Topical compositions for the treatment of cutaneous leishmaniasis

Abstract

The present invention relates to a composition comprising a combination of a (halogenoacetamido)benzoate, a flavonol and a terpene, and, as example, relates to a composition comprising the combination of ethyl 3-(2-chloroacetamido)benzoate, dihydroquercetin and bisabolol. Said composition is for use in the treatment of leishmaniasis, especially cutaneous or mucosal leishmaniasis, the composition being applied topically for concomitantly treating both parasitic infection and skin inflammation of the infected area induced by leishmaniasis.

Claims

1. A composition comprising a combination of a (halogenoacetamido)benzoate, a flavonol and a terpene, wherein the (halogenoacetamido)benzoate is ethyl 3-(2-chloroacetamido)benzoate or ethyl 3-(2-bromooacetamido)benzoate, the flavonol is selected from the group consisting of quercetin, kaempferol, dihydroquercetin, dihydrokaempferol, and mixture thereof, the terpene is selected from the group consisting of linanol, bisabolol, beta caryophyllene and a mixture thereof.

2. The composition according to claim 1, wherein the concentration of the (halogenoacetamido)benzoate ranges from 0.01% to 2% in weight of the total weight of the composition (w/w).

3. The composition according to claim 1, wherein the concentration of the flavonol ranges from 0.05% to 10% in weight of the total weight of the composition (w/w).

4. The composition according to claim 1, wherein the concentration of the terpene ranges from 0.01% to 3.0% in weight of the total weight of the composition (w/w).

5. The composition according claim 1, comprising ethyl 3-(2 chloroacetamido)benzoate, dihydroquercetin, bisabolol, and a pharmaceutically acceptable vehicle.

6. The composition according to claim 5, comprising from 0.1% to 0.7% w/w ethyl 3-(2-chloroacetamido)benzoate, from 0.2% to 3% w/w dihydroquercetin, from 0.1% to 0.5% w/w bisabolol, and the pharmaceutically acceptable vehicle.

7. The composition according claim 1, wherein the composition further comprises at least one of animal fat, vegetable fat, fatty alcohols, glycols or mixtures thereof.

8. The composition according to claim 1, wherein the composition further comprises at least one surfactant, pigment, stabilizer, emollient, humectant, or mixtures thereof.

9. The composition according to claim 1, wherein the composition is a cream, a gel, an ointment, a solution, an emulsion, an oil-in-water emulsion, a mask, a stick, a milk, a lotion, a serum, a paste, a foam, or a suspension.

10. The composition of claim 1 wherein the terpene is a monoterpene or a sesquiterpene.

11. A method for the treatment of leishmaniasis and any, leishmaniasis associated inflammation of an infected area, comprising administering to a subject in need thereof the composition of claim 1.

12. The method of claim 11, wherein the composition is for topical application, and the leishmaniasis is cutaneous leishmaniasis or mucosal leishmaniasis.

13. A delivery device comprising the composition according to claim 1.

14. A process of manufacturing the composition according to claim 1 comprising a step of blending a (halogenoacetamido)benzoate, a flavonol and a terpene with a pharmaceutical acceptable vehicle.

Description

DETAILED DESCRIPTION

(1) Composition

(2) In a first aspect the present invention relates to a composition comprising a combination of a (halogenoacetamido)benzoate, a flavonol and a terpene, and, as example, relates to a composition comprising the combination of ethyl 3-(2-chloroacetamido)benzoate, dihydroquercetin and bisabolol. Ethyl 3-(2-chloroacetamido)benzoate (ECAB), also known as 3-(2-chloroacetylamino)benzoic acid ethyl ester, or ethyl 3-(chloroacetyl)aminobenzoate (CAS number [58915-19-8]), is a compound of formula (I):

(3) ##STR00001##

(4) In one embodiment, the concentration of the (halogenoacetamido)benzoate, for instance ECAB, in the composition according to the invention ranges from 0.01% to 2.0% w/w (i.e. in weight, by weight of the total composition), preferably from 0.1% to 1% w/w, more preferably from 0.3% to 0.7% w/w.

(5) Dihydroquercetin (DHQ) is the common name of 3,3′,4′,5,7-pentahydroxyflavone dehydrate, also called 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one dehydrate, also known as taxifolin (CAS number [480-18-2]).

(6) In one embodiment, DHQ is extracted from a type of larch wood, preferably from Siberian larch. In an embodiment, DHQ containing powder contains at least 96% w/w by weight of DHQ and corresponds to the technical requirements and sanitary rules on the basis of analytical and microbiological reports.

(7) In one embodiment of the present invention, the concentration of the flavonol, for instance DHQ, in the composition according to the invention ranges from 0.05% to 10% w/w (i.e. in weight, by weight of the total composition), preferably from 0.1% to 5.0% w/w, more preferably from 0.2% to 3%. In a specific example DHQ may be present at a concentration from 1.0% to 2.0% w/w.

(8) Bisabolol is the common name of 6-methyl-2-(4-methyl-3-cyclohexen-1-yl)-5-hepten-2-ol, or 1-methyl-4-(1,5-dimethyl-1-hydroxyhex-4(5)-nyl)cyclohexen-1, also known as levomenol (CAS number [23089-26-1]). Bisabolol is a sesquiterperne found in various plants, including herbal tea and chamomile.

(9) In one embodiment, the concentration of the terpene, for instance bisabolol, in the composition according to the invention ranges from 0.01% to 3.0% w/w (i.e. in weight, by weight of the total composition), preferably ranges from 0.05% to 2.5% w/w, more preferably from 0.05% to 2.0% w/w, even more preferably from 0.1% to 2.0% w/w.

(10) In one embodiment, the composition according to the invention comprises or consists of ECAB, DHQ and bisabolol, in association with any acceptable vehicle. According to one embodiment, the composition according to the invention comprises ECAB, DHQ and bisabolol, in association with a pharmaceutically acceptable vehicle.

(11) In one embodiment, the composition according to the invention comprises: from 0.01% to 2.0% w/w of ECAB, preferably from 0.05% to 1% w/w, more preferably from 0.1% to 0.7% w/w, and from 0.05% to 10% w/w of DHQ, preferably from 0.1% to 5.0% w/w, more preferably from 0.2% to 3.0% w/w, and from 0.01% to 3.0% w/w of bisabolol, preferably from 0.05% to 2.5% w/w, more preferably from 0.05% to 2.0% w/w, even more preferably from 0.1% to 2.0% w/w, and a pharmaceutically or cosmetically acceptable vehicle.

(12) In one embodiment, the composition according to the invention further comprises at least one compound selected from the group comprising animal fat, vegetable fat, higher alcohols, such as fatty alcohols, glycols, mineral oil or a mixture thereof. In one embodiment, the composition according to the invention comprises an acceptable vehicle which comprises at least one compound selected from the group comprising animal fat, vegetable fat, higher alcohols, glycols, mineral oil or a mixture thereof.

(13) A non-limitative example of animal fat is stearic acid. Examples of vegetable fat include, but are not limited to linoleic acid, jojoba oil (also called oil Simmondsia chinensis), sweet almond oil, avocado oil or a mixture thereof. Fatty alcohols are preferably with more than 10 carbon atoms, more preferably more than 12 carbon atoms, examples include, but are not limited to cetearyl alcohol, stearyl alcohol, cetylic alcohol. Examples of glycols include, but are not limited to propylene glycol. Examples of mineral oil include, but are not limited to paraffin oil.

(14) In one embodiment, the composition according to the invention further comprises at least one component selected from the group comprising surfactants, pigments, stabilizers, emollients, humectants or a mixture thereof.

(15) Examples of surfactants include, but are not limited to PEG-100 stearate, PEG-20 stearate or a mixture thereof. Examples of stabilizers include, but are not limited to carbomer. Examples of pigments include, but are not limited to zinc oxide. Examples of emollients include, but are not limited to caprylic/capric triglyceride, dicapryl ether, glyceryl stearate, glyceryl monostearate or a mixture thereof. Examples of humectants include, but are not limited to glycerin, sorbitol or a mixture thereof.

(16) In one embodiment, the composition according to the invention further comprises perfume, such as for example citronellol, geraniol, limonene, cinnamyl alcohol, butyl phenyl methylpropional, or a mixture thereof.

(17) In one embodiment, the composition according to the invention further comprises preservatives such as, for example, imidazolidinyl urea.

(18) In one embodiment, the composition according to the invention further comprises water.

(19) In one embodiment, the composition according to the invention is designed for topical administration. In one embodiment, the composition according to the invention is in a form adapted to topical administration, such as, for example, in the form of a cream, a gel, an ointment, a solution, an emulsion, a mask, a milk, a lotion, a serum, a paste, a stick, a foam or a suspension. In a preferred embodiment, the composition according to the invention is a cream or a stick. In another preferred embodiment, the composition according to the invention is a gel. In a further preferred embodiment, the composition according to the invention is an oil-in-water emulsion.

(20) In an embodiment, the composition according to the invention is a therapeutic composition. In one embodiment, the composition according to the invention is a pharmaceutical composition.

(21) Treatment of Leishmaniasis

(22) In a second aspect, this invention relates to a composition comprising a combination of a (halogenoacetamido)benzoate, a flavonol and a terpene, preferably comprising ethyl 3-(2-chloroacetamido)benzoate, dihydroquercetin and bisabolol for use in the treatment of leishmaniasis, preferably visceral leishmaniasis, cutaneous leishmaniasis or mucosal leishmaniasis, more preferably cutaneous leishmaniasis or mucosal leishmaniasis, and the associated inflammation of the infected area.

(23) The term “treatment of leishmaniasis” comprises treating the inflammation in the infected areas due to, or associated with, leishmaniasis. By “infected areas” is meant any part of the body where inflammation caused by leishmaniasis is present. Examples of such infected areas are, without limitation, skin and mucosa.

(24) In a third aspect, the invention relates to a method of treating a subject suffering from leishmaniasis by administering an effective amount of a composition comprising ethyl 3-(2-chloroacetamido)benzoate (ECAB), dihydroquercetin (DHQ) and bisabolol or any composition comprising a (halogenoacetamido)benzoate, a flavonol and a terpene to a subject in need thereof.

(25) In a fourth aspect, the invention relates to the use of a composition comprising ethyl 3-(2-chloroacetamido)benzoate (ECAB), dihydroquercetin (DHQ) and bisabolol or any composition comprising a (halogenoacetamido)benzoate, a flavonol and a terpene in the manufacture of a medicament for the treatment of leishmaniasis.

(26) In one embodiment, the leishmaniasis is visceral leishmaniasis, cutaneous leishmaniasis or mucosal leishmaniasis. In a particular embodiment, the leishmaniasis is cutaneous leishmaniasis.

(27) In one embodiment, the subject is infected by Leishmania aethiopica, Leishmania amazonensis, Leishmania braziliensis, Leishmania donovani, Leishmania guyanensis, Leishmania infantum, Leishmania lainsoni, Leishmania lindenbergi, Leishmania mexicana, Leishmania major, Leishmania naiffi, Leishmania panamensis, Leishmania peruviana, Leishmania shawi, Leishmania tropica and/or Leishmania venezuelensis. In a particular embodiment, the subject is infected by Leishmania amazonensis, Leishmania donovani, and/or Leishmania major.

(28) In one embodiment, leishmaniasis related symptoms is an inflammation induced by leishmaniasis parasite infection in skin or mucosa.

(29) In one embodiment, treating leishmaniasis means preventing and/or reducing visible signs of leishmaniasis. The term “visible signs of leishmaniasis” includes but is not limited to skin or mucosal lesions such as papules, nodular plaques and open or closed sores.

(30) In one embodiment, treating leishmaniasis means preventing and/or limiting cutaneous or mucosal discomfort induced by leishmaniasis. Examples of discomfort induced by leishmaniasis include, but are not limited to, itching and pain.

(31) In an embodiment, the composition used in the treatment according to the invention is a therapeutic composition. In one embodiment, the composition used in the treatment according to the invention is a pharmaceutical composition.

(32) In one embodiment, the composition used in the treatment according to the invention is for external use. In one embodiment, the composition is for topical application, preferably for use in the treatment of cutaneous leishmaniasis or mucosal leishmaniasis. In an embodiment, the treatment according to the invention requires the composition to be applied on inflamed skin or mucosa.

(33) In one embodiment, an amount of composition used in the treatment according to the invention is applied which is sufficient to cover the afflicted area of the skin or mucosa with a thin layer of the composition.

(34) In one embodiment, the composition used in the treatment according to the invention may be applied one, two, three or more times a day. In one embodiment, the composition used in the treatment according to the invention may be applied during 7, 14 or 21 days or until the visible symptoms of leishmaniasis disappear.

(35) Device and Kit

(36) In a fifth aspect, the invention relates to a device including a composition comprising ethyl 3-(2-chloroacetamido)benzoate (ECAB), dihydroquercetin (DHQ) and bisabolol or any composition comprising a (halogenoacetamido)benzoate, a flavonol and a terpene according to the invention.

(37) In one embodiment, the device is a delivery device. In one embodiment, the device is a medical device.

(38) In a sixth aspect, the invention relates to a kit comprising the composition a composition comprising ethyl 3-(2-chloroacetamido)benzoate (ECAB), dihydroquercetin (DHQ) and bisabolol or any composition comprising a (halogenoacetamido)benzoate, a flavonol and a terpene according to the invention, and/or a device comprising the composition according to the invention.

(39) Process of Manufacture

(40) In a seventh aspect, the invention relates to a process for manufacturing the composition according to the invention. In an embodiment, the process of the invention comprises a step of blending ECAB, DHQ and bisabolol or any composition comprising a (halogenoacetamido)benzoate, a flavonol and a terpene, with an acceptable vehicle. In one embodiment, the process of the invention comprises a preliminary step of dissolving DHQ or any flavonol in jojoba oil (Simmondsia chinensis) or sweet almond oil before blending the three active components with an acceptable vehicle.

Examples

(41) The present invention is further illustrated by the following examples.

(42) Compositions According to the Invention

(43) Examples of compositions comprising ECAB, DHQ, bisabolol and a pharmaceutically acceptable vehicle being an oil/water emulsion are presented in the table 1 below.

(44) TABLE-US-00001 TABLE 1 Composition ECAB DHQ bisabolol example (% w/w) (% w/w) (% w/w) [Vehicle] 1 0.3 0.2 0.1 qsp 100% 2 0.4 0.5 0.5 qsp 100% 3 0.5 1.0 1.0 qsp 100% 4 0.6 2.0 1.5 qsp 100% 5 0.7 3.0 2.0 Qsp 100% 6 1.0 5.0 3.0 Qsp 100%

(45) From the knowledge of the inventor, it is the first time that a topical formulation targeting both the parasite and the cells responsible for the inappropriate immune response is proposed for the treatment of cutaneous leishmaniasis.

(46) A trial is being performed on dogs having leishmaniasis.

(47) Infected dogs have been treated by topical formulation of example 6 in the form of a cream containing, as active ingredients, ethyl 3-(2 chloroacetamido)benzoate (1% w/w), dihydroquercetin 5% w/w) and bisabolol (3% w/w).

(48) Preliminary data coming from this going on trial in dogs having leishmaniasis show an objective response in the treated dog population as evidenced by a significant reduction of the size of the cutaneous lesions.