FR3039399A1 - CREAM FOR THE ADMINISTRATION OF STEROIDS AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

The invention relates to a method for preparing an emulsion [water type oil W / O] comprising the following steps: a) Dissolution of at least one active ingredient selected from the group of topical corticosteroids in an oily phase ; b) Dissolving at least one chlorocresol-free preservative in an aqueous phase and raising the temperature above the phase inversion temperature; c) mixing and homogenization of the aqueous phase in the oily phase; d) Temperature rise of the mixture obtained above the phase inversion temperature; e) cooling of the mixture; characterized in that: - the concentration of preservative expressed as a percentage by weight relative to the total weight of the emulsion is less than 5%; the steps a) and b) being performed independently and in any order. The invention also relates to the emulsion obtained by the process according to the invention and its use.

Description

CREAM FOR STEROID ADMINISTRATION AND PROCESS FOR PREPARING THE SAME

The present invention relates to creams, ointments and ointments for topical use for the administration of steroids in the form of emulsions and more particularly creams dermocorticoïdes. The invention also relates to the creams and the process for obtaining these creams and emulsions.

[0002] Dermocorticoids have been used in dermatology since the 1950s, following the demonstration of the effectiveness of hydrocortisone in local application in certain cutaneous pathologies.

[0003] Many inflammatory, dysimmunitary or tumoral dermatological pathologies are sensitive to topical corticosteroids, but the dosage form of the topical corticosteroid, and therefore the excipients used, can modify the anti-inflammatory activity of the specialty.

[0004] Also, the side effects of irritation or intolerance types can occur during prolonged applications, most of the time these side effects are caused by the steroids itself and it is therefore imperative to provide galenic forms whose excipients be the best tolerated possible.

By corticosteroids is meant steroid active ingredients used in the local treatment of dermatological conditions.

Topical corticosteroids are divided into four classes according to their chemical origin: Group A: derivatives of the hydrocortisone and prednisolone type, [0008] group B: triamcinolone derivatives, [0009] group C: derivatives of betamethasone type, and [00010] group D: derivatives of hydrocortisone butyrate, with two subgroups, DI and D2.

[00011] These active ingredients are used in local application. Six classic preparations are distinguished according to the composition of their three "states of aggregation" (liquid, fat and solid): solution (liquid), cream (oil in water), ointment (water in oil), suspension (solid in liquid) , paste (solid in fat) and powder (solid).

[00012] Betamethasone (group C) in the form of a dipropionate is marketed in particular under the trade name Diprosone® in cream form by the Merck Sharp and Dohme (MSD) laboratory in the category of topical corticosteroids. Commercializations in the form of a gel, for example under the trade name Diprolene® by the Merck Sharp and Dohme laboratory (MSD), also exist.

As mentioned above the excipents can affect the activity and for example the cream form is classified in the strong dermocoticoids while the gel form is classified in very strong dermocoticoids because of the presence of propylene glycol in the formula.

[00014] Various dosage forms of topical administration of betamethasone dipropionate have been developed especially by the Shchering Company.

From US4070462 filed in 1976, occlusive gel forms comprising water-miscible solvents in fatty phases which give better results than the conventional forms emulsified. They preferably include emulsifiers such as propylene glycol stearate. Their water-free shapes prevent the use of preservatives.

From US44482539 filed in 1983, a cream form of betamethasone dipropionate comprising in particular propylene glycol, a polymer of acrylic acid (carbomer) and an aqueous phase.

When the dosage forms comprise water it is necessary to include preservatives in the formulations. Among the most used preservatives and especially in the form marketed under the trade name of Diprosone®, is chlorocresol.

[00018] According to the "Handbook of Pharmaceutical Excipients", chlorocresol is conventionally used as an antimicrobial preservative in topical cosmetic and pharmaceutical formulations. It is used for example in European patent EP 146 065 (describing a betamethasone dipropionate cream) as a "preferred" preservative at a concentration of 0.03 and 0.2%.

Unfortunately, it can be irritating to the skin, eyes, mucous membranes, and has been implicated in different reactions when used as an excipient. Sensitization reactions may be the consequence of prolonged application to the skin. Test patches have shown that it may be the first irritant cause of a cream at concentrations above 0.2%. Chlorocresol can sometimes be the cause of allergic contact dermatitis. Cases of cross-sensitization have also been attributed to chlorocresol.

Faced with these undesirable toxic effects, it was necessary for the skilled person to find an alternative to this preservative. Still according to the European patent EP 146 065, other preservatives are usable as sorbic acid, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and benzyl alcohol.

The latter, also used as an antimicrobial preservative in topical pharmaceutical preparations, has the advantage of having no adverse effects, if not in the context of parenteral administration in children under the age of 20 years. 3 years (according to the recommendations of the AFSSPAPS 2009), a framework that is not that of use of the invention.

However, following the substitution of chlorocresol with benzyl alcohol, surprisingly during the production of a DIPROSONE type cream according to the conventional embodiment of the oil-in-water emulsions (where, according to US Pat. 6,075,056, the "active principle is dissolved in the oily phase consisting of the melting of the lipophilic excipients, before being mixed with the aqueous phase previously carried out, the emulsion then being homogenized"), several problems of stability of the unpredictable emulsion and never documented appeared.

During the implementation process, during the cooling phase, the emulsion takes on a grainy appearance before returning to a correct appearance. Nevertheless, the emulsion formed is coarse and the texture obtained is not that expected.

In addition, the cream becomes unstable at 40 ° and liquefies thereby causing a phase shift.

Gold 40 ° C is the temperature at which the stability tests are performed (Design of cosmetic products: the formulation, A-M.Pensé-L'Héritier, Lavoisier, July 2014).

Following this problem, a cream comprising betamethasone dipropionate containing benzyl alcohol as a preservative is unsuitable for marketing, due to an unsuitable texture and instability to temperature resulting in a phase shift.

Surprisingly in the presence of benzyl alcohol, the formation of a stable emulsion could be obtained only by the use of the technique of the phase inversion (PU) temperature. This technique makes it possible to obtain emulsions whose granulometry is fine. Indeed, if an emulsion passes through the phase inversion temperature, its phase behavior undergoes a transition and the type of emulsion changes.

However, this technique is difficult to use in pharmacy where most of the active ingredients are sensitive to high temperatures and / or many other processes such as that described in EP0463962 will be preferred.

The process described in EP0463962 is a process for the preparation of microspheres of fatty substances, non-soluble in water, loaded with an active substance among which betamethasone dipropionate which can not be formulated for application any because of their lack of physical or chemical stability, either vis-à-vis the formulation medium or vis-à-vis the storage conditions in particular vis-à-vis atmospheric oxygen or vis-à-vis the conditions of their preparation.

[00030] The article by Khattak SU et al., Indian J. Pharm, is also known. Sci., 2012 Mar 74 (2): 133-40 that betamethasone dipropionate such as betamethasone valerate is heat sensitive which is also reported in the British Pharmacopoeia.

The substitution of chlorocresol with benzyl alcohol seemed impossible because of the requirement to bring the mixture to a temperature above the phase reversal temperature.

However, by implementing the method according to the invention described below, the Applicant has succeeded in preparing a stable emulsion in which the preservative is benzyl alcohol and in which the active ingredient surprisingly is not not degraded.

The invention relates to a method for preparing an emulsion [water type in oil W / O] comprising the following steps: a) Dissolution of at least one active ingredient selected from the group of topical corticosteroids in an oily phase ; b) Dissolving at least one chlorocresol-free preservative in an aqueous phase and raising the temperature above the phase inversion temperature; c) mixing and homogenization of the aqueous phase in the oily phase; d) Temperature rise of the mixture obtained above the phase inversion temperature; e) cooling of the mixture; characterized in that: the concentration of preservative expressed as a weight percentage relative to the total weight of the emulsion is less than 5%; the steps a) and b) being performed independently and in any order.

In one embodiment, the cooling of the mixture is carried out slowly up to 30 ° C.

During this cooling phase a thickening of the cream occurs.

By preservative is meant any natural or chemical substance capable of preserving the components of a cosmetic product from a microbial contamination. In the present invention the preservatives are free of chlorocresol and are selected from the group consisting of benzoic acid, salicylic acid, sorbic acid, formic acid or benzyl alcohol, and combinations thereof.

In one embodiment, the preservatives are selected from the group consisting of phenoxyethanol and parabens.

In a preferred embodiment, the preservative is benzyl alcohol.

In one embodiment, the concentration of preservative expressed as a weight percentage relative to the total weight of the emulsion is less than 3%. In one embodiment, the concentration of preservative expressed as a percentage by weight relative to the total weight of the emulsion is less than 2% [0110] Corticosteroids are glucocorticoids which have an action on protein and carbohydrate metabolism. Natural glucocorticoids are cortisone and hydrocortisone (or cortisol). Synthetic glucocorticoids are either short-acting (prednisone), intermediate-acting (paramethasone) or long-acting (betamethasone). Medications are called nti-inflammatory steroids when they are used for this purpose.

In one embodiment, the active ingredient chosen from the glucocorticoid group is a betamethasone ester.

In one embodiment, the active ingredient is betamethasone dipropionate.

In a mode of réalsation, the method according to the invention is characterized in that it further comprises a step b ') of dissolution in the aqueous phase of an emulsifier or surfactant chosen from the group of emulsifiers nonionic ethoxylates, prior to step b).

In a mode of realaiastion, the ethoxylated nonionic emulsifier is selected from cetostearyl propylene glycol ethers.

By surfactant or emulsifier is meant a compound that modifies the surface tension between two surfaces. The surfactant compounds are amphiphilic molecules, that is to say that they have two parts of different polarities, one lipophilic (miscible in oil) and apolar, the other hydrophilic (miscible in water) and polar. This property also makes it possible to solubilize two immiscible phases.

In one embodiment, cetostearyl ethers of propylene glycol are the products sold by BASF under the name Kolliphor® CS 12, the number of which is CAS 68439-49-6 and listed in the European Pharmacopoeia under the name: Macrogol Cetostearyl Ether 12, or under the name Kolliphor® CS 20 CAS 68439-49-6 and listed in European Pharmacopoeia under the name Macrogol Cetostearyl Ether 20.

In one embodiment, the surfactant or emulsifier is selected from the group of surfactants or emulsifiers whose HLB is between 10 and 20, preferably between 12 and 16, more preferably 14 and 15.

In one embodiment, the process according to the invention is characterized in that the oily phase comprises at least one lipophilic excipient chosen from glycerides which are esters of glycerol and of fatty acids, in particular glycerides. natural origin as oils of vegetable or animal origin, butters, waxes, heml-synthetic glycerides.

[00050] Among the oils, mention will be made of sweet almond oil, peanut oil, corn oil, olive oil and castor oil.

Among the butters, mention will be made of kariét butter and cocoa butter.

Among the waxes include beeswax, camauba wax, jojoba wax, lanolin.

In one embodiment, the process according to the invention is characterized in that the oily phase comprises at least one non-glyceride lipophilic excipient, in particular fatty acids, fatty alcohols, liquid esters, solid esters, mineral hydrocarbons, silicones.

Among the fatty acids, there will be mentioned stearic acid, oleic acid.

Among the fatty alcohols include cetyl alcohol, stearyl alcohol, keto-stearyl alcohol.

Among the liquid esters, mention will be made of isopropyl myristate and cetiols.

Among the solid esters, mention may be made of polyethylene glycol stearates, ethylene glycol stearates.

Among the mineral hydrocarbons, mention will be made of petroleum jelly, liquid petroleum jelly or paraffin.

In one embodiment, the oily phase further comprises a thickener.

In one embodiment, the method according to the invention is characterized in that the thickener is selected from the group of fatty alcohols or waxes.

In one embodiment, the method according to the invention is characterized in that the thickener is cetostearyl alcohol.

In one embodiment, the method according to the invention is characterized in that the aqueous phase further comprises a pH adjuster.

By pH adjuster is meant weak acids or bases used for the purpose of modulating the pH, to make more suitable said formulation to be used on humans.

In one embodiment, the process according to the invention is characterized in that the pH adjuster is lactic acid.

By phase inversion is meant the transformation of an oil-in-water emulsion into a water-in-oil emulsion (or vice versa). It can be caused by a change in composition or a change in temperature. It is reversible but shows a hysteresis. This phenomenon makes it possible to prepare very fine emulsions by bringing little mechanical energy to the system.

The term "phase inversion temperature" (PIT) is the threshold temperature which causes a change in affinity of the emulsifier for the phases in the presence, it is called phase inversion. The influence of the temperature on the hydrophilicity of the ethoxylated surfactants results in a change in the direction of the emulsion during heating, or cooling.

In one embodiment, the method according to the invention is characterized in that the phase inversion temperature is greater than or equal to 80 ° C, preferably greater than 90 ° C and preferably greater than 95 ° C.

In one embodiment, the process according to the invention is characterized in that the concentration of active ingredient, expressed as a percentage by weight relative to the total weight of the emulsion, is between 0.04 and 0.1% of betamethasone.

In one embodiment, the process according to the invention is characterized in that the concentration of active ingredient, expressed as a weight percentage relative to the total weight of the emulsion, is 0.064% of betamethasone dipropionate, ie 0, 05% corresponding to 0.05% of betamethasone.

In one embodiment, the method according to the invention is characterized in that the preservative concentration expressed as a percentage by weight relative to the total weight of the emulsion is between 0.1% and 1.5%.

In one embodiment, the method according to the invention is characterized in that the preservative concentration expressed as a percentage by weight relative to the total weight of the emulsion is between 0.5% and 1.5%.

In one embodiment, the method according to the invention is characterized in that the preservative concentration expressed as a weight percentage relative to the total weight of the emulsion is between 0.8% and 1.2%.

In one embodiment, the method according to the invention is characterized in that the preservative concentration expressed as a percentage by weight relative to the total weight of the emulsion is 1%.

In one embodiment, the process according to the invention is characterized in that the oily phase concentration expressed as a weight percentage relative to the total weight of the emulsion is between 20 and 40%.

In one embodiment, the process according to the invention is characterized in that the oily phase concentration expressed as a weight percentage relative to the total weight of the emulsion is between 25 and 30%.

In one embodiment, the process according to the invention is characterized in that the concentration in aqueous phase expressed as a weight percentage relative to the total weight of the emulsion is between 60 and 80%.

In one embodiment, the process according to the invention is characterized in that the concentration in aqueous phase expressed as a weight percentage relative to the total weight of the emulsion is between 70 and 75%.

The invention also relates to the emulsion obtained by the method according to the invention described above, comprising between 0.5 and 1.5% preservative free of cresol and between 0.04 and 0.1%. of active ingredient.

In one embodiment, the emulsion according to the invention comprises 1% of benzyl alcohol and 0.064 of betamethasone dipropionate.

In one embodiment, the size of the globules measured under the microscope is less than 20 microns.

In one embodiment, the size of the globules measured under the microscope is between 8 and 16 pm.

It also relates to the use of an emulsion according to the invention in application to the skin.

It also relates to the emulsion according to the invention, intended to be used in the treatment of contact eczema, atopic dermatitis, lichenification, stasis dermatitis, psoriasis, lichen, nonparasitic purigo, dyshidrosis, genital sclera-atrophic lichen, annular granuloma, discoid lupus erythematosus, seborrheic dermatitis, pruritus, mycosis fungoides, parasitic prurigo. The invention will be better understood on reading the following examples:

Examples

Example 1

An oily phase comprising the following ingredients is carried out:

After mixing and homogenizing, the temperature is raised to about 95.degree.

Then the active orincioe is added:

By maintaining the temperature above 95 ° C.

An aqueous phase comprising the following ingredients is carried out;

The mixing is carried out and the temperature is raised to about 95 ° C, then the benzyl alcohol is added maintaining the temperature above 95 ° C.

The two phases are then mixed with a homogenization time of at least 10 minutes.

After the homogenization phase, the mixture is stirred with cooling to about 60 ° C, then a lactic acid solution to obtain a final mass percentage based on the total composition of 0.0007% is added to the mixture.

The mixture is then cooled slowly to 30 ° C. The thickening occurs at about 40 ° C. The emulsion obtained is fine and stable at 40.degree.

Counterexamples:

Against example 1:

The same composition as that prepared in Example 1 is prepared at a temperature not exceeding 80 ° C, the emulsion is formed after a granular passage during cooling. The resulting emulsion is coarse and of inappropriate texture. There is a rapid phase separation during storage in climatic chambers.

Against example 2:

An example with 2% benzyl alcohol is prepared by bringing the temperature of the mixture above 95 ° C.

A fine emulsion is obtained with a thickening temperature slightly above 30 ° C, which causes a defect in stability and a phase shift during storage at room temperature.

Claims (13)

A process for the preparation of an emulsion [water type in W / O oil] comprising the following steps: a) Dissolving at least one active ingredient selected from the group of topical corticosteroids in an oily phase; b) Dissolving at least one chlorocresol-free preservative in an aqueous phase and raising the temperature above the phase inversion temperature; c) mixing and homogenization of the aqueous phase in the oily phase; d) Temperature rise of the mixture obtained above the phase inversion temperature; e) cooling of the mixture; characterized in that: the concentration of preservative expressed as a weight percentage relative to the total weight of the emulsion is less than 2%; the steps a) and b) being performed independently and in any order. 2. Method according to claim 1, characterized in that the preservative is selected from the group consisting of benzoic acid, salicylic acid, sorbic acid, formic acid or benzyl alcohol. Method according to any one of the preceding claims, characterized in that the active ingredient selected from the group of topical corticosteroids is selected from the group of glucocorticoids. 3. Method according to any one of the preceding claims, characterized in that the active ingredient selected from the glucocorticoid group is a betamethasone ester. 4. Method according to any one of the preceding claims, characterized in that it further comprises a step b ') of dissolution in the aqueous phase of an emulsifier or surfactant chosen from the group of nonionic emulsifiers ethoxylated in the aqueous phase, prior to step b). 5. Method according to any one of the preceding claims, characterized in that the oily phase comprises at least one liquid paraffin or petrolatum. 6. Method according to claim 8, characterized in that the oily phase further comprises a thickener. 7. Method according to any one of the preceding claims, characterized in that the aqueous phase further comprises a pH adjuster. 8. Method according to any one of the preceding claims, characterized in that the concentration of active ingredient expressed as a weight percentage relative to the total weight of the emulsion is between 0.04 and 0.1% of betamethasone. 9. Method according to any one of the preceding claims, characterized in that the preservative concentration expressed as a weight percentage relative to the total weight of the emulsion is 1%. 10. Process according to any one of the preceding claims, characterized in that the concentration of oily phase expressed as a weight percentage relative to the total weight of the emulsion is between 20 and 40%. 11. Process according to any one of the preceding claims, characterized in that the concentration in the aqueous phase expressed as a percentage by weight relative to the total weight of the emulsion is between 60 and 80%. 12. Method according to any one of the preceding claims, characterized in that the phase inversion temperature of the mixture of step c) is greater than or equal to 80 ° C, preferably greater than 90 ° C and preferably greater than or equal to 90 ° C. equal to 95 ° C. 13. Emulsion obtained by the process according to any one of the preceding claims comprising between 0.5 and 1.5% preservative free of cholocresol and between 0.04 and 0.1% of active ingredient.