ES2343775B1 - GALENIC FORMULATION OF TOPICAL APPLICATION IN THE FORM OF ANHYDRA BASED CONTAINING EXTRACT OF LINOLEIC ACID AND CORRESPONDING PREPARATION AND USE METHODS. - Google Patents

Abstract

Galenic formulation of topical application in the form of anhydrous base containing linoleic acid extract and corresponding preparation and use methods. The present invention relates to a galenic formulation in the form of a stable anhydrous base containing vegetable extract rich in linoleic acid in a linear silicone of low degree of polymerization, a thickening fatty component, a paraffinic emollient agent, a volatile silicone, an antioxidant agent and other components and the process for preparing said formulation.

Description

Galenic formulation of topical application in the form of anhydrous base containing linoleic acid extract and corresponding preparation and use methods.

Field of the Invention

The present invention relates to a galenic formulation in the form of a stable anhydrous base, which contains plant extract rich in linoleic acid in a linear silicone of low degree of polymerization, a thickening fatty body, a paraffinic emollient agent, a volatile silicone, an agent antioxidant and other components and the process for preparing said formulation. The invention also relates to a use of the formulation according to the invention.

State of the art

Topical applications have been used for centuries for therapeutic or cosmetic dermatological purposes, both to treat skin disorders, and to improve their appearance and surface condition.

Among the many and varied active substances used, the literature in general and that of patents in particular, shows how over the years there has been interest in cosmetic or pharmaceutical formulations containing linoleic acid, conjugated or not, derivatives thereof or extracts Vegetables with high content, in order to demonstrate and use the dermatological properties of said acid.

Thus, for example, in EP 1,341,517 they use conjugates of linoleic acid with vitamin A and with chitosan, the latter contributes with a moisturizing and antimicrobial effect. WO 00/37040 describes the use of glyceryl monolinoleate.

In FR 2,845,596, to treat or prevent the effects of linoleic acid deficiencies, they have a formulation based on amides and sugar esters of linoleic acid. ES 2,105,974 encapsulated linoleic acid, together with urea, water and glyceramides, is formulated in liposomes to achieve intensive skin hydration. In ES 2,136,105 the invention presents formulations of phospholipids acylated with linoleic acid. In ES 2,253,772 zinc salts of conjugated linoleic acids are used for the treatment of skin conditions. In ES 2,191,979 it presents cosmetic preparations of the water-oil type with conjugated linoleic acid together with other fat-soluble compounds and with a specific pH and humectants. In ES 2,208,377, based on the abundant literature on the interest of both linoleic acid and retinol, they formulate a composition based on linoleic acid or its derivatives and retinoic acid, retinol or a retinyl ester, also on base emulsions water oil.

On the other hand, it highlights the importance of formulations as emulsions mainly in the water-oil form described in the previous documents and in others, mostly based on hydrocarbon components. On some occasions, relatively low components of silicone oils are incorporated into the hydrocarbon components of the fatty phase. Such is the case of patent EP 872.244 in which Andiroba extract is formulated containing, among other acids, linoleic acid, in water-oil based emulsions but containing silicones in amounts of the order of 2% -7%; in ES 2,091,108 they associate ceramides and a vegetable source of linoleic acid, preferably wheat germ oil, in water-oil emulsions also with low silicon content. In the aforementioned patent ES 2,208,377, water-fat phases with contents below 7.5% in silicones are also used.

In this line, to overcome problems of instability of the aqueous emulsions of conjugated linoleic acid, in WO 2004/045506 it is formulated with amino acids and / or macromolecules such as DNA, RNA and peptides.

In patents ES 2.104.302 and ES 2.105.555 it is made clear that the formulations of vegetable oils present stability problems, particularly in the preparation of oil-water emulsions. However, the invention discovers that by associating these vegetable oils with the self-emulsifying composition described in WO 92/06778, in the presence of a coemulsifier and a gelling agent, it is possible to obtain fine and stable emulsions, ie not they show degassing after two months at 45 ° C. Therefore, a dermatological or cosmetic composition is claimed in the form of a stable oil-in-water emulsion, characterized in that it contains at least one vegetable oil consisting of at least 40% of linoleic acid triglycerides, a self-emulsifying composition based on an alcohol. fatty and an alkylpolioside, as well as a coemulsifier and also a saturated fatty alcohol gelling agent. Of the different examples presented in these patents, in some cases it is formulated with a silicone content of 10%.

In US Patent 7,175,836, a wider use is made of silicones to try to solve these types of problems. Thus, the invention discovers a water-oil composition to improve the appearance of the facial surface containing, in order to overcome problems of degradation of components and stability that this type of emulsions usually present, linoleic acid conjugated with emulsifying silicone as a surfactant type copolymer copolymer, crosslinked silicone elastomers containing vinyl groups and a vehicle for silicone elastomers also based on silicones. While the formulations use a large number of components and are quite complex.

Technological progress has provided additional advantages to the formulations through new vehicles and active components: increased efficiency, stability, reduction of adverse effects, ease of penetration, economy in active ingredients through better vehiculization, etc. It is important to obtain and apply new anhydrous excipients as vehicles of active principles that are not very soluble and / or insoluble in water or unstable in their presence, as well as for their contribution to greater stabilization of the compositions. Thus, it is common to use mixtures of silicones alone or associated with other fatty compounds, to obtain anhydrous semi-solid preparations with high chemical inertia (compatible, stable, little sensitive to temperature, etc.), great extensibility and easy to use. Apply to the skin.

For example, US 6,103,250 describes anhydrous antiperspirant formulations, based on polar silicone elastomers as emulsifiers containing polar or hydroxylic groups, in order to improve the aesthetic characteristics of the formulations. They are applied to water sensitive ingredients, and in particular formulations with ascorbic acid are presented. Normally very complex formulations result with a large number of components. Also, related to hydroxylated silicones, patents WO 98/10793 and ES 2,190,175 disclose formulations of hydrophobic gels containing volatile silicones and dimethiconol (hydroxylated silicone polymer, especially suitable for hydrophilic assets), interestingly formulating on a base of Vitamin E acetate - itself is a pharmaceutical asset widely used in pharmacy and in cosmetics for the treatment of skin disorders - in order to increase the stability of the formulation or the penetration of the active ingredients, mainly lipophilic active ingredients, and in particular castor oil.

ES 2,093,412 describes the association of low viscosity silicone oils with waxes, resins and silicone gums to improve the cosmetic qualities of the formulations that are obtained in powder form.

ES 2,213,215 describes a substantially anhydrous and mainly solid formulation, but without containing traditional wax materials, and with different active materials: deodorants, antiperspirants, insect repellents and antifungal. The formulation is achieved by the incorporation of a silicone gel composed of volatile silicone and a cross-linked organopolymylan or silicone rubber material obtained by reacting a siloxane polymer with vinyl end groups and a hydride cross-linking agent. Related, in part, to said crosslinked silicones, in US Patent 135,379 develop formulations with active ingredients derived from vitamin D for the treatment of psoriasis by anhydrous compositions containing the solubilized active ingredients. These are achieved by using hydroxylated solvents, particularly aliphatic alcohols of up to six carbons (ethanol, ethanol, isopropanol, etc.), and crosslinked elastomeric siliconized agents with dienic chains formulated with volatile silicones as their vehicles.

ES 2,177,098 to solve technical problems in the incorporation of silicone rubber and its improvement in compatibility with other ingredients of the fat phase on an industrial scale, describes the use of silicone rubber, especially diphenyl dimethicone rubber, dissolved in silicone. volatile for obtaining cosmetic or pharmaceutical compositions, in particular dermatological.

Therefore, it is obvious that research and development in the field of pharmaceutical and cosmetic formulations is current and intense in order to improve the qualities of such formulations. Especially, the effort is important in the formulation based on elastomers or silicone polymers, that is to say silicones with a high degree of polymerization that give rise to elastomers, gums, resins, etc., which are previously obtained or formulated in volatile silicones before of its incorporation into the final composition. This, on the other hand, has led in many cases, both to the need to obtain or synthesize said elastomers, to preform them with simpler silicones and to obtain complex compositions.

Thus, the research in the aforementioned fields demonstrates the interest and need for effective and alternative pharmaceutical and cosmetic formulations for topical application on the skin in order to treat both conditions and unwanted visible signs.

Compendium of the invention

The structural importance of the essential fatty acids in the skin is today widely known and explained, as well as the cosmetic application on it, since they are considered essential in its barrier and reparative function (B. Härtel, SQFW-Journal, 124 ( 13) 889-900, 1998).

Linoleic acid (AL) is an essential unsaturated fatty acid. The organism cannot synthesize it and must have an exogenous contribution through the diet. AL belongs to the group of omega 6 acids and is the most abundant polyunsaturated fatty acid in the skin. Its de fi cit, as well as that of other essential fatty acids, causes the skin to suffer excessive loss of water and become dry and flaky, being its main mission the maintenance of the epidermal barrier, to avoid water loss (B. Härtel, SQFW-Journal, 124 (13) 889-900, 1998). It is particularly abundant in sunflower oils, corn, safflower, wheat germ, grape seed and peanut.

According to some studies, the concentration of linoleic acid or the absence of its metabolites is usually lower in people with atopic dermatitis than in healthy subjects (R. Pelta, E. Vivas, Piel y Allergia, Editorial Díaz de Santos, 1997; AJ Vásquez, Medunab, vol. 5, 2002; Wolleberg A, et. Al. Allergy vol. 55, 2000). Also, the antipruritic activity of the lipid residue of barley rich in linoleic acid in dry skin has been described (Rojas C. et al.

I.F.S.C.C. International, p. 127-134, 1999) by formulation and application in water-oil emulsions.

In order to achieve synergy through the increase of the barrier effect that is potentially capable of creating a galenic formulation and the contribution of assets based on structural elements of the skin capable of balancing the deficiency in some of its polyunsaturated fatty acid components , as well as minimizing the annoying and unpleasant symptoms in dry and dermatological skin, the authors have carried out research to find an anhydrous galenic formulation that enhances the barrier effect effectively preventing water loss and that is capable of incorporating stable extracts rich in linoleic acid that provide the therapeutic advantages of it.

On the other hand, in relation to the issues and complexities set forth above in the cited literature, the inventors of this patent application have discovered that, surprisingly, linoleic acid oil formulations are possible in anhydrous systems that enhance the barrier effect, free of complex materials of silicones in the form of waxes, elastomers, resins, etc., and in general free of polymers of high degree of polymerization of silicones, crosslinked or not, with or without functionalization of these, and that present good qualities of galenic formulation for linoleic acid extract: ease of application and extensibility, skin-friendly, oxidation stability, and industrialization j maintaining these characteristics without affecting the good characteristics mentioned of the composition and without affecting its stability or that of the formulation once industrialized.

Especially, for the incorporation of the active extract, an anhydrous based formulation has been developed, containing fl uid silicones such as linear (non-crosslinked) dimethicones with a low degree of polymerization, which allows an improvement in the characteristics, and without the need to be previously formulated in any other silicone, volatile or not, as usual in the aforementioned patents, or in any other preformulation vehicle.

The good stability of the anhydrous system according to the invention has been obtained in particular thanks to a substantial modification in the type of silicones selected and combined, maintaining a content in them greater than 50%, and the presence of the antioxidant agent.

The galenic formulation described in this invention has general application in the skin of the human body, but especially in areas where the dry skin is presented with greater intensity such as the feet.

The formulation also consists of at least one fatty component of glyceryl esters or triglycerides of saturated or unsaturated fatty acids, a paraffinic emollient, a low concentration antioxidant element and a volatile silicone to increase the characteristics of fluidity and extensibility.

The present invention also refers to the process or method of obtaining the formulation object of the patent and its use as a dermatological preparation for the feet.

Detailed description of the invention

The present invention describes a galenic formulation in the form of an anhydrous base with a barrier effect for topical use, in which an extract of linoleic acid is formulated as a dermatological and antipruritic agent in a composition containing a low polymerization silicone.

Especially a formulation with good galenic-technical and physicochemical characteristics has been developed, containing fl uid silicones such as linear dimethicones (not cross-linked) with a low degree of polymerization, not formulated in any other silicone, volatile or not, or in any other preformulation vehicle. Its use and incorporation is carried out independently of the other components of the composition and therefore without prior preformulation.

The formulation also comprises at least one thickening fatty component such as glyceryl esters of saturated or unsaturated fatty acids and triglycerides of saturated or unsaturated fatty acids, an emollient agent of the paraffin type, an antioxidant element and a volatile silicone to increase the characteristics. of fluidity, extensibility and pleasantness.

Other minor components, such as other emollients, preservatives, perfumes, pigments, etc., commonly used in this type of formulations may also be present in the composition.

As extracts of linoleic acid, vegetable extracts based on fatty acids containing a percentage of linoleic acid greater than 40% are preferred. Particularly preferred is the depleted barley lipid extract, in addition to being more rich in linoleic acid, due to the additional supply of vitamins it contains as nutrient elements. The preferred content in the formulation is from 1% to 10%, preferably between 3 and 7% by weight of extract with respect to the weight of the formula.

Within the scope of the invention the dimethicones used of formula (CH3) 3-O - ((CH3) 2Si-O) n-Si (CH3) 3 are pharmaceutical grade and low polymerization dimethicones, with a viscosity of between 20 cSt and 400 cSt, preferably between 20 cSt and 200 cST and more preferably between 50 cSt and 150 cSt. The preferred content in the formulation is from 1% to 5% of the weight of the formula.

Among the thickening fatty components, glyceryl esters of saturated or unsaturated fatty acids and triglycerides of saturated or unsaturated fatty acids are preferred. The fatty acids may be from C12 to C26 and preferably from C16 to C24. Saturated fatty acids are selected from both classes of acids. They can be incorporated in amounts of between 10% and 25% and preferably less than 20%.

Among the emollient base components can be used for liquid, solid or semi-solid ends, preferably liquid or semi-solid ones. Among the latter, liquid paraffins are particularly chosen. The concentration is selected between 15% and 25% of the weight of the formula and more preferably between 20% and 25%.

The volatile silicones used have the formula [- (CH3) 2SiO-] n, preferably pharmaceutical grade volatile silicones with n = 4.5 or 6 and more preferably decamethylcyclopentasiloxane (n = 5) are selected. The amount to be used may be between 40% and 60%, but between 45% and 55% by weight of the total composition is preferred.

The total silicon content according to the present invention is greater than 50%.

As an antioxidant component, vitamin E acetate is preferred at a concentration of between 0.1 and 2% and more preferably between 0.3% and 1%.

The present invention also refers to the process of preparing the described anhydrous formulation, characterized in that all components are incorporated during the process individually and by a simple process.

The process is characterized by the initial mixing and fusion of saturated fatty acid, paraffin and dimethicone. The volatile silicone is subsequently incorporated at a temperature between 60 ° C and 95 ° C, preferably between 70 ° C and 90 ° C. After cooling to a temperature below the previous one, the other components are incorporated.

This results in a formulation with a simple and stable composition that, after being cooled, is packaged directly.

Examples 1,2 and 3 illustrate the formulation of the galenic composition according to the present invention, as well as the results obtained in the stability and efficiency studies of the barrier effect.

Results of the stability and effectiveness studies of the barrier effect are provided.

Examples

Example 1

The process for preparing formulation 1 and 2 is described as a typical example of the formulations of the invention.

In a reaction vessel, glyceryl dibehenate, liquid paraffin and dimethicone are added and the mixture is heated until melted.

In another reaction vessel, the linoleic extract is melted and added to the previous mixture at a temperature below 60 ° C.

The other final components are added, also hot, and stirring greater than 2,000 rpm is maintained. Once the emulsion of all components is achieved, it is allowed to cool and packaged.

Formulation 1: Formulation 2:

Example 2

Stability

The following table shows the results of the stability tests of both formulations obtained at different temperatures and 12 months after their formulation.

Time: Newly manufactured product

Time: fridge / 12 months

Time: 25ºC / 12 months

The stability results show how the described formulations are stable for a prolonged period of time (12 months) in a refrigerator at 25 ° C, in which the galenic characteristics of the initial formulation are maintained.

Barrier effect

The barrier effect has been evaluated from the variation of skin perspiration (transepidermal water lost or TEWL) before and after application of the product obtained according to the formulation.

The test has been carried out by applying 2 mg / cm2 of product in the same area of the forearm (about 50 cm2) of 20 volunteers for 15 days.

Measurements of skin perspiration were performed with a Tewameter® on day 0 (t0), before applying the product, and on day 15 (t15), one hour after application. The results are expressed in g · h − 1 · m − 2.

At time 0, before treatment, the value of the TEWL has been:

9.36 g · h − 1 · m − 2 ± 2.25. (mean, affected by the standard deviation).

The value of TEWL, after 15 days of treatment has been:

8.31 g · h − 1 · m − 2 ± 2.05.

The decrease in perspiration was 9.3%, being statistically significant (t-test, p = 0.015).

Therefore, the results show the existence of a barrier effect after the application of the galenic formulation object of the present invention.

Claims (25)

one.

Topical galenic formulation in the form of an anhydrous base, which contains linoleic acid extract and comprises at least one dimethicone, a thickening fatty component, an emollient agent, a volatile silicone and an antioxidant agent.

2.

Formulation according to claim 1, characterized in that said linoleic acid extract is a plant extract with a percentage of linoleic acid greater than 40%.

3.

Formulation according to claim 1, characterized in that said vegetable extract is depleted barley lipid extract.

Four.

Formulation according to claim 1, characterized in that the extract content is from 1% to 10%, preferably between 3 and 7%, by weight of extract with respect to the weight of the formulation.

5.

Formulation according to any of claims 1 to 4, characterized in that said dimethicone is a linear dimethicone of low polymerization degree.

6.

Formulation according to claim 5, characterized in that said dimethicone has a viscosity between 20 cSt and 400 cSt, preferably between 20 cSt and 200 cST and more preferably between 50 cSt and 150 cSt.

7.

Formulation according to one of claims 5 or 6, characterized in that the concentration of said dimethicone in the formulation is from 1% to 5% of the weight of the formulation.

8.

Galenic formulation according to claim 1, characterized in that said thickening fatty component is a compound of the group consisting of glyceryl esters of saturated or unsaturated fatty acids and triglycerides of saturated or unsaturated fatty acids.

9.

Formulation according to claim 8, characterized in that said saturated or unsaturated fatty acids are from C12 to C26, and preferably from C16 to C24.

10.

Formulation according to one of claims 8 or 9, characterized in that said thickening fatty component is a glyceryl ester of saturated fatty acids, and said thickening fatty component is in a concentration between 10% and 25%, and preferably between 10 % and 20%, of the weight of the formulation.

eleven.

Formulation according to any one of claims 1 to 10, characterized in that said emollient agent is a compound of the group consisting of liquid, solid or semi-solid paraffins, preferably liquid or semi-solid, and most preferably liquid paraffins.

12.

Formulation according to claim 11, characterized in that said emollient agent is a liquid paraffin and is at a concentration between 15% and 25% of the weight of the formulation, and preferably between 20% and 25% of the weight of the formulation.

13.

Formulation according to any of claims 1 to 12, characterized in that said volatile silicone is a cyclic silicone of formula [- (CH3) 2SiO-] n, of pharmaceutical grade with n = 4.5 or 6.

14. Formulation according to claim 13, wherein said cyclic silicone is decamethylcyclopentasiloxane.

fifteen.

Formulation according to claim 14, characterized in that said cyclic silicone is in a concentration between 40% and 60%, and preferably between 45% and 55%, by weight of the formulation.

16.

Formulation according to any one of claims 1 to 15, characterized in that said antioxidant agent is vitamin E acetate with a concentration between 0.1 and 2%, and more preferably between 0.3% and 1%, by weight of the formulation.

17.

Formulation according to any of the preceding claims, characterized in that it comprises other minor components of the group consisting of emollients, preservatives, perfumes, and pigments.

18.

Method for preparing a galenic formulation according to any of claims 1-17, characterized in that said linoleic acid extract is incorporated in a composition containing at least said low polymerization dimethicone.

19.

Method for preparing a galenic formulation according to any of claims 1-17, characterized in that said linoleic acid extract is incorporated into a formulation containing at least said low polymerization dimethicone, and at least said thickening fatty component, said emollient agent and said volatile silicone .

twenty.

Method according to one of claims 18 or 19, characterized in that said linoleic acid extract is incorporated at a concentration of 1% to 10% by weight of said formulation.

twenty-one.

Method according to one of claims 18 or 19, characterized in that said linoleic acid extract is incorporated at a concentration between 3% and 7% by weight of said formulation.

22

Method according to any of claims 18 to 21, characterized in that said dimethicone is incorporated at a concentration of 1 to 5% by weight of said formulation.

2. 3.

Method for preparing a galenic formulation according to any of claims 1-17, characterized in that said antioxidant agent is incorporated into an anhydrous system that already contains said linoleic acid extract.

24.

Use of a galenic formulation according to any of claims 1 to 17, to make a dermatological preparation for the feet.

SPANISH OFFICE OF THE PATENTS AND BRAND SPAIN REPORT ON THE STATE OF THE TECHNIQUE @ Int. Cl .: See additional sheet @ ES 2 343 775 @ Application number: 200803721 @ Date of submission of the application: 29.12.2008 @ Priority date: RELEVANT DOCUMENTS

Category

56 @ Documents cited Claims Affected

TO

WO 2007073878 A1 (UNILEVER PLC) 05.07.2007, page 2, 1-24

line 3 - page 9, line 12; examples VI-XII.

TO

US 2005112072 A (WANG et al.) 05.25.2005, examples 5.6. 1-24

TO

US 6200964 B1 (SINGLETON et al.) 13.03.2001, column 1, 1-24

line 35 - column 7, line 50.

TO

US 6146664 A (SIDDIQUI) 14.11.2000, column 4, 1-24

line 28 - column 5, line 59; column 8, line 6 - column 10,

line 41.

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been produced Dg for all claims D for claims no:

Date of realization of the report 26.07.2010

Examiner N. Vera Gutiérrez Page 1/4

Application number: 200803721  REPORT OF THE STATE OF THE TECHNIQUE CLASSIFICATION OF THE OBJECT OF THE APPLICATION  A61K 31/201 (2006.01) A61K 47/34 (2006.01) A61P 17/00 (2006.01) Minimum documentation sought (classification system followed by the classification symbols) A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, search terms used) INVENES, EPODOC, CAS, WPI, BIOSIS, MEDLINE, EMBASE, NPL State of the Art Report (additional sheet) Page 2/4 Application number: 200803721  WRITTEN OPINION Date of Completion of Written Opinion: 07.27.2010 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims 1-24 YES

Claims

NO

Inventive activity

Claims 1-24 YES

(Art. 8.1 LP 11/1986)

Claims NO

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base: This opinion has been made on the basis of the patent application as published. Report on the State of the Art (Written Opinion) Page 3/4 Application number: 200803721  WRITTEN OPINION 1. Documents considered: The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

WO 2007073878 A1  

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on patents on novelty and inventive activity; quotes and explanations in support of this statement The invention relates to a galenic formulation of topical application in the form of an anhydrous base, which contains linoleic acid extract and comprises at least one dimethicone, a thickening fatty component, an emollient agent, a volatile silicone and an antioxidant agent. It also refers to its method of preparation and its use as a dermatological preparation for the feet. Document D01 describes water-in-oil emulsions containing conjugated linoleic acid, a silicone type surfactant and a silicone elastomer dissolved in a dimethicone fluid, as well as other additional components such as antioxidants, thickeners, etc. Formulations for cosmetic use are prepared in examples VI through XII, taking advantage of the effect of luminosity on the skin provided by linoleic acid. Documents that disclose topically applied formulations in the form of anhydrous base containing an extract of linoleic acid and the rest of the components detailed in claim 1 of the application have not been found in the state of the art. In addition, it is not considered obvious that a person skilled in the art conceives a galenic formulation with these characteristics from what is disclosed in the prior art. Consequently, the invention set forth in claims 1-24 of the application meets the requirements of novelty and inventive activity set forth in Articles 6.1 and 8.1 of the Patent Law. Report on the State of the Art (Written Opinion) Page 4/4