse forms of the disease, they respond well to general antibiotic therapy with cyclins. However, these treatments have unpleasant side effects for the patient, such as irritation or intolerance.

In addition, due to the multi-factor aspect of rosacea, there are many therapies against this condition, but we are still looking for an effective and safe treatment for the patient.

The work of the Applicant has made it possible to demonstrate the interaction of metronidazole with the secretion of certain interleukins, and more particularly with the secretion of interleukin 5, of interleukin 6 and of interleukin 10, involved in particular in the inflammatory process of rosacea.

An infection with Demodex folliculorum triggers a humoral immune response. The humoral immune response involves activation of type 2 helper T cells (Th2). The differentiation of naive T cells into Th2 cells is induced by interleukin 6. Th2 cells then produce interleukin 4, interleukin 5 and interleukin 10, which stimulate the activation of B cells and the production of antibody.

Interleukin 5 (IL-5), also called "eosinophil colony stimulating factor", is secreted by T lymphocytes. It can be classified among hematopoietic growth factors because it stimulates growth, differentiation and activity eosinophils which play an important role in the fight against parasitic infections. Interleukin 5 also acts on eosinophils as a chemotactic agent. IL-5 induces the proliferation of B lymphocytes and their secretion of immunoglobulins.

Interleukin 6 (IL-6), also called "hepatocyte stimulating factor", "hybridoma growth factor" or "B cell stimulating factor", is a glycoprotein secreted in particular by T cells, monocytes and fibroblasts. It stimulates the growth and differentiation of B cells into plasma cells and increases the generation of platelets. It causes, by activation of hepatocytes, the secretion of proteins inflammation like fibrinogen and reactive protein C. It has a proinflammatory role.

Interleukin 10 (IL-10) is produced by T cells, B cells and mast cells. IL-10 acts in particular at the level of B lymphocytes: increase in the viability of small B lymphocytes and increase in the expression of HLA class II molecules. This interleukin is also involved in the regulation of mast cell proliferation.

Metronidazole, or (methyl-2-nitro-5-imidazolyl) -2-ethanol, is known in the prior art for its antibacterial, antiparasitic and antiprotozoal properties. It exerts a selective toxicity with respect to anaerobic microorganisms as well as hypoxic cells. At the level of the latter, metronidazole is reduced to derivatives capable of altering the DNA structure of these cells.

The Applicant's work has made it possible to demonstrate the involvement of certain interleukins in an inflammatory skin process, and more particularly the involvement of interleukin 5, interleukin 6 and interleukin 10 in skin inflammation. , and more particularly in the inflammatory component of rosacea.

The Applicant has now highlighted the interesting properties of metronidazole on skin inflammation, and more particularly on the inflammatory component in rosacea.

It was surprisingly found that the use of metronidazole resulted in a change in the secretion of interleukins, and more particularly in the secretion of NL-5, IL-6 and IL-10. It has also been found that the use of metronidazole results in an inhibition of the secretion of interleukins, and more particularly of the secretion of IL-5, IL-6 and IL-10.

As indicated above, the invention aims to offer a new method of treating skin inflammation consisting in administering to a subject suffering from such inflammation, an effective amount of metronidazole, in which metronidazole is capable of modifying and / or inhibit the secretion of at least one interleukin. More particularly, the invention aims to offer a new method of treatment of skin inflammation consisting in administering to a subject suffering from such inflammation, an effective amount of metronidazole, in which metronidazole is capable of modifying and / or d '' inhibit the secretion of one, two or three interleukins chosen from the group comprising IL-5, 1L-6 and IL-10.

Consequently, the invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition intended for the treatment of skin inflammation, and preferably of the inflammatory component in rosacea.

More particularly, the invention relates to the use of metronidazole for the preparation of a pharmaceutical composition, intended for the treatment of skin inflammation, said inflammation resulting from the secretion of at least one interleukin, two or three interleukins chosen from the group comprising IL-5, IL-6 and IL-10.

The invention relates more particularly to the use of metronidazole for the preparation of a pharmaceutical composition intended for treating the inflammatory component of rosacea; composition in which metronidazole is capable of modifying, advantageously to inhibit, the secretion of at least one interleukin chosen from the group comprising IL-5, IL-6 and IL-10.

The invention also relates to the use of metronidazole for the preparation of a pharmaceutical composition as defined above, in which metronidazole is capable of modifying, advantageously to inhibit, the secretion of two or three interleukins chosen from the group comprising IL-5, IL-6 and IL-10.

More particularly, the pharmaceutical composition which is the subject of the present invention is a dermatological composition, for topical application to the skin.

By treatment of skin inflammation is meant according to the present invention the treatment and / or prevention of skin inflammation. By treatment of the inflammatory component of rosacea is meant according to the present invention, the treatment and / or prevention of rosacea, in one or more of the stages described above.

According to a first embodiment of the invention, the composition is intended for the treatment of the first stage of rosacea.

According to a second embodiment of the invention, the composition is intended for the treatment of the second stage of rosacea.

According to a third embodiment of the invention, the composition is intended for the treatment of the third stage of rosacea.

According to a fourth embodiment of the invention, the composition is intended for the treatment of the fourth stage of rosacea.

According to a preferred mode of implementation, the composition contains 0.0001 to 20% of metronidazole, preferably from 0.1 to 2% of metronidazole, and more preferably of the order of 0.75 to 1% of metronidazole expressed by weight relative to the total weight of the composition.

Of course the present invention relates, in addition to the use of metronidazole, the use of derivatives thereof. The term derivatives means compounds which are distinguished from metronidazole, by substitution, addition or deletion of one or more chemical groups and having substantially the same activity.

Advantageously, the compositions of the invention comprise, in addition to metronidazole, at least one other therapeutic agent capable of increasing the effectiveness of the treatment. By way of nonlimiting examples of such agents, mention may be made of antibiotics, antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritics, keratolytics, antiseborrhoeics, antihistamines, sulfides, immunosuppressive or antiproliferative products. The compositions of the invention may also comprise any additive usually used in the pharmaceutical, dermatological field, compatible with metronidazole. Mention may in particular be made of sequestrants, antioxidants, sun filters, preservatives, for example DL-alpha-tocopherol, fillers, electrolytes, humectants, dyes, bases or common acids, mineral or organic, fragrances, essential oils, cosmetic active ingredients, moisturizers, vitamins, essential fatty acids, sphingolipids, self-tanning compounds such as DHA, soothing and protective agents for the skin such as allantoin, penetrating agents , gelling agents. Of course, those skilled in the art will take care to choose this or these optional additional compounds, and / or their quantity, in such a way that the advantageous properties of the composition according to the invention are not, or not substantially, altered. These additives can be present in the composition in an amount of 0 to 20% by weight relative to the total weight of the composition.

Examples of sequestering agents that may be mentioned include ethylenediaminetetraacetic acid (EDTA), as well as its derivatives or its salts, dihydroxyethylglycine, citric acid, tartaric acid, or mixtures thereof.

Examples of preservatives that may be mentioned include benzaikonium chloride, phenoxyethanol, benzyl alcohol, diazolidinylurea, parabens, or mixtures thereof.

Examples of humectants that may be mentioned include glycerin and sorbitol.

The compositions of the invention may contain one or more penetrating agents in preferential concentrations ranging from 0 to 20% and more preferably ranging from 0.6 to 3% by weight relative to the total weight of the composition. Among the penetrating agents, use is preferably made, without this list being limiting, of compounds such as propylene glycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycol, ethoxydiglycol.

Advantageously, the compositions according to the invention may also contain one or more surfactants in preferential concentrations ranging from 0 to 10% and more preferably ranging from 0.1 to 2%. The compositions of the present invention may be in all the galenical forms normally used for topical application, in particular in the form of aqueous, hydroalcoholic or oily solutions, of lotion-type dispersions, of aqueous, anhydrous or lipophilic gels, of emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or vice versa (W / O), or of suspensions or emulsions of soft, semi-liquid or solid consistency of cream, gel or ointment type or microemulsions, micro capsules, micro particles or vesicular dispersions of ionic and / or nonionic type.

Preferably the creams can be formulated from a mixture of mineral oil, or a mixture of beeswax and water which emulsifies instantly, in which the metronidazole is added, dissolved in a small amount oil such as almond oil. Ointments can be formulated by mixing a solution of metronidazole in an oil such as almond oil in heated paraffin, then allowing the mixture to cool.

As examples of compositions according to the invention, mention may be made of those comprising an active phase containing (expressed as a percentage by weight):

- 0 to 90%, preferably 5 to 25%, especially 10 to 20%, of water;

- 0 to 10%, preferably 0 to 2%, especially 0 to 0.5%, of surfactant;

- 0 to 20%, preferably 0 to 10%, in particular 2 to 5%, of propenetrant;

- 0.0001 to 20%, preferably 0.1 to 2%, of metronidazole; and an aqueous phase comprising a gelling agent, and water.

The aqueous phase of a composition according to the invention in the form of an emulsion may comprise water, floral water such as blueberry water, or natural thermal or mineral water, for example chosen from Vittel water, Vichy basin water, Uriage water, Roche Posay water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-Bains, water from Néris- les-Bains, water from Allevard-les-Bains, water from Digne, water from Maizières, water from Neyrac-les-Bains, water from Lons-le-Saunier, Eaux Bonnes, water from Rochefort, water from Saint Christau, water from Fumades and water from Tercis-les-bains, water from Avène or Aix les Bains water. Said aqueous phase may be present at a content of between 10 and 90% by weight relative to the total weight of the composition, preferably between 20 and 80% by weight.

By way of nonlimiting examples, there may be mentioned gelling agents of the polyacrylamide family such as the Sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 mixture sold under the name Simulgel 600 by the company Seppic, the polyacrylamide / isoparaffin C13-14 / laureth-7 like, for example, that sold under the name of Sepigel 305 by the company Seppic, the family of acrylic polymers coupled to hydrophobic chains such as the PEG-150 / decyl / SMDI copolymer sold under the name of Aculyn 44 ( polycondensate comprising at least as elements, a polyethylene glycol with 150 or 180 moles of ethylene oxide, decyl alcohol and methylene bis (4-cyclohexylisocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol ( 39%) and water (26%)), the family of modified starches such as modified potato starch sold under the name Structure Solanace or their mixtures.

The preferred gelling agents come from the family of polyacrylamides such as Simulgel 600 or Sepigel 305 or their mixtures. The gelling agent as described above can be used at preferential concentrations ranging from 0.1 to 15% and, more preferably, ranging from 0.5 to 5%.

The gels can preferably be prepared by dispersing or dissolving metronidazole in an appropriate ratio, in a gel of carbomer, poloxamer or cellulosic type.

Other advantages and characteristics of the invention will appear from the examples below concerning the activity of metronidazole.

Example 1 Activity of Metronidazole on the Secretion of Interleukins

Materials and methods :

The secretion of IL-5, IL-6 and IL-10 was measured on peripheral blood mononuclear cells (PBMC) according to the method used by Endo

(Endo et al., 1993, Int Arch Allergy Immunol, vol.101, pages 425-430). PBMCs are isolated from peripheral venous blood treated with heparin, separated by density gradient centrifugation and suspended in RPMI 1640 medium. To stimulate the secretion of interleukins, the PBMCs are cultured in the presence of Concavalin A at 20 μg / ml. Then the cells are incubated for 48 h at 37 ° C in the presence of metronidazole. The culture supernatant is then recovered and used to test the level of secretion of the interleukins. The productions of IL-5, IL-6 and IL-0 are quantified using enzyme immunoassay kits (R&D System). The tests are performed in duplicate according to the manufacturer's recommendations. The results are expressed (table 1) as a percentage of control value and as a percentage of variation of control values.

The production of IL-5, IL-6 and IL-10 by the PBMCs are studied in the presence of metronidazole at 10 μM. Table 1

Metronidazole therefore inhibits the secretion of interleukin-5, interleukin-6 and interleukin-10

Claims

1) Use of metronidazole for the preparation of a pharmaceutical composition intended for treating skin inflammation.

2) Use according to claim 1, characterized in that said skin inflammation results from the secretion of at least one interleukin chosen from the group comprising IL-5, IL-6 and IL-10.

3) Use according to claim 1 or 2, characterized in that said skin inflammation results from the secretion of two or three interleukins chosen from the group comprising IL-5, IL-6 and IL-10.

4) Use according to any one of claims 1 to 3, characterized in that said inflammation is the inflammatory component of rosacea and in that metronidazole is capable of modifying the secretion of at least one interleukin chosen from the group comprising IL-5, IL-6 and IL-10.

5) Use according to any one of claims 1 to 4, characterized in that metronidazole is capable of modifying the secretion of two or three interleukins chosen from the group comprising IL-5, IL-6 and IL-10.

6) Use according to any one of claims 1 to 5, characterized in that metronidazole inhibits the secretion of at least one interleukin chosen from the group comprising IL-5, IL-6 and IL-10.

7) Use according to any one of claims 1 to 6, characterized in that metronidazole inhibits the secretion of two or three interleukins chosen from the group comprising IL-5, IL-6 and IL-10.

8) Use according to any one of claims 1 to 7, characterized in that said pharmaceutical composition is a dermatological composition for topical application. 9) Use according to any one of claims 1 to 8, characterized in that the composition is intended for the treatment of at least one stage of rosacea.

10) Use according to any one of claims 1 to 9, characterized in that the composition is intended for the treatment of the first stage of rosacea.

11) Use according to any one of claims 1 to 10, characterized in that the composition is intended for the treatment of the second stage of rosacea.

12) Use according to any one of claims 1 to 11, characterized in that the composition is intended for the treatment of the third stage of rosacea.

13) Use according to any one of claims 1 to 12, characterized in that the composition is intended for the treatment of the fourth stage of rosacea.

14) Use according to any one of claims 1 to 13, characterized in that the composition contains of the order of 0.0001 to 20% by weight and preferably 0.1 to 2% of metronidazole, and more preferably on the order of 0.75 to 1% by weight of metronidazole.

15) Use according to any one of claims 1 to 14, characterized in that said composition additionally contains another active agent chosen from the group of antibiotics, antibacterials, antivirals, antiparasitics, antifungals, anesthetics, analgesics, antiallergics, retinoids, anti-free radicals, antipruritics, keratolytics, antiseborrheics, antihistamines, sulfides, immunosuppressive or antiproliferative products.

16) Use according to any one of claims 1 to 15, characterized in that the composition contains an additive chosen from the group of sequestrants, antioxidants, sun filters, preservatives, fillers, electrolytes, humectants, dyes, bases or common acids, mineral or organic, perfumes, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingolipids, compounds self-tanners, soothing and protective agents for the skin, penetrating agents, gelling agents or a mixture of these.