PIERRET, Jean-Dominique (Cote Nature - Aubepine, 806 chemin de Peidessalle, Valbonne, 06560, FR)
DOLFI, Fabrizio (11-1, les hauts de Veyriere, Valbonne, F-06560, FR)
LOESCHE, Christian (1 Place des Cines, Valbonne, Valbonne, 06560, FR)
TREMEL, Nadège (Résidence Côté Nature, 806 chemin de Peidessalle, Valbonne, F-06560, FR)
PIERRET, Jean-Dominique (Cote Nature - Aubepine, 806 chemin de Peidessalle, Valbonne, 06560, FR)
DOLFI, Fabrizio (11-1, les hauts de Veyriere, Valbonne, F-06560, FR)
LOESCHE, Christian (1 Place des Cines, Valbonne, Valbonne, 06560, FR)
| Purified Water QS 100.00
EXAMPLE 4
An illustration is given here of a concrete formulation example in accordance with the invention which is provided in the form of a blend powder for capsule for oral use:
Tropisetron HCl 5 mg
Mannitol 83,5mg Corn starch 10 mg
Anhydrous colloidal Silica 0.5 mg
Magnesium Stearate 1 mg
Claims
1. Use of an effective amount of at least a compound chosen from tropisetron and its salts for the manufacture of a pharmaceutical composition for the treatment of inflammatory skin disorders and/or inflammatory skin diseases.
2. Use according to claim 1, wherein the inflammatory skin disorders and/or inflammatory skin diseases are induced by the presence of a pathogenic agent.
3. Use according to claim 1 or 2, wherein the amount of tropisetron or its salts present in said pharmaceutical composition ranges from about 0.0001% to 20% by weight with respect to the total weight of the pharmaceutical composition.
4. Use according to claim 1 or 3, wherein said skin disorder and/or skin disease is selected from the group consisting of eczema, psoriasis, rosacea, acne vulgaris, ulcers, seborrhoeic dermatitis and irritations induced by chemical, physical or mechanical agents.
5. Use according to one of claims 1 to 4, wherein said skin disease is rosacea.
6. Use according to anyone of preceding claims, characterized in that the composition is adapted to a topical administration.
7. Use according to anyone of claims 1 to 5, characterized in that the composition is adapted to an oral administration.
8. Use of an effective amount of at least a compound chosen from tropisetron and its salts for the manufacture of a topical pharmaceutical composition for the treatment of rosacea.
9. Use according to claim 5, wherein the pharmaceutical composition is for the treatment of all subtypes of rosacea.
10. Use according to claim 5, wherein the pharmaceutical composition is for the treatment of early stages of rosacea.
11. Use according to claim 5, wherein the pharmaceutical composition is for the treatment of erythematotelangiectatic rosacea.
12. Use according to claim 5, wherein the pharmaceutical composition is for the treatment of papulopustular rosacea.
13. Use according to claim 5, wherein the pharmaceutical composition is for the treatment of phymatous rosacea.
14. Use according to claim 5, wherein the pharmaceutical composition is for the treatment of ocular rosacea.
15. Composition comprising an effective amount of a compound chosen from tropisetron and its salts, and a topical pharmaceutically acceptable carrier therefore.
16. Composition according to claim 15, characterized in that it is in the form of a gel.
17. Composition according to claim 15, characterized in that it is in the form of a cream.
18. Composition according to claim 15, characterized in that it is in the form of a lotion.
19. Cosmetic use of a composition according to claim 15 for alleviating skin aspect. |
Method of Treating Inflammatory skin diseases using tropisetron, and Pharmaceutical Compositions Thereof
The present invention generally relates to the use of tropisetron as an active principle in the manufacture of pharmaceutical compositions, more particularly dermatological compositions, intended for the treatment of inflammatory skin disorders/diseases, and particularly for the treatment of rosacea.
Tropisetron, or (+)1H- Indole-3-carboxilic acid (3-en<io)-8-methyl-8- azabicyclo[3.2.1]oct-3-yl-ester, is a product which is already known per se, and is disclosed and claimed in U.S. Patent 4,789,673. Tropisetron acts as a potent and selective antagonist of the neuronal 5ηT receptor type 3, found associated with neurones of both peripheral (for example on sensory nerve endings in the skin) and central origin. Specifically, tropisetron has been approved in the past in palliative therapy to prevent or treat chemotherapy induced nausea and vomiting and to treat post-operative nausea and vomiting.
In addition, this compound has been showed recently as being useful as analgesic and anti-inflammatory agent: for instance, in vivo data obtained by Mϋller and Stratz who found tropisetron to be potent inhibitor of inflammation diseases such as rheumatic arthritis in "Local treatment of tendinopathies and myofascial pain syndrome with the 5- HT3 receptor antagonist tropisetron" Mϋller W et al. - Scand J. Rheumatol 2004; 119:44-48.
More broadly in "Physiology and pathophysiology of the 5-HT3 receptor" (Farber L et al. - Scand J Rheumatol Suppl. 2004;(119):2-8), effects of 5-HT3 receptor antagonists have been described in the following disorders: intestinal effects (particularly in IBS and diarrhoea treatment) ; cardiac effects ; central nervous system related disorders like anxiety, drug addiction, cognitive functions and thermoregulation, in nociception and pain particularly with rheumatoid arthritis, tendinopathies and myofascial pain as well as long-lasting analgesic and antiphlogistic effect (by local or intra-articular injection), chronic fatigue syndrome and certain forms of pruritus.
There is, however, no published data regarding the use of tropisetron in order to treat an inflammatory skin disorder/disease and preferably rosacea.
Thus, the subject of the present invention is the use of an effective amount of at least a compound chosen from tropisetron and its salts for the manufacture of a pharmaceutical composition for the treatment and/or prevention of inflammatory skin disorders and/or inflammatory skin diseases, particularly inflammatory skin disorders and/or skin diseases induced by the presence of a pathogenic agent (for example virus, bacterian or genetic agent) and preferentially for the treatment of rosacea, preferably by the oral or topical routes.
By effective amount, it is meant a sufficient amount to prevent and/or treat inflammatory skin disorders and/or skin diseases, and particularly to treat rosacea, by the oral or topical routes.
Additionally, the present invention provides a novel method of treating inflammatory skin disorders and/or skin diseases, particularly to treat inflammatory skin disorders and/or skin diseases induced by the presence of a pathogenic agent and preferentially to treat rosacea, preferably by the topical or oral routes, by topically applying or orally administering a pharmaceutical composition comprising tropisetron or its salts. By salts of tropisetron, we mean its ionic salts, and preferably its hydrochloride salt.
For the purpose of the instant invention, the inflammatory skin disorders and/or skin diseases induced by the presence of a pathogenic agent are understood as being at least partially caused by or resulting from or being the skin manifestation(s) of the presence of a living pathogen like virus, yeast, fungus, protozoon, bacterial agent or genetic alteration.
Among other causes, rosacea is for example due to the pathogen Demodex folliculorum. Likewise, acnea, and notably acnea vulgaris, is due to Propionibacterium acnes.
Rosacea is a common, but often overlooked, skin condition of uncertain etiology that can lead to significant facial disfigurement, ocular complications, and severe emotional
distress. A reviewed standard classification system for rosacea was published in the June 2004 issue of the Journal of the American Academy of Dermatology. Developed by the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea and reviewed by rosacea experts worldwide, it describes primary and secondary features of rosacea (as described below) and recognizes 4 patterns of signs and symptoms, designated as subtypes:
Subtype 1: erythematotelangiectatic rosacea.
Subtype 1 is characterized by flushing and persistent central facial erythema. Telangiectases are common but not essential for the diagnosis. Subtype 2: papulopustular rosacea.
Subtype 2 includes persistent central facial erythema with transient papules, pustules, or both in a central facial distribution. Burning and stinging may also be reported. Subtype 3: phymatous rosacea. This subtype may include thickening skin, irregular surface nodularities, and enlargement. Phymatous rosacea occurs most commonly as rhinophyma but may appear elsewhere, including the chin, forehead, cheeks, and ears. Patulous, expressive follicles may appear in the phymatous area, and telangiectases may be present. Subtype 4: ocular rosacea. Ocular rosacea may include watery or bloodshot appearance (interpalpebral conjunctival hyperemia), foreignbody sensation, burning or stinging, dryness, itching, light sensitivity, blurred vision, telangiectasia of the conjunctiva and lid margin, or lid and periocular erythema. Blepharitis, conjunctivitis, and irregularity of the eyelid margins also may occur. Meibomian gland dysfunction presenting as chalazion, or chronic infection as manifested by hordeolum (stye), are common. Some patients may experience loss of vision as a result of corneal complications (punctate keratitis, corneal infiltrates, ulcers, or marginal keratitis). An ophthalmologic consultative approach to treatment may be required.
Central facial erythema and telangiectasis are predominant in the early stages of rosacea. This progresses to a chronic inflammatory infiltrate with central facial papules and pustules. Intermittent or chronic facial edema may also occur. Some patients develop
rhinophyma, a coarse hypertrophy of the connective tissue and sebaceous glands of the nose evident as small knobby bumps on the nose.
The predominant, presenting complaints of rosacea are intermittent, central facial flushing and erythema. Itching is typically absent; however, many patients complain of a stinging pain (which can be severe) associated with flushing episodes. These flushing episodes are often socially embarrassing and can occur unpredictably or can be linked to environmental, chemical, food, or emotional triggers. Common triggers include exposure to the sun, cold weather, sudden emotion (laughter or embarrassment), hot beverages, and alcohol consumption.
According to the present invention, tropisetron is administered by any routes, i.e. orally enterally, parenterally (subcutaneously, cutaneously, intravenously, intramuscularly), topically or ocularly, but preferentially as mentioned earlier by oral, topical or ocular routes.
Therefore, topical tropisetron (in cream, gel, or lotion form, for example) or oral tropisetron (in tablets, capsules, powder, syrup or liquid forms for instance) administered once or twice daily is effective for the treatment of rosacea subtypes, particularly early stages of rosacea and preferably facial flushing and erythema.
The present invention also teaches that topical or oral tropisetron is appropriate to treat each subtype symptoms (disclosed previously) separately or in combination and hence can reduce pustular and papular rosacea, ocular rosacea and telangiectasis in some patients.
As a consequence, the invention relates to the use of an effective amount of at least a compound chosen from tropisetron and its salts for the manufacture of a pharmaceutical composition for treating rosacea. It also relates to the use of tropisetron or its salts for the manufacture of a topical pharmaceutical composition for the treatment of all subtypes of rosacea and preferably for the treatment of early stages of rosacea, i.e. wherein the rosacea is treated at a stage in which facial flushing and skin redness is evident.
In another embodiment, the present invention also relates to the use of tropisetron or its salts for the manufacture of a topical pharmaceutical composition for the treatment of erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and/or ocular rosacea.
Rosacea is a chronic, relapsing disorder, and a long-term treatment is generally required. Control of symptoms can be successfully maintained by topical or oral use of tropisetron.
Other characteristics, aspects, objectives and advantages of the invention will become still more clearly apparent on reading the description which follows and various concrete, but in no way limiting, examples intended to illustrate it.
In a preferred embodiment, the pharmaceutical composition of the invention is intended for topical use. More particularly, the pharmaceutical composition is a dermatological composition.
Such a composition according to the present invention is a composition, in particular for the topical treatment of inflammatory skin disorders/diseases, comprising an effective amount of a compound chosen from tropisetron and its salts and a topical pharmaceutically acceptable carrier therefore. By topical pharmaceutically acceptable carrier, it is meant a carrier compatible with the skin, hair and/or mucous membranes, which is applied topically.
The dermatological composition is more generally intended for the treatment, by the topical route, of skin diseases or complaints having at least a vascular lesion, one inflammatory component or, at the same time, one inflammatory and one infectious components.
More particularly, the skin diseases or disorders correspond to skin inflammations accompanying any type of dermatosis such as eczema, psoriasis, rosacea, acne vulgaris, ulcers, seborrhoeic dermatitis and irritations induced by chemical, physical or mechanical
agents or others. The present invention is especially useful in the topical treatment of rosacea using tropisetron or its salts.
In what follows, "topical route" is understood to mean any technique for administration of a product by direct application to a surface (or external) part of the body, such as the skin or eye.
By the topical route, the pharmaceutical compositions comprising tropisetron or its salts, which are therefore more particularly intended for the treatment of the skin or mucous membranes, can be provided in the form of ointments, creams, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be provided in the form of lipid or polymer vesicles or nanospheres or microspheres or in the form of polymer patches or hydrogels making possible a controlled release formulation. These compositions by the topical route can moreover be provided either in anhydrous form or in an aqueous form, according to the clinical indication. Formulations for topical use which are particularly highly suitable in the context of the implementation of the present invention are given in particular in the examples of the present specification.
In a preferred embodiment of the invention, the topical composition is in the form of a gel, a cream or a lotion.
By the ocular route, compositions of the present invention are mainly eyewashes or eye drops.
For the purposes of the present invention, oral route is understood as any technique for administration of a product by digestive absorption.
By oral route, compositions of the present invention are tablets, capsules, pills, coated- tablets, powders, granules, syrups, emulsions, solutions, suspensions as well as microspheres or nanospheres or lipidic or polymeric vesicles for slow or controlled- release.
The compositions, preferably for topical or oral use, according to the invention contain tropisetron or its salts at a concentration preferably of between 0.0001% and 20% by weight with respect to the total weight of the pharmaceutical composition, more preferably at a concentration comprised between 0.01% and 1%.
According to a specific and preferred embodiment of the present invention, the overall content of the tropisetron or its salts does not exceed 20% of the total weight of the composition. Preferably, the medicinal compositions are topically applied once or twice a day, for a period of maximum 3 months.
In addition, the said composition could also be used for a cosmetic use for alleviating skin aspect. In particular, said composition can improve the appearance of skin and/or skin radiance and/or skin roughness.
The medicinal compositions according to the invention can, of course, additionally contain inert or even pharmacodynamically or cosmetically active additives or combinations of these additives and in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients such as glycerine; hydrating agents such as glycerol, PEG 400, thiamorpholinone and its derivatives or alternatively urea; antiseborrhoeic or anti-acne agents, such as S- carboxymethylcysteine, S-benzylcysteamine, their salts or their derivatives, or benzoyl peroxide; fungicides such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; carotenoids and in particular beta-carotene; antipsoriatic agents such as anthralin and its derivatives; and finally 5,8,11,14-eicosatetraynoic acid and 5,8,11-eicosatriynoic acid and their esters and amides; metronidazole, ivermectine, and other agents used for treating rosacea; anti-inflammatory agents such as NSAIDs (Non Steroidal Anti-Inflammatory Drugs).
The compositions according to the invention can also contain flavor-improving agents, preserving agents, such as the esters of para-hydroxybenzoic acid, stabilizing agents, moisture-regulating agents, pH-regulating agents, agents for modifying osmotic pressure,
emulsifying agents, UV-A and UV-B screening agents, and antioxidizing agents, such as alpha-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
Of course, a person skilled in the art will take care of choosing the optional compound(s) to be added to the pharmaceutical composition so that the advantageous properties intrinsically attached to the composition are not, or not substantially, detrimentally affected by the envisaged addition.
A number of examples intended to illustrate various concrete formulations in accordance with the invention will now be given, without implied limitation.
EXAMPLE 1
An illustration is given here of a concrete formulation example in accordance with the invention which is provided in the form of a gel for topical use: Tropisetron HCl 0.75 g
Carbopol 980 (Goodrich) 0.6 g Polyethylene glycol 400 3 g
Sodium hydroxide q.s. pH 5
Preserving agents q.s.
Demineralized water q.s. for 100 g
EXAMPLE 2
An illustration is given here of a concrete formulation example in accordance with the invention which is provided in the form of a cream for topical use: Tropisetron HCl 0.75 g
Methyl glucose sesquistearate 1 g
Stearyl alcohol 0.5 g
Liquid paraffin oil 6 g
Polyethylene glycol 400 2 g Methyl glucose sesquistearate polyoxyethylenated with 20 mol of EO 5 g
Carbopol 981 (Goodrich) 0.4 g
Glycerol 7 g
Cyclomethicone 4 g
Sodium hydroxide q.s. pH 5 Preserving agents q.s.
Demineralized water q.s.for 100 g
EXAMPLE 3
An illustration is given here of a concrete formulation example in accordance with the invention which is provided in the form of a lotion for topical use:
Tropisetron HCl 0.75 g Benzyl alcohol 1.30
Glycerol 7.00
Stearyl alcohol 2.00
Light mineral oil 6.00
Carbomer 941 0.15 Glyceryl Stearate 3.00
Potassium Sorbate 0.20
Cyclomethicone 4.00
PEG-8 2.00
Steareth-21 3.00 Lactic acid QS PH adjustment
Sodium Hydroxyde QS pH adjustment
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