CN1728983A - Process for the chemical stabilization of a solubilized retinoid in a solvent using a base - Google Patents

Abstract

The invention relates to a process for the chemical stabilization of a solubilized retinoid within a pharmaceutical composition, and to an aqueous composition obtained by this process. The invention further relates to the use of the aqueous composition in cosmetics and dermatology.

Description

Process for chemically stabilizing solubilized retinoids in solvents with bases

The present invention relates to a process for chemically stabilizing solubilized retinoids in pharmaceutical compositions by adding a base capable of salifying the retinoids, and to aqueous compositions obtained by this process.

Certain retinoids are known to be poorly soluble and lack chemical stability in pharmaceutical or cosmetic compositions (Szuts "solubility of retinoids in water", Arch. Biochem. Biophys. 1991, 287: 297- 304). One possible solution to this problem is to incorporate the active ingredient in dispersed form in order to solubilize it. However, dispersed active ingredients are less readily released from topical formulations than solubilized active ingredients. Therefore, in order to increase the release of the active ingredient, it has proven advantageous to endeavor to formulate the active ingredient in a solubilized form.

Furthermore, a finished product, especially in the case of a pharmaceutical or cosmetic composition, must maintain accurate physicochemical references throughout its lifetime so that its medicinal or cosmetic quality can be guaranteed. Among these benchmarks, rheological properties must be preserved. They define the behavior and texture of the composition when applied, as well as the release properties of the main ingredient.

In particular, the formulation of the retinoid as a gel or oil-in-water emulsion is advantageous for topical treatments such as acne treatment, especially because it avoids leaving a greasy feel on the skin. Formulations as water-in-oil emulsions may be preferable for the treatment of psoriasis.

Currently, the retinoids according to the present invention are not readily soluble and lack stability in oily solvent media as well as in aqueous solvents which are compatible with the formulation of topical compositions of the gel or emulsion type.

In patent application WO 85/02767 entitled "Pharmaceutical compositions containing drugs that are unstable or poorly soluble in water and processes for their preparation", Janssen Pharmaceutica states that "if the molecule has an acidic or basic group, the It is possible to increase its solubility in water by forming a salt, but this leads to a decrease in potency or a decrease in chemical stability." Therefore, according to this prior art, those skilled in the art are discouraged from salting the active ingredients in an attempt to impart chemical stability to them.

Now, surprisingly, the applicants have developed a chemical stabilization method for solubilized retinoids by adding a base capable of salifying them, said retinoids becoming in gel or emulsion form Soluble and chemically stable in aqueous compositions. The composition obtained with the method according to the invention comprises at least one solubilized retinoid compound which therefore has good chemical stability, i.e. it does not show degradation of the active ingredient over time at temperatures between 4 and 40°C ; The composition further has good physical stability, that is, it does not show a decrease in viscosity over time at a temperature of 4 to 40° C., and does not show phase separation or exudation over time at high temperatures.

Surprisingly, the applicants have discovered a method that provides excellent chemical stabilization of the solubilized retinoid compound by adding a base to salify it in situ in an aqueous composition.

Accordingly, the present invention relates to a process for the chemical stabilization of solubilized retinoids in aqueous compositions by the addition of a base. The invention further relates to an aqueous composition obtained by the process of the invention, comprising in a physiologically acceptable medium at least one retinoid compound and at least one base capable of salifying the active ingredient, making it possible to Solubilizes and gives it chemical stability.

Advantageously, the aqueous composition according to the present invention comprises an active phase comprising the retinoid compound, a cosolvent and a base capable of salifying the retinoid compound, an active phase comprising water and optionally another solvent, coagulant An aqueous phase of gelling agents and emulsifiers in the case of emulsions, and an oily phase which may also contain emulsifiers and additives in the case of emulsions. "Aqueous composition according to the invention" is understood to mean a composition containing a high percentage of water, ideally exceeding 50%.

The composition according to the invention, more precisely the active phase, contains at least one retinoid, a retinoid precursor or a retinoid derivative.

"Retinoid" (retinoid) is understood to refer to any compound containing a group capable of forming a salt with a base and capable of binding to RAR and/or RXR receptors. "Retinoid precursors" are understood to mean their transient biological precursors or substrates as well as their chemical precursors. "Retinoid derivatives" are understood to mean both their metabolizing organisms and their chemical derivatives.

The retinoid is preferably a propargyl alcohol derivative, particularly preferably a racemic compound or one of the enantiomers of the formula:

That is, 2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-1-propynyl] Benzoic acid, S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl )-1-propynyl]benzoic acid or R-(-)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydro-5,5,8,8- Tetramethylnaphthalen-2-yl)-1-propynyl]benzoic acid.

For the purposes of the present invention, individual enantiomers of these compounds or mixtures thereof, including racemic mixtures, may be used.

Of course, the amount of retinoid in a composition according to the invention will more particularly depend on the retinoid involved and the quality of treatment desired.

Based on the total weight of the composition, the preferred concentration of the retinoid compound is between 0.0001 and 20 wt%.

The active phase of the composition according to the invention also contains co-solvents of the glycol type or other co-solvents which have an affinity for the aqueous medium. These hydrophilic solvents, which act as co-solvents, also make it possible to reduce the amount of base, thereby lowering the pH compared to that of glycol-free compositions. Therefore, the resulting pH is closer to that of the skin. Furthermore, diols are known to improve the penetration of active ingredients.

Non-limiting examples of co-solvents that may be mentioned are PEG-6 tris(caprylic/capric)glyceride (Softigen 767), nonylphenol ethoxylate (10) ether (Renex 690), sorbitan Ethylene (20) Ether Stearate (Tween 60), Sorbitan (20) Ether Stearate (Polysorbate 60), Cremophore RH 60, PEG-35 Castor Oil, Arlasolve, Dimethyl Iso Sorbitol, Labeasol, PEG-8 tris(caprylic/capric)glycerides, phenoxyethanol, or glycols such as propylene glycol, dipropylene glycol, butylene glycol, polyethylene glycol 400 (PEO-400), and ethyl diol Glycol ether. Preferred co-solvents according to the invention are propylene glycol and dipropylene glycol.

The concentration of co-solvent in the composition according to the invention is 5-50%, preferably 10-20%.

The active phase of the compositions according to the invention contains at least one base capable of salifying the retinoid compound.

Non-limiting examples of bases that may be mentioned are inorganic bases such as sodium hydroxide (NaOH) or lithium hydroxide (LiOH), organic bases such as N-methyl-D-glucamine or tromethamine, ammonia (NH ₄ OH), basic amino acids such as L-lysine, L-arginine, L-ornithine or glycine, or various bases such as D-glucosamine or N-methylglucamine.

Preferred bases for compositions according to the invention are sodium hydroxide or L-lysine.

The base is preferably used at a concentration in the range of 0.5 to 10 molar equivalents based on the retinoid compound.

The retinoid is solubilized and salified in the presence of the base, i.e.

a) in the active phase composed of the co-solvent and the base, simply by magnetic stirring,

b) In the aqueous phase consisting of solvent, co-solvent and base, the aqueous phase may also contain additives such as those described in the text of the invention.

The aqueous phase of the composition according to the invention contains a solvent such as water, a flower perfume such as cornflower water, or a natural thermal or mineral water selected from such as Vittel water, Vichy source water, Uriage water, Roche Posay Water, Bourboule water, Enghien-les-Bains water, Saint Gervais-les-Bains water, Néris-les-Bains water, Allevard-les-Bains water, Digne water, Maizières water, Neyeac-les-Bains water, Lons-le - Water of Saunier, Bonnes, Rochefort, Saint Christau, Fumades, Tercis-les-Bains, Avène and Aix-les-Bains, an alcohol such as ethanol, or another hydrophilic solvent.

The preferred solvent is water, present in the form of a gel at a concentration preferably above 50%, especially preferably above 75%.

The compositions according to the invention are preferably in the form of hydrogels.

"Hydrogel" is understood to mean a composition comprising in the aqueous phase a viscoelastic body formed from a colloidal suspension (gelling agent).

Non-limiting examples of gelling agents that may be mentioned are acrylic derivatives of the Carbopol type (supplier: NOvéon) or of the Sepigel 305 type (supplier: SEPPIC), of the Natrosol type (supplier: Aqualon) or of the Methocel type ( Supplier: Dow Chemical), xanthan gum of the Keltrol type (supplier: KELCO), or a mixture thereof.

Preferred gelling agents are those derived from the family of acrylic derivatives such as Carbopol 980.

The above-mentioned gelling agent can be used at a concentration preferably in the range of 0.05 to 15%, especially preferably in the range of 0.1 to 5%.

Another composition according to the invention is an emulsion, thus comprising an emulsifier in the aqueous phase, and an oily phase.

Non-limiting examples of emulsifiers that may be mentioned are glycerol (and) PEG-100 stearate, polyethoxylated fatty acid esters sold under the name Arlacel 165 by the company ICI or under the name Simusol 165 by the company SEPPIC, polyethoxylated fatty acid esters such as Arlatone 983, polyethoxylated (2) stearyl alcohol, sorbitan ester sold under the name Brij 72, related to polyethoxylated (21) stearyl alcohol sold under the name Beij 721 by the ICI company For example, sorbitan oleate sold under the name of Arlacel 80 by ICI or sold under the name of Crill 4 by Croda, and sorbitan hemioleate sold under the name of Arlacel 83 by ICI or under the name of Montane 83 by SEPPIC, Or sorbitan isostearate, fatty alcohol ether with high HLB that is HLB is greater than or equal to 7, such as cetearyl alcohol polyoxyethylene (20) ether (Ceteareth- 20) or cetearyl alcohol polyoxyethylene (12) ether (Ceteareth-12) sold by Cognis under the name Eumulgin B1, or fatty alcohol ethers with low HLB, that is, HLB lower than 7, such as stearyl polyoxyethylene Vinyl (2) ethers such as Steareth-2.

A preferred emulsifier according to the invention is ceteareth-20.

The compositions according to the invention advantageously comprise up to 15% by weight of a suitable emulsifying system, preferably 0.05 to 8% by weight, especially preferably 0.1 to 2% by weight, based on the total weight of the composition.

Examples of oil phase constituents that may be mentioned are oils, especially mineral oils (liquid paraffin), oils of vegetable origin (avocado oil, soybean oil), oils of animal origin (lanolin oil), synthetic oils (perhydroquinone squalene), silicone oils (cyclomethicone) and fluorinated oils (perfluoropolyethers). Other fatty substances which may be used are fatty alcohols such as cetyl alcohol, fatty acids, waxes and gums, especially silicone gums.

It is preferred to use liquid paraffin.

The compositions according to the invention may also contain any additives commonly used in the cosmetic or pharmaceutical field, such as cyclodextrins, co-emulsifiers, chelating agents, antioxidants, sunscreens, preservatives, fillers, electrolytes, humectants, colorants agents, customary mineral or organic bases or acids, fragrances, essential oils, cosmetic active ingredients, hydrating agents, vitamins, essential fatty acids, sphingolipids, artificial tanning compounds such as DHA, skin emollients and protectants such as allantoin. Of course, the person skilled in the art will carefully select this or these optional auxiliary compounds and/or their amounts so that the advantageous properties of the composition according to the invention are not affected or are not substantially affected.

These additives may be present in the composition in an amount of 0 to 20 wt%, based on the total weight of the composition.

Examples of cyclodextrins that may be mentioned are β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

Examples of chelating agents that may be mentioned are ethylenediaminetetraacetic acid (EDTA) and its derivatives or salts, dihydroxyethylglycine, citric acid, tartaric acid or mixtures thereof.

Examples of anti-irritants that may be mentioned are aloe vera, allantoin, oatmeal or tocopheryl acetate.

Examples of preservatives that may be mentioned are alkylbenzyldimethylammonium chloride, phenoxyethanol, benzyl alcohol, N-(hydroxymethyl)-N-(1,3-bishydroxymethyl-2, 5-Dioxy-4-imidazolidinyl)-N'-(hydroxymethyl)urea, parabens or mixtures thereof.

Examples of humectants that may be mentioned are glycerin and sorbitol.

A preferred pH value for the composition according to the invention is a pH close to the pH of the skin, ie between 5-7, preferably between 5.5-6.

Accordingly, the present invention relates to a method of chemically stabilizing a solubilized retinoid in a pharmaceutical composition by adding a base capable of salifying the retinoid.

In particular, the present invention relates to a process for chemically stabilizing a solubilized retinoid compound of the formula:

The present invention further relates to pharmaceutical or cosmetic aqueous compositions obtained by the method of the present invention.

Specifically, the present invention relates to a pharmaceutical or cosmetic aqueous composition obtained by the method of the present invention and used in the form of a hydrogel for topical application to the skin, skin outer membrane or mucous membrane, characterized in that it is in a For topical administration to the adventitia or mucous membranes a compatible physiologically acceptable medium contains the following ingredients:

a) 0.01-5% retinoid compound of the following formula:

b) 1 to 10 molar equivalents of an inorganic base capable of making the retinoid compound into a salt;

c) 0.01 to 5% of an acrylic derivative as a gelling agent;

d) 40-80% water as the main solvent; and

e) 5-20% of a diol as co-solvent.

A preferred aqueous composition according to the present invention is characterized in that it comprises:

a) 0.1% S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2- base)-1-propynyl]benzoic acid;

b) 2 molar equivalents of sodium hydroxide for salifying the retinoid compound;

c) 0.5% Carbopol 980;

d) 65-75% water; and

e) 15% propylene glycol.

The present invention further relates to a composition as described above as a medicine.

The invention further relates to the cosmetic and dermatological use of the novel compositions as described above.

When the compositions according to the invention are intended especially for dermatological use, an important parameter is the release and penetration parameters of the active ingredient, which the applicant also proposes to improve by means of the formulations according to the invention.

Surprisingly, the Applicants have found that the preferred formulations described above provide very good results in terms of release and penetration through the skin, proving to be even better than simple gelatin containing a high proportion of penetrating diols. Glue the results provided. Thus, the compositions obtained according to the invention, in addition to the good chemical stability of the retinoids, also have good active ingredient release/penetration.

Due to the remarkable activity of retinoids in the field of cell differentiation and proliferation, the composition of the present invention is especially suitable for the following therapeutic fields:

1) For the treatment of dermatological complaints associated with keratinization disorders involving differentiation and proliferation, especially for the treatment of acne vulgaris, comedones, polymorphic acne, rosacea, cystic acne, acne macules, senile acne Acne, secondary acne such as solar acne, medicated acne, or acneiform keloids, and hidradenitis suppurativa;

2) For the treatment of other types of keratinization disorders, especially ichthyosis (xeroderma), ichthyosis-like states, follicular keratosis, palmoplantar keratosis, leukoplakia and leukoplakia states, and skin or mucous membranes (cheek) lichen;

3) For the treatment of other dermatological complaints associated with keratinization disorders with an inflammatory and/or immunoallergic component, especially all forms of psoriasis, whether cutaneous, mucous membranes or nails , rheumatism, even psoriasis, or atopic dermatitis such as eczema, or respiratory atopy, or gingival hypertrophy; these compounds can be used in certain inflammatory complaints that do not show keratinization disorders, such as folliculitis;

4) For the treatment of all cutaneous or epidermal proliferations, whether benign or malignant, of viral or not origin, such as common warts, flat warts, molluscum contagiosum and epidermal dysplasia verrucous, and oral or bright red papillomatosis and hyperplasia that can be induced by ultraviolet light, especially in the case of actinic keratoses;

5) For repairing or preventing skin aging, whether photoinduced or chronic, or for reducing pigmentation, or any pathological symptoms associated with chronic aging or photochemical aging;

6) for the treatment of healing disorders or skin ulcers in prophylactic or healing capacity, for preventing or repairing atrophic striae, or for promoting healing;

7) For the prevention and treatment of sebaceous gland disorders, such as acne-like hyperseborrheic dermatitis or simple seborrheic dermatitis;

8) For the treatment of any skin complaints of fungal origin, such as athlete's foot and tinea versicolor;

9) For the treatment of dermatological complaints with immune components;

10) for the treatment of skin disorders caused by exposure to ultraviolet radiation; and

11) For the treatment of dermatological complaints associated with inflammation or infection of the tissues surrounding the hair follicle, especially those due to fine organism colonization or infection, especially impetigo, seborrheic dermatitis, folliculitis or vulgaris , or those involving any bacteriological or fungal agent.

The compositions according to the invention are especially suitable for the prophylactic or therapeutic treatment of acne vulgaris or psoriasis.

The compositions according to the invention are also suitable for use in the cosmetic field, especially for treating acne-prone skin, for causing hair regrowth or preventing hair loss, for combating an oily appearance of the skin or hair, for providing protection against the harmful effects of the sun protection, for the treatment of physiological dry skin, or for the prevention and/or control of photoinduced or chronic aging.

The compositions according to the invention are also suitable for body and hair hygiene.

The present invention also relates to the use of a base for the solubilization of a retinoid compound in a pharmaceutical composition comprising at least one retinoid compound, a primary solvent and a co-solvent for chemical stabilization by salt formation.

The formulation examples given below provide an illustration of the process according to the invention and the compositions obtained therewith, without limiting its scope. Results relating to physical and chemical stability as well as results relating to release and penetration of active ingredients are also given in an illustrative manner.

Example 1: Chemical Stabilization Method for Solubilizing Retinoid Compounds in Pharmaceutical Compositions According to the Invention Law

The retinoid is solubilized and salified in the presence of the base, i.e.

a) in the effective phase composed of the co-solvent and the base, simply stir by magnetic force;

b) In the aqueous phase composed of solvent, co-solvent and base, the aqueous phase may also contain additives such as those described in the text of the invention.

The following examples relate to compositions whose active and/or aqueous phases are prepared by the method described.

Example 2: Hydrogel business name INCI name % Water Methylparaben Glyceryl Allantoin EDTA 2 NaCARBOPOL 980 NF Water Methylparaben Glycerol Allantoin Sodium Acetate Carbomer 75.880.155.000.200.100.50 Sodium hydroxide (10% solution) sodium hydroxide 2.00 Propylene glycol S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)- 1-propynyl]benzoic acid sodium hydroxide (1% solution) Propylene Glycol Active Ingredient Sodium Hydroxide 15.000.101.07

program:

- Active phase: this is prepared by magnetic solubilization of propylene glycol, sodium hydroxide and retinoids using the method of Example 1a).

- Aqueous phase: under the action of heat (80° C.), ensure complete solubilization of methylparaben, glycerol, allantoin and EDTA.

Then, ensure complete dispersion of Carbopol in this phase. The gel is neutralized and the active phase is incorporated into it.

Example 3: Hydrogels with Cyclodextrins business name INCI name % Water Methylparaben Glycerin CARBOPOL 980 NF Water Methylparaben Glycerol Carbomer 40.430.155.000.50 Sodium hydroxide (10% solution) sodium hydroxide 2.00 Propylene Glycol β-Cyclodextrin Sodium Hydroxide (1% Solution) S-(+)-2-Hydroxy-4-[3-Hydroxy-3-(5,6,7,8-Tetrahydro-5,5, 8,8-Tetramethylnaphthalen-2-yl)-1-propynyl]benzoic acid Active ingredients of water propylene glycol cyclodextrin sodium hydroxide 45.005.000.751.070.10

program:

The active phase - in this case also the aqueous phase - is prepared by solubilization of the retinoid in the presence of aqueous sodium hydroxide solution, propylene glycol and cyclodextrin by the method of Example 1 b).

Example 4: Oil-in-water emulsion business name INCI name % MARCOL 172EUMULGIN B2BHT Propylparaben Mineral Oil Ceteareth-20 Butylated Hydroxytoluene Propyl Paraben 10.000.500.050.15 Water glycerol allantoin CARBOPOL 980 NFPEMULEN TR1 Water Glycerol Allantoin Carbomer Acrylate/C10-30 Alkyl Acrylate Crosslinked Copolymer 65.785.000.200.150.30 Sodium hydroxide (10% solution) sodium hydroxide 1.70 Propylene glycol S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)- 1-propynyl]benzoic acid Propylene glycol active ingredient 15.000.10 Sodium hydroxide (1% solution) sodium hydroxide 1.07

program:

- Active phase: this is prepared by magnetic solubilization of propylene glycol, sodium hydroxide and retinoids using the method of Example 1a).

- Aqueous phase: Water, glycerol and allantoin were weighed and placed in a formulation beaker, heated to 80°C.

Stir with Rayneri to ensure complete dissolution of Carbopol and Pemulen.

- Oil phase: Weigh the oil phase comprising Marcol 172, Eumulgin B2, BHT and Propylparaben and raise the temperature to 80°C.

Emulsification was carried out at 80°C for 20 minutes with Rayneri stirring, followed by gradual cooling to 50°C.

At 50° C., the gelling agent is neutralized under stirring and the active phase is added.

Embodiment 5: oil-in-water emulsifier business name INCI name % MARCOL 172EUMULGIN B2BHT Mineral Oil Ceteareth-20 Butylated Hydroxytoluene 10.000.500.05 Water Glycerin CARBOPOL 980 NF Phenoxyethanol PEMULEN TR1 Water Glycerol Carbomer Phenoxyethanol Acrylate/C10-30 Alkyl Acrylate Crosslinked Copolymer The right amount to 100 5.000.21.000.30 Sodium hydroxide (10% solution) sodium hydroxide 1.80 Dipropylene glycol S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl )-1-propynyl]benzoic acid sodium hydroxide (1% solution) Dipropylene glycol active ingredient sodium hydroxide 15.000.101.07

program:

- Active phase: this is prepared by magnetic solubilization of dipropylene glycol, sodium hydroxide and retinoids using the method of Example 1a).

- Aqueous phase: Water, glycerol and phenoxyethanol were weighed into a formulation beaker and warmed to 80°C.

Stirring with Rayneri ensures complete solubilization of Carbopol and Pemulen.

- Oil phase: Weigh the oil phase containing Marcol 172, Eumulgin B2, BHT, and raise the temperature to 80°C.

Emulsification was carried out at 80°C for 20 minutes with Rayneri stirring, and then gradually cooled to 50°C.

At 50°C, the gelling agent was neutralized with stirring and the active phase was added.

Example 6: Hydrogel business name INCI name % Water Methylparaben BHT Glycerin Allantoin CARBOPOL 980 NF Water Methylparaben Butylated Hydroxytoluene Glycerol Allantoin Carbomer 75.930.150.055.000.200.50 Sodium hydroxide (10% solution) sodium hydroxide 2.00 Propylene glycol S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)- 1-propynyl]benzoic acid sodium hydroxide (1% solution) Propylene Glycol Active Ingredient Sodium Hydroxide 15.000.101.07

program:

- Active phase: this is prepared using example 1 a) by magnetic solubilization of propylene glycol, sodium hydroxide and retinoid.

- Aqueous phase: under the action of heat (80° C.), ensure complete dissolution of methylparaben, allantoin and BHT. Then ensure complete dispersion of Carbopol in this phase. The gel is neutralized and the active phase is incorporated therein.

Example 7: Hydrogel business name INCI name % Water Methylparaben BHT Glycerin Allantoin CARBOPOL 980 NF Water Methylparaben Butylated Hydroxytoluene Glycerol Allantoin Carbomer 75.930.150.055.000.200.50 Sodium hydroxide (10% solution) sodium hydroxide 2.00 Dipropylene glycol S-(+)-2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl )-1-propynyl]benzoic acid sodium hydroxide (1% solution) Dipropylene glycol active ingredient sodium hydroxide 15.000.101.07

program:

- Active phase: this is prepared by magnetic solubilization of dipropylene glycol, sodium hydroxide and retinoids using the method of Example 1a).

- Aqueous phase: under the action of heat (80° C.), ensure complete dissolution of methylparaben, glycerol, allantoin and BHT.

Then, ensure complete dispersion of Carbopol in this phase. The gel is neutralized and the active phase is incorporated therein.

Example 8: Hydrogel business name INCI name % Water Methylparaben BHT Glycerin Aloe Vera CARBOPOL 980 NF Water Methylparaben Butylated Hydroxytoluene Glycerol Aloe Vera Carbomer 75.930.150.055.000.200.50 Sodium hydroxide (10% solution) sodium hydroxide 2.00 Dipropylene glycol 2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-1-propyne base] benzoic acid sodium hydroxide (1% solution) Dipropylene glycol active ingredient sodium hydroxide 15.000.101.07

program:

- Active phase: this is prepared by magnetic solubilization of dipropylene glycol, sodium hydroxide and retinoids using the method of Example 1a).

- Aqueous phase: under the action of heat (80°C), ensure complete dissolution of methylparaben, glycerin, aloe vera, BHT and water.

Then, ensure complete dispersion of Carbopol in this phase. The gel is neutralized and the active phase is incorporated therein.

Example 9: Stability

9.A.S-(+)-2-Hydroxy-4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl Naphthalene-2-yl)-1-propynyl]benzoic acid (hereinafter referred to as the active ingredient in this embodiment) in the simplified Chemical Stability of Salt Formation and Non-Salt Formation in Monoglycol Gels

In order to verify the chemical stability of the active ingredient when it forms a salt or not, 5 simple compositions were prepared.

Composition details for these recipes:

Composition (%) Formula No.1 Formula No.2 Recipe No.3 Recipe No.4 Recipe No.5 Active ingredients 0.1 in unsalted form 0.1 In the form of a salt from an added base 0.1 In the form of a salt from an added base 0.1 In the form of a salt from an added base 0.1 In the form of a salt from an added base Propylene Glycol 75 75 75 75 75 ethanol 5 5 5 5 5 water 20 18 18 18 18 L-lysine 1.02 equivalent lithium hydroxide 1.02 equivalent sodium hydroxide 1.02 equivalent Triethanolamine 1.02 equivalent

Active ingredient concentrations were determined at 0, 15 and 28 days and the results are presented in the table below: formula Theoretical Concentration (%m/m) Concentration at 0 (%) 15-day concentration (%) 28 day concentration (%) Recipe 1 99 98 64 47 Recipe 2 103 98 95 97 Recipe 3 99 99 98 99 Recipe 4 99 100 96 98 Recipe 5 99 100 96 99

These results show that the chemical stability is excellent in the case where the active ingredient exists in the form of a salt.

9.B. Example 2: Physical and Chemical Stability of Hydrogels Physical stability after 1 month at room temperature and 45°C NNC ¹ Physical stability after 2 months at room temperature and 45°C NNC Chemical stability of TO 99.4% Chemical stability after 1 month at room temperature 45°C 97.7%97.6% Chemical stability after 3 months at room temperature 45°C 99.4%97.6%

9.C. Example 3: Physical and Chemical Stability of Cyclodextrin Gels Physical stability after 1 month at room temperature and 45°C NNC Physical stability after 2 months at room temperature and 45°C NNC Chemical stability of TO 100.1% Chemical stability after 1 month at room temperature 45°C 100.0%99.6% Chemical stability after 3 months at room temperature 45°C 102.2% 101.7%

9.D. Example 5: Physicochemical Stability of Oil-in-Water Emulsions Physical stability after 1 month at room temperature and 45°C NNC Physical stability after 2 months at room temperature and 45°C NNC Chemical stability of TO 100.7% Chemical stability after 1 month at room temperature 45°C 98.8%98.4% Chemical stability after 2 months at room temperature 45°C 100.7%99.5% Chemical stability after 3 months at room temperature 45°C 98.7%97.6%

All of the compositions according to the invention described above have excellent physical and chemical stability of the solubilized active ingredient.

¹ NNC = no significant change.

Example 8: Results related to release/permeation of active ingredients

The two gels of Examples 6 and 7 were tested by comparison with a simple diol gel enriched in penetrating diol, having the following formulation, in order to evaluate the release and penetration of the active ingredient in the preferred formulation according to the invention level.

Experimental program:

The ex vivo release/permeation of active ingredients from compositions according to the invention can be assessed using whole human skin. The test formulation was applied to a glass diffusion cell (3 ml; 1 cm ² ) for 16 hours. Use whole skin without skin tumors. The skin was mounted on a diffusion cell, and the dermis was brought into contact with a physiological saline solution (receiving liquid) supplemented with 0.25 wt% emulsifier. The system is maintained in a static manner (the receiving fluid is not renewed over time).

Abdominal and/or breast flaps derived from cosmetic surgery are used. The formulation was applied to the 3 different skin samples at a rate of 10 mg formulation/cm ² . These applications are carried out without occlusion. When these applications were repeated, the formulations were applied a total of 6 times.

When these applications were complete, the surface excess was removed for each diffusion cell, and the recipient fluid and skin were sampled. The epidermis (including the stratum corneum) is separated from the dermis. The total balance of active ingredient is calculated for each test formulation, taking into account the excess and the amount found in the skin and in the receiving fluid. The concentration of the active ingredient was determined by HPLC with APCI/MS/MS detection (limit of quantification: 1 ng.ml ^-1 ).

Simple Glycol Gel: business name INCI name % Propylene Glycol Pure Rectified Ethanol Refined Water L-Lysine (50% solution) 2-Hydroxy-4-[3-Hydroxy-3-(5,6,7,8-Tetrahydro-5,5,8,8- Tetramethyl-2-naphthyl)-1-propynyl]benzoic acid KLUCEL HF Propylene Glycol Alcohol Water Lysine Active Ingredient Hydroxypropyl Cellulose 75.005.0018.8220.0780.11

Release/Penetration Results: formula The amount of active ingredients measured in the receiving medium simple diol gel 0.35±0.06μg (3.6% administered dose) According to the gel of embodiment 7 0.69±0.25μg (8.0% administered dose) According to the gel of embodiment 6 1.05±0.13μg (11.4% administered dose)

These results show that, in addition to the chemical stabilization of the active ingredient, the optimized formulation according to the invention increases the bioavailability of the active ingredient in the skin (respectively 2-3 times compared to the reference gel).

Claims (14)

1. the chemical stabilizing method of solubilization optic yellow kind compound in a kind of medical composition that comprises at least a A1 vitamin group chemical compound, a kind of main solvent and a kind of cosolvent is characterized in that a kind of alkali adds for making this A1 vitamin group chemical compound salify.

2. according to the method for claim 1, it is characterized in that this A1 vitamin group chemical compound has formula (Ia):

3. with the method waterborne compositions that obtain, that be used for topical use of claim 1 or 2, comprise following ingredients at least:

A) from the deutero-A1 vitamin group chemical compound of propargyl alcohol;

B) be used to make the salifiable alkali of this A1 vitamin group chemical compound

C) main solvent; With

D) cosolvent.

4. according to the waterborne compositions of claim 3, it is characterized in that this A1 vitamin group chemical compound has formula (Ia):

5. according to the compositions of claim 3 or 4, it is characterized in that being used to make the salifiable alkali of this A1 vitamin group chemical compound to be selected from inorganic base, organic base and basic amino acid.

6. according to the compositions of claim 5, it is characterized in that being used to make the salifiable alkali of this A1 vitamin group chemical compound is sodium hydroxide.

7. according to the compositions of claim 6, it is characterized in that, is benchmark with this effective ingredient, and this alkali is that the concentration with 1～10 molar equivalent exists.

According in the claim 3～7 any one, be the waterborne compositions of local application gel form, it is characterized in that it comprises:

A) the A1 vitamin group chemical compound of 0.01～5wt% following formula:

B) 1～10 molar equivalent is used to make the salifiable inorganic base of this A1 vitamin group chemical compound;

C) 0.01～5wt% acrylate derivative as gelating agent;

D) 40～80wt% is as the water of main solvent; With

E) 5～20wt% is as the glycol of cosolvent.

9. according to the waterborne compositions of claim 8, it is characterized in that it comprises:

A) 0.1% S-(+)-2-hydroxyl-4-[3-hydroxyl-3-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl naphthalene-2-yl)-1-propinyl] benzoic acid;

B) 2 molar equivalents are used to make the salifiable sodium hydroxide of this A1 vitamin group chemical compound;

c)0.5％ Carbopol 980；

D) 65～75% water; With

E) 15% propylene glycol.

10. according to any one compositions in the claim 3～9, as a kind of medicine.

11. the purposes according to the compositions of any one in the claim 3～10 is used to make a kind of pharmaceutical preparation, the dermatological main suit that this pharmaceutical preparation can be used for preventing or treatment and cell differentiation and/or propagation imbalance and/or keratinization imbalance interrelate.

12. the purposes according to the compositions of any one in the claim 3～11 is used to make a kind of pharmaceutical preparation, this pharmaceutical preparation is used for prevention or treatment acne or psoriasis.

13. cosmetic use according to the compositions of any one in the claim 3～12, be used for the treatment of easy generation acne skin, be used to cause that hair regeneration is long or anti-loss, be used to prevent and treat skin or hair oil outward appearance, be used to provide protection, be used for the treatment of the physiological dry skin or be used to prevent and/or prevent and treat photo-induced or chronic aging sun adverse effect.

14. the purposes of alkali is used for making the solubilization optic yellow kind compound of the medical composition that comprises at least a A1 vitamin group chemical compound, main solvent and cosolvent to reach chemically stable by salify.