EP1737495A1

EP1737495A1 - Novel pharmaceutical or cosmetic carriers containing cylcic acetals

Info

Publication number: EP1737495A1
Application number: EP05739633A
Authority: EP
Inventors: Jean-David Rodier; Bruno Mahler
Original assignee: Gattefosse SA
Current assignee: Gattefosse SA
Priority date: 2004-04-21
Filing date: 2005-03-21
Publication date: 2007-01-03
Also published as: WO2005105149A1; FR2869232B1; US20080280997A1; BRPI0509994A; FR2869232A1

Abstract

The use of a cyclic acetal obtained by reacting an aliphatic aldehyde having 2 to 4 carbon atoms with a polyol having 3 to 6 carbon atoms and at least three hydroxy functions, including two on vicinal carbons or carbons having one carbon atom therebetween, as a pharmaceutical or cosmetic carrier, is disclosed.

Description

NEW PHARMACEUTICAL OR COSMETIC EXCIPIENTS BASED ON CYCLIC ACETALS

The invention relates to new pharmaceutical or cosmetic excipients based on cyclic acetals. It also relates to pharmaceutical or cosmetic compositions incorporating said excipients.

In the following description and in the claims, the term "excipient" means a neutral substance of variable nature into which are introduced the elements called "active and preservatives", optionally dyes and perfumes, the whole constituting a cosmetic composition or pharmaceutical.

Cyclic acetals result in known manner from the reaction between an aldehyde and a polyol having at least two hydroxyl functions, thus leading to the formation of acetal rings comprising five or six atoms.

Document US-A-4031 112 describes emulsifiers used in industry, in particular in the field of printing. In practice, these emulsifiers are obtained by an oxyalkylation reaction carried out on cyclic acetals. The latter are obtained from aldehyde advantageously comprising from 5 to 20 carbon atoms, although formaldehyde, acetaldehyde, propionaldehyde or butyraldehyde are not expressly excluded. Furthermore, the polyols used are generally polyols comprising from 3 to 6 carbon atoms and in particular glycerol or even pentaerythritol. The oxyalkylation reaction is then carried out in two stages by bringing together the cyclic acetal obtained with, advantageously, propylene oxide.

Document GB-A-5 49213 describes the use of cyclic acetals as an anti-inflammatory in cosmetic compositions, in particular in sunscreen compositions. In practice, cyclic acetals are obtained by reaction of an aldehyde on a diol. The aldehydes and diols used for the manufacture of anti-i-iflammatory are listed exhaustively and only certain combinations are exemplified. Among the aldehydes which can be used, acetaldehyde, propionaldehyde and butyraldehyde are especially mentioned. Furthermore, contrary to the teaching of this document which discloses the use of diol, glycerin or glycerol, that is to say a triol, is cited among the usable diols. However, the document does not expressly describe the possibility of reacting glycerol with an aldehyde comprising a small number of carbon atoms. Furthermore and above all, nothing is indicated concerning the possibility of using the cyclic acetals described, as pharmaceutical or cosmetic excipients.

To the knowledge of the Applicant, document EP-A-12143 describes for the first time the possibility of using certain cyclic acetals in cosmetic compositions, in particular for their emollient activity. Are described in particular for this application, the cyclic acetals resulting from the reaction between an aliphatic aldehyde comprising from 8 to 31 carbon atoms and a diol. Preparation No. 7 however describes a cyclic acetal obtained from glycerol and an oxoaldehyde itself prepared by the oxo or hydroformylation process from a mixture of C ₁₂ and C ₁ α-olefin. The emo properties of the product thus obtained are then compared with other products obtained from the same oxoaldehyde, but having reacted on different polyols, such as for example ethylene glycol, 1,2-propylene glycol and pentaerythritol. . As the results show, the emollient properties of the cyclic acetals obtained from glycerol and pentaerythritol are much lower than those obtained with ethylene glycol or even 1,2-propylene glycol.

Document US-A-5 175 143 describes new perfumes based on cyclic acetals which can be used in different presentations, such as toilet soaps, deodorants, etc. The cyclic acetals described are obtained from cyclic aldehydes and 1- 3 diol. Document US-A-5,917,059 relates exclusively to a process for the preparation of cyclic acetal, without particular application. The improved process consists in reacting an aldehyde having from 1 to 6 carbon atoms with a polyol having at least 2 hydroxyls. Advantageously cited are diols and triols having 2 to 12 carbon atoms, in particular glycerol and trimethylol propane.

Document EP-A-268460 describes a therapeutic composition comprising, as a penetration promoter, a dioxolane and / or a dioxane substituted with at least one R group, at least one of which is a C4 to C8 alkyl or alkenyl group. This molecule has the following formula:

where R is C4 alkyl or alkenyl. In practice, these molecules are obtained by reacting a C5 aldehyde (pentanal or valeraldehyde) on glycerol. A mixture of 2-butyl-1,3-dioxolane-4-hydroxymethyl and 2-butyl-1,3-dioxan-5-ol is obtained. The main drawback of these molecules is that they are not miscible in water, which limits their use as a pharmaceutical or cosmetic excipient. This product is subsequently referred to as BDM.

Document US-A-5 686 098 describes a salting-out patch of stradiol. To improve penetration of stradiol in the skin, the patch also contains mono-isopropylidene glycerol resulting from the reaction between acetone and glycerol. The product obtained marketed under the name Solketal ^® has the following formula:

Document GB-A-2075833 describes an injectable solution containing, as active ingredient, a mixture of trimethoprim and sulfamethoxypyridazine in a solvent itself resulting from a mixture of 4-hydroxymethyl-1,3 dioxolane and 5 hydroxy- 1.3 dioxane obtained from formaldehyde.

Document FR-A-2 789 586 describes the use of certain cyclic acetals, in particular solketa 11, as an absorption promoter.

In the context of his research, the Applicant has found that certain cyclic acetals obtained from aliphatic aldehydes and from specific polyols had notably the following properties, of miscibility, and of activity promoter, by making interesting products as pharmaceutical excipients or cosmetics.

In the following description and in the claims, by the expression "activity promoter", the improvement in the activity of a molecule is expressed in the presence of the products of the invention. In the absence of these, the active molecule considered is not very active or inactive in the formula studied.

In other words, the invention relates to new pharmaceutical or cosmetic excipients based on cyclic acetal. These excipients are characterized in that the cyclic acetal is the product of the reaction between an aliphatic aldehyde comprising from 2 to 4 carbon atoms and a polyol comprising from 3 to 6 carbon atoms and at least three hydroxyl functions, of which two at fewer are located on vicinal carbons or separated by a carbon.

Of course, the excipient may contain the cyclic acetals described above alone or as a mixture between them.

The Applicant has found that the cyclic acetals obtained by reaction of saturated, linear or branched aldehydes, having a low number of carbon atoms, in practice between 2 and 4, for example, a polyol comprising in practice from 3 to 6 carbon atoms and advantageously having 3 to 6 OH functions, at least two of which are located on the vicinal carbons or separated by a carbon, were interesting for the desired application.

In particular, the Applicant has shown that cyclic acetals of the invention had the following properties or better miscibility as close molecules, such as for example solketal ^® or the molecules described in EP-A-268460. More generally, it has been demonstrated that the cyclic acetals of the invention were soluble in many oils and alcohols used in pharmacy and cosmetics and in water, and were capable of dissolving many active ingredients which are soluble or insoluble in water. In addition, they are compatible with gelling agents and can be incorporated into emulsions, microemulsions, etc. Finally, they are also endowed with an activity promoting effect of active molecules, cosmetic or pharmaceutical.

In an advantageous embodiment, the cyclic acetal results from the reaction between propanai (propionaldehyde) and glycerol. Because of the possible cyclization between the hydroxyl functions of glycerol located in positions 1 and 3 (functions separated by a carbon) or in positions 1 and 2 (vicinals) with the carbonyl function of propionaldehyde, the reaction leads to a mixture of two molecules, respectively 2-ethyl-4-hydroxymethyl-1,3-dioxolane and 2-ethyl-1,3-dioxan-5-ol of formula:

This mixture is designated in the following description "EDM".

A mixture of the same type also showing satisfactory results for the envisaged application is that corresponding to 2-propyl-4-hydroxyrnéthyι-l, 3-dioxolane with 2-propyl-l, 3-dioxan-5-ol obtained by reaction between butyraldehyde and glycerol.

This mixture is designated in the following description "PDM".

For these two mixtures, the Applicant has found that mixtures enriched in one or the other of the constituents of the mixture (dioxane or dioxolane) or in cis isomer or in trans isomer of the two types of molecules, do not modify the properties obtained .

Interesting properties are also obtained with 2-methyl-5-ethyl-5-hydroxymethyl-1,3-dioxane obtained by reaction between acaidehyde and trimethylol propane (2-ethyl-2-hydroxymethyH, 3-propanediol). The product obtained in this case contains a mixture of cis-trans isomers of the same molecule. Indeed, only one dioxane cycle is obtained by this process. In this case, the hydroxyl functions are separated from a carbon atom. In the following description, the product obtained is designated "FTE" and has the following formula:

The processes for preparing cyclic acetals are well known and are of two types, respectively a process with solvent, in particular toluene and a process without solvent. These methods are described below.

The invention naturally relates to a pharmaceutical or cosmetic composition incorporating the excipient described above.

In particular, the cyclic acetals forming part of the invention can be used for their solubilizing properties of active principles which are sparingly or not soluble in water or in oil, and as activity promoter probably resulting from a promoter effect. 'absorption.

The composition containing the cyclic acetals of the invention can be in all the galenical forms normally used for topical application to the skin or the hair, in particular in the form of an aqueous solution, of an oil-in-water emulsion or water-in-oil or multiple, a silicone emulsion, a microemulsion or nanoemulsion, an aqueous gel.

This composition can be more or less fluid and have the appearance of, among other things, a white or colored cream, an ointment, a milk, a lotion, a serum, a gel. The composition can contain the usual adjuvants in the cosmetic and dermatological fields, such as fatty phases, emulsifiers and co-emulsifiers, hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, perfumes , fillers, hydrophilic and lipophilic filters, dyes, neutralizers, penetrating agents, and polymers.

The amounts of these various adjuvants are those conventionally used in the fields considered, and for example from 0.01 to 30% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase or into the aqueous phase.

As fatty phases which can be used, it is possible to use vegetable oils and fats, mineral oils, oils of animal origin (for example lanolin), synthetic oils (for example isopropyl myristate, octyldodecyl, isostearyl iso stearate, decyl oleate , isopropyl palmitate), silicone oils (cyclomethicone, dimethicone) and fluorinated oils. It is also possible to use fatty alcohols, fatty acids, waxes and gums and in particular silicone gums.

As emulsifiers and coemulsifiers which can be used, mention may, for example, be made of polyglycerol and fatty acid esters, sucrose and fatty acid esters, sorbitan and fatty acid esters, fatty acid and sorbitane esters oxyethylenated, fatty alcohol and PEG ethers, glycerol and fatty acid esters, alkyl sulfates, alkyl ether sulfates, alkyl phosphates, alkyl polyglucosides, silicone emulsifiers.

As hydrophilic gelling agents, mention may in particular be made of carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides such as xanthan gum, guar gum, natural gums such as cellulose gum and derivatives, and clays.

As lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids, hydrophobic silica and ethylcellulose.

As active agents, depigmentants, emollients, moisturizers, anti-seborrheics, anti-acne, keratolytic and / or desquamating agents, anti-wrinkle and tightening agents, draining agents, anti-aging agents can be used in particular. irritants, soothing agents, slimming agents such as xanthic bases (caffeine), vitamins and their mixtures, matifying agents, anti-aging active agents such as retinol, anti-wrinkle agents, essential oils.

In the event of incompatibility between them, the active agents indicated above can be incorporated into spherules, in particular ionic or non-ionic vesicles and / or nanoparticles (nanocapsules and / or nanospheres), so as to isolate them from each other others in the composition.

As preservatives which can be used, mention may be made of benzoic acid, its salts and its esters; sorbic acid and its salts; parabens, their salts and esters; triclosan; imidazoHdinyl urea; phenoxyethanol; DMDM hydantoin; diazohdinyl urea; chlorphenesin.

As antioxidants which can be used, mention may be made of BHA, BHT, TBHQ, propyl gallate, tocopherols and their esters, tocotrienols, ascorbyl palmitate, rosemary extracts, green tea extract, chlorogenic acid, beta-carotene, flavonoids, chelating agents such as 1ΕDTA and its salts, citric acid. As useful solvents, mention may be made of water, ethanol, glycerin, propylene glycol, butylene glycol, sorbitol.

As fillers which may be used, mention may be made of talc, kaolin, mica, serecite, magnesium carbonate, aluminum silicate, magnesium silicate, organic powders such as nylon.

As filters which can be used, mention may be made of the UVA and UNB filters conventionally used such as benzophenone-3, butyl methoxydibenzoyl methane, octocrylene, octyl methoxycinnamate, 4-methylbenzylidene camphor, octyl salycylate, titanium dioxide and zinc oxide in their micrometric and nanometric forms.

As coloring materials which can be used, mention may be made of lipophilic dyes, hydrophilic dyes, pigments and nacres usually used in cosmetic or dermatological compositions, and their mixtures.

As neutralizers which can be used, mention may be made of sodium hydroxide, triethanolamine, raminomethyl propanol and potassium hydroxide.

As suitable penetrating agents, there may be mentioned alcohols and glycols (ethanol, propylene glycol), Fethoxydigrycol, alcohols and fatty acids (oleic acid), esters of fatty acids, dimethyl isosorbide.

The composition containing an excipient from the invention can be used as a care product, as a cleaning product, and / or as a skin makeup product, as a sun protection product, or as a hair product, for example as a shampoo or hair conditioner.

The invention and the advantages which result therefrom will emerge more clearly from the exemplary embodiments in support of the appended figures. EXAMPLE 1 Process for the synthesis of TEDM with and without solvent

1 / Synthesis with azeotropic solvent 92 g (1 mole) of glycerol, 0.45 g of p-toluenesulfonic acid and 150 ml of cyclohexane are mixed in a stirred reactor. 69 g (1.2 mole) of propanai is poured drop by drop using a pressure-compensated ampoule. After adding the aldehyde, the reaction medium is heated to at least 69 ° C., temperature of the water / cyclohexane azeotrope. The separation of water and cyclohexane is done using a Dean-Stark. Heating is maintained until the theoretical amount of water has been recovered. The cyclohexane is evaporated under reduced pressure and the reaction product (EDM) purified by distillation under reduced pressure using a vigorous column. The mass yield of the reaction is 70% and the product has a purity greater than 99%. NMR and gas chromatographic analyzes coupled to a mass spectrometer (GC-MS) confirm that the product obtained is a mixture of 2-ethyl-1,3-dioxolane-4-hydroxymethyl and 2-ethyl-1,3-dioxan -5-ol.

2 / Synthesis without solvent 92 g of glycerol (1 mole), 0.45 g of p-toluenesulfonic acid are introduced into a stirred reactor. 58 g (1 mole) of propanai is added dropwise, over 1 hour, using a pressure-compensated ampoule. The mixture is heated at 46 ° C for 5 hours. The reaction water is removed by distillation under reduced pressure (50 mbar). It is recovered between 30 and 35 ° C at the head of the reactor. The EDM is then purified by distillation under reduced pressure (10 bar) using a vigorous column. The mass yield of the reaction is 70% and the product has a purity greater than 99%. NMR and GC-MS analyzes confirm that the product obtained is a mixture of 2-ethyl-1,3-dioxolane-4-hydroxymethyl and 2-ethyl-1,3-dioxan-5-ol. EXAMPLE 2: Following properties of EDM. PPM and FTE

1 / Miscibility in water The BDM molecule is produced according to the same process as that of Example 1 (without solvent), from pentanal and glycerol. The product obtained is confirmed by GC-MS analysis. Its solubility in water is around 2 g in 100g of water. Beyond that we see a disturbance appear.

Cyclic acetal resulting from the reaction of formaldehyde on glycerol

Conclusion: As shown in the table above, the molecules of the invention are miscible in water unlike BDM.

2 / Solubility in oils

ΦCyclic acetal resulting from the reaction of formaldehyde on glycerol

Conclusion: As the table above shows, while remaining miscible in water, the cyclic acetals of the invention have better solvent power than the SOLKETAL ® or glycerol formai. This property testifies to their better compatibility with hpophile constituents for cosmetic and pharmaceutical use and thus to their wider range of use.

3 / Solubility of 1ΕDM in oils and alcohols The solubility of EDM is studied in various oils, alcohols and in water. The solubility results are expressed in g of EDM which can be incorporated into 100 g of oil or of ester before the appearance of a cloudiness.

Conclusion: EDM is very soluble in many esters, in hydrophilic solvents and in vegetable oils. 4 / Solubilization of filters by FTE. SHS. PDM The solubility of two organic UV filters (benzophenone-3 and 1,2-butyl methoxydibenzoylmethane) is evaluated in 1ΕTP, EDM and PDM.

Protocol: - Homogenize the mixture 30 seconds using a Nortex, - spend 15 minutes with ultrasound (to be renewed if the filter is immiscible up to 60 minutes maximum), - for the following percentages, add always an identical amount of UV filter in a fixed starting quantity of solvent.

The solubility is expressed in g of filter soluble in 100 g of final solution.

Conclusion:

The molecules tested are better filter solubilizers than

SOLKETAL ^® .

5 / Solubilization of active in 1ΕDM The solubility of various active in EDM was studied. It is expressed in g of active ingredient soluble in 100 ml of EDM.

(1) BASF (2) ROCHE

Conclusion:

The cosmetic active agents are very soluble in the EDM solvent. EXAMPLE 3 Solubilization with EDM of Water-Insoluble Assets

Five hydrophobic active agents were dissolved in water, using EDM. In the following table, it is indicated which mass of solvent (g) must be added to dissolve lg of a mixture consisting of 98% water and 2% active. The lower the amount of solvent to be added, the greater its solubilizing power.

(1) MERCK (2) Uniqema

Conclusion: EDM has the power to dissolve hydrophobic active ingredients in water. It performs better than Arlasolve DMI (Dimethyl Isosorbide), another solvent on the cosmetic market.

EXAMPLE 4; Stability of the pH of an EDM solution The stability of solutions at different pH, after the introduction of 5% EDM is studied.

1. Buffer solutions The different solutions are prepared: - for pH 3 to 7 using citric acid and Na ₂ HPO, - for pH 8 to 10 using boric acid, KC1 and of NaOH.

2. Results

Conclusion:

The variations observed are of the order of 0.1 pH units, which is not significant. Therefore, EDM has no influence on the pH of buffer solutions from 3 to 10.

EXAMPLE 5 Compatibility of PEDM with the constituents of a cosmetic formula

1. Compatibility with gelling agents

We tested the influence of 5% of EDM in gels produced from gaffers of different chemical natures.

Conclusion:

EDM has good compatibility with the gaffers from different families tested. Indeed, none of the formulated gels is broken by the addition of EDM. 2. Emulsion compatibility 2.1 - O / W emulsion

Conclusion: The addition of EDM in the emulsion does not significantly modify its viscosity and stability.

2.2 - Emulsion and Bi-gel Bi-gel is a surfactant-free emulsion.

Conclusion: The emulsion obtained is perfect. EDM is compatible with the constituents of a Bi-gel emulsion.

3. Microemulsion compatibility

Conclusion: EDM can be formulated in microemulsions.

EXAMPLE 6 In Vitro Evaluation of the Capacity of EDM to Increase the Depigmenting Activity of Koiiαue Acid (Effect Promoting the Activity of the Molecule)

We want to assess, in vitro, the ability of EDM to increase the level of efficacy of kojic acid on pigmented human epidermis reconstructed in vitro. - The result obtained is compared with several emulsions: Emulsion reference ALE 1833 / A: excipient formula, without kojic acid - ALE 1833 / B: formula with 2% kojic acid - ALE 1833 / C: formula with 2% acid Kojique and 5% EDM - Positive control: MélanexDuo® Cream ALE 1833A Cream

ALE 1833B Cream

ALE 1833C Cream

General methodology The study is based on the evaluation of the degree of pigmentation of pigmented human epidermis after treatment with the various products under test.

The depigmenting activity of the various formulas is evaluated by measuring the level of melanin produced by a suspension of cells. The melanin level is determined by measuring the optical density at 405 nm of cell extracts obtained from the epidermis treated with the test products.

The depigmenting activity is then calculated according to the following formula: AD% = [CMΘI (excipient) - CMel (product) / CMel (excipient)] X 100 CMei (e cipient): melanin level in the cell extracts obtained from epidermis treated with the excipient formula ALE 1833 / A CMel (product): melanin level in terms of cell extracts obtained from epidermis treated with the formula ALE 1833 / B or ALE 1833 / C The test is carried out in triplicate.

The preliminary cytotoxicity study is carried out to verify the viability of the cells in the presence of the constituents of the experiment "Application on D0 (= day of study start) and Dl (= D0 + 24 Hours) of the ALE 1833 formulas / A, B, C, at a rate of 5 mg / cm ² on the stratum corneum of unpigmented human epidermis. Incubation of the epidermis at 37 ° C. "Assessment of tissue viability using an MTT test (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazohum bromide) at D + 2.

The results summarized in Figure 1 are obtained:

The depigmenting activity of the products under study is evaluated in the following manner "Application, on D0, Dl, D2, D3, and D6, of the ALE 1833 / A, B, C and MelanexDuo® Cream formulas , at a rate of 2.5 mg / cm ² on the stratum corneum of pigmented human epidermis. Incubation of the epidermis at 37 ° C. in an air-CO ₂ oven. "Determination of the melanin level on D7, 24 hours after the last application.

FIG. 1 is a diagram representing the cytotoxicity of the formulas containing ALE 1833 A, B and C.

As this figure shows, whatever the formula, no significant decrease in tissue viability is observed after treatment.

FIG. 2 is a diagram representing the depigmenting activity of the ALE 1833 B and C formulas. As this figure shows, without EDM, the formula ALE1833 / B containing kojic acid has no depigmenting activity. With EDM, the same formula has depigmenting activity.

Conclusion:

EDM makes it possible to increase the activity of certain active cosmetic molecules probably by a promoter effect of cutaneous absorption.

EXAMPLE 7; Example of cosmetic composition incorporating a cyclic acetal of the invention

Slimming cream

Night cream

Self-tanning fluid (microemulsion)

Anti-aging cream

Shampoo (anti-dandruff)

Claims

1 / Use as a pharmaceutical or cosmetic excipient of cyclic acetal corresponding to the product of the reaction between an aliphatic aldehyde comprising from 2 to 4 carbon atoms and a polyol comprising from 3 to 6 carbon atoms and at least three hydroxyl functions. two of which are located on vicinal carbons or separated by a carbon atom.

2 / Use according to claim 1, characterized in that the polyol contains from 3 to 6 hydroxyl functions.

3 / Use according to one of claims 1 to 2, characterized in that the cyclic acetal results from the reaction between propionaldehyde and glycerol.

4 / Use according to one of claims 1 to 2, characterized in that the cyclic acetal results from the reaction between butyraldehyde and glycerol.

5 / Use according to one of claims 1 to 2, characterized in that the cyclic acetal results from the reaction between acetaldehyde and triméfhylolpropane.

6 / A pharmaceutical or cosmetic composition comprising the excipient, as described in one of claims 1 to 5.

7 / Use according to one of claims 1 to 6, for its solubihsant effect of poorly soluble or insoluble active ingredients in water or oils.

8 / Use according to one of claims 1 to 6, for its activity promoting effect.