WO2021140131A1 - Use of taxodione as an anti-glycation agent - Google Patents

Abstract

The invention relates to the use of taxodione to inhibit protein glycation.

Description

DESCRIPTION

TITLE: Use of taxodione as an anti-glycation agent Technical field of the invention

The present invention relates to the cosmetic or therapeutic use of taxodione to inhibit protein glycation as well as to a cosmetic composition comprising taxodione.

Technical background

Reactive Carbonyl Species (RCS) are compounds with highly reactive carbonyl groups and described for their detrimental effects on proteins, nucleic acids and lipids. They are often generated as metabolic products during lipid peroxidation and glycation (Negre-Salvayre et al., 2008; Semchyshyn, 2014). They are also involved in the formation of advanced glycation end products (AGEs for Advanced Glycation End-products) and advanced lipoxidation end products (ALEs for Advanced Lipoxidation End-products) (Semchyshyn, 2014). RCS, AGEs and ALEs accumulate during aging and oxidative stress related diseases such as atherosclerosis, diabetes and neurodegenerative diseases (Miyata et al., 2000; Gkogkolou et al., 2012; Aldini et al., 2012; Aldini et al. al., 2013; Vistoli et al., 2013; Ayala et al., 2014; Semchyshyn, 2014). Their accumulation in skin tissue leads to premature aging.

Advanced glycation end products (AGEs) are formed by a non-enzymatic reaction between the aldehyde group of reducing sugars and a protein such as collagen or albumin. The reaction is well known as the Maillard reaction. During these reactions, an unstable Schiff's base is initially formed and rearranged into more stable ketoamines (Amadori products). After oxidation, ketoamines lead to the formation of various advanced glycation end products (AGEs), such as pentosidine (fluorescent compound) and N-carbomethyl lysine (CML, non-fluorescent compound) (Cervantes-Laurean et al. , 2006; Aldini et al., 2013).

Glycation occurs naturally with dermal proteins, such as collagen, clinical signs increase steadily with age (Grasser et al., 2012). Collagen is the main structural protein in the extracellular matrix of various connective tissues in the body such as tendons, ligaments, and skin. AGEs accumulate in the tissues with age and reduce elasticity (Cervantes-Laurean et al., 2006), in particular the elasticity of the skin. Aminoguanidine, also known as pimagedin, was one of the first substances identified as inhibitors of AGE formation (Joglekar et al., 2017). However, some side effects have appeared in clinical trials with diabetic patients (Gkogkolou et al., 2012; Joglekar et al., 2017). Many spices and herbs have been shown to inhibit albumin glycation in vitro. Flavonoids and biflavonoids are described as having an interesting anti-glycation effect (Gkogkolou et al., 2012; Hori et al., 2012). Patent application FR2951085A1 describes that various antioxidant molecules are known to inhibit the glycation reaction. It was subsequently shown that an antioxidant activity was not necessarily linked to the inhibition of the formation of AGEs (A. Schinkovitz et al., Fitoterapia 131 (2018) 182-188 and S. Morel et al. , Phytochemistry Letters 6 (2013) 498-503).

New compounds that inhibit the formation of AGEs that are both effective and without adverse effects continue to be researched.

Summary of the invention

The inventors identified from extracts a compound, taxodione, which inhibits the formation of advanced glycation end products and does not exhibit the toxic or adverse effects of known AGE formation inhibitors.

Also, an object of the present invention relates to the taxodione and / or a composition comprising at least 0.001% of taxodione for its use for inhibiting the glycation of proteins.

This use can be therapeutic. The invention therefore relates to taxodione and / or a composition comprising at least 0.001% taxodione for its use as a medicament, preferably as a medicament which inhibits the glycation of proteins. This use can also be non-therapeutic and in particular cosmetic. The invention therefore relates to the non-therapeutic use of taxodione in a cosmetic composition and / or a cosmetic composition comprising at least 0.001% of taxodione for inhibiting the glycation of proteins in the skin and / or nails and / or for prevent and / or fight against the signs of aging of the skin and / or nails.

The invention also relates to a cosmetic composition comprising at least 0.001% by weight of taxodione and at least 10% of fatty phase.

Detailed description of the invention

Definitions Taxodione (CAS 19026-31 -4) is a diterpene also called (4bS, 8aS) - 4b, 5,6,7,8,8a-hexahydro-4-hydroxy-2-isopropyl-4b, 8,8-trimethylphenanthrene -3,9-dione or 11-hydroxyabieta-7,9 (11), 13-triene-6,12-dione, having the chemical structure below

[Chem 1]

The taxodione of the various compositions according to the invention (cosmetic or therapeutic composition) and / or for the various therapeutic or non-therapeutic uses according to the invention preferably comes from rosemary stems, more preferably from an extract of rosemary stems.

Taxodione can in particular be extracted from rosemary stems by any chemical or mechanical process.

According to a preferred embodiment, the taxodione is extracted from rosemary stems by chemical extraction with an organic or hydroalcoholic solvent such as hexane or ethanol.

For example, rosemary stems can be reduced to a dry powder; the dry powder can be macerated in an organic or aqueous-alcoholic solvent for a given time, preferably at least 5 days; ultrasound can optionally be applied; the liquid phase can be recovered and the solvent can be evaporated.

The extract of rosemary stems can include at least 0.5% taxodione, at least 1% taxodione, at least 2.5% taxodione, at least 5% taxodione, at least 7.5% taxodione, at least 10% of taxodione or at least 15% of taxodione.

Cosmetic composition

The cosmetic composition according to the invention comprises at least 0.001% by weight of taxodione and at least 10% of fatty phase. Taxodione has lipophilic properties (logP around 4). It is therefore a good candidate for its incorporation into cosmetic formulations, in particular cosmetic formulations having a high level of fatty phase.

Thus, the cosmetic composition can comprise at least 10%, at least 20%, at least 30%, at least 50% or at least 70% of fatty phase.

The cosmetic composition can be selected from the group consisting of a gel, an anhydrous composition such as oil, an ointment or a butter and an emulsion such as a cream or a milk.

Preferably, the cosmetic composition is anhydrous. It then comprises only a fatty phase. More preferably, the cosmetic composition is an oil.

The inventors have shown that taxodione inhibited the peroxidation of lipids and therefore proved to be a particularly advantageous preservative, in particular for compositions with a high oily phase content. Also, according to one embodiment, the cosmetic composition does not include an additional preservative (ie other than taxodione).

Advantageously, the taxodione of the cosmetic composition can come from rosemary stems. Also, the cosmetic composition comprises, according to a preferred embodiment, an extract of rosemary stems.

Typically, the composition comprises a cosmetically effective amount of taxodione with one or more excipients.

A cosmetically effective amount here means the amount which is sufficient to produce an inhibitory effect on protein glycation.

The effect of the cosmetic composition according to the invention can be easily verified by various assays, using tests (as disclosed in the examples below) or appropriate in vivo or in vitro models, in particular by comparison with an inhibitor of glycation of known proteins such as aminoguanidine.

In one embodiment, the cosmetic composition comprises at least 0.05% by weight, preferably at least 0.1% by weight, more preferably at least 1% by weight, at least 5% by weight or at least 10% by weight of taxodione.

Typically, the cosmetic composition is intended for topical application, preferably application to the skin and / or nails, more preferably application to the skin.

The cosmetic composition according to the invention can comprise an active principle other than taxodione. It may be an anti-aging compound such as hyaluronic acid, retinol, coenzyme Q10, collagen and / or vitamin C and / or a compound having another activity, for example moisturizing activity. , a UV filter and / or an anti-inflammatory agent. According to an alternative embodiment, the cosmetic composition does not comprise rosmarinic acid, ursolic acid, carnosol and / or carnosic acid.

The cosmetic composition according to the invention is preferably intended to be used for preventing and / or combating the signs of aging of the skin and / or of the nails.

Cosmetic use of taxodione as an anti-glycation agent The invention relates to the non-therapeutic use of taxodione in a cosmetic composition and / or of a cosmetic composition comprising at least 0.001% by weight of taxodione to inhibit the glycation of proteins of the skin and / or nails, preferably skin proteins.

Inhibition of protein glycation can be readily verified by various assays, using appropriate tests such as preferably that of Derbre et al. (2012) described in the examples or that of André et al. (2018). Suitable tests may also consist of methods measuring the expression of AGE receptors (Adeshara et al. 2018; Huang et al. 2019).

The evaluation of the inhibition of the glycation of proteins can be made by comparison with a reference compound known to have an inhibitory activity of the glycation of proteins such as aminoguanidine. Thus, it may be considered that a compound which has a glycation inhibiting activity greater than or equal to aminoguanidine is an anti-glycation agent. For example, according to the test of Derbré et al. exemplified, a composition is considered to inhibit BSA glycation if the minimum inhibitory concentration (IC ₅ o) is less than 0.17 mg / ml and as an inhibitor of collagen glycation if the minimum inhibitory concentration (IC ₅₀ ) is less than 1 mg / ml. A pure compound is considered as an inhibitor of BSA glycation if the minimum inhibitory concentration (IC ₅₀ ) is less than 1.5 mM and as an inhibitor of collagen glycation if the minimum inhibitory concentration (IC ₅₀ ) is less than 10 mM .

The skin proteins that can be inhibited from glycation are typically collagen and / or elastin.

The nail proteins whose glycation can be inhibited are typically keratin. By inhibiting the glycation of proteins such as collagen, elastin and / or keratin, taxodione helps prevent and / or fight against the signs of aging of the skin and / or nails linked to the glycation of proteins.

Also, an embodiment of the present invention relates to the non-therapeutic use of taxodione in a cosmetic composition and / or of a cosmetic composition comprising at least 0.001% by weight of taxodione for preventing and / or controlling against the signs of aging of the skin and / or nails linked to protein glycation.

In addition, the inventors have shown that in addition to its ability to inhibit protein glycation, taxodione can be used to inhibit lipid peroxidation.

Thus, the taxodione can be used in a cosmetic composition to inhibit the peroxidation of skin and / or nail lipids, preferably together with its use to inhibit the glycation of skin and / or nail proteins.

Inhibition of lipid peroxidation can easily be verified by various assays, using appropriate assays such as the TBARS test described in the examples.

By inhibiting the peroxidation of lipids, taxodione makes it possible to prevent and / or fight against the signs of aging of the skin and / or nails associated with the peroxidation of lipids. Also, one embodiment of the present invention relates to the non-therapeutic use of taxodione in a cosmetic composition and / or of a cosmetic composition comprising at least 0.001% by weight of taxodione for preventing and / or combating the signs of aging. of the skin and / or of the nails linked to the peroxidation of lipids, preferably together with the prevention and / or the fight against the signs of aging of the skin and / or of the nails linked to the glycation of proteins.

More generally, the present invention relates to the non-therapeutic use of taxodione in a cosmetic composition for preventing and / or combating the signs of aging of the skin and / or nails.

Taxodione can be used in a cosmetic composition in particular for stimulating the elasticity of the dermis and the epidermis, strengthening dermo-epidermal cohesion, preventing, limiting the loss of firmness and / or improving the elasticity properties of the epidermis. .

The present invention also relates to a cosmetic treatment process for preventing and / or combating the signs of aging of the skin and / or nails, in which a cosmetic composition comprising taxodione is applied to the skin and / or nails. Typically, the cosmetic composition will be applied to a subject having or wishing to prevent signs of aging, in particular those caused by the glycation of proteins and possibly those caused by the peroxidation of lipids. The present invention also relates to the use of taxodione in the manufacture of a cosmetic composition intended for preventing and / or combating the signs of aging of the skin and / or nails, in particular those caused by the glycation of proteins and optionally. those caused by lipid peroxidation. Typically, in this manufacturing process the taxodione is added to at least one cosmetic excipient. For the cosmetic uses and methods according to the aforementioned invention, the cosmetic composition is preferably applied topically, more preferably to the skin.

For the uses and methods according to the invention, the cosmetic composition may comprise a cosmetically effective amount of taxodione with one or more excipients. A cosmetically effective amount here means the amount which is sufficient to produce an inhibitory effect on protein glycation. The cosmetic composition can comprise at least 0.001% by weight of taxodione. In one embodiment, the cosmetic composition comprises at least 0.05% by weight, preferably at least 0.1% by weight, more preferably at least 1% by weight, at least 5% by weight or at least 10% by weight of taxodione.

Advantageously, the taxodione of the cosmetic composition can come from rosemary stems. Also, the cosmetic composition comprises, according to a preferred embodiment, an extract of rosemary stems.

This cosmetic composition can comprise at least 10%, at least 20%, at least 30%, at least 50% or at least 70% of fatty phase.

The cosmetic composition according to the invention defined above is that preferred for the cosmetic uses and processes according to the invention.

Therapeutic use of taxodione as an anti-glycation agent Due to its anti-glycation activity, taxodione can also be used for therapeutic purposes.

Thus, the present invention also relates to taxodione for its use as a medicament, more particularly for its use as a medicament for inhibiting the glycation of proteins.

EFAs are involved in many pathologies including pathologies such as diabetes, renal failure, atherosclerosis, neurodegenerative diseases and amyloidosis.

The taxodione or the composition comprising at least 0.001% taxodione can therefore be used in the treatment or prevention of a pathology selected from the group consisting of diabetes, renal failure, atherosclerosis of neurodegenerative diseases and amyloidosis.

The present invention also relates to a method of treatment or prevention in a subject to be treated, in particular a subject suffering from or having a risk of suffering from diabetes, renal failure, atherosclerosis, neurodegenerative diseases and / or. amyloidosis comprising administration of taxodione to said subject. The present invention also relates to the use of taxodione in the manufacture of a medicament, preferably a protein glycation inhibitor medicament, more preferably a medicament for treating a pathology selected from the group consisting of diabetes, insufficiency. renal, atherosclerosis, neurodegenerative diseases and amyloidosis.

The present invention also relates to a composition comprising taxodione, preferably a composition comprising at least 0.001% taxodione, for its use as a medicament, preferably as a protein glycation inhibitor medicament, even more preferably for its use in the treatment or prevention of a pathology selected from the group consisting of diabetes, renal failure, atherosclerosis, neurodegenerative diseases and amyloidosis.

Typically the composition, called therapeutic composition, comprises a so-called therapeutically effective dose of the active principle: taxodione.

The effective dose is determined and adjusted depending on factors such as the composition used, the route of administration, the physical characteristics of the individual considered, such as sex, age and weight, concomitant drugs and other factors that those skilled in the art will be able to determine. For example, it is well known to those skilled in the art to start doses of the active ingredient at levels lower than those required to obtain the desired therapeutic effect and to gradually increase the dose until the desired effect. is reached. However, the daily dosage of the products can vary over a wide range of 0.01 to 1000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1, 0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 ,

250 and 500 mg of the active principle for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains about 0.01 mg to about 500 mg of the active ingredient, typically 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is usually provided at a dosage level of 0.0002 mg / kg to about 20 mg / kg of body weight per day, in particular about 0.001 mg / kg to 7 mg / kg of body weight per day. day.

In one embodiment, the so-called therapeutic composition intended for use as a medicament comprises at least 0.001% by weight of taxodione, at least 0.05% by weight of taxodione, at least 0.1% by weight of taxodione, at least 1% by weight, at least 5% by weight of taxodione or at least 10% by weight of taxodione. Advantageously, the taxodione of the therapeutic composition can be obtained from rosemary stems. Also, the therapeutic composition comprises, according to a preferred embodiment, an extract of rosemary stems. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted as limiting the scope of the present invention.

Brief description of the figures

[Fig. 1] FIG. 1 shows the measurement according to the method described in Derbré et al. (2012) of the percentage of pentosidine-like AGEs (pentosidine-like AGEs) on BSA as a function of the log concentration of aminoguanidine, ethanolic extract (RBEJ7), hexane extract (RBHex) or taxodione.

[Fig. 2] FIG. 2 shows the measurement according to the method described in Derbré et al. (2012) of the percentage of pentosidine-like AGEs (pentosidine-like AGEs) on collagen as a function of the log concentration of aminoguanidine, ethanolic extract (RBEJ7), hexane extract (RBHex) or taxodione.

Examples

Material and methods

Maceration was carried out from 150 g of crushed rosemary stems, in the dark, at room temperature, with 900 g of absolute ethanol; manual stirring was carried out every 24 hours for seven days. The stem extract was then filtered and evaporated under reduced pressure to dryness. 5.3 g of ethanolic extract were obtained and called RBEJ7.

100 g of crushed rosemary stems were placed in 1 L of hexane in an ultrasonic bath for 15 min. The extract was then filtered. The stem residue was replaced in 1 L of clean hexane in an ultrasonic bath for 15 min. After filtration, the ultrasonic extraction was repeated once. Finally, the filtered extracts obtained from the 3 successive extractions were combined and dried by evaporation under reduced pressure. 1.12 g of hexane extract was obtained and named RBHex.

Isolation of taxodione

From the ethanolic extract, 50 mg of pure taxodione were obtained as previously described (Morel et al., 2019). Quantification of the taxodione by HPLC The quantification of the taxodione contained in the extracts was carried out by HPLC at 330 nm with a previously validated method (Morel et al., 2019).

HPLC analysis was performed on an Ultimate 3000 (Thermo Fisher Scientific Inc., San Jose, USA) which included a quaternary pump module, an automatic injector and a DAD detector. The system was driven using Chromeleon software. Chromatographic separation was performed on a C18 Hypersyl ODS column (250 mm x 4.6 mm, 5 µm, Thermo Fisher Scientific Inc., San Jose, USA), with a column maintained at 35 ° C. The fractions were eluted at a flow rate of 1 ml / min using solvent A (water / formic acid 99.1: 0.1v / v) and solvent B (acetonitrile). The gradient used for the analysis was 0-10 min, 85% A; 10-20 min, 85-65% A; 20-25 min, 65-30% A; 25-30 min, 30% A; 30-50 min, 30-20% A; 50-60 min, 20-10% A; 60-70 min, 10-85% A; 70-80 min 85% A. The identification of taxodione in the crude extract was based on comparison with the retention time and UV spectrum of a sample of pure taxodione.

Evaluation of the anti-AGE effects of taxodione and extracts

Two methods were used to evaluate the anti-AGE effects of the extracts, one with BSA (bovine serum albumin) as protein and the second with collagen as protein, both have been previously described by Derbré et al. (2012).

The effect on AGE formation was measured according to the previously published method (Derbré et al., 2012). Briefly, ten microliters of each extract or compound were placed in dark-bottom 96-well plates (Fisher Scientific, Illkirch, France) and mixed with 90 µL of a solution containing BSA (11 mg / L) or collagen (0.1 mg / ml), D-ribose (0.25 M for BSA and 0.5 M for collagen) and phosphate buffer (50 mM, _{0.02% NaN 3} , pH 7.4 ). The plates were then incubated for 24 h at 37 ° C, before analysis by fluorescence detection (Aexc: 335 nm, Aem: 385 nm) using an Infinité M200 plate reader (Tecan, Lyon, France) . Aminoguanidine was used as a positive control.

A TBARS test (compounds reactive with thiobarbituric acid) was carried out according to the method of Lavaud et al. (2015) with some modifications. Dried and pasteurized egg yolk is used as a source of lipids (phospholipids, triacylglycerols) and proteins. Briefly, 30 µl of sample at different concentrations was added to a mixture containing 300 µl of egg yolk emulsified with 0.1 M phosphate buffer pH 7.4 and 30 µl of Fe ²⁺ (1 mM). After 1 h incubation at 37 ° C, 150 µl of 15% TC A and 300 mI of 1% TBA was added and was kept in a boiling water bath for 20 min. After cooling and centrifugation, the formation of TBARS was measured by absorbance at 532 nm. The results were expressed as a median inhibitory concentration (IC ₅ o) (mg / ml).

Results

Quantification of taxodione in ethanolic and hexane extracts

[Table 1]

Anti-g Ivcation activity

Effects of rosemary stem extracts and taxodione on glycation

[Table 2]

As indicated in Table 2, ethanolic and hexane extracts are capable of inhibiting pentosidine-type AGEs on BSA but not on collagen. Taxodione is capable of inhibiting pentosidine-type AGEs with an IC ₅ o value of 0.5 mM. Taxodione has a superior effect to aminoguanidine, conventionally used as a reference control (Hori et al., 2012; Park et al., 2018). While aminoguanidine is less active on collagen than on BSA (CI ₅ o = 1.5 mM and 10 mM respectively), taxodione retains the same efficacy on the 2 substrates (0.5 mM).

Effect on lipid peroxidation

Effects of rosemary stem extracts and taxodione on lipid peroxidation

[Table 3]

As shown in Table 3, the ethanolic and hexane extracts were able to inhibit peroxidation in a complex mixture of lipids. Taxodione showed comparable activity to that of Trolox, the reference compound. It should be noted that the hexane extract is more active than the ethanolic extract which suggests a correlation between the taxodione content and the lipid anti-peroxidation activity of the extracts.

References

Throughout this application, various references describe the state of the art to which the invention belongs.

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Aldini G., Vistoli G., Stefek M., Chondrogianni N., Grune T., Sereikaite J., Sadowska- Bartosz I., Bartosz G. (2013) Molecular strategies to prevent, inhibit, and degradé advanced glycoxidation and advanced lipoxidation end products, Free Radical Research, 47 (1): 93-137.

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Claims

1. Non-therapeutic use of taxodione in a cosmetic composition and / or a cosmetic composition comprising at least 0.001% by weight of taxodione for inhibiting glycation of skin and / or nail proteins.

2. Non-therapeutic use according to claim 1 characterized in that the taxodione is further used to inhibit the peroxidation of lipids in the skin and / or nails.

3. Non-therapeutic use of taxodione in a cosmetic composition and / or a cosmetic composition comprising at least 0.001% by weight of taxodione for preventing and / or combating the signs of aging of the skin and / or nails.

4. Non-therapeutic use according to claim 3, characterized in that the signs of aging of the skin and / or of the nails are the signs of aging of the skin and / or of the nails linked to the glycation of proteins.

5. Non-therapeutic use according to claim 3 or 4, characterized in that the signs of aging of the skin and / or of the nails are the signs of aging of the skin and / or of the nails associated with the peroxidation of lipids.

6. Use of taxodione in the manufacture of a cosmetic composition intended for preventing and / or combating the signs of aging of the skin and / or nails.

7. Cosmetic treatment process for preventing and / or combating the signs of aging of the skin and / or nails, characterized in that a cosmetic composition comprising taxodione is applied to the skin and / or nails.

8. Cosmetic composition characterized in that it comprises at least 0.001% by weight of taxodione and at least 10% of fatty phase.

9. Taxodione and / or a composition comprising at least 0.001% taxodione for its use as a drug that inhibits protein glycation.

10. Use according to any one of claims 1 to 6, process according to claim 7, cosmetic composition according to claim 8 and / or taxodione and / or composition comprising at least 0.001% of taxodione for its use according to claim 9 characterized in what taxodione comes from rosemary stems.

11. Use according to any one of claims 1 to 6, process according to claim 7, cosmetic composition according to claim 8, characterized in that the cosmetic composition comprises an extract of rosemary stems.

12. Taxodione and / or composition comprising at least 0.001% of taxodione according to claim 9, characterized in that the medicament comprises an extract of rosemary stems.