WO2009129627A1

WO2009129627A1 - Novel resveratrol compositions

Info

Publication number: WO2009129627A1
Application number: PCT/CA2009/000546
Authority: WO
Inventors: Pascale CLÉMENT; Mikaela Teris
Original assignee: Pharmascience Inc.
Priority date: 2008-04-25
Filing date: 2009-04-24
Publication date: 2009-10-29
Also published as: CA2629979A1

Abstract

The present invention relates to compositions for topical use comprising solubilized resveratrol in a stable emulsion in a solvent system which does not cause irritation to the skin, wherein the solvent system comprises dimethyl isosorbide. The compositions according to present invention can preferably be used for transdermal applications for the treatment of various skin diseases such as psoriasis, acne and herpes simplex virus. The present invention also relates to the process to make such compositions.

Description

NOVEL RESVERATROL COMPOSITIONS

Field of the Invention

The present invention is directed to novel stable compositions for topical use containing solubilized resveratrol. In particular, the present invention is directed to topical compositions containing solubilized resveratrol in an emulsion with solvents which do not cause skin irritation.

Background of the Invention

Resveratrol (3,5,4'-trihydroxystilbene) is a molecule that was isolated from the roots of white hellebore around 1940. Resveratrol (including trans-resveratrol, cis-resveratrol, cis- resveratrol glucoside and trans-resveratrol glucoside) is present in wine, particularly red wine, and in the early 1990's it was speculated to be the reason for the cardio-protective efficacy of wine.

Resveratrol is a poorly soluble compound and compositions containing it have a tendency to exhibit crystal precipitation when insufficient solvent is used to solubilize it. It is also well known that this molecule is very sensitive to external sources and can undergo degradation upon exposure to heat or light.

Emulsions are understood as being mixtures of two immiscible substances. An emulsion consists of a dispersed phase and a continuous phase. The dispersed phase is generally understood to be the phase which is not the predominant phase in terms of weight (or volume). For example, butter and margarine are known to be water-in-oil emulsions. Milk on the other hand is known to be an oil-in-water emulsion. In general, emulsions are cloudy, in light of the numerous phase interfaces which scatter light passing through the emulsion. Emulsions also tend to be unstable and revert back to their separated states. To create an emulsion there must be stirring or any other type of mixing of the two phases and the emulsifier in order to create a homogenous mixture.

Resveratrol is known to create instability in emulsion systems. It is therefore challenging to incorporate resveratrol in concentration above 0.1% in an emulsion. Incorporation of resveratrol in an emulsion usually causes a phase separation and a colour change to yellowish-brown. It is not known by which mechanism resveratrol is causing phase separation or colour change in emulsion systems.

International Patent Application WO 2001/30314 (Pillai, et al, published May 3, 2001) relates to cosmetic skin care compositions containing resveratrol in combination with selected retinoids. Also disclosed are methods of conditioning the skin by application of such cosmetic skin care compositions. This application discloses compositions comprising a cosmetically acceptable vehicle which acts as diluant, dispersant or carrier for resveratrol and the retinoid. The composition presented contains between 0.00001 and 10% by weight of resveratrol, and most preferably in the range of from 0.1 to 5% by weight. With the exception of the alcoholic lotion, the compositions do not include a solvent. The resveratrol present in those compositions is understood to be in a solid state and no indication is given as to the stability of the proposed compositions.

United States Patent Application Publication No. 2002/0173472 (Pezzuto, et al, published November 21, 2002) is directed towards the topical administration of resveratrol, noting that it is extremely effective in preventing or treating certain skin conditions, disorders and diseases, for example, skin conditions associated with inflammation, skin damage associated with exposure to the sun, and the effects of natural aging. This application discloses pharmaceutical formulations, in particular, microemulsions, for administering resveratrol.

In the topical formulations disclosed in the application, it is preferable to include solubilizers and/ or skin permeation enhancers, along with emulsifiers, emollients and preservatives, though only the microemulsion compositions are composed of solubilized resveratrol. The two compositions contain 10% of resveratrol (trans-resveratrol), diethylene glycol monoethyl ether (available commercially as Transcutol®), PEG-8 Caprylic/Capric triglycerides (Labrasol™), PEG 400, and water. The compositions disclosed in the application can contain up to 90% by weight of solvent. Formulations with high concentration of solvent can be very irritating to the skin if applied on damaged or sensitive skin or if the application area is large. This application does not provide any data as to the stability (physical and chemical) of the resveratrol contained in the disclosed compositions. In International Patent Application WO 2004/103265 (Kim et ah, published December 2, 2004) there are disclosed whitening and antioxidative cosmetic compositions containing resveratrol and methods for preparing such compositions. The application discloses a stabilized cosmetic composition including resveratrol as a main component and either a primary stabilizer selected from cyclodextrin, polyethyleneglycol and a mixture thereof, or a combination of the primary stabilizer and a secondary stabilizer selected from an alpha-lipoic acid, a water-soluble whitening composition, a phellodendron extract, an alteromonas ferment extract, and a mixture thereof, and a method for preparing same. It also states that the solubility of resveratrol in those compositions is enhanced in polyol or ethanol and problems such as crystal precipitation at low temperature, off-flavor and discolouration upon exposure to sun light can be solved. However, the chemical stability of the compositions disclosed in this application is poor. The most stable composition disclosed exhibits an approximately 5% decrease in the assay value after 3 months, regardless of whether the composition is stored at room temperature (approximately 25°C), 4°C or 40⁰C. Further, the application does not disclose any stability data of more than 3 months of storage. Furthermore, cyclodextrins were used to stabilize resveratrol. The size of cyclodextrins makes it unlikely that the encapsulated resveratrol would be able to cross the skin barrier. Therefore, the resveratrol in those compositions would be unlikely to reach sites of action located in the epidermis or dermis.

In International Patent Application WO 2006/029484 (Declercq, et ah, published March 23, 2006) there are disclosed topical compositions containing phosphorylated polyphenols in combination with a topically acceptable carrier. The phosphorylated polyphenols have a higher water solubility in comparison with non-phosphorylated polyphenols. The composition presented contained propylene glycol which could act as a solvent. However, the low concentration of phosphorylated resveratrol (0.2 %) present in this composition is easily solubilized in the water phase. It is stated that these compositions provide a greater stability of biological activity as well as compositional integrity than is possible with unmodified polyphenol. This application also provides a method for rendering water-soluble an insoluble polyphenol, however, no long term stability data is provided. In Canadian Patent No. 2,266,763 (Breton et ah, published October 10, 1999) there are disclosed compositions containing at least one hydroxystilbene designed to encourage exfoliation of the skin. However, there are no indications as to whether the resveratrol present in those compositions is solubilized. The compositions disclosed contain between 0.1% and 5 % of resveratrol and butylene glycol is the only excipient which can help in the solubilization of resveratrol. This document does not provide any data regarding the stability of the compositions.

In French Patent No. 2,862, 533 (Rubinstein, published April 28, 2006) there are disclosed compositions containing at least one hydroxystilbene which is to be used to promote a slimming effect. Some of the compositions presented contained an encapsulated active in its solid form. The emulsifier used is either a polymer or non-ionic.

In European Patent Application No. 0 953 346 and United States Patent Application Publication No. 2003/0031693 there are disclosed compositions comprising at least one hydroxystilbene (for EP 0 953 346) as well as at least one ascorbic acid compound (for US 2003/0031693) to promote a slimming effect or for treating skin afflictions. The compositions disclosed contain between 0.1 and 1 % of resveratrol and no solvent is used. They present classic water-in-oil emulsions made with non-ionic surfactants and oily solutions. Both applications present the same compositions but give no indication as to their stability.

In light of the prior art, there remains the need to have compositions containing solubilized resveratrol and having acceptable stability to optimize the delivery of resveratrol in the skin more effectively than those provided to date.

Summary of Invention

The inventors have surprisingly and unexpectedly discovered that they could prepare compositions for topical use containing solubilized resveratrol in a stable emulsion in a solvent system which does not cause irritation to the skin. Furthermore, it was also unexpected that resveratrol could be used in the compositions at such high concentrations, up to 15% (more preferably up to 8 %) by weight of the formulation products. In one aspect of the present invention, there is provided a stable composition which contains solubilized resveratrol for topical use in a mammal. Preferably, the mammal is a human.

In an embodiment of the present invention, the compositions for topical use comprise solubilized resveratrol in an emulsion, one or more solvent, and an emulsifier.

In a preferred embodiment, the solvent present in the composition is dimethyl isosorbide. Another solvent that can be used in the compositions according to the present invention is diethylene glycol monoethyl ether. In a further embodiment, a mixture containing both dimethyl isosorbide and diethylene glycol monoethyl ether can be used. The use of dimethyl isosorbide increases the tolerability of the formulation in comparison with classic solvents.

The emulsifier used to stabilize the compositions can be a non-ionic emulsifier, a cationic emulsifier or a polymer. Preferably, the emulsifier is a cationic emulsifier.

Oil-in-water and water-in-oil emulsions, as well as gels, ointments and solutions, can be formulated as stable compositions according to the present invention where the amount of trans-resveratrol present can range up to about 15% by weight of the composition. A person skilled in the art will know that the desired range of resveratrol contained within the compositions of the present invention depends on the indication for the use thereof.

According to a preferred embodiment of the present invention, the compositions for topical use comprise:

(i) from about 0.01 to about 15% by weight of trans-resveratrol;

(ii) from about 1.0 to about 90% by weight of dimethyl isosorbide alone or in a mixture with another solvent; and

(iii) from about 0.01 to about 10% by weight of an emulsifier selected from the group consisting of cationic and non-ionic emulsifiers.

Preferably, the compositions for topical use according to the present invention comprise:

(i) from about 1 to about 10% by weight of trans-resveratrol; (ii) from about 2 to about 60% by weight of dimethyl isosorbide alone or in a mixture with another solvent; and

Also preferably, the compositions for topical use according to the present invention comprise:

(i) from about 2 to about 8% by weight of trans-resveratrol;

(ii) from about 4 to about 60% by weight of dimethyl isosorbide alone or in a mixture with another solvent; and

Preferably, the weight to weight of resveratrol to the solvent system, ranges as follows: a) for a composition comprising 1% resveratrol, there should be from 1 to 10% of solvent, more preferably from 3 to 7% and most preferably approximately

O /a, b) for a composition comprising 5% resveratrol, there should be from 10 to 40% of solvent, more preferably from 20 to 30% and most preferably approximately 25%; c) for a composition comprising 10% resveratrol, there should be from 40 to 60% of solvent, more preferably from 45 to 55% and most preferably approximately 50%; and d) for a composition comprising 15% resveratrol, there should be from 60 to 90% of solvent, more preferably from 70 to 80% and most preferably approximately 75%.

It is known in the field that the amount of emulsifier required to form an emulsion depends on a number of factors including: emulsifier type, % dispersed phase, the nature of phase to be emulsified, the desired droplet size and the nature and concentration of active ingredient.

These several factors render it difficult to give precise concentration ranges of emulsifier which are expected to form a stable emulsion. It is also known that a mixture of 2 or more emulsifiers of different type can optimize the stability of the emulsion. However, given the above and the experiments conducted, the inventors have determined that cationic and polymeric emulsifiers can form stable emulsions of resveratrol when used in a range from 0.1 to 10%, more preferably ranging from 0.2 to 5% by weight of the composition. Non-ionic emulsifiers can form stable emulsions of resveratrol when used in a range ranging from 1 to 15%, more preferably ranging from 2 to 10% by weight of the composition.

In one aspect of the present invention, there is provided the use of compositions for the treatment of psoriasis, acne and herpes simplex virus are presented as well as cosmetic compositions for wrinkle reduction.

In another aspect of the present invention, there is provided a process to make a composition according to present invention, comprises the following steps:

(1) preparing a first mixture by solubilizing the resveratrol in a solvent system comprising dimethyl isosorbide;

(2) preparing a second mixture made up of an aqueous phase by incorporating hydrophilic excipients together;

(3) preparing a third mixture comprising an oil phase by incorporating hydrophobic excipients together with an emulsifier;

(4) mixing the second and third mixtures together; and

(5) adding the first mixture to the mixture obtained in step (4).

Preferably, the second mixture and the third mixture are each heated to approximately the same temperature to ensure that all hydrophobic and hydrophilic elements are well dissolved. Preferably, the temperature is selected from 70 to 8O⁰C. Also preferably, once the second mixture and the third mixture are combined the resulting mixture is cooled down prior to the addition of the resveratrol containing mixture (the first mixture). In addition, in a preferred embodiment, one or more steps of pH adjustments are also included to ensure that the resulting mixture is stable.

Detailed Description

Formulations containing resveratrol can either be water-in-oil or oil-in-water emulsions. They can also be solutions or gels. Resveratrol formulations can be used in transdermal systems or in other systems for topical delivery like ophthalmic, ottic or nail delivery.

The compositions of the present invention are topical compositions containing a solubilized active ingredient in a stable emulsion. The active ingredient present in the topical compositions of the present invention is resveratrol (including trans-resveratrol, cis- resveratrol, cis-resveratrol glucoside and trans-resveratrol glucoside). In the preferred embodiments of the present invention, the active ingredient is trans-resveratrol. Trans- resveratrol, derived from synthetic and natural origin, is commercially available from several sources including Sochinaz SA and Orchid Pharmaceuticals. It is understood that other forms of resveratrol, including cis-resveratrol, cis-resveratrol glucoside and trans- resveratrol glucoside, can also be used in the compositions of the present invention. The amount of resveratrol present in the compositions of the present invention range from 0.01 to 15% by weight, and is preferably in an amount ranging from about 2 to about 8% by weight.

In one embodiment of the present invention, the compositions for topical use contain solubilized resveratrol in an emulsion, with one or more solvents, preferably dimethyl isosorbide and an emulsifier, preferably a cationic emulsifier.

Solvents which may be included in the topical compositions of the present invention include one or more of pharmaceutically acceptable solvents, such as, for example dimethyl isosorbide, polyethylene glycol 200 to 600, diethylene glycol monoethyl ether, ethanol, hexylene glycol and PEG-8 caprylic/capric glycerides. The total amount of solvent present in the compositions of the invention may be from 0.1% to about 90% weight percent.

Dimethyl isosorbide (known chemically as 1,4:3,6 dianhydro-2,5-di-o-methyl-D- glucitol), is available commercially from Croda under the trademark Arlasolve DMI. A purified version commercialized under the trademark Super Refined Arlasolve DMI is also available. Dimethyl isosorbide is a unique solubilizer, emulsifier and emollient with unusual properties. It is practically non-toxic, water soluble, oil soluble, has a high boiling point and low freezing point. Dimethyl isosorbide is miscible with many organic solvents, pH stable, non-greasy, non-drying, non-irritating, colourless, practically odourless, inert and non-volatile. The amount of dimethyl isosorbide present in the compositions of the present invention range from about 1 to about 90% by weight of the composition, and is preferably present in the composition in the range from about 3 to about 50% by weight of the composition.

The use of dimethyl isosorbide increases the tolerability of the formulation in comparison with classic solvents.

In another embodiment, the solvent used is diethylene glycol monoethyl ether, and in yet another embodiment, the solvent used may be a mixture containing both dimethyl isosorbide and diethylene glycol monoethyl ether.

Emulsifiers which may be included in the topical compositions include any pharmaceutically or cosmetically acceptable emulsifier. Such emulsifiers include but are not limited to: fatty acid esters of polyethylene glycol, such as PEG-100 stearate; fatty acid esters of polyols, such as glyceryl stearate; polymeric emulsifiers, such as poloxamers; and cationic emulsifiers such as polyquaternium-37 and behentrimonium methosulfate. Preferably, the emulsifier is a cationic emulsifier, such as polyquaternium-37. Most preferably, the emulsifier is a polyquaternium-37.

The emulsions also contain two other types of compounds (in addition to the emulsifiers): hydrophilic excipients and hydrophobic excipients. Whether an excipient is hydrophobic or hydrophilic would be clear to a person skilled in the art.

The excipients (also referred to as ingredients) present in the compositions of the present invention include excipients commonly used in compositions directed at topical use such as dermatological compositions. Such ingredients include but are not limited to: antioxidants, moisturizers, thickeners, emollient, wetting agents, bases, preservatives and protective agents. These excipients are present in amounts which are used in conventional topical compositions and, for example, preferably constitute from 0.01% to 20% relative to the total weight of the composition.

Emollients which may be included in the topical compositions of the present invention include any pharmaceutically acceptable emollient which include but are not limited to: mineral oils, oils of plant origins, oils of animal origins, synthetic oils, silicone oils and fluoro oils. Fatty alcohols, fatty acids and waxes can also be used as fatty substances. The amount of emollient present in the compositions of the invention may be from about 1.0% to about 90% by weight of the composition, and preferably up to 20%, and most preferably up to 10% by weight of the composition.

Moisturizers which may be included in the compositions according to the present invention include any pharmaceutically acceptable moisturizer, such as, for example, glycerin, sodium hyaluronate, or propylene glycol. Preferably, the moisturizer is glycerin. The amount of moisturizer present in the compositions of the invention may range from 0.1 to about 10% by weight of the total composition.

Thickeners which may be included in the topical compositions of the present invention include any pharmaceutically acceptable hydrophilic or lipophilic thickener. Such thickeners include but are not limited to: cetyl alcohol, stearyl alcohol, carbomers, natural gums and clays, poloxamers, and bentones. The thickeners may be present in the compositions of the invention in an amount ranging from about 0.1 to about 20% by weight of the total composition. A person skilled in the art will understand that, for example, a carbomer is generally present in amounts ranging from about 0.1 to about 0.5% by weight of the composition, while a cetyl alcohol is generally present in amounts ranging from about 3 to about 5% by weight of the composition and a poloxamer can be present in amounts ranging up to about 20% by weight of the composition.

Preservatives which may be included in the topical compositions of the present invention include any pharmaceutically or cosmetically acceptable preservatives. Such preservatives include but are not limited to, for example, methylparaben, propylparaben, caprylyl glycol, ethylhexylglycerin, imidurea. Preferably, the preservative is a combination of methylparaben and propylparaben. The preservatives present in the compositions of the invention may be present in amounts ranging from about 0.05 to about 1% by weight of the composition.

Bases which may be included in the topical compositions of the present invention include any pharmaceutically acceptable base. Such bases include but are not limited to, for example, sodium hydroxide, triethanolamine and sodium lactate. Preferably, the base is triethanolamine. The amount of base present in the composition of the invention may range from about 0.1 to about 5 %, depending upon the strength of the base.

Other active agents which may be included in the topical compositions of the present invention include any pharmaceutically or cosmetically acceptable actives. Such active agents include, but are not limited to, for example, proteins or protein hydrolysates, amino acids, polyols, urea, allantoine, sugars and sugar derivatives, vitamins, plant extracts and hydroxyl acids. These other active agents may be present in amounts ranging from 0.01 to 20%.

The compositions according to the present invention were formulated according to conventional pharmaceutical techniques.

The compositions of the present invention presented excellent stability after 3 days when stored at 5O⁰C. A person skilled in the art will understand that the stability is determined by the lack of phase separation and lack in change of texture and/ or colour, two very critical parameters in assessing stability of topical products. The use of the word stable in the present description is meant to illustrate that the emulsion containing the active ingredient does not have major physical modifications (phase separation, change in viscosity, colour or odour) over time.

Process for Preparing Compositions

The process for preparing a composition according to the present invention comprises the following steps:

1) preparing a first mixture by solubilizing the resveratrol in a solvent system comprising dimethyl isosorbide;

2) preparing a second mixture made up of an aqueous phase by incorporating hydrophilic excipients together; 3) preparing a third mixture comprising an oil phase by incorporating hydrophobic excipients together with an emulsifier;

4) mixing the second and third mixtures together;

5) adding the first mixture to the mixture obtained in step (4).

Preferably, the second mixture and the third mixture are each heated to approximately the same temperature to ensure that all hydrophobic and hydrophilic elements are well dissolved. Preferably, the temperature is selected from 70 to 8O⁰C. Also preferably, once the second mixture and the third mixture are combined the resulting mixture is allowed to cool prior to the addition of the emulsifier and consequently prior to the addition of the resveratrol containing mixture (the first mixture). Preferably, additional steps for adjusting the pH are included to ensure that the resulting mixture is stable. The inventors have noticed that the speed of the addition of the mixture containing resveratrol to the mixture of step (4) (above) has an effect on the quality of the stability that is desired and the quality of the emulsion. Consequently, the inventors have determined that is was preferable to add the first mixture at a rate which allows proper and thorough mixing within the mixture of step (4).

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to persons skilled in the art.

Examples

The following examples are illustrative of the applicability of the present invention and are not intended to limit its scope. Modifications and variations can be made therein without depending from the spirit and scope of the invention. Although any method and material whether similar or equivalent to those described herein can be used in the practice for testing the present invention, the preferred methods and materials as described.

All of the percentages given hereinabove and below are percentages by weight (i.e. w/w). Example 1

The solubility (in % (g/100g)) of resveratrol in a number of solvents was studied The solubility was assessed by visual inspection of the solutions prepared

TABLE I - Solubility (in % (j^lOOg)) of resveratrol in a number of solvents

Transcutol P density (25°C) = 0 988 g/ml

** Arlasolve DMI density (25°C) = 1 1635 g/ml

*** Carbowax 400 density (25°C) = 1 128 g/ml

Example 2 Stability in solution

Several solutions of resveratrol in different solvents were stored at 40⁰C for 1 month and the visual appearance was evaluated This accelerates the interaction, if any, between the solvent and the resveratrol

No changes m visual appearance were observed for the three compositions listed above in Table I

Example 3

The chemical stability of resveratrol was studied on a 10% w/v resveratrol solution m Arlasolve DMI after 1 month at 40⁰C

TABLE II - Chemical stability of resveratrol on a 10% w/v resveratrol solution in

Arlasolve DMI after 1 month at 40⁰C

Example 4

A composition according to the present invention containing 250% by weight resveratrol is disclosed in Table III

TABLE III - Composition according to the present invention containing 2.50% resveratrol for use in the treatment of psoriasis

The composition disclosed m Table III is an oil-in-water beige emulsion with 25% of solubihzed resveratrol The pH of this composition is around 7 This emulsion was stable after 3 days at 50⁰C No phase separation was observed

Example 5

The long term stability of the composition obtained in Example 4 was studied The cream obtained from Example 4 was packaged in aluminum tubes and placed in a stability chamber at 40⁰C/ 75% relative humidity The results for stability study are set out m Table IV below The results indicate that the resveratrol m the composition of Example 4 was stable for 6 months at 40⁰C/ 75% relative humidity TABLE IV - Stability at 40°C/75% RH

Example 6

A GMP batch (of 50 kg) of the identical formulation as set out in Example 4 (above) was manufactured and placed in a complete International Conference on Harmonisation ("ICH") stability program. The results in Tables V and VI were obtained using with a validated HPLC method.

The process for the manufacture of this batch is set out below. The entire manufacturing process is done under sodium lamps to prevent the isomerization of the trans-resveratrol.

Step 1: The dimethyl isosorbide and the diethylene glycol monoethyl ether are added in a stainless steel container and mixed at a speed of 40 +/- 10 rpm for a minimum of 5 minutes.

Step 2: The resveratrol is sprinkled over the solvent solution of

Step 1 under constant mixing until a clear solution is obtained. The stainless steel container is covered after the resveratrol addition.

Step 3: Purified water is poured in a Coulter tank and heated at

73-75°C.

Step 4: Carbomer 940 is added to the water of Step 3 under medium speed agitation with a Leeson mixer. The suspension is mixed until the Carbomer is hydrated.

Step 5: Glycerin and Methylparaben are added to the mix of Step

4 and the solution is stirred until complete dissolution.

Step 6: The following excipients are added in a stainless steel container and heated at 73-75°C under mixing: Glyceryl stearate & PEG- 100 stearate, Cetyl ester wax, White wax, Cetyl alcohol, Stearyl alcohol, Medium chain triglycerides, Propylparaben, and Dimethicone. Mixing is done at moderate speed until everything is melted and mixed uniformly.

Step 7: The phase of Step 6 is slowly added to the phase of Step 5 under homogenization with a homogenizer.

Step 8: The homogenization is continued for 20 minutes after the incorporation of the oil phase.

Step 9: The mix of Step 8 is cooled down to 40 +/-2⁰C with mixing at a reduced speed. Step 10: The phase of Step 2 is slowly added to the emulsion of

Step 9 under agitation. The pH is measured and noted in the batch record.

Step 11: Triethanolamine and Purified water are mixed in a small container and added in aliquot to the emulsion of Step 10 until a pH of 7.0 +/- 0.1 is obtained.

Step 12: The emulsion of Step 11 is cooled down to 25 +/- 2°C. The pH is measured at the top and bottom of the tank and the viscosity is taken on a sample.

The bulk cream was subsequently packaged in aluminium tubes.

TABLE V - Stability at 40°C/75% RH

TABLE VI - Stability at 25°C/60% RH

Example 7 - Composition for the treatment of acne

This is a silky off-white oil in water emulsion-gel containing 2.0% of solubilized resveratrol. The pH is slightly acidic due to the presence of a cationic emulsifier. This composition was found to be stable after 3 days stored at 50⁰C. No phase separation was observed.

TABLE VII - Composition according to the present invention containing 2% resveratrol

TABLE VIII - Stability results for the composition of Example 7 at 25°C in glass bottle

TABLE IX - Stability results for the composition of Example 7 @ 50⁰C in glass bottle

Example 8 - Composition for the treatment of Herpes simplex virus (HSV)

The composition according to Example 8 is set out in Table X below The composition is a shiny-yellowish oil in water emulsion-gel containing 8% of solubihzed lesveratrol This emulsion-gel has a very low viscosity This composition is stable after 3 days at room temperature (25°C) and at 50⁰C No phase separation was observed

TABLE X - Composition according to the present invention for use in the treatment of

HSV

TABLE XI - Stability results for the composition of Example 8 @ 25⁰C in glass bottle

TABLE XII - Stability results for the composition of Example 8 @ 50⁰C in glass bottle

Example 9 - Composition containing a cationic emulsifier (oil-in-water emulsion)

TABLE XIII - Composition according to the present invention containing 2% resveratrol and a cationic emulsifier

Example 10 - Composition for use as an anti-wrinkle cream

TABLE XIV - Composition according to the present invention for use as an anti-wrinkle cream containing 2.50% resveratrol

Example 11

Table XV discloses the components, and quantity of components, of a composition according to the present invention containing 250% by weight of resveratrol This composition is a silky shiny off-white cream This composition was found to be stable after 3 days at room temperature (25°C) and 50⁰C No phase separation was observed (see Tables XVI and XVII)

TABLE XV - Composition according to the present invention containing 2.50% resveratrol

TABLE XVI - Stability results for the composition of Example 11 @ 25⁰C in glass bottle

TABLE XVII - Stability results for the composition of Example 11 @ 50⁰C in glass bottle

Example 12

Table XVIII discloses the components, and quantity of components, of a composition according to the present invention containing 2.50% by weight of resveratrol. This composition is a silky shiny off-white cream. This composition was found to be stable after 3 days at room temperature (25°C) and 50⁰C. No phase separation was observed (see Tables XIX and XX). TABLE XVIII - Composition according to the present invention containing 2.50% resveratrol

TABLE XIX - Stability results for the composition of Example 12 @ 25°C in glass bottle

TABLE XX - Stability results for the composition of Example 12 @ 50⁰C in glass bottle

Example 13

Table XXI discloses the components, and quantity of components, of a composition according to the present invention containing 8% by weight of resveratrol This composition is a silky shiny off-white cream This composition was found to be stable after 3 days at room temperature (25°C) No phase separation was observed (see Table XXII) TABLE XXI - Composition according to the present invention containing 8 % resveratrol

TABLE XXII - Stability results for the composition of Example 12 @ 25° in glass bottle

Claims

What is claimed:

1. A composition for topical use comprising solubilized resveratrol in a stable emulsion in a solvent system, the solvent system comprising dimethyl isosorbide, and wherein the composition does not cause irritation to the skin.

2. The composition according to claim 1, wherein the resveratrol is present in concentrations ranging up to 15% by weight of the composition.

3. The composition according to claim 2, wherein the resveratrol is present in concentrations ranging up to 8% by weight of the composition.

4. The composition according to any one of claims 1 to 3, wherein the solvent system further comprises a second solvent.

5. The composition according to claim 4, wherein the second solvent is diethylene glycol monoethyl ether.

6. The composition according to any one of claims 1 to 5, further comprising an emulsifier.

7. The composition according to claim to 6, wherein the emulsifier is selected from the group consisting of: non-ionic emulsifier, a cationic emulsifier and polymer.

8. The composition according to claim 6, wherein the emulsifier is selected from the group consisting of: fatty acid esters of polyethylene glycol, such as PEG-100 stearate; fatty acid esters of polyols, such as glyceryl stearate; polymeric emulsifiers, such as poloxamers; cationic emulsifiers ,such as polyquaternium-37 and behentrimonium methosulfate; and combinations thereof.

9. The composition according to any one of claims 1 to 8, wherein the composition is in the form of an oil-in-water emulsion, water-in-oil emulsion, gel, ointments or solution.

10. A composition for topical use comprising solubilized resveratrol in a stable emulsion comprising an emulsifier in the presence of a solvent system, the solvent system consisting of dimethyl isosorbide.

11. A composition for topical use comprising solubilized resveratrol in a stable emulsion comprising an emulsifier in the presence of a solvent system, the solvent system consisting of diethylene glycol monoethyl ether.

12. A composition for topical use comprising solubilized resveratrol in a stable emulsion comprising an emulsifier in the presence of a solvent system, the solvent system consisting of dimethyl isosorbide and diethylene glycol monoethyl ether.

13. The composition according to any one of claims 10 to 12, wherein the emulsifier is selected from the group consisting of: fatty acid esters of polyethylene glycol, such as PEG- 100 stearate; fatty acid esters of polyols, such as glyceryl stearate; polymeric emulsifiers, such as poloxamers; cationic emulsifiers, such as polyquaternium-37 and behentrimonium methosulfate; and combinations thereof.

14. The composition according to any one of claims 1 to 13, wherein the composition further comprises one or more of the following excipients: antioxidants, moisturizers, thickeners, emollients, wetting agents, bases, preservatives and protective agents.

15. The composition according to any one of claims 1 to 14, wherein the composition further comprises emollients selected from the group consisting of: mineral oils, oils of plant origins, oils of animal origins, synthetic oils, silicone oils, fluoro oils, fatty alcohols, fatty acids and waxes.

16. The composition according to any one of claims 1 to 15, wherein the composition further comprises moisturizers selected from the group consisting of: glycerin, sodium hyaluronate, and propylene glycol.

17. The composition according to any one of claims 1 to 16, wherein the composition further comprises thickeners selected from the group consisting of: pharmaceutically acceptable hydrophilic or lipophilic thickener, such as cetyl alcohol, stearyl alcohol, carbomers, natural gums and clays, poloxamers, and bentones.

18. The composition according to any one of claims 1 to 17, wherein the composition further comprises preservatives selected from the group consisting of: methylparaben, propylparaben, caprylyl glycol, ethylhexylglycerin, and imidurea.

19. The composition according to any one of claims 1 to 18, wherein the composition further comprises bases selected from the group consisting of: pharmaceutically acceptable base, such as sodium hydroxide, triethanolamine and sodium lactate.

20. The composition according to any one of claims 1 to 19, wherein the composition comprises an additional active agent, in addition to resveratrol, wherein the additional active agent selected from the group consisting of: proteins or protein hydrolysates, amino acids, polyols, urea, allantotne, sugars and sugar derivatives, vitamins, plant extracts and hydroxyl acids.

21. The composition according to claim 20, wherein the other active agents are present in amounts ranging from 0.01 to 20%.

22. A composition for topical administration comprising:

from about 0.01 to about 15% by weight of solubilized trans-resveratrol;

from about 1.0 to about 90% by weight of dimethyl isosorbide, alone or in a mixture with another solvent; and

from about 0.01 to about 10% by weight of an emulsifier selected from the group consisting of cationic and non-ionic emulsifiers.

23. A composition for topical administration comprising:

from about 1 to about 10 % by weight of solubilized trans-resveratrol;

from about 2 to about 60% by weight of dimethyl isosorbide alone or in a mixture with another solvent; and

24. A composition for topical administration comprising:

from about 2 to about 8 % by weight of solubilized trans-resveratrol;

from about 4 to about 60 % by weight of dimethyl isosorbide alone or in a mixture with another solvent; and

25. The composition according to any one of claims 1 to 24, for use in the treatment of psoriasis.

26. The composition according to any one of claims 1 to 24, for use in the treatment of acne.

27. The composition according to any one of claims 1 to 24, for use in the treatment of herpes simplex virus.

28. The composition according to any one of claims 1 to 24, for use in wrinkle reduction.

29. A process to prepare a composition according to any one of claims 1 to 28, comprising the following steps:

(4) mixing the second and third mixtures together; and

(5) adding the first mixture to the mixture obtained in step (4).