WO2020065085A1 - Pharmaceutical composition comprising brimonidine, and uses thereof - Google Patents

Pharmaceutical composition comprising brimonidine, and uses thereof Download PDF

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Publication number
WO2020065085A1
WO2020065085A1 PCT/EP2019/076365 EP2019076365W WO2020065085A1 WO 2020065085 A1 WO2020065085 A1 WO 2020065085A1 EP 2019076365 W EP2019076365 W EP 2019076365W WO 2020065085 A1 WO2020065085 A1 WO 2020065085A1
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WIPO (PCT)
Prior art keywords
aqueous phase
composition
composition according
brimonidine
oils
Prior art date
Application number
PCT/EP2019/076365
Other languages
French (fr)
Inventor
Claire Mallard
Gareth Winckle
Emmanuelle GUTIERREZ
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Galderma Research & Development
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Publication of WO2020065085A1 publication Critical patent/WO2020065085A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine

Definitions

  • the present invention relates to the field of pharmaceutical compositions suitable for topical administration. It relates more particularly to a pharmaceutical composition in the form of an emulsion comprising brimonidine, its salts or its derivatives, as well as its use as a drug, more particularly in the prevention and / or treatment of dermatological conditions, in particular human such as rosacea.
  • Rosacea is a chronic inflammatory disease of the facial skin that can have a significant impact on the lives of those affected. It manifests as redness on the face, mainly on the forehead, cheeks and nose, accompanied by inflammatory pimples (papules and pustules). Skin with rosacea tends to be very dry and sensitive. Skin that suffers from rosacea is very sensitive and reactive skin. Avoid rubbing the skin, washing it under hot water. Mild, no-rinse, alcohol-free, and soap-free cleaners should be used, along with a suitable moisturizer.
  • compositions intended for a known topical application can cause side effects which can limit their use and therefore their effectiveness.
  • active ingredients have the major drawback of inducing irritation which can lead to poor tolerance of the product. This can thus create, on the part of the patient, behavior of non-observance of the treatment and dissatisfaction with the said treatment.
  • Brimonidine is a highly selective alpha-2-adrenergic receptor agonist. It has been used as monotherapy or as a fan ⁇ adjuvant therapy to lower intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (HTO) since its approval in 1996. Brimonidine has also been shown to be useful in the treatment of various skin disorders, such as acne rosacea, erythema caused by acne rosacea, see, for example, application US 10/853 585, application US10 / 626 037 and application US 12/193 098.
  • Application FR3041537 describes a new pharmaceutical composition containing brimonidine, intended for topical application without rinsing which is in the form of a foam which advantageously does not contain foaming surfactants, as well as its use in the treatment of rosacea.
  • MIRVASO TM marketed by the company GALDERMA TM is a topical medication indicated to treat the symptoms of facial erythema associated with rosacea in adults. MIRVASO should be applied once every 24 hours, at the most convenient time for the patient.
  • the maximum recommended daily dose is 1 g of gel in total, divided into 5 peas. Each amount of gel equivalent to a pea is intended to be applied to each of the following 5 areas of the face: forehead, chin, nose and cheeks. The duration of use depends on the persistence of facial erythema.
  • MIRVASO efficacy of MIRVASO in the treatment of moderate to severe facial erythema associated with rosacea has been demonstrated in two randomized blinded clinical trials of the same methodology versus the MIRVASO vehicle.
  • MIRVASO gel has a unanimously proven efficacy.
  • An object of the present invention is to provide a pharmaceutical composition of the O / W emulsion type comprising a high proportion of fatty phase, which overcomes the drawbacks of the prior art by incorporating only very small quantities of surfactant.
  • high proportion of fatty phase in an O / W emulsion is meant, within the meaning of the present invention, a proportion of at least 10% by weight of fatty phase relative to the total weight of the emulsion.
  • the invention relates to the field of pharmaceutical compositions suitable for topical administration. It relates more particularly to a pharmaceutical composition in the form of an emulsion comprising, as active ingredient, brimonidine, its salts or its derivatives, as well as its use as a drug, more particularly in the prevention and / or treatment of dermatological conditions in particular human.
  • a problem which the present invention proposes to solve consists in developing a pharmaceutical composition which is well tolerated as non-irritant or very slightly irritant compared to the compositions of the prior art. Furthermore, an additional problem which the present invention proposes to solve is to improve the skin penetration of the compositions comprising brimonidine relative to the existing compositions, as well as to improve the solubilization of brimonidine. Finally, an additional problem which the invention proposes to solve is to develop pharmaceutical compositions which are economical, easy and quick to prepare.
  • a pharmaceutical composition in a form suitable for topical administration comprising fife of active ingredient brimonidine, its salts or its derivatives, characterized in that it is in the form of '' an oil-in-water emulsion (O / W) comprising:
  • a fatty phase representing between 10% and 60% by weight of the total weight of the composition (w / w);
  • An aqueous phase comprising at least 0.01% by weight of the total weight of the composition (w / w) of water-soluble polyvinyl alcohol (PVA).
  • the second object is a pharmaceutical composition according to the invention, for its use in the treatment and / or prevention of dermatological conditions, preferably rosacea.
  • the third object of the invention is a process for preparing a pharmaceutical composition according to the invention, comprising the following steps:
  • aqueous phase comprising water-soluble polyvinyl alcohol (PVA), brimonidine, its salts or its derivatives, and optionally a second active principle;
  • PVA polyvinyl alcohol
  • an oily phase comprising an oil chosen from the group of mineral oils, vegetable oils, synthetic oils and possibly other hydrophobic compounds and optionally a second active principle;
  • the last object of the invention is a process for preparing a pharmaceutical composition according to the invention, comprising the following steps of: solubilization, at a temperature above 40 ° C, of water-soluble polyvinyl alcohol (PVA) in a aqueous phase comprising brimonidine, its salts or its derivatives e ⁇ optionally a second active principle;
  • PVA water-soluble polyvinyl alcohol
  • aqueous phase comprising an oil chosen from the group of mineral oils, vegetable oils, synthetic oils e ⁇ optionally other hydrophobic compounds e ⁇ a second active principle;
  • the Applicant has in particular been able to develop a pharmaceutical composition in a form suitable for topical administration making it possible to significantly increase the skin penetration of brimonidine, its salts or its derivatives. Consequently, the concentration of the active principle and of the associated solvent can be reduced enough to limit their side effects e ⁇ in particular the irritation linked to the active principle.
  • composition developed by the Applicant is ⁇ stable and ⁇ well tolerated.
  • compositions according to the invention allow a prolonged release of the active principle. This results in a longer duration of action and a better tolerance profile.
  • FIG. 1 represents the penetration results of different compositions comprising the active ingredient Brimonidine Tartrafe through membranes of human epidermis (ng / cm 2 ).
  • FIG. 2 represents the results of penetration of different compositions comprising the active ingredient Brimonidine Tartrafe through membranes of human epidermis (ng / cm 2 ).
  • FIG. 3 represents the results of penetration of different compositions comprising the active ingredient Brimonidine Tartrafe through membranes of human epidermis (ng / cm 2 ).
  • the invention relates to a new pharmaceutical composition in the form of an oil-in-water emulsion (Fl / E).
  • An emulsion is the mixture of two immiscible liquids under the effect of mechanical agitation forming a dispersed system. This dispersion remains as long as the agitation lasts, but as soon as the latter ceases, there is coalescence of the globules and the liquids separate.
  • the formulation of an emulsion aims to bring to the mixture the product or products which will allow or facilitate the stabilization of the system.
  • This or these products are therefore essential to the formulation and to the conservation in terms of physicochemical stability of an emulsion; they are called emulsifiers, surfactants, emulsifiers, wetting agents or even surfactants.
  • the surfactants must be incorporated in a relatively large amount which can be up to 20% by weight of the total weight of the emulsion in order to obtain adequate stability at temperature and over time.
  • compositions in the form of an emulsion do not appear, therefore, to be prima fade, suitable for the treatment of dermatological pathologies such as in particular rosacea.
  • composition which is the subject of the invention comprises brimonidine, its salts or its derivatives at a concentration advantageously between 0.01% and 5% by weight of the total weight of the composition (w / w).
  • salts or selfs it is meant the salts of a compound of interest which are safe and effective for topical use in mammals and which have a desired biological activity.
  • Pharmaceutically acceptable salts ⁇ include salts of acidic or basic groups present in the specified compounds.
  • Pharmaceutically acceptable acid addition salts ⁇ include, but are not limited to, hydrochloride, hydrobromide, iodhydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate salts , pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)).
  • Certain compounds used in the present invention can form pharmacologically acceptable salts with different amino acids.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diehanolamine salts.
  • hydrate designates a compound of interest, or a pharmacologically acceptable salt thereof which additionally comprises a stoichiometric or non-stoichiometric amount of water linked to it by non-covalent intermolecular forces .
  • the brimonidine used in the compositions according to the invention is ⁇ brimonidine tartrate.
  • the concentration of brimonidine, its salts or its derivatives in the composition is preferably between 0.01% and ⁇ 1% by weight of the total weight of the composition (w / w), preferably between 0.05% and ⁇ 0, 5% w / w.
  • the concentration of brimonidine, its salts or its derivatives in the composition is exactly 0.01%, 0.02%, 0.03%, 0.06% or 0.09% w / w, preferably 0, 33% or 0.66% w / w.
  • compositions which is the subject of the invention are in a topical form in particular adapted to its place of administration (skin, scalp, hair, etc.), preferably skin lesions.
  • the composition is in the form of an oil-in-water (O / W) emulsion comprising a fatty phase and an aqueous phase.
  • the fatty phase represents at least 10% by weight of the total weight of the composition (w / w).
  • fatty phase representing between 10% and 60% by weight of the total weight of the composition (w / w).
  • the fatty phase represents between 15% and 50% by weight of the total weight of the composition (w / w).
  • the fatty phase represents between 20% and 30% w / w.
  • the fatty phase is free of surfactant.
  • the small amount of surfactant present in the aqueous phase is sufficient to ensure the stability of the emulsion and the composition thus obtained is well tolerated and non-irritant.
  • the addition of an additional surfactant in the fatty phase is optional but does not a priori bring anything in terms of improving the stability of the emulsion.
  • the fatty phase represents at most 60% by weight of the total weight of the composition. Indeed, above this value, there is a risk of phase shift of the emulsion which can occur a few days after the manufacture of the emulsion, this risk increasing, for a given proportion of surfactants, when the proportion of fatty phase increases beyond 60% by weight relative to the total weight of the emulsion.
  • the fatty phase represents approximately 15% to 50% by weight of the total weight of the vehicle.
  • the fatty phase of the composition according to the invention may contain one or more oils chosen from vegetable oils, mineral oils, silicone oils, synthetic oils and fluorinated oils.
  • KOLLICREAM TM DO Decyl oleate
  • CRODAMOL TM OO oleyl oleate
  • paraffin oils As mineral oils which can be used according to the invention, there may be mentioned paraffin oils, and preferably liquid paraffin oils such as PRIMOL 352 (ore oil), MARCOL 52 (ore oil) sold by the company EXXON MOBIL
  • a significant fatty phase rate is particularly advantageous for dermatological compositions intended for the care of dry skin.
  • the aqueous phase of the oil-in-water (Fl / E) emulsion according to the invention comprises at least 0.01% by weight of the total weight of the composition (w / w) of a water-soluble surfactant which is a polyvinyl alcohol (PVA) water-soluble, e ⁇ preferably a partially hydrolyzed polyvinyl alcohol.
  • a water-soluble surfactant which is a polyvinyl alcohol (PVA) water-soluble, e ⁇ preferably a partially hydrolyzed polyvinyl alcohol.
  • the aqueous phase comprises between 0.05% and 0.5% by weight of the total weight of the composition (w / w) water-soluble polyvinyl alcohol (PVA).
  • the concentration of PVA in the composition is between 0.2% and 0.4% w / w, preferably 0.2%, 0.225%, 0.25%, 0.275%, 0.325%, 0.35 %, 0.375% and 0.4% w / w.
  • composition according to the invention may also comprise one or more compatible additives, which do not modify the characteristics specific to the emulsions. Mention may be made, as additives compatible with cosmetic and / or dermatological use, of gelling agents such as PEMULEN TR-1 (acrylate / C 10-30 alkyl acrylate crosspolymer), PEMULEN TR-2 (acrylate / C 10-30 alkyl acrylate crosspolymer), CARBOPOL 980 NF (carbomer) sold by the company LUBRIZOL, SIMULGEL 600 PHA (acrylamide / sodiumacryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80) sold by SEPPIC, SATIAXANE UCX 91 1 (xanthan gum), SATIAGILNE US 171 E (alginate) sold by the company CARGILL, KLUCEL MF (hydroxypropyl cellulose), BENECEL K 100 M (methylhydroxypropyl cellulose), NATROSOL
  • preservatives such as METHYL PARAHYDROXYBENZOATE (methyl 4-hydroxybenzoate) and PROPYL PARAHYDROXYBENZOATE (propyl paraben) sold by the company SHARON, PHENOXETOL (phenoxyethanol) sold by the company CLARIANT, antioxidants, isotonizers, chelating agents, buffers, polymers, fillers, hydrophilic or lipophilic gelling agents, hydrophilic filters, hydrophilic compounds such as alcohols, absorbers odor, humectants, and emollients.
  • preservatives such as METHYL PARAHYDROXYBENZOATE (methyl 4-hydroxybenzoate) and PROPYL PARAHYDROXYBENZOATE (propyl paraben) sold by the company SHARON, PHENOXETOL (phenoxyethanol) sold by the company CLARIANT, antioxidants, isotonizers, chelating agents, buffers, poly
  • these adjuvants should not harm the properties of the composition according to the invention, that is to say good tolerance and the absence of irritability of the skin.
  • the composition also comprises a second active principle which is preferably chosen from antibiotics, anfibacterial agents, anfivirals, anfiparasitics, antifungals, anesthetics, analgesics, analgesics, anfiallergic agents, acne anfi, antimitotics, antipruritics, antihistamines, immunosuppressants, corficosteroids, keratolytics, anti angiogenic agents, anti-inflammatory drugs don ⁇ phosphodiesterase 4 inhibitors, anti-cancer agents, anti -neoplastic, natural extracts, anthracene derivatives, psoralens, anti-proliferatives (analogues of vitamin D, ...), anti-alopecics (analogues of prostaglandin), anti-herpes, photosensitizers, depigmentants, hormones, retinoids, vasoconstrictors and / or a mixture thereof.
  • a second active principle which is preferably chosen from
  • an active pharmaceutical ingredient that can be used according to the invention, mention may be made of a second active ingredient chosen from acetaminophen, acetylsalicylic acid, acitretin, azelaic acid, acyclovir , adapalene, alclometasone, alpha-tocopherol, amcinonide, amorolfine, amphotericin B, tetracycline, benzoyl peroxide, betamethasone, calcipotriol, calcitriol, ciclopirox, clindamycin , crisaborole, clobetasol, crotamiton, cyproheptadine, dapsone, desonide, diclofenac, diflucortolone, difluprednate, dioxyanthranol, econazole, efinaconazole, erythromycin, estradiol, etretinate , fluocinol
  • HEXYLENE GLYCOL USP / NF hexylene glycol
  • PROPANEDIOL-1 PROPANEDIOL-1
  • 2 propylene glycol
  • GLYCERINE 4810 VEGETALE glycerol
  • OLEON KOLLISOLV PEG 400 polyethylene glycol
  • TRANSCUTOL HP ethoxydiglycol
  • the solvent used is ⁇ hexylene glycol.
  • the pharmaceutical composition according to the invention may contain other additional ingredients such as an adjuvant, an antioxidant, a chelating agent, a surfactant, a foaming agent, an agent wetting agent, an emulsifying agent, a viscosifier, a buffering agent or a preservative.
  • additional ingredients such as an adjuvant, an antioxidant, a chelating agent, a surfactant, a foaming agent, an agent wetting agent, an emulsifying agent, a viscosifier, a buffering agent or a preservative.
  • the pharmaceutical composition according to the invention can contain a permeation or penetration improving agent.
  • permeation or penetration improving agent means a compound which makes it possible to significantly improve the skin penetration of the active ingredient according to the invention.
  • oleic acid As an example of an agent for improving permeation or penetration, there may be mentioned oleic acid, oleic alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acid, dimethylsulfoxide or polar lipids or N- methyl-2-pyrrolidone.
  • the pharmaceutical composition according to the invention may contain a hydrotropic agent disorganizing the structure of the stratum corneum and thus making it possible to further increase the penetration through the surface layer of the skin.
  • hydrotropic agent As an illustrative example of a hydrotropic agent, mention may be made of sodium xylene sulfonate isopropyl alcohol, and preferably propylene glycol.
  • the invention also relates to a pharmaceutical composition according to the invention, for its use in the treatment and / or prevention of dermatological conditions.
  • composition which is the subject of the invention is suitable for use in the prevention and / or treatment of dermatological conditions, in particular human, as defined below:
  • non-cancerous lesions such as abnormal proliferation of keratinocyte in the epidermis, seborrheic keratoses, infections of the human papilloma virus including vulva infraepithelial neoplasia, vaginal infraepithelial neoplasia, common warts, molluscum confagiosum or infections by the herpes virus.
  • pre-cancerous lesions such as actinic keratosis, atypical junctional melanocytic lesions, melanocytic hyperplasia atypical, atypical intraepidermal melanocytic hyperplasia or atypical intraepidermal melanocytic proliferation.
  • cancerous lesions such as basal cell carcinoma, squamous cell carcinoma, Dubreuilh melanosis, in situ melanoma, melanoma, Bowen's disease, in situ squamous cell carcinoma, arsenical keratosis, radiation keratosis, PUVA kefafosis , Bowenoid papulosis, sebaceous carcinoma, porocarcinoma, extramammary disease, Merkel cell carcinoma, Kaposi's sarcoma or cutaneous T-cell lymphoma.
  • the invention relates to a pharmaceutical composition as described above, for its use for the prevention and / or the treatment of pathologies responding to brimonidinne such as rosacea.
  • the subject of the invention is also a process for preparing a pharmaceutical composition according to the invention, comprising the following steps of: preparation, at a temperature above 40 ° C., of a first aqueous phase comprising polyvinyl alcohol water-soluble (PVA), brimonidine, its salts or derivatives, e ⁇ optionally a second active ingredient;
  • PVA polyvinyl alcohol water-soluble
  • an oily phase comprising an oil chosen from the group of mineral oils, vegetable oils, silicone oils, synthetic oils e ⁇ fluorinated oils e ⁇ possibly other hydrophobic compounds e ⁇ optionally a second active principle;
  • the last object of the invention is a process for preparing a pharmaceutical composition according to the invention, comprising the following steps of: solubilization, at a temperature above 40 ° C, of water-soluble polyvinyl alcohol (PVA) in a aqueous phase comprising brimonidine, its salts or its derivatives and optionally a second active principle;
  • PVA water-soluble polyvinyl alcohol
  • aqueous phase comprising an oil chosen from the group of mineral oils, vegetable oils, silicone oils, synthetic oils and fluorinated oils and optionally other hydrophobic compounds and a second active principle;
  • Studies 1 and 2 use a specific IVSP model based on the heat separated epidermis (HSE).
  • Figures 1 and 2 show the results of penetration of the active ingredient Brimonidine Tartrate through human epidermis membranes (ng / cm 2 ) for formulas A, C, D, E and F.
  • FIG. 3 represents the results of penetration of the active ingredient Brimonidine Tartrate through membranes of human epidermis (ng / cm 2 ) for the formulas B, G, H, I e ⁇ K.
  • the reference PVA emulsion, formula B represents a release profile similar to that of the “low dose” gel, 0.12% Brimonidine gel.
  • Adding solvents such as PEG400, or propylene glycol + glycerin + PEG 400 can improve the release profile.
  • Example 2 Optimization of the process for preparing the composition according to the invention
  • composition of the placebo formula (without active ingredient) is shown in Table 4 below.
  • the conventional manufacturing process involves the following steps: a first aqueous phase is carried out containing partially hydrolyzed polyvinyl alcohol dissolved in water at
  • the fatty phase is then inserted at RT (room temperature) in the first aqueous phase under Ultra-Turrax for 90s with increase in speed by one unit every 15sec.
  • RT room temperature
  • Ultra-Turrax for 90s with increase in speed by one unit every 15sec.
  • the resulting intermediate product is ⁇ called the premix;
  • an annexed aqueous phase is ⁇ prepared containing the remaining water, hydrophilic compounds and gelling agents; - the pre-mix is ⁇ then slowly inserted into this annexed aqueous phase ⁇ the pH is ⁇ adjusted.
  • the industrial constraint lies in the initial quantity used for the manufacture of the pre-emulsion. It is insufficient (12.875%) to be carried out in the main manufacturing tank. Auxiliary tank agitation systems are not ⁇ powerful enough to sufficiently shear the premix.
  • the idea is to get rid of the intermediate pre-emulsion step and use only one phase to facilitate industrial production.
  • Polyvinyl alcohol is dissolved at 85 ° C with stirring, in the total amount of water in the formula. Then cooled to room temperature.
  • the fatty phase is then added to carry out the emulsification, before or after the gelling of the aqueous phase.
  • the pH is adjusted at the end of manufacturing.
  • the proposal to improve the process for manufacturing the composition according to the invention allows transposition to an industrial scale.

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Abstract

The invention relates to a pharmaceutical composition in a form suitable for topical administration, comprising, as active ingredient, brimonidine, salts thereof or derivatives thereof. The invention is characterized in that it is in the form of an oil-in-water (O/W) emulsion comprising a fatty phase representing between 10% and 60% by weight of the total weight of the composition (w/w), and an aqueous phase comprising at least 0.01% by weight of the total weight of the composition (w/w) of water-soluble polyvinyl alcohol (PVA).

Description

COMPOSITION PHARMACEUTIQUE COMPRENANT DE LA BRIMONIDINE, ET SES  PHARMACEUTICAL COMPOSITION COMPRISING BRIMONIDINE, AND ITS
UTILISATIONS  USES
Domaine technique Technical area
La présente invention concerne le domaine des compositions pharmaceutiques adaptées à une administration par voie topique. Elle concerne plus particulièrement une composition pharmaceutique sous forme d’émulsion comprenant de la brimonidine, ses sels ou ses dérivés, ainsi que son utilisation en tan† que médicament, plus particulièrement dans la prévention et/ou le traitement des affections dermatologiques notamment humaines telles que la rosacée.  The present invention relates to the field of pharmaceutical compositions suitable for topical administration. It relates more particularly to a pharmaceutical composition in the form of an emulsion comprising brimonidine, its salts or its derivatives, as well as its use as a drug, more particularly in the prevention and / or treatment of dermatological conditions, in particular human such as rosacea.
Technique antérieure Prior art
La rosacée est une maladie inflammatoire chronique de la peau du visage qui peut avoir un impact important sur la vie des personnes touchées. Elle se manifeste par des rougeurs sur le visage, principalement sur le front, les joues et le nez, accompagnées de boutons inflammatoires (papules et pustules) . La peau atteinte de rosacée tend à être très sèche et sensible. La peau qui souffre de rosacée est une peau très sensible et très réactive. Il faut éviter de frotter la peau, de la laver sous l'eau chaude. Des nettoyants doux sans rinçage, sans alcool et sans savon doivent être utilisés ainsi qu'une crème hydratante adaptée.  Rosacea is a chronic inflammatory disease of the facial skin that can have a significant impact on the lives of those affected. It manifests as redness on the face, mainly on the forehead, cheeks and nose, accompanied by inflammatory pimples (papules and pustules). Skin with rosacea tends to be very dry and sensitive. Skin that suffers from rosacea is very sensitive and reactive skin. Avoid rubbing the skin, washing it under hot water. Mild, no-rinse, alcohol-free, and soap-free cleaners should be used, along with a suitable moisturizer.
En outre, certains composés utilisés dans les compositions destinées à une application topique connue peuvent entraîner des effets secondaires qui peuvent en limiter l'utilisation et donc l'efficacité. Par exemple, certains actifs présentent l'inconvénient majeur d'induire de l'irritation pouvant entraîner une tolérance médiocre du produit. Cela peut ainsi créer de la par† du patient un comportement de non observance du traitement et du mécontentement à l'égard dudit traitement. In addition, certain compounds used in the compositions intended for a known topical application can cause side effects which can limit their use and therefore their effectiveness. For example, some active ingredients have the major drawback of inducing irritation which can lead to poor tolerance of the product. This can thus create, on the part of the patient, behavior of non-observance of the treatment and dissatisfaction with the said treatment.
Il existe donc un besoin de mettre au point de nouvelles formes galéniques palliant les inconvénients cités précédemment en termes de tolérance, d'efficacité et d'observance. Dans ce genre de pathologies à long terme et pour lesquelles on traite les symptômes sans savoir éradiquer la maladie, il existe également un besoin de disposer de nouvelles formes galéniques permettant un meilleur contrôle de la dose dans lesquelles la brimonidine est soluble, stable, bien tolérée, efficace et agréable à appliquer. There is therefore a need to develop new dosage forms overcoming the drawbacks mentioned above in terms of tolerance, effectiveness and compliance. In this kind of long pathologies term and for which the symptoms are treated without knowing how to eradicate the disease, there is also a need for new galenical forms allowing better control of the dose in which brimonidine is soluble, stable, well tolerated, effective and pleasant to apply.
La brimonidine est un agoniste des récepteurs alpha-2-adrénergiques hautement sélectif. Elle a été utilisée en monothérapie ou en fan† que thérapie adjuvante pour abaisser la pression intraoculaire (PIO) dans le traitement du glaucome et de l'hypertension oculaire (HTO) depuis son approbation en 1996. La brimonidine s'est également avérée être utile dans le traitement de différents troubles cutanés, tels que l'acné rosacée, un érythème causé par l'acné rosacée, voir, par exemple, la demande US 10/853 585, la demande US10/626 037 et la demande US 12/ 193 098.  Brimonidine is a highly selective alpha-2-adrenergic receptor agonist. It has been used as monotherapy or as a fan † adjuvant therapy to lower intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (HTO) since its approval in 1996. Brimonidine has also been shown to be useful in the treatment of various skin disorders, such as acne rosacea, erythema caused by acne rosacea, see, for example, application US 10/853 585, application US10 / 626 037 and application US 12/193 098.
La demande FR3041537 décrit une nouvelle composition pharmaceutique contenant de la brimonidine, destinée à une application topique non rincée qui se présente sous la forme d'une mousse qui ne contient avantageusement pas de tensioactifs moussants, ainsi que son utilisation dans le traitement de la rosacée.  Application FR3041537 describes a new pharmaceutical composition containing brimonidine, intended for topical application without rinsing which is in the form of a foam which advantageously does not contain foaming surfactants, as well as its use in the treatment of rosacea.
Le produit MIRVASO™ commercialisé par la société GALDERMA™ est un médicament topique indiqué pour traiter les symptômes de l'érythème facial associé à la rosacée chez l'adulte. MIRVASO doit être appliqué une fois par 24 heures, au moment qui convient le mieux pour le patient.  The product MIRVASO ™ marketed by the company GALDERMA ™ is a topical medication indicated to treat the symptoms of facial erythema associated with rosacea in adults. MIRVASO should be applied once every 24 hours, at the most convenient time for the patient.
La dose quotidienne maximale recommandée est de 1 g de gel au total, divisé en 5 petits pois. Chaque quantité de gel équivalente à un pois est destinée à être appliquée sur chacune des 5 zones du visage suivantes : front, menton, nez et joues. La durée d'utilisation est fonction de la persistance de l'érythème facial.  The maximum recommended daily dose is 1 g of gel in total, divided into 5 peas. Each amount of gel equivalent to a pea is intended to be applied to each of the following 5 areas of the face: forehead, chin, nose and cheeks. The duration of use depends on the persistence of facial erythema.
L'efficacité de MIRVASO dans le traitement de l'érythème facial modéré à sévère associé à la rosacée a été démontrée dans deux essais cliniques de même méthodologie randomisés, en aveugle, versus le véhicule de MIRVASO. Le gel MIRVASO présente une efficacité unanimement avérée. Cependant, il serait avantageux et utile d'augmenter l'efficacité de la Brimonidine Tarfrate dans le traitement de la rosacée et de diminuer l'irritation provoquée par son application topique. The efficacy of MIRVASO in the treatment of moderate to severe facial erythema associated with rosacea has been demonstrated in two randomized blinded clinical trials of the same methodology versus the MIRVASO vehicle. MIRVASO gel has a unanimously proven efficacy. However, it would be advantageous and useful to increase the effectiveness of Brimonidine Tarfrate in the treatment of rosacea and to decrease the irritation caused by its topical application.
Résumé de l’invention Summary of the invention
Un but de la présente invention est de proposer une composition pharmaceutique du type émulsion H/E comportant une proportion élevée de phase grasse, qui remédie aux inconvénients de l'art antérieur en n'incorporan† que de très faibles quantités d'agent fensioactif.  An object of the present invention is to provide a pharmaceutical composition of the O / W emulsion type comprising a high proportion of fatty phase, which overcomes the drawbacks of the prior art by incorporating only very small quantities of surfactant.
Par proportion élevée de phase grasse dans une émulsion H/E, on entend, au sens de la présente invention, une proportion d'au moins 10 % en poids de phase grasse par rapport au poids total de l'émulsion. By high proportion of fatty phase in an O / W emulsion, is meant, within the meaning of the present invention, a proportion of at least 10% by weight of fatty phase relative to the total weight of the emulsion.
Plus particulièrement, l’invention concerne le domaine des compositions pharmaceutiques adaptées à une administration par voie topique. Elle concerne plus particulièrement une composition pharmaceutique sous forme d’émulsion comprenant comme principe actif de la brimonidine, ses sels ou ses dérivés, ainsi que son utilisation en fan† que médicament, plus particulièrement dans la prévention et/ou le traitement des affections dermatologiques notamment humaines.  More particularly, the invention relates to the field of pharmaceutical compositions suitable for topical administration. It relates more particularly to a pharmaceutical composition in the form of an emulsion comprising, as active ingredient, brimonidine, its salts or its derivatives, as well as its use as a drug, more particularly in the prevention and / or treatment of dermatological conditions in particular human.
Problème technique Technical problem
Considérant ce qui précède, un problème que se propose de résoudre la présente invention consiste à développer une composition pharmaceutique qui soit bien tolérée car non-irritante ou très faiblement irritante par rapport aux compositions de l’art antérieur. Par ailleurs, un problème additionnel que se propose de résoudre la présente invention est d’améliorer la pénétration cutanée des compositions comprenant de la brimonidine par rapport aux compositions existantes, ainsi que d’améliorer la solubilisation de la brimonidine. Enfin, un problème additionnel que se propose de résoudre l’invention est de mettre au point des compositions pharmaceutiques qui soient économiques, faciles et rapides à préparer.  Considering the above, a problem which the present invention proposes to solve consists in developing a pharmaceutical composition which is well tolerated as non-irritant or very slightly irritant compared to the compositions of the prior art. Furthermore, an additional problem which the present invention proposes to solve is to improve the skin penetration of the compositions comprising brimonidine relative to the existing compositions, as well as to improve the solubilization of brimonidine. Finally, an additional problem which the invention proposes to solve is to develop pharmaceutical compositions which are economical, easy and quick to prepare.
Solution technique La solution à ce problème posé a pour premier objet une composition pharmaceutique sous une forme adaptée à une administration par voie topique comprenant à fifre de principe actif de la brimonidine, ses sels ou ses dérivés, caractérisée en ce qu’elle se présente sous forme d’une émulsion huile-dans-eau (H/E) comportant : Technical solution The solution to this problem posed has for first object a pharmaceutical composition in a form suitable for topical administration comprising fife of active ingredient brimonidine, its salts or its derivatives, characterized in that it is in the form of '' an oil-in-water emulsion (O / W) comprising:
- une phase grasse représentant entre 10% et 60% en poids du poids total de la composition (p/p) ; et - A fatty phase representing between 10% and 60% by weight of the total weight of the composition (w / w); and
- une phase aqueuse comprenant au moins 0,01 % en poids du poids total de la composition (p/p) d’alcool polyvinylique hydrosoluble (PVA).  - An aqueous phase comprising at least 0.01% by weight of the total weight of the composition (w / w) of water-soluble polyvinyl alcohol (PVA).
Elle a pour deuxième objet une composition pharmaceutique selon l’invention, pour son utilisation dans le traitement ef/ou la prévention des affections dermatologiques, préférentiellement la rosacée. The second object is a pharmaceutical composition according to the invention, for its use in the treatment and / or prevention of dermatological conditions, preferably rosacea.
L’invention a pour troisième objet un procédé de préparation d’une composition pharmaceutique selon l’invention, comprenant les étapes suivantes de :  The third object of the invention is a process for preparing a pharmaceutical composition according to the invention, comprising the following steps:
préparation, à une température supérieure à 40°C, d’une première phase aqueuse comprenant de l’alcool polyvinylique hydrosoluble (PVA), la brimonidine, ses sels ou ses dérivés, et éventuellement un deuxième principe actif ;  preparation, at a temperature above 40 ° C, of a first aqueous phase comprising water-soluble polyvinyl alcohol (PVA), brimonidine, its salts or its derivatives, and optionally a second active principle;
préparation d’une phase grasse comprenant une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles de synthèse et éventuellement d’autres composés hydrophobes et éventuellement un deuxième principe actif ;  preparation of an oily phase comprising an oil chosen from the group of mineral oils, vegetable oils, synthetic oils and possibly other hydrophobic compounds and optionally a second active principle;
ajout, à température ambiante, de la phase grasse sur la première phase aqueuse ou inversement ;  adding, at room temperature, the fatty phase to the first aqueous phase or vice versa;
récupération d’un produit intermédiaire ;  recovery of an intermediate product;
préparation d’une phase aqueuse annexe comprenant de l’eau et éventuellement des composés hydrophiles et des gélifiants ;  preparation of an additional aqueous phase comprising water and optionally hydrophilic compounds and gelling agents;
insertion du produit intermédiaire dans la phase aqueuse annexe ; et récupération de la composition pharmaceutique ainsi obtenue. Enfin, l’invention a pour dernier objet un procédé de préparation d’une composition pharmaceutique selon l’invention, comprenant les étapes suivantes de : solubilisation, à une température supérieure à 40°C, d’alcool polyvinylique hydrosoluble (PVA) dans une phase aqueuse comprenant la brimonidine, ses sels ou ses dérivés e† éventuellement un deuxième principe actif ; insertion of the intermediate product in the additional aqueous phase; and recovering the pharmaceutical composition thus obtained. Finally, the last object of the invention is a process for preparing a pharmaceutical composition according to the invention, comprising the following steps of: solubilization, at a temperature above 40 ° C, of water-soluble polyvinyl alcohol (PVA) in a aqueous phase comprising brimonidine, its salts or its derivatives e † optionally a second active principle;
refroidissement à température ambiante de ladite phase aqueuse ; préparation d’une phase grasse comprenant une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles de synthèse e† éventuellement d’autres composés hydrophobes e† un deuxième principe actif ;  cooling said aqueous phase to ambient temperature; preparation of a fatty phase comprising an oil chosen from the group of mineral oils, vegetable oils, synthetic oils e † optionally other hydrophobic compounds e † a second active principle;
ajout, à température ambiante, de la phase grasse sur la phase aqueuse ou inversement, avant ou après gélification de la phase aqueuse ; e†  adding, at room temperature, the fatty phase to the aqueous phase or vice versa, before or after gelling of the aqueous phase; e †
récupération de la composition pharmaceutique ainsi obtenue.  recovery of the pharmaceutical composition thus obtained.
Avantages apportés Benefits
Le Demandeur a notamment pu développer une composition pharmaceutique sous une forme adaptée à une administration par voie topique permettant d’augmenter significativement la pénétration cutanée de la brimonidine, ses sels ou ses dérivés. Par conséquent, la concentration du principe actif et du solvant associé peu† être suffisamment diminuée pour limiter leurs effets secondaires e† notamment l’irritation liée au principe actif.  The Applicant has in particular been able to develop a pharmaceutical composition in a form suitable for topical administration making it possible to significantly increase the skin penetration of brimonidine, its salts or its derivatives. Consequently, the concentration of the active principle and of the associated solvent can be reduced enough to limit their side effects e † in particular the irritation linked to the active principle.
En outre, la composition pharmaceutique développée par le Demandeur es† stable e† bien tolérée. In addition, the pharmaceutical composition developed by the Applicant is † stable and † well tolerated.
De façon avantageuse, certaines compositions selon l’invention permettent une libération prolongée du principe actif. Ceci entraîne une durée d'action plus longue e† un meilleur profil de tolérance. Advantageously, certain compositions according to the invention allow a prolonged release of the active principle. This results in a longer duration of action and a better tolerance profile.
Dans cette description, à moins qu’il ne soi† spécifié autrement, il es† entendu que, lorsqu’un intervalle es† donné, il inclut les bornes supérieure e† inférieure dudit intervalle. De même, lors d’une référence à un composé, elle inclut toute forme pharmaceufiquemen† acceptable e† notamment les isomères, les sels, les solvatés e† les polymorphes. En particulier si un composé présente une activité optique, le composé référencé inclura le mélange racémique des différents isomères. Brève description des dessins In this description, unless it is specified otherwise, it is understood that, when a given interval is given, it includes the upper and lower bounds of said interval. Likewise, when referring to a compound, it includes any acceptable form of pharmaceutical formulation including isomers, salts, solvates and polymorphs. In particular if a compound has optical activity, the referenced compound will include the racemic mixture of the different isomers. Brief description of the drawings
L’invention e† les avantages qui en découlent seront mieux compris à la lecture de la description e† des modes de réalisation non limitatifs qui suivent, illustrés au regard des dessins annexés dans lesquels :  The invention and the advantages which result therefrom will be better understood on reading the description and of the nonlimiting embodiments which follow, illustrated with reference to the appended drawings in which:
La Figure 1 représente les résultats de pénétration de différentes compositions comprenant l’actif Brimonidine Tartrafe à travers des membranes d’épiderme humain (ng/cm2). FIG. 1 represents the penetration results of different compositions comprising the active ingredient Brimonidine Tartrafe through membranes of human epidermis (ng / cm 2 ).
La Figure 2 représente les résultats de pénétration de différentes compositions comprenant l’actif Brimonidine Tartrafe à travers des membranes d’épiderme humain (ng/cm2). FIG. 2 represents the results of penetration of different compositions comprising the active ingredient Brimonidine Tartrafe through membranes of human epidermis (ng / cm 2 ).
La Figure 3 représente les résultats de pénétration de différentes compositions comprenant l’actif Brimonidine Tartrafe à travers des membranes d’épiderme humain (ng/cm2). FIG. 3 represents the results of penetration of different compositions comprising the active ingredient Brimonidine Tartrafe through membranes of human epidermis (ng / cm 2 ).
Description des modes de réalisation  Description of the embodiments
L’invention concerne une nouvelle composition pharmaceutique sous forme d’une émulsion huile dans eau (Fl/E).  The invention relates to a new pharmaceutical composition in the form of an oil-in-water emulsion (Fl / E).
Une émulsion es† le mélange de deux liquides non miscibles sous l'effet d'une agitation mécanique formant un système dispersé. Cette dispersion subsiste tant que dure l'agitation mais dès que cette dernière cesse, il y a coalescence des globules e† les liquides se séparent.  An emulsion is the mixture of two immiscible liquids under the effect of mechanical agitation forming a dispersed system. This dispersion remains as long as the agitation lasts, but as soon as the latter ceases, there is coalescence of the globules and the liquids separate.
La formulation d'une émulsion vise à apporter au mélange le ou les produits qui vont permettre ou faciliter la stabilisation du système. Ce ou ces produits sont donc essentiels à la formulation e† à la conservation en termes de stabilité physico-chimique d'une émulsion ; ils sont appelés émulsifiants, surfactants, émulgateurs, agents mouillants ou encore tensioactifs. Les tensioactifs doivent être incorporés en une quantité relativement importante pouvant aller jusqu'à 20% en poids du poids total de l'émulsion pour obtenir une stabilité adéquate à la température et dans le temps. The formulation of an emulsion aims to bring to the mixture the product or products which will allow or facilitate the stabilization of the system. This or these products are therefore essential to the formulation and to the conservation in terms of physicochemical stability of an emulsion; they are called emulsifiers, surfactants, emulsifiers, wetting agents or even surfactants. The surfactants must be incorporated in a relatively large amount which can be up to 20% by weight of the total weight of the emulsion in order to obtain adequate stability at temperature and over time.
Or les tensioactifs son† connus pour leur caractère irritant, ce qui limite fortement leur utilisation dans les domaines pharmaceutiques et notamment dermatologiques. However, the surfactants are known for their irritant nature, which greatly limits their use in the pharmaceutical and especially dermatological fields.
De telles compositions sous forme d’émulsion n’apparaissen† ainsi pas être, prima fade, adaptées au traitement de pathologies dermatologiques telles que notamment la rosacée.  Such compositions in the form of an emulsion do not appear, therefore, to be prima fade, suitable for the treatment of dermatological pathologies such as in particular rosacea.
En effet, des effets indésirables liés à l'utilisation de tensioactifs son† observés dans le cadre d'applications dermiques, en particulier des effets allergisants, des irritations cutanées (visage, corps, cuir chevelu), ces effets pouvant se révéler particulièrement gênants pour des peaux sèches et/ou sensibles.  Indeed, undesirable effects linked to the use of sound surfactants † observed in the context of dermal applications, in particular allergenic effects, skin irritations (face, body, scalp), these effects being able to prove to be particularly troublesome for dry and / or sensitive skin.
Ce problème est d'autan† plus important lorsque l'émulsion est très riche en huile puisqu'il est nécessaire d'augmenter de la même façon la proportion de tensioactif de façon à stabiliser la composition et éviter son déphasage. This problem is all the more important when the emulsion is very rich in oil since it is necessary to increase the proportion of surfactant in the same way so as to stabilize the composition and avoid its phase shift.
La composition objet de l’invention comprend de la brimonidine, ses sels ou ses dérivés à une concentration avantageusement comprise entre 0,01 % et 5% en poids du poids total de la composition (p/p). The composition which is the subject of the invention comprises brimonidine, its salts or its derivatives at a concentration advantageously between 0.01% and 5% by weight of the total weight of the composition (w / w).
Par sels ou selfs) pharmaceutiquemen† acceptable(s), on entend les sels d'un composé d'intérêt qui son† sûrs et efficaces pour une utilisation topique chez des mammifères et qui possèdent une activité biologique souhaitée. Les sels pharmaceutiquemen† acceptables comprennent des sels de groupes acides ou basiques présents dans les composés spécifiés. Les sels d'addition acide pharmaceutiquemen† acceptables comprennent, mais ne son† pas limités à, des sels de chlorhydrate, bromhydrate, iodhydrate, nitrate, sulfate, bisulfate, phosphate, phosphate acide, isonicotinate, acétate, lactate, salicylate, citrate, tartrate, pantothénate, bitartrate, ascorbate, succinate, maléate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, méthanesulfonate, éthanesulfonate, benzènesulfonate, ptoluènesulfonate e† le pamoate (c'est- à-dire le 1 ,1 '-méthylène-bis-(2-hydroxy-3-naphtoate)). Certains composés utilisés dans la présente invention peuvent former des sels pharmaceufiquement acceptables avec différents acides aminés. Des sels de base adaptés comprennent, mais ne sont pas limités à, des sels d'aluminium, calcium, lithium, magnésium, potassium, sodium, zinc, et diéfhanolamine. Pour une revue sur les sels pharmaceufiquement acceptables, voir BERGE ET AL, 66 J. PHARM. SCI. 1 -19 (1977). Dans le présent contexte, le terme « hydrate » désigne un composé d'intérêt, ou un sel pharmaceufiquement acceptable de celui-ci qui comprend en outre une quantité stoechiométrique ou non stoechiométrique d'eau liée à celui-ci par des forces intermoléculaires non covalentes. By pharmaceutically acceptable salts or selfs, it is meant the salts of a compound of interest which are safe and effective for topical use in mammals and which have a desired biological activity. Pharmaceutically acceptable salts † include salts of acidic or basic groups present in the specified compounds. Pharmaceutically acceptable acid addition salts † include, but are not limited to, hydrochloride, hydrobromide, iodhydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate salts , pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, ptoluenesulfonate and pamoate (i.e., 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)). Certain compounds used in the present invention can form pharmacologically acceptable salts with different amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diehanolamine salts. For a review of pharmacologically acceptable salts, see BERGE ET AL, 66 J. PHARM. SCI. 1-19 (1977). In the present context, the term “hydrate” designates a compound of interest, or a pharmacologically acceptable salt thereof which additionally comprises a stoichiometric or non-stoichiometric amount of water linked to it by non-covalent intermolecular forces .
De préférence, la brimonidine utilisée dans les compositions selon l’invention es† le tartrate de brimonidine.  Preferably, the brimonidine used in the compositions according to the invention is † brimonidine tartrate.
La concentration de brimonidine, ses sels ou ses dérivés dans la composition es† préférentiellement comprise entre 0,01 % e† 1 % en poids du poids total de la composition (p/p), préférentiellement entre 0,05% e† 0,5% p/p. The concentration of brimonidine, its salts or its derivatives in the composition is preferably between 0.01% and † 1% by weight of the total weight of the composition (w / w), preferably between 0.05% and † 0, 5% w / w.
Alternativement, la concentration de brimonidine, ses sels ou ses dérivés dans la composition es† exactement de 0,01 %, 0,02%, 0,03%, 0,06% ou 0,09% p/p, préférentiellement 0,33% ou 0,66% p/p.  Alternatively, the concentration of brimonidine, its salts or its derivatives in the composition is exactly 0.01%, 0.02%, 0.03%, 0.06% or 0.09% w / w, preferably 0, 33% or 0.66% w / w.
Comme il ressort notamment des figures 1 , 2 e† 3, la pénétration cutanée de la brimonidine des compositions objet de l’invention es† améliorée par rapport aux compositions témoins. Ainsi, il devient possible e† envisageable de limiter la concentration en actif contenue dans la composition. Ceci présente l’avantage de diminuer l’irritation de la composition e† d’en augmenter sa stabilité. As is apparent in particular from FIGS. 1, 2 e † 3, the skin penetration of brimonidine of the compositions object of the invention is improved compared to the control compositions. Thus, it becomes possible and conceivable to limit the concentration of active ingredient contained in the composition. This has the advantage of reducing the irritation of the composition and of increasing its stability.
Avec une concentration en principe actif inférieure à 0,5%, ladite composition pharmaceutique diminue les risques de toxicité liés à son application topique. La composition objet de l’invention se présente sous une forme topique notamment adaptée à son lieu d’administration (peau, cuir chevelu, cheveux, etc.), préférentiellement les lésions cutanées. La composition se présente sous forme d’une émulsion huile-dans-eau (H/E) comportant une phase grasse et une phase aqueuse. With a concentration of active ingredient of less than 0.5%, said pharmaceutical composition reduces the risks of toxicity linked to its topical application. The composition which is the subject of the invention is in a topical form in particular adapted to its place of administration (skin, scalp, hair, etc.), preferably skin lesions. The composition is in the form of an oil-in-water (O / W) emulsion comprising a fatty phase and an aqueous phase.
Selon l'invention, la phase grasse représente au moins 10% en poids du poids total de la composition (p/p). De préférence, phase grasse représentant entre 10% et 60% en poids du poids total de la composition (p/p). De préférence encore, la phase grasse représente entre 15% et 50% en poids du poids total de la composition (p/p). En effet, pour une telle gamme de proportion de phase grasse, on observe un bon compromis entre une émulsion stable contenant suffisamment de phase grasse pour une application en dermatologie (notamment pour les peaux sèches) et une bonne tolérance tissulaire.  According to the invention, the fatty phase represents at least 10% by weight of the total weight of the composition (w / w). Preferably, fatty phase representing between 10% and 60% by weight of the total weight of the composition (w / w). More preferably, the fatty phase represents between 15% and 50% by weight of the total weight of the composition (w / w). Indeed, for such a range of fatty phase proportion, there is a good compromise between a stable emulsion containing enough fatty phase for application in dermatology (especially for dry skin) and good tissue tolerance.
Plus préférentiellement encore, la phase grasse représente entre 20% et 30% p/p. Even more preferably, the fatty phase represents between 20% and 30% w / w.
De préférence, la phase grasse es† exempte de tensioactif.  Preferably, the fatty phase is free of surfactant.
En effet, la faible quantité de tensioactif présent dans la phase aqueuse suffi† à assurer la stabilité de l'émulsion e† la composition ainsi obtenue es† bien tolérée e† non irritante. L'ajout d'un tensioactif supplémentaire dans la phase grasse es† optionnelle mais n'apporte a priori rien en termes d'amélioration de la stabilité de l'émulsion. In fact, the small amount of surfactant present in the aqueous phase is sufficient to ensure the stability of the emulsion and the composition thus obtained is well tolerated and non-irritant. The addition of an additional surfactant in the fatty phase is optional but does not a priori bring anything in terms of improving the stability of the emulsion.
Avantageusement, la phase grasse représente au plus 60% en poids du poids total de la composition. En effet, au-dessus de cette valeur, il y a un risque de déphasage de l'émulsion pouvant intervenir quelques jours après la fabrication de l'émulsion, ce risque augmentant, pour une proportion donnée de tensioactifs, lorsque la proportion de phase grasse augmente au-delà de 60% en poids par rapport au poids total de l'émulsion. Advantageously, the fatty phase represents at most 60% by weight of the total weight of the composition. Indeed, above this value, there is a risk of phase shift of the emulsion which can occur a few days after the manufacture of the emulsion, this risk increasing, for a given proportion of surfactants, when the proportion of fatty phase increases beyond 60% by weight relative to the total weight of the emulsion.
De préférence encore, la phase grasse représente environ 15% à 50% en poids du poids total du véhicule. La phase grasse de la composition selon l'invention peut contenir une ou plusieurs huiles choisies parmi les huiles végétales, les huiles minérales, les huiles siliconées, les huiles de synthèse et les huiles fluorées. More preferably, the fatty phase represents approximately 15% to 50% by weight of the total weight of the vehicle. The fatty phase of the composition according to the invention may contain one or more oils chosen from vegetable oils, mineral oils, silicone oils, synthetic oils and fluorinated oils.
A titre d'huile de synthèse utilisable selon la présente invention, on peu† notamment citer : As synthetic oil which can be used according to the present invention, there may be mentioned in particular:
• PRISORINE™ 3505 LQ (acide isostearique) ; • PRISORINE ™ 3505 LQ (isostearic acid);
• SCHERCEMOL™ DIA ESTER (Diisopropyl adipate) ;  • SCHERCEMOL ™ DIA ESTER (Diisopropyl adipate);
• CRODAMOL™ IPIS (Isopropyl isostearate) ; • CRODAMOL ™ IPIS (Isopropyl isostearate);
• CRODAMOL™ IPM (Isopropyl myristate) ;  • CRODAMOL ™ IPM (Isopropyl myristate);
· SCHERCEMOL™ 1688 (Cetearyl ethyl hexanoate) ;  · SCHERCEMOL ™ 1688 (Cetearyl ethyl hexanoate);
• CERAPHYL™ 41 (Cl 2-15 Alkyl lactacte) ; • CERAPHYL ™ 41 (Cl 2-15 Alkyl lactacte);
• CERAPHYL™ 31 (Lauryl lactate) ;  • CERAPHYL ™ 31 (Lauryl lactate);
• CRODAMOL™ ML (Myristyl lactate) ; • CRODAMOL ™ ML (Myristyl lactate);
• KOLLICREAM™ DO (Decyl oleate) ; · CRODAMOL™ OO (oleyl oleate) ;  • KOLLICREAM ™ DO (Decyl oleate); CRODAMOL ™ OO (oleyl oleate);
• LIPO™ PGO-3 (polyglyceryl-3 oleate) ;  • LIPO ™ PGO-3 (polyglyceryl-3 oleate);
• ARLAMOL™ PSI 1 E-LQ (PPG-1 1 Stearyl ether);  • ARLAMOL ™ PSI 1 E-LQ (PPG-1 1 Stearyl ether);
• SILKLFLO™ 366 (polyisodecene hydrogéné) ; • SILKLFLO ™ 366 (hydrogenated polyisodecene);
• MARCOL™ 52 (huile minérale) ;  • MARCOL ™ 52 (mineral oil);
· MARCOL™ 82 (huile minérale) ;  · MARCOL ™ 82 (mineral oil);
• PRIMOL™ 352 (huile minérale) ;  • PRIMOL ™ 352 (mineral oil);
• PARLEAM™ (polyisobutene hydrogéné) ; • PARLEAM ™ (hydrogenated polyisobutene);
• SQUALANE™ PE (Squalane) ;  • SQUALANE ™ PE (Squalane);
• e† préférentiellement CRODAMOL IPP (palmitate d’isopropyl), le CRODAMOL DA-LQ (diisopropyl adipate), l’ARLAMOL PS 15 E (PPG-15 stearyl ether), la PRISORINE 3515-LQ (Isostearyl alcohol), le CRODAMOL AB-LQ (Cl 2-15 alkyl benzoate, le CRODAMOL EO-LQ (Ethyl oleate) vendu par la société CRODA, le LABRAFIL Ml 944 CS (Aprcot kernel oil PEG-6 esters), le CAPRYOL 90 (propylene glycol monocaprylate) vendu par la société GATTEFOSSE, le KOLLICREAM OD (octyl dodecanol), le KOLLICREAM OA (oleyl alcohol), le KOLLICREAM 3C (Cocoyl caprylocaprate) vendu par la société BASF, l’ISOLAN GO 33 (polyglyceryl-3 oleate) vendu par la société EVONIK, le MIGLYOL 812 N (caprylic/capric triglycéride) vendu par la société CREMER OLEO. • e † preferably CRODAMOL IPP (isopropyl palmitate), CRODAMOL DA-LQ (diisopropyl adipate), ARLAMOL PS 15 E (PPG-15 stearyl ether), PRISORINE 3515-LQ (Isostearyl alcohol), CRODAMOL AB -LQ (Cl 2-15 alkyl benzoate, CRODAMOL EO-LQ (Ethyl oleate) sold by CRODA, LABRAFIL Ml 944 CS (Aprcot kernel oil PEG-6 esters), CAPRYOL 90 (propylene glycol monocaprylate) sold by GATTEFOSSE, KOLLICREAM OD (octyl dodecanol), KOLLICREAM OA (oleyl alcohol) , KOLLICREAM 3C (Cocoyl caprylocaprate) sold by BASF, ISOLAN GO 33 (polyglyceryl-3 oleate) sold by EVONIK, MIGLYOL 812 N (caprylic / capric triglyceride) sold by CREMER OLEO.
Comme huiles végétales utilisables selon l'invention, on peut citer les huiles de jojoba, avocat, sésame, tournesol, maïs, soja, carthame, pépins de raisin, olive, amande douce, ricin, moringa, coco, palme, bourrache, colza, germe de blé, lin, onagre, argon, calendula et coton, et préférentiellement G HUILE DE TOURNESOL RAFFINE ET WINTERISEE ( helianthus aannuus (sunflower) seed oil) vendue par la société OLVEA e† G HUILE D’AMANDE DOUCE RAFFINEE ( prunus amygdalus dulcis (sweet almond) oil). As vegetable oils which can be used according to the invention, mention may be made of jojoba, avocado, sesame, sunflower, corn, soybean, safflower, grape seed, olive, sweet almond, castor, moringa, coconut, palm, borage, rapeseed oils, wheat germ, flax, evening primrose, argon, calendula and cotton, and preferably G REFINED SUNFLOWER SUN OIL (helianthus aannuus (sunflower) seed oil) sold by the company OLVEA e † G REFINED SWEET ALMON OIL (prunus amygdalus dulcis (sweet almond) oil).
Comme huiles minérales utilisables selon l'invention, on peu† citer les huiles de paraffine, e† de préférence les huiles de paraffine liquide comme le PRIMOL 352 (minerai oil), le MARCOL 52 (minerai oil) vendues par la société EXXON MOBIL As mineral oils which can be used according to the invention, there may be mentioned paraffin oils, and preferably liquid paraffin oils such as PRIMOL 352 (ore oil), MARCOL 52 (ore oil) sold by the company EXXON MOBIL
Un taux de phase grasse important es† particulièrement intéressant pour les compositions dermatologiques destinées au soin des peaux sèches.  A significant fatty phase rate is particularly advantageous for dermatological compositions intended for the care of dry skin.
La phase aqueuse de l’émulsion huile dans eau (Fl/E) selon l’invention comprend au moins 0,01 % en poids du poids total de la composition (p/p) d’un tensioactif hydrosoluble qui es† un alcool polyvinylique (PVA) hydrosoluble, e† de manière préférée un alcool polyvinylique partiellement hydrolysé.  The aqueous phase of the oil-in-water (Fl / E) emulsion according to the invention comprises at least 0.01% by weight of the total weight of the composition (w / w) of a water-soluble surfactant which is a polyvinyl alcohol (PVA) water-soluble, e † preferably a partially hydrolyzed polyvinyl alcohol.
Le PVA es† connu pour ses fonctions d’agent filmogène ou de contrôle de la viscosité bien qu’il soi† peu utilisé en cosmétique e† dans le domaine pharmaceutique. C’est également un émulsifiant, ayant la capacité d’abaisser la tension superficielle de l’eau e† peu† donc être utilisé comme stabilisateur d’émulsion huile-eau. De préférence, la phase aqueuse comprend entre 0,05% et 0,5% en poids du poids total de la composition (p/p) d’alcool polyvinylique hydrosoluble (PVA). PVA is known for its functions as a film-forming agent or for controlling viscosity, although it is seldom used in cosmetics and in the pharmaceutical field. It is also an emulsifier, having the capacity to lower the surface tension of water and can be used as an oil-water emulsion stabilizer. Preferably, the aqueous phase comprises between 0.05% and 0.5% by weight of the total weight of the composition (w / w) water-soluble polyvinyl alcohol (PVA).
Plus préférentiellement encore, la concentration en PVA dans la composition est comprise entre 0,2% et 0,4% p/p, préférentiellement 0,2%, 0,225%, 0,25%, 0,275%, 0,325%, 0,35%, 0,375% et 0,4% p/p.  Even more preferably, the concentration of PVA in the composition is between 0.2% and 0.4% w / w, preferably 0.2%, 0.225%, 0.25%, 0.275%, 0.325%, 0.35 %, 0.375% and 0.4% w / w.
La composition selon l'invention peut en outre comprendre un ou plusieurs additifs compatibles, qui ne modifient pas les caractéristiques propres aux émulsions. A titre d’additifs compatibles avec un usage cosmétique et/ou dermatologique, on peut citer par exemple les agents gélifiants tel que le PEMULEN TR-1 (acrylate/C 10-30 alkyl acrylate crosspolymer), le PEMULEN TR-2 (acrylate/C 10-30 alkyl acrylate crosspolymer), le CARBOPOL 980 NF (carbomer) vendu par la société LUBRIZOL, le SIMULGEL 600 PHA (acrylamide/sodiumacryloyldimethyltaurate copolymer/isohexadecane/ polysorbate 80) vendu par la société SEPPIC, le SATIAXANE UCX 91 1 (xanthan gum), le SATIAGILNE US 171 E (alginate) vendu par la société CARGILL, le KLUCEL MF (hydroxypropyl cellulose), le BENECEL K 100 M (methylhydroxypropyl cellulose), le NATROSOL 250 HHX (hydroxyethylcellulose) vendu par la société ASHLAND, le ROQUETTE BEAUTY ST 30(aluminium starch) vendu par la société ROQUETTE, le VIVAPUR MCG (microcristalline cellulose) vendu par la société JRS, le NASHA POWDER COSMTICS vendu par la société Q-MED.  The composition according to the invention may also comprise one or more compatible additives, which do not modify the characteristics specific to the emulsions. Mention may be made, as additives compatible with cosmetic and / or dermatological use, of gelling agents such as PEMULEN TR-1 (acrylate / C 10-30 alkyl acrylate crosspolymer), PEMULEN TR-2 (acrylate / C 10-30 alkyl acrylate crosspolymer), CARBOPOL 980 NF (carbomer) sold by the company LUBRIZOL, SIMULGEL 600 PHA (acrylamide / sodiumacryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80) sold by SEPPIC, SATIAXANE UCX 91 1 (xanthan gum), SATIAGILNE US 171 E (alginate) sold by the company CARGILL, KLUCEL MF (hydroxypropyl cellulose), BENECEL K 100 M (methylhydroxypropyl cellulose), NATROSOL 250 HHX (hydroxyethylcellulose) sold by ASHLAND, ROQUETTE BEAUTY ST 30 (aluminum starch) sold by the company ROQUETTE, VIVAPUR MCG (microcrystalline cellulose) sold by the company JRS, NASHA POWDER COSMTICS sold by the company Q-MED.
A titre d'additifs compatibles avec un usage cosmétique et/ou dermatologique, on peut encore citer par exemple les agents conservateurs tels que le METHYL PARAHYDROXYBENZOATE (4-hydroxybenzoate de methyl) et le PROPYL PARAHYDROXYBENZOATE (propyl paraben) vendu par la société SHARON, le PHENOXETOL (phenoxyethanol) vendu par la société CLARIANT, les antioxydants, les isotonisants, les agents chélatants, les tampons, les polymères, les charges, les gélifiants hydrophiles ou lipophiles, les filtres hydrophiles, des composés hydrophiles tels que les alcools, les absorbeurs d'odeur, les humectants, et les émollients. Bien entendu, l'homme de l'art veillera à choisir le ou les éventuels adjuvants à ajouter aux compositions selon l'invention, ainsi que leur concentration, de manière que les propriétés avantageuses attachées intrinsèquement aux compositions conformes à l'invention ne soient pas, ou substantiellement pas altérées par l'addition envisagée. As additives compatible with cosmetic and / or dermatological use, mention may also be made, for example, of preservatives such as METHYL PARAHYDROXYBENZOATE (methyl 4-hydroxybenzoate) and PROPYL PARAHYDROXYBENZOATE (propyl paraben) sold by the company SHARON, PHENOXETOL (phenoxyethanol) sold by the company CLARIANT, antioxidants, isotonizers, chelating agents, buffers, polymers, fillers, hydrophilic or lipophilic gelling agents, hydrophilic filters, hydrophilic compounds such as alcohols, absorbers odor, humectants, and emollients. Of course, those skilled in the art will take care to choose the optional adjuvant (s) to be added to the compositions according to the invention, as well as their concentration, so that the advantageous properties intrinsically attached to the compositions according to the invention are not , or substantially unaffected by the proposed addition.
En particulier, ces adjuvants ne devront pas nuire aux propriétés de la composition selon l'invention, c'est-à-dire une bonne tolérance et l'absence d'irritabilité de la peau. In particular, these adjuvants should not harm the properties of the composition according to the invention, that is to say good tolerance and the absence of irritability of the skin.
Selon un mode avantageux de réalisation de l’invention, la composition comprend en outre un second principe actif qui est préférentiellement choisi parmi les antibiotiques, les agents anfibactériens, les anfiviraux, les anfiparasitaires, les antifongiques, les anesthésiques, les analgésiques, les antalgiques, les agents anfiallergiques, les anfi acnéiques, les antimitotiques, les antiprurigineux, les antihistaminiques, les immunosuppresseurs, les corficostéroïdes, les kératolytiques, les anti angiogéniques, les anti-inflammatoires don† les inhibiteurs de la phosphodiesterase 4, les anti-cancéreux, les anti-néoplasiques, les extraits naturels, les dérivés anthracéniques, les psoralènes, les anti prolifératifs (analogues de la vitamine D, ...), les anti-alopéciques (des analogues de la prostaglandine), les anti-herpétiques, les photosensibilisants, les dépigmentants, les hormones, les rétinoïdes, les vasoconstricteurs et/ou un mélange de ceux-ci.  According to an advantageous embodiment of the invention, the composition also comprises a second active principle which is preferably chosen from antibiotics, anfibacterial agents, anfivirals, anfiparasitics, antifungals, anesthetics, analgesics, analgesics, anfiallergic agents, acne anfi, antimitotics, antipruritics, antihistamines, immunosuppressants, corficosteroids, keratolytics, anti angiogenic agents, anti-inflammatory drugs don † phosphodiesterase 4 inhibitors, anti-cancer agents, anti -neoplastic, natural extracts, anthracene derivatives, psoralens, anti-proliferatives (analogues of vitamin D, ...), anti-alopecics (analogues of prostaglandin), anti-herpes, photosensitizers, depigmentants, hormones, retinoids, vasoconstrictors and / or a mixture thereof.
A titre d’exemple non limitatif d’ingrédient pharmaceutiquemen† actif utilisable selon l’invention, on peut citer comprend un deuxième principe actif choisi parmi l’acétaminophène, l’acide acétylsalicylique, l’acitrétine, l’acide azélaique, l’acyclovir, l’adapalène, l’alclometasone, l’alpha-tocophérol, l’amcinonide, l’amorolfine, l’amphotéricine B, la tétracycline, le peroxyde de benzoyle, la bétaméthasone, le calcipotriol, le calcitriol, le ciclopirox, la clindamycine, le crisaborole, le clobetasol, le crotamiton, la cyproheptadine, la dapsone, le desonide, le diclofénac, le diflucortolone, le difluprednate, le dioxyanthranol, l’econazole, l’efinaconazole, l’érythromycine, l’estradiol, l’étrétinate, l’acétonide de fluocinolone, le fluticasone, l’acide fusidique, la mometasone, l’acide glycolique, l’acide glycyrrhétinique, l’halobetasol, hydrocortisone, l’hydroquinone, l’ibuprofène, l’imiquimod, l’isotrétinoïne, l’ivermectine, le kétoconazole, l’acide kojique, l’acide lactique, la lidocaïne, l’acide malique, le mequinol, le méthoxsalène, le métronidazole, le miconazole, le minoxidil, l’octopirox, l’oxymetazoline, la pilocaine, la pyridoxine, la progestérone, le rétinol, le pimecrolimus, le resiquimod, le rucinol, le tacrolimus, le tazarotène, la terbinafine, la tétracaïne, la thenaldine, le travopost, la trétinoïne, la trimeprazine, le trifarotène, le pyrithione de zinc, ainsi que les sels ou dérivés de ces principes actifs, pris seul ou en mélange, préférentiellement le métronidazole ou l’ivermectine. By way of nonlimiting example of an active pharmaceutical ingredient that can be used according to the invention, mention may be made of a second active ingredient chosen from acetaminophen, acetylsalicylic acid, acitretin, azelaic acid, acyclovir , adapalene, alclometasone, alpha-tocopherol, amcinonide, amorolfine, amphotericin B, tetracycline, benzoyl peroxide, betamethasone, calcipotriol, calcitriol, ciclopirox, clindamycin , crisaborole, clobetasol, crotamiton, cyproheptadine, dapsone, desonide, diclofenac, diflucortolone, difluprednate, dioxyanthranol, econazole, efinaconazole, erythromycin, estradiol, etretinate , fluocinolone acetonide, fluticasone, fusidic acid, mometasone, glycolic acid, glycyrrhetinic acid, halobetasol, hydrocortisone, hydroquinone, ibuprofen, imiquimod, isotretinoin, ivermectin, ketoconazole, kojic acid, lactic acid , lidocaine, malic acid, mequinol, methoxsalene, metronidazole, miconazole, minoxidil, octopirox, oxymetazoline, pilocaine, pyridoxine, progesterone, retinol, pimecrolimus, resiquimod, rucinol, tacrolimus, tazarotene, terbinafine, tetracaine, thenaldine, travopost, tretinoin, trimeprazine, trifarotene, zinc pyrithione, as well as the salts or derivatives of these active substances, taken alone or in mixture, preferably metronidazole or ivermectin.
Comme il ressort de la figure 1 , le Demandeur a pu mettre en évidence que certains solvants permettaient d’obtenir des compositions particulièrement avantageuses. As can be seen from FIG. 1, the Applicant has been able to demonstrate that certain solvents make it possible to obtain particularly advantageous compositions.
Parmi les solvants testés et préférés, on peu† citer l’HEXYLENE GLYCOL USP/NF (hexylene glycol) vendu par la société PHARMACO-AAPER, le PROPANEDIOL-1 ,2 (propylene glycol) vendu par la société MERCK, la GLYCERINE 4810 VEGETALE (glycerol) vendu par la société OLEON le KOLLISOLV PEG 400 (polyethylene glycol) vendu par la société BASF ou encore le TRANSCUTOL HP (ethoxydiglycol)vendu par la société GATTEFOSSE, l’ETHANOL 96% VOL PH. EUR. (alcohol) vendu par la société CARGILL, le SR ARLASOLV DMI (dimethyl isosorbide) vendu par la société CRODA, le PROCIPIENT DMSO (dimethyl sulfoxide) vendu par la société GAYLORD CHEMICAL COMPAGNY. Plus préférentiellement, le solvant utilisé es† l’hexylène glycol. Among the solvents tested and preferred, there may be mentioned † HEXYLENE GLYCOL USP / NF (hexylene glycol) sold by the company PHARMACO-AAPER, PROPANEDIOL-1, 2 (propylene glycol) sold by the company MERCK, GLYCERINE 4810 VEGETALE (glycerol) sold by the company OLEON KOLLISOLV PEG 400 (polyethylene glycol) sold by the company BASF or else TRANSCUTOL HP (ethoxydiglycol) sold by the company GATTEFOSSE, ETHANOL 96% VOL PH. EUR. (alcohol) sold by CARGILL, SR ARLASOLV DMI (dimethyl isosorbide) sold by CRODA, PROCIPIENT DMSO (dimethyl sulfoxide) sold by GAYLORD CHEMICAL COMPAGNY. More preferably, the solvent used is † hexylene glycol.
Selon un mode de réalisation avantageux de l’invention, la composition pharmaceutique selon l’invention peu† contenir d’autres ingrédients supplémentaires comme un adjuvant, un anti-oxydant, un agent chélateur, un tensio-actif, un agent moussant, un agent mouillant, un agent émulsifiant, un viscosifiant, un agent tampon ou un conservateur.  According to an advantageous embodiment of the invention, the pharmaceutical composition according to the invention may contain other additional ingredients such as an adjuvant, an antioxidant, a chelating agent, a surfactant, a foaming agent, an agent wetting agent, an emulsifying agent, a viscosifier, a buffering agent or a preservative.
Selon un autre mode réalisation avantageux, la composition pharmaceutique selon l’invention peu† contenir un agent améliorant de la perméation ou de la pénétration. Par agent améliorant de la perméation ou la pénétration, on entend un composé permettant d’améliorer significativement la pénétration cutanée de l’ingrédient actif selon l’invention. According to another advantageous embodiment, the pharmaceutical composition according to the invention can contain a permeation or penetration improving agent. The term “permeation or penetration improving agent” means a compound which makes it possible to significantly improve the skin penetration of the active ingredient according to the invention.
A fifre d’exemple illustratif d’agent améliorateur de la perméation ou pénétration on peut citer l’acide oléique, l’alcool oléique, l’éthoxydiglycol, le laurocapram, l’acide alkanecarboxylique, le diméthylsulfoxide ou les lipides polaires ou le N-méthyl-2-pyrrolidone. As an example of an agent for improving permeation or penetration, there may be mentioned oleic acid, oleic alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acid, dimethylsulfoxide or polar lipids or N- methyl-2-pyrrolidone.
Selon un mode de réalisation avantageux, la composition pharmaceutique selon l’invention peut contenir un agent hydrotropique désorganisant la structure du stratum corneum et permettant ainsi d’augmenter davantage la pénétration à travers la couche superficielle de la peau.  According to an advantageous embodiment, the pharmaceutical composition according to the invention may contain a hydrotropic agent disorganizing the structure of the stratum corneum and thus making it possible to further increase the penetration through the surface layer of the skin.
A titre d’exemple illustratif d’agent hydrotropique on peut citer le xylène sulfonate de sodium l’alcool isopropylique, et préférentiellement le propylène glycol.  As an illustrative example of a hydrotropic agent, mention may be made of sodium xylene sulfonate isopropyl alcohol, and preferably propylene glycol.
L’invention a également pour objet une composition pharmaceutique selon l’invention, pour son utilisation dans le traitement et/ou la prévention des affections dermatologiques.  The invention also relates to a pharmaceutical composition according to the invention, for its use in the treatment and / or prevention of dermatological conditions.
Plus particulièrement, la composition pharmaceutique objet de l’invention est adaptée à une utilisation dans la prévention et/ou le traitement des affections dermatologiques notamment humaines, telles que définies ci- après :  More particularly, the pharmaceutical composition which is the subject of the invention is suitable for use in the prevention and / or treatment of dermatological conditions, in particular human, as defined below:
1 ) les lésions non cancéreuses comme la prolifération anormale de kératinocyte dans l’épiderme, les kératoses séborrhéiques, les infections au virus du papillome humain incluant la néoplasie vulvaire infraépithéliale, la néoplasie vaginale infraépithéliale, les verrues communes, le molluscum confagiosum ou les infections par le virus de l’herpès.  1) non-cancerous lesions such as abnormal proliferation of keratinocyte in the epidermis, seborrheic keratoses, infections of the human papilloma virus including vulva infraepithelial neoplasia, vaginal infraepithelial neoplasia, common warts, molluscum confagiosum or infections by the herpes virus.
2) les lésions pré-cancéreuses comme la kératose actinique, les lésions mélanocytaires jonctionnelles atypiques, l’hyperplasie mélanocytaire atypique, l’hyperplasie mélanocytaire intraépidermiques atypique ou la prolifération mélanocytaire intraépidermique atypique. 2) pre-cancerous lesions such as actinic keratosis, atypical junctional melanocytic lesions, melanocytic hyperplasia atypical, atypical intraepidermal melanocytic hyperplasia or atypical intraepidermal melanocytic proliferation.
3) les lésions cancéreuses comme le carcinome basocellulaire, le carcinome épidermoïde, la mélanose de Dubreuilh, le mélanome in situ, le mélanome, la maladie de Bowen, le carcinome épidermoïde in situ, la kératose arsenicale, la kératose par rayonnement, la kéfafose PUVA, la papulose Bowenoïde, le carcinome sébacé, le porocarcinome, la maladie de Page† extramammaire, le carcinome à cellules de Merkel, le sarcome de Kaposi ou le lymphome cutané à cellules T.  3) cancerous lesions such as basal cell carcinoma, squamous cell carcinoma, Dubreuilh melanosis, in situ melanoma, melanoma, Bowen's disease, in situ squamous cell carcinoma, arsenical keratosis, radiation keratosis, PUVA kefafosis , Bowenoid papulosis, sebaceous carcinoma, porocarcinoma, extramammary disease, Merkel cell carcinoma, Kaposi's sarcoma or cutaneous T-cell lymphoma.
De préférence, l’invention a pour objet une composition pharmaceutique telle que décrite ci-dessus, pour son utilisation pour la prévention et/ou le traitement des pathologies répondant à la brimonidinne telles que la rosacée. L’invention a encore pour objet un procédé de préparation d’une composition pharmaceutique selon l’invention, comprenant les étapes suivantes de : préparation, à une température supérieure à 40°C, d’une première phase aqueuse comprenant de l’alcool polyvinylique hydrosoluble (PVA), la brimonidine, ses sels ou ses dérivés, e† éventuellement un deuxième principe actif ; Preferably, the invention relates to a pharmaceutical composition as described above, for its use for the prevention and / or the treatment of pathologies responding to brimonidinne such as rosacea. The subject of the invention is also a process for preparing a pharmaceutical composition according to the invention, comprising the following steps of: preparation, at a temperature above 40 ° C., of a first aqueous phase comprising polyvinyl alcohol water-soluble (PVA), brimonidine, its salts or derivatives, e † optionally a second active ingredient;
préparation d’une phase grasse comprenant une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles siliconées, des huiles de synthèse e† des huiles fluorées e† éventuellement d’autres composés hydrophobes e† éventuellement un deuxième principe actif ;  preparation of an oily phase comprising an oil chosen from the group of mineral oils, vegetable oils, silicone oils, synthetic oils e † fluorinated oils e † possibly other hydrophobic compounds e † optionally a second active principle;
ajout, à température ambiante, de la phase grasse sur la première phase aqueuse ou inversement ;  adding, at room temperature, the fatty phase to the first aqueous phase or vice versa;
récupération d’un produit intermédiaire ;  recovery of an intermediate product;
préparation d’une phase aqueuse annexe comprenant de l’eau e† éventuellement des composés hydrophiles e† des gélifiants ;  preparation of an additional aqueous phase comprising water e † optionally hydrophilic compounds e † gelling agents;
insertion du produit intermédiaire dans la phase aqueuse annexe ; et récupération de la composition pharmaceutique ainsi obtenue.insertion of the intermediate product in the additional aqueous phase; and recovering the pharmaceutical composition thus obtained.
Enfin, l’invention a pour dernier objet un procédé de préparation d’une composition pharmaceutique selon l’invention, comprenant les étapes suivantes de : solubilisation, à une température supérieure à 40°C, d’alcool polyvinylique hydrosoluble (PVA) dans une phase aqueuse comprenant la brimonidine, ses sels ou ses dérivés et éventuellement un deuxième principe actif ; Finally, the last object of the invention is a process for preparing a pharmaceutical composition according to the invention, comprising the following steps of: solubilization, at a temperature above 40 ° C, of water-soluble polyvinyl alcohol (PVA) in a aqueous phase comprising brimonidine, its salts or its derivatives and optionally a second active principle;
refroidissement à température ambiante de ladite phase aqueuse ; préparation d’une phase grasse comprenant une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles siliconées, des huiles de synthèse et des huiles fluorées et éventuellement d’autres composés hydrophobes et un deuxième principe actif ;  cooling said aqueous phase to ambient temperature; preparation of a fatty phase comprising an oil chosen from the group of mineral oils, vegetable oils, silicone oils, synthetic oils and fluorinated oils and optionally other hydrophobic compounds and a second active principle;
ajout, à température ambiante, de la phase grasse sur la phase aqueuse ou inversement, avant ou après gélification de la phase aqueuse ; et  adding, at room temperature, the fatty phase to the aqueous phase or vice versa, before or after gelling of the aqueous phase; and
récupération de la composition pharmaceutique ainsi obtenue.  recovery of the pharmaceutical composition thus obtained.
Exemples Examples
La présente invention va maintenant être illustrée au moyen des exemples suivants :  The present invention will now be illustrated by means of the following examples:
Exemple 1 : Evaluation du profil de libération du principe actif BrimonidineEXAMPLE 1 Evaluation of the Release Profile of the Active Ingredient Brimonidine
Tartrate contenu dans des compositions selon l’invention. Tartrate contained in compositions according to the invention.
Le Demandeur a mis au point les formules A à K selon l’invention, don† les composants son† détaillés aux tableaux 1 , 2 et 3 ci-dessous. Tableau 1 : Formules A, B, C et D selon l’invention :  The Applicant has developed formulas A to K according to the invention, so † the components are † detailed in Tables 1, 2 and 3 below. Table 1: Formulas A, B, C and D according to the invention:
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000019_0001
Figure imgf000020_0001
Tableau 2 : Formules E, F, G et H selon l’invention :
Figure imgf000020_0002
Figure imgf000021_0001
Table 2: Formulas E, F, G and H according to the invention:
Figure imgf000020_0002
Figure imgf000021_0001
Tableau 3 : Formules I, J et K selon l’invention :
Figure imgf000021_0002
Figure imgf000022_0001
Table 3: Formulas I, J and K according to the invention:
Figure imgf000021_0002
Figure imgf000022_0001
Etudes supportives Ex-vivo : Ex-vivo supportive studies:
Deux études de libération pénétration cinétique ont été menées pour comparer le profil de libération de l’actif dans les différentes bases avec les différents additifs seul ou en association. Two kinetic penetration release studies were carried out to compare the release profile of the active ingredient in the different bases with the different additives alone or in combination.
Les formules son† évaluées en comparaison du gel de référence MIRVASO™ et d’un gel contenant une concentration plus faible de Brimonidine tartrate (0.1 %). The formulas are evaluated in comparison with the reference gel MIRVASO ™ and a gel containing a lower concentration of Brimonidine tartrate (0.1%).
Les études n°l et 2 utilisent un modèle spécifique d'IVSP basé sur l'épiderme séparé par la chaleur (HSE). Studies 1 and 2 use a specific IVSP model based on the heat separated epidermis (HSE).
Les résultats de la première étude son† repris aux figures 1 et 2.  The results of the first study are shown in Figures 1 and 2.
Les figures 1 et 2 représentent les résultats de pénétration de l’actif Brimonidine Tartrate à travers des membranes d’épiderme humain (ng/cm2) pour les formules A, C, D, E et F. Figures 1 and 2 show the results of penetration of the active ingredient Brimonidine Tartrate through human epidermis membranes (ng / cm 2 ) for formulas A, C, D, E and F.
De manière surprenante, les profils de libération des émulsions on† été modifiés par rapport à la référence MIRVASO Gel formulation 0,33% Gel. La formule A contenant de l’Hexylène gylcol libère beaucoup plus que la formule de référence. Surprisingly, the emulsion release profiles have been modified compared to the reference MIRVASO Gel formulation 0.33% Gel. Formula A containing Hexylene gylcol releases much more than the reference formula.
Les autres formulations C, D, E et F testées présentent des profils similaires à la référence avec une légère augmentation pour la formule contenant de l’acide hyaluronique réticulé.  The other formulations C, D, E and F tested have profiles similar to the reference with a slight increase for the formula containing crosslinked hyaluronic acid.
La figure 3 représente les résultats de pénétration de l’actif Brimonidine Tartrate à travers des membranes d’épiderme humain (ng/cm2) pour les formules B, G, H, I e† K. FIG. 3 represents the results of penetration of the active ingredient Brimonidine Tartrate through membranes of human epidermis (ng / cm 2 ) for the formulas B, G, H, I e † K.
L'émulsion de PVA de référence, formule B, représente un profil de libération similaire à celle du gel « low dose », Gel à 0,12% Brimonidine.  The reference PVA emulsion, formula B, represents a release profile similar to that of the “low dose” gel, 0.12% Brimonidine gel.
L’ajout de solvants tels que PEG400, ou propylene glycol + glycérine + PEG 400 permet d’améliorer le profil de libération. Adding solvents such as PEG400, or propylene glycol + glycerin + PEG 400 can improve the release profile.
La diminution de la concentration de l’actif combiné à l'ajout de 7% d’Hexylène glycol permet de légèrement augmenter la pénétration sans modifier le profil.  The decrease in the concentration of the active ingredient combined with the addition of 7% of Hexylene glycol makes it possible to slightly increase the penetration without modifying the profile.
Ainsi, les présents essais démontrent qu’on observe un effet positif des solvants sur la base PVA.  Thus, the present tests demonstrate that a positive effect of the solvents on the PVA base is observed.
Exemple 2 : Optimisation du procédé de préparation de la composition selon l’invention Example 2: Optimization of the process for preparing the composition according to the invention
La composition de la formule placébo (sans actif) es† reprise dans le tableau 4 ci-dessous.  The composition of the placebo formula (without active ingredient) is shown in Table 4 below.
Tableau 4 : Table 4:
Figure imgf000023_0001
i. Procédé classique de préparation d’une composition selon l’invention.
Figure imgf000023_0001
i. Conventional process for the preparation of a composition according to the invention.
Le procédé classique de fabrication reprend les étapes suivantes : une première phase aqueuse es† réalisée contenant de l’alcool polyvinylique partiellement hydrolysé solubilisé dans de l’eau àThe conventional manufacturing process involves the following steps: a first aqueous phase is carried out containing partially hydrolyzed polyvinyl alcohol dissolved in water at
85°C ; 85 ° C;
une phase grasse es† réalisée en parallèle contenant l’huile e† les composés hydrophobes ;  an oily phase es † carried out in parallel containing the oil and the hydrophobic compounds;
la phase grasse es† ensuite insérée à TA (température ambiante) dans la première phase aqueuse sous Ultra-Turrax pendant 90s avec augmentation de la vitesse d’une unité toutes les 15sec. Le produit intermédiaire résultant es† appelé pré-mix ;  the fatty phase is then inserted at RT (room temperature) in the first aqueous phase under Ultra-Turrax for 90s with increase in speed by one unit every 15sec. The resulting intermediate product is † called the premix;
une phase aqueuse annexe es† préparée contenant l’eau restante, les composés hydrophiles e† les gélifiants ; - le pré-mix es† alors inséré lentement dans ceffe phase aqueuse annexe e† le pH es† ajusté.  an annexed aqueous phase is † prepared containing the remaining water, hydrophilic compounds and gelling agents; - the pre-mix is † then slowly inserted into this annexed aqueous phase † the pH is † adjusted.
Ce procédé, facilement réalisable au laboratoire, préconise la mise en oeuvre de ratios décrit ainsi :  This process, easily carried out in the laboratory, recommends the implementation of ratios described as follows:
0,33 < (Eau + PVA) / phase huileuse < 1  0.33 <(Water + PVA) / oily phase <1
- 0,007 < %PVA / %huile < 0,02  - 0.007 <% PVA /% oil <0.02
- Phase aqueuse > phase huileuse  - Aqueous phase> oily phase
- 0,1 < % TA < 0,5 - 0.1 <% TA <0.5
10 < % huile < 60  10 <% oil <60
La caractérisation de la formule es† reprise dans le tableau 5 ci- dessous :  The characterization of the formula is shown in Table 5 below:
Tableau 5 :
Figure imgf000024_0001
Figure imgf000025_0001
Table 5:
Figure imgf000024_0001
Figure imgf000025_0001
La contrainte industrielle réside dans la quantité initiale mise en œuvre pour la fabrication de la pré-émulsion. Elle est insuffisante (12,875%) pour être réalisée dans la cuve principale de fabrication. Les systèmes d’agitation des cuves annexes ne son† pas assez puissants pour suffisamment cisailler le prémix. The industrial constraint lies in the initial quantity used for the manufacture of the pre-emulsion. It is insufficient (12.875%) to be carried out in the main manufacturing tank. Auxiliary tank agitation systems are not † powerful enough to sufficiently shear the premix.
La préparation d’une pré-émulsion vivement cisaillée représente une forte contrainte industrielle. Le procédé classique étant difficilement transposable, un nouveau procédé de fabrication a été mis au point.  The preparation of a strongly sheared pre-emulsion represents a strong industrial constraint. Since the conventional process is difficult to transpose, a new manufacturing process has been developed.
ii. Procédé amélioré de préparation d’une composition selon l’invention.  ii. Improved process for preparing a composition according to the invention.
L’idée est de s’affranchir de l’étape intermédiaire de pré-émulsion et de n’employer qu’une seule phase pour faciliter la production industrielle. The idea is to get rid of the intermediate pre-emulsion step and use only one phase to facilitate industrial production.
L’alcool polyvinylique est solubilisé à 85°C sous agitation, dans la quantité totale d’eau de la formule. Puis refroidi à température ambiante.  Polyvinyl alcohol is dissolved at 85 ° C with stirring, in the total amount of water in the formula. Then cooled to room temperature.
La phase grasse est ensuite ajoutée pour procéder à l’émulsification, avant ou après la gélification de la phase aqueuse.  The fatty phase is then added to carry out the emulsification, before or after the gelling of the aqueous phase.
Le pH est ajusté en fin de fabrication.  The pH is adjusted at the end of manufacturing.
Les procédés on† été évalués à différentes échelles : The processes have been evaluated on different scales:
- 400g au Rotor Stator  - 400g with Rotor Stator
1 ,5kg au Magic Plan†  1.5kg at the Magic Plan †
7 kg au Becomix  7 kg Becomix
La caractérisation et la stabilité de la formule obtenue selon ce procédé amélioré est reprise dans le tableau 6 ci-dessous : Tableau 6 : The characterization and stability of the formula obtained according to this improved process is shown in Table 6 below: Table 6:
Figure imgf000026_0001
Figure imgf000026_0001
Selon le type d’équipement utilisé, on notera une différence d’aspect microscopique (taille de globules plus ou moins importante) et de viscosité. Ces différences ne sont pas critiques et n’influent pas sur la stabilité du produit. Depending on the type of equipment used, there will be a difference in microscopic appearance (more or less large cell size) and viscosity. These differences are not critical and do not affect the stability of the product.
Conclusion  Conclusion
La proposition d’amélioration du procédé de fabrication de la composition selon l’invention permet une transposition à l’échelle industrielle.  The proposal to improve the process for manufacturing the composition according to the invention allows transposition to an industrial scale.
Il est important de maintenir un cisaillement important lors de l’étape d’émulsification.  It is important to maintain significant shear during the emulsification step.

Claims

REVENDICATIONS
1. Composition pharmaceutique sous une forme adaptée à une administration par voie topique comprenant à fifre de principe actif de la brimonidine, ses sels ou ses dérivés, caractérisée en ce qu 'elle se présente sous forme d’une émulsion huile-dans-eau (H/E) comportant : 1. Pharmaceutical composition in a form suitable for topical administration comprising fife of active ingredient brimonidine, its salts or its derivatives, characterized in that it is in the form of an oil-in-water emulsion ( M / E) comprising:
- une phase grasse représentant entre 10% et 60% en poids du poids total de la composition (p/p) ; et  - A fatty phase representing between 10% and 60% by weight of the total weight of the composition (w / w); and
- une phase aqueuse comprenant au moins 0,01% en poids du poids total de la composition (p/p) d’alcool polyvinylique hydrosoluble (PVA).  - An aqueous phase comprising at least 0.01% by weight of the total weight of the composition (w / w) of water-soluble polyvinyl alcohol (PVA).
2. Composition selon la revendication 1 , caractérisée en ce que le principe actif utilisé es† le tartrate de brimonidine. 2. Composition according to claim 1, characterized in that the active principle used is † brimonidine tartrate.
3. Composition selon l’une des revendications 1 ou 2, caractérisée en ce que la concentration du principe actif utilisé es† comprise entre 0,01 % e† 1%, en poids du poids total de la composition, préférentiellement entre 0,05% e† 0,5%. 3. Composition according to one of claims 1 or 2, characterized in that the concentration of the active principle used is † between 0.01% and † 1%, by weight of the total weight of the composition, preferably between 0.05 % e † 0.5%.
4. Composition selon l’une des revendications précédentes, caractérisée en ce qu’elle comprend un deuxième principe actif choisi parmi l’acétaminophène, l’acide acétylsalicylique, l’acitrétine, l’acide azélaique, l’acyclovir, l’adapalène, l’alclometasone, l’alpha-tocophérol, l’amcinonide, l’amorolfine, l’amphotéricine B, la tétracycline, le peroxyde de benzoyle, la bétaméthasone, le calcipotriol, le calcitriol, le ciclopirox, la clindamycine, le crisaborole, le clobetasol, le crotamiton, la cyproheptadine, la dapsone, le desonide, le diclofénac, le diflucortolone, le difluprednate, le dioxyanthranol, l’econazole, l’efinaconazole, l’érythromycine, l’estradiol, l’étrétinate, l’acétonide de fluocinolone, le fluticasone, l’acide fusidique, la mometasone, l’acide glycolique, l’acide glycyrrhétinique, l’halobetasol, l’ hydrocortisone, l’hydroquinone, l’ibuprofène, l’imiquimod, l’isotrétinoïne, l’ivermectine, le kétoconazole, l’acide kojique, l’acide lactique, la lidocaïne, l’acide malique, le mequinol, le méfhoxsalène, le métronidazole, le miconazole, le minoxidil, l’octopirox, l’oxymetazoline, la pilocaine, la pyridoxine, la progestérone, le rétinol, le pimecrolimus, le resiquimod, le rucinol, le tacrolimus, le tazarotène, la terbinafine, la tétracaïne, la thenaldine, le travopost, la trétinoïne, la trimeprazine, le trifarotène, le pyrithione de zinc, ainsi que les sels ou dérivés de ces principes actifs, pris seul ou en mélange, préférentiellement le métronidazole ou l’ivermectine. 4. Composition according to one of the preceding claims, characterized in that it comprises a second active principle chosen from acetaminophen, acetylsalicylic acid, acitretin, azelaic acid, acyclovir, adapalene, alclometasone, alpha-tocopherol, amcinonide, amorolfine, amphotericin B, tetracycline, benzoyl peroxide, betamethasone, calcipotriol, calcitriol, ciclopirox, clindamycin, crisaborole, clobetasol, crotamiton, cyproheptadine, dapsone, desonide, diclofenac, diflucortolone, difluprednate, dioxyanthranol, econazole, efinaconazole, erythromycin, estradiol, etretinate, acetonide fluocinolone, fluticasone, fusidic acid, mometasone, glycolic acid, glycyrrhetinic acid, halobetasol, hydrocortisone, hydroquinone, ibuprofen, imiquimod, isotretinoin, ivermectin , ketoconazole, kojic acid, lactic acid, lid ocaine, malic acid, mequinol, mehoxsalene, metronidazole, miconazole, minoxidil, octopirox, oxymetazoline, pilocaine, pyridoxine, progesterone, retinol, pimecrolimus, resiquimod, rucinol, tacrolimene, tazar terbinafine, tetracaine, thenaldine, travopost, tretinoin, trimeprazine, trifarotene, zinc pyrithione, as well as the salts or derivatives of these active ingredients, taken alone or as a mixture, preferably metronidazole or ivermectin .
5. Composition selon l’une des revendications précédentes, caractérisée en ce que la phase grasse représente entre 15% et 50% en poids du poids total de la composition, préférentiellement entre 20% et 30%. 5. Composition according to one of the preceding claims, characterized in that the fatty phase represents between 15% and 50% by weight of the total weight of the composition, preferably between 20% and 30%.
6. Composition selon l’une des revendications précédentes, caractérisée en ce que la phase grasse comprend au moins une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles siliconées, des huiles de synthèse et des huiles fluorées. 6. Composition according to one of the preceding claims, characterized in that the fatty phase comprises at least one oil chosen from the group of mineral oils, vegetable oils, silicone oils, synthetic oils and fluorinated oils.
7. Composition selon l’une des revendications précédentes, caractérisée en ce que la phase aqueuse comprend entre 0,05% et 0,5% en poids du poids total de la composition d’alcool polyvinylique hydrosoluble (PVA). 7. Composition according to one of the preceding claims, characterized in that the aqueous phase comprises between 0.05% and 0.5% by weight of the total weight of the composition of water-soluble polyvinyl alcohol (PVA).
8. Composition selon l’une des revendications précédentes, pour son utilisation dans la prévention ef/ou le traitement des affections dermatologiques notamment humaines, préférentiellement la rosacée. 8. Composition according to one of the preceding claims, for its use in the prevention and / or treatment of dermatological conditions, in particular human, preferably rosacea.
9. Procédé de préparation d’une composition selon l’une quelconque des revendications 1 à 8, comprenant les étapes suivantes de : 9. A method of preparing a composition according to any one of claims 1 to 8, comprising the following steps of:
- préparation, à une température supérieure à 40°C, d’une première phase aqueuse comprenant de l’alcool polyvinylique hydrosoluble (PVA), la brimonidine, ses sels ou ses dérivés, et éventuellement un deuxième principe actif ;  - preparation, at a temperature above 40 ° C, of a first aqueous phase comprising water-soluble polyvinyl alcohol (PVA), brimonidine, its salts or its derivatives, and optionally a second active principle;
- préparation d’une phase grasse comprenant une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles de synthèse et éventuellement d’autres composés hydrophobes et éventuellement un deuxième principe actif ; - preparation of a fatty phase comprising an oil chosen from the group of mineral oils, vegetable oils, synthesis and possibly other hydrophobic compounds and possibly a second active ingredient;
- ajout, à température ambiante, de la phase grasse sur la première phase aqueuse ou inversement ;  - addition, at room temperature, of the fatty phase on the first aqueous phase or vice versa;
- récupération d’un produit intermédiaire ;  - recovery of an intermediate product;
- préparation d’une phase aqueuse annexe comprenant de l’eau et éventuellement des composés hydrophiles et des gélifiants ;  - preparation of an additional aqueous phase comprising water and optionally hydrophilic compounds and gelling agents;
- insertion du produit intermédiaire dans la phase aqueuse annexe ; - insertion of the intermediate product in the additional aqueous phase;
- et récupération de la composition pharmaceutique ainsi obtenue. - And recovery of the pharmaceutical composition thus obtained.
10. Procédé de préparation d’une composition selon l’une quelconque des revendications 1 à 8, comprenant les étapes suivantes de : 10. A method of preparing a composition according to any one of claims 1 to 8, comprising the following steps of:
- solubilisation, à une température supérieure à 40°C, d’alcool polyvinylique hydrosoluble (PVA) dans une phase aqueuse comprenant la brimonidine, ses sels ou ses dérivés et éventuellement un deuxième principe actif ;  - solubilization, at a temperature above 40 ° C, of water-soluble polyvinyl alcohol (PVA) in an aqueous phase comprising brimonidine, its salts or its derivatives and optionally a second active principle;
- refroidissement à température ambiante de ladite phase aqueuse ; - cooling at room temperature of said aqueous phase;
- préparation d’une phase grasse comprenant une huile choisie dans le groupe des huiles minérales, des huiles végétales, des huiles de synthèse et éventuellement d’autres composés hydrophobes et un deuxième principe actif ; - preparation of a fatty phase comprising an oil chosen from the group of mineral oils, vegetable oils, synthetic oils and optionally other hydrophobic compounds and a second active principle;
- ajout, à température ambiante, de la phase grasse sur la phase aqueuse ou inversement, avant ou après gélification de la phase aqueuse ; et  - Adding, at room temperature, the fatty phase to the aqueous phase or vice versa, before or after gelling of the aqueous phase; and
- récupération de la composition pharmaceutique ainsi obtenue.  - recovery of the pharmaceutical composition thus obtained.
PCT/EP2019/076365 2018-09-28 2019-09-30 Pharmaceutical composition comprising brimonidine, and uses thereof WO2020065085A1 (en)

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CN1799545A (en) * 2005-01-07 2006-07-12 杨武 Compound ocular medicinal composition
US20120156244A1 (en) * 2008-08-01 2012-06-21 Alpha Synergy Development Inc. Nasal Compositions and Uses Thereof
US20120076738A1 (en) * 2010-09-28 2012-03-29 Michael Graeber Combination treatment for dermatological conditions
US20140205589A1 (en) * 2011-06-29 2014-07-24 Galderma Research & Development New stable anesthetic composition for reducing skin reactions
FR3041537A1 (en) 2015-09-29 2017-03-31 Galderma Res & Dev BRIMONIDINE CONTAINING CHEMICAL FOAM WITHOUT RINSE AND USE THEREOF FOR TREATING ROSACEA.

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