WO2018178596A1 - Composition containing nitrocellulose, a plasticiser, a volatile solvent and an active agent, uses thereof as a dressing - Google Patents

Composition containing nitrocellulose, a plasticiser, a volatile solvent and an active agent, uses thereof as a dressing Download PDF

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Publication number
WO2018178596A1
WO2018178596A1 PCT/FR2018/050798 FR2018050798W WO2018178596A1 WO 2018178596 A1 WO2018178596 A1 WO 2018178596A1 FR 2018050798 W FR2018050798 W FR 2018050798W WO 2018178596 A1 WO2018178596 A1 WO 2018178596A1
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Prior art keywords
film
agents
composition
forming
weight
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PCT/FR2018/050798
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French (fr)
Inventor
Claire-helene BRACHAIS
Odile CHAMBIN
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Urgo Recherche Innovation Et Developpement
Universite De Bourgogne
Institut National Superieur Des Sciences Agronomiques De L'alimentation Et De L'environnement
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Publication of WO2018178596A1 publication Critical patent/WO2018178596A1/en

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Classifications

    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C08L1/16—Esters of inorganic acids
    • C08L1/18—Cellulose nitrate, i.e. nitrocellulose

Definitions

  • the subject of the present invention is a film-forming liquid composition capable of forming a film on the skin, superficial body growths or mucous membranes enabling the controlled release of active (s).
  • the subject of the present invention is a film-forming liquid composition
  • a film-forming liquid composition comprising at least one film-forming nitrocellulose polymer, at least one plasticizer, at least one volatile solvent and at least one active ingredient.
  • the invention also relates to a process for obtaining a film from said liquid composition.
  • the invention also relates to the use of a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol to control the release of active (s) film obtained from such a liquid composition.
  • Wound healing is a natural biological phenomenon, with human and animal tissue capable of repairing localized lesions through their own repair and regeneration processes.
  • the inflammatory phase that begins following the trauma by the implementation of inflammatory and vascular phenomena, such as the formation of a blood clot composed among other fibrin, mediated by different cellular and molecular factors, and forming a temporary matrix called fibrinous tissue Or "yellow" fabric.
  • the granulation phase which is characterized by the arrival at the site of the wound fibroblasts and new endothelial cells necessary for the neovascularization of the damaged tissue. Once activated, the fibroblasts turn into myofibroblasts and thus participate in the maturation of the granulation tissue.
  • the epithelialization phase which is characterized by the reorganization of the extracellular matrix. For example, type 3 collagen is replaced by type 1 collagen. Most cells proliferate. These have an invasive behavior at first, like myofibroblasts, fibroblasts and endothelial cells, and then see their activity decrease significantly. This phase eventually leads to a remodeled scar, flexible and no longer causing pain in the frame however, a normal scar process of the wound. However, sometimes, at this stage, pathological scars appear due to poor completion of the final stages of healing.
  • the wound pharmaceutical active agents capable of intervening at different stages of healing, such as antibacterial agents, antiseptics, anti-inflammatories or painkillers, for example.
  • Application FR 2 956 322 proposes, for example, dressings comprising a compound chosen from the group consisting of polysulfated oligosaccharides having 1 to 4 monosaccharides, their salts or their derivatives, included in the coating or impregnation mass of the dressing, in order to to ensure effective bioavailability of the active ingredient on the patient's scar site.
  • the application FR 2 993 182 proposes a dressing comprising at least one micro-adherent interface, said microadherent interface comprising an active agent, said dressing having undergone treatment with ethylene oxide to allow significant release and extended active ingredient contained in the dressing.
  • the dressing-type systems comprising active principles that can be released in a controlled and progressive manner are generally complex structures comprising at least one support, an absorbent material, and a coated screen comprising the active ingredient.
  • these dressings can be rigid and uncomfortable for patients. They are therefore mainly reserved for the treatment of important wounds but less adapted to small wounds or cuts.
  • Dressings of film-forming types obtained from film-forming compositions intended to be applied, with or without an applicator, on tissues such as skin, superficial body growths (nails or hair), mucous membranes, have been developed.
  • the Applicant has therefore sought to develop a film-forming liquid dressing allowing controlled release, on the skin, integuments or mucous membranes, of the active ingredients it contains.
  • the product of the invention may be advantageously applied to an area of the skin having affections and for which release of active (s) is required.
  • the Applicant has discovered that the use of a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol in a film-forming composition based on nitrocellulose, a volatile solvent and at least one a particular active agent makes it possible to obtain a film in which the release of the asset is controlled.
  • a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol
  • a specific release profile will be obtained. Indeed, depending on the chosen active ingredient and the desired pharmacological action, preference will be given, depending on the case, a rapid release or, on the contrary, a gradual release. For example, when one wishes to treat pain, especially with anesthetic, a quick release of the asset will be preferred. To promote healing or relieve irritation, long-term release will be more appropriate.
  • the subject of the present invention is therefore a film-forming liquid composition intended to be applied to the skin, superficial body growths or mucous membranes comprising a film-forming nitrocellulose polymer, at least one plasticizer, at least one volatile solvent and at least one active agent selected from the group consisting of -bacterial, anti-viral, anti-fungal, anti-pain, anti-inflammatory, depigmenting agents, keratolytic agents, anesthetics, moisturizers, antidiabetics and vitamins.
  • Optimized active release profiles have been obtained, in the context of the present invention, by the implementation of a film based on nitrocellulose.
  • Other cellulose polymers such as, for example, hydroxypropylcellulose, whose properties of solubility in water and in organic solvents differ significantly from those of nitrocellulose, can not give the same profiles of release of assets taking into account of their biodegradable character.
  • composition according to the invention comprises at least one film-forming nitrocellulose polymer.
  • nitrocellulose is preferably chosen from nitrocelluloses of high viscosity, in particular nitrocellulose of quality between S 1/2 and RS 20 seconds according to the American standard which corresponds to a quality of between 8E and 21E according to the European standard.
  • nitrocellulose grade 10E or 11E is preferred according to the European standard corresponding to the quality RS 15 seconds according to the American standard.
  • the nitrocellulose may be chosen in particular from nitrocellulose RS 5 sec. and RS 15 sec. marketed by the company HERCULES, products DHL® 120/170, DHL® 25/45 or DHX® 40/70 marketed by Nobel Enterprises, nitrocellulose E 840® and E 620® produced by Wolff Cellulosics, and products marketed under the references E80®, E70®, E60® and E40® by SNPE-Bergerac.
  • the nitrocellulose may be provided in dry form or in solution in a solvent such as isopropanol or ethanol.
  • the film-forming nitrocellulose polymer in particular nitrocellulose, is present in the film-forming liquid composition according to the invention in a content ranging from 5% to 20% by dry weight, more preferably from 6% to 12% by dry weight relative to to the total weight of the composition.
  • the molecular weight Mn of the film-forming nitrocellulose polymer is advantageously between 60,000 and 80,000.
  • the composition according to the invention comprises at least one plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol.
  • the plasticizer is preferably present in the composition in a content ranging from 1% to 60% by dry weight, more preferably from 1% to 40% by dry weight relative to the total weight of the composition.
  • the volatile solvent chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol.
  • compositions of the invention also contain a volatile solvent, which solubilizes the film forming nitrocellulose polymer.
  • This solvent makes it possible to solubilize some or all of the ingredients of the composition and participates in the formation of a uniform film on the skin during the application of the composition, by virtue of its rapid evaporation.
  • volatile solvent means a solvent capable of evaporating rapidly on contact with the skin.
  • volatile solvent is understood to mean a compound which is liquid at ambient temperature (20 ° C.) and at atmospheric pressure and has a vapor pressure at 20 ° C. of greater than 20 mmHg and preferably of between 20 and 300 mmHg. more preferably between 30 and 200 mmHg. Water is excluded from this definition. Volatile solvents or volatile solvent mixtures having a boiling point above 50 ° C (at atmospheric pressure) are preferred.
  • ketones such as methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, isophorone, cyclohexanone, acetone;
  • alcohols such as ethanol, isopropanol, n-propanol, n-butanol, diacetone alcohol, 2-butoxyethanol, cyclohexanol;
  • esters such as ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, isopentyl acetate;
  • ethers such as diethyl ether, dimethyl ether or dichlorodiethyl ether;
  • the volatile solvent is advantageously chosen from ethanol, ethyl acetate and their mixtures.
  • the volatile solvent is a mixture of ethyl acetate and ethanol, preferably in mass proportions of between 1/1 and 3/1, preferably of order of 2/1.
  • the amount of volatile solvent is for example 60 to 90% by weight relative to the total weight of the composition, preferably 70 to 90% by weight relative to the total weight of the composition.
  • the film-forming liquid composition according to the invention is preferably anhydrous, that is to say substantially free of water. It preferably contains less than 2% by weight of water. Active (s)
  • composition according to the invention also comprises at least one active ingredient.
  • the active ingredient is preferably chosen from pharmaceutical active ingredients chosen from:
  • anti-bacterials such as polymyxin B, penicillins (amoxycillin), clavulanic acid, tetracyclines, minocycline, chlorotetracycline, aminoglycosides, amikacin, gentamicin, neomycin, silver and its salts (Sulfadiazine argentic), probiotics;
  • anti-virals such as Acyclovir, Famciclovir, Itonavir;
  • antifungal agents such as polyenes, Nystatin, Amphotericin B, Natamycin, imidazoles (Miconazole, Ketoconazole, Clotrimazole, Ecconazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Thiabendazole, Tioconazole) triazoles (Fluconazole, Itraconazole, Ravuconazole, Posaconazole, Voriconazole), allylamines, Terbinafine, Amorolfine, Naftifine, Butenafine; Flucytosine (antimetabolite), Griseofulvin, Caspofungin, Micafungin;
  • anti-pain agents such as paracetamol, codeine, dextropropoxyphene, tramadol, morphine and its derivatives, corticosteroids and derivatives;
  • anti-inflammatories such as glucocorticoids, nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, ketoprofen, flurbiprofen, diclofenac, aceclofenac, ketorolac, meloxicam, piroxicam, tenoxicam, Naproxen, Indomethacin, Naproxcinod, Nimesulide, Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib, Phenylbutazone, Niflumic acid, Mefenamic acid, Beta-18-glycyrrhetinic acid;
  • depigmenting agents such as kojic acid (Kojic Acid SL®-Quimasso (Sino Lion)), Arbutin (Olevatin® - Quimasso (Sino Lion)), the mixture of palmitoylpropyl of sodium and white water lily extract (Sepicalm® - Seppic), undecylenoyl phenylalanine (Sepiwhite® - Seppic), licorice extract obtained by fermentation of Aspergillus and ethoxydiglycol (Gatuline Whitening® - Gattefossé), octadecenedioic acid (ODA White®
  • keratolytic agents such as salicylic acid, zinc salicylate, ascorbic acid, alpha hydroxylated acids (glycolic acid, lactic acid, malic acid, citric acid, tartaric acid), extracts of silver maple, Griottier, tamarind urea, topical retinoid Keratoline® (Sederma), proteases obtained by fermentation of Bacillus Subtilis, the product Linked-Papain® (SACI-CFPA), papain (proteolytic enzyme from papaya fruit);
  • SACI-CFPA the product Linked-Papain®
  • papain proteolytic enzyme from papaya fruit
  • Restructuring assets for example, resuscitators of dander
  • resuscitators of dander such as silica derivatives, vitamin E, chamomile, calcium, horsetail extract, silk ester lip;
  • anesthetics such as benzocaine, lidocaine, dibucaine, pramoxine hydrochloride, bupivacaine, mepivacaine, prilocaine, etidocaine,
  • moisturizing agents such as glycerine
  • antidiabetic agents such as metformin
  • the active agent (s) is (are) present in the composition according to the invention in a content ranging, for example, from 0.01% to 50% by weight relative to the total weight of the composition, advantageously from 0.1% to 20% by weight. % by weight relative to the total weight of the composition.
  • composition according to the invention may also contain flavors or bitterness agents (such as denatonium benzoate), perfumes, or preservatives.
  • flavors or bitterness agents such as denatonium benzoate
  • perfumes such as denatonium benzoate
  • preservatives such as denatonium benzoate
  • an auxiliary film-forming agent may advantageously be added.
  • the auxiliary film-forming agent is, of course, different from the organic solvent present in the film-forming liquid composition according to the invention.
  • Such an auxiliary film-forming agent may be chosen from all the compounds known to those skilled in the art, as being capable of fulfilling the desired function, and in particular be chosen from plasticizers other than castor oil, polyethylene glycol, dibutyl sebacate and glyceryl tributyrate, and the coalescing agents of the film-forming polymer (s).
  • the composition may further comprise at least one other plasticizer and / or a coalescing agent.
  • fatty alcohols such as octyldodecanol, 2-butyloctanol, 2-hexyl decanol, 2-undecylpentadecanol, oleyl alcohol;
  • fatty acids such as oleic acid, linoleic acid, linolenic acid;
  • glycol esters such as triacetin (or glyceryl triacetate);
  • propylene glycol derivatives and in particular propylene glycol phenyl ether, propylene glycol diacetate, dipropylene glycol ethyl ether, tripropylene glycol methyl ether, propylene glycol butyl ether;
  • esters of acids especially carboxylic acids, such as citrates, phthalates, adipates, carbonates, tartrates, phosphates,
  • oxyethylenated derivatives such as oxyethylenated oils, especially vegetable oils, such as sesame oil, castor oil, almond oil, canola oil, hazelnut oil, Pistachio oil, linseed oil, borage oil, hemp oil, jojoba oil, sunflower oil, wheat germ oil, corn oil and / or corn germ, peanut oil, avocado oil, safflower oil, rapeseed oil, olive oil, argan oil, sunflower oil , grape seed oil, soybean oil, walnut oil, pumpkin seed oil, palm oil, coconut oil, and mixtures thereof.
  • the oil can also be a derivative of one of the vegetable oils mentioned above. It may be hydrogenated oil or not, peroxidized or not.
  • auxiliary film-forming agent may range from 0.5 to 15% by weight, and in particular from 1 to 10% by weight relative to the total weight of the composition.
  • composition according to the invention may comprise, in addition to the nitrocellulose previously described, a secondary film-forming polymer.
  • film-forming polymers that can be used in the composition of the present invention, mention may be made of synthetic polymers, of free radical type or of polycondensate type, polymers of natural origin, and mixtures thereof.
  • the film-forming polymer may be chosen in particular from polyurethanes, acrylic polymers, vinyl polymers, polyvinylbutyrals, alkyd resins, resins derived from aldehyde condensation products, such as arylsulfonamide formaldehyde resins such as toluene sulfonamide formaldehyde resin, epoxy arylsulfonamide resins or ethyl tosylamide resins, the copolymer of polyvinyl methyl ether and maleic anhydride (PVM / MA).
  • toluene sulfonamide formaldehyde resin "Ketjentflex MS80" from the company Akzo or “Santolite MHP”, “Santolite MS 80” from the company Fonsonnier or “Resimpol 80” from the company PAN AMERICANA, the alkyd resin “BECKOSOL ODE 230-70-E” from the company DAINIPPON, the acrylic resin “ACRYLOID B66" of the company ROHM & HAAS, the polyurethane resin "TRIXENE PR 4127" from the company BAXENDEN.
  • the secondary film-forming polymer may be present in the composition according to the invention in a solids content ranging from 1 to 15% by weight, preferably ranging from 1 to 10% by weight, relative to the total weight of the composition.
  • composition according to the present invention is in the form of a liquid intended to be applied using a suitable applicator, such as a brush or a palette.
  • compositions according to the present invention are intended to be applied to wounds or scars, whether they are related to an accident, a disease or the consequences of a surgical procedure, or burns. These compositions can also be applied to all skin conditions. Examples include acne, chickenpox, shingles, rosacea, first-degree burns, eczema, hyperpigmentation, lucite, vitiligo, xerosis, porphyria, stretch marks, psoriasis, insect bites.
  • the invention therefore relates to the composition as defined above for its use in the protection of burns, in particular light burns, superficial skin wounds, or scars.
  • the compositions according to the invention are also useful for the treatment of ampoules, cracks, or crevices.
  • the composition according to the present invention can also be applied to wounds not totally healed provided that they are not oozing and that they have been previously decontaminated.
  • the invention also relates to the use of a composition as defined above for the preparation of a dressing intended to protect burns, superficial skin wounds or scars. Preparation of a film
  • the subject of the invention is a process for obtaining a film from a film-forming composition as described above, characterized in that:
  • composition as described above is applied to the tissues such as the skin, the superficial body growths or the mucous membranes so as to form a uniform liquid film,
  • the thickness of the films obtained is for example greater than 500 nm, preferably between 1 and 300 ⁇ , more preferably between 2 and 200 ⁇ .
  • the invention also relates to a film that can be obtained from such a process.
  • the subject of the invention is the use of a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol, preferably chosen from glyceryl tributyrate and polyethylene.
  • glycol preferably polyethylene glycol to control the release of active (s) a film obtained from the previously described composition.
  • the subject of the invention is the use of polyethylene glycol, dibutyl sebacate and glyceryl tributyrate for controlling the release of active substance (s) from the film obtained from the composition comprising
  • At least one nitrocellulose film-forming polymer present in the composition in a solids content ranging from 5% to 20% by weight, preferably ranging from 6% to 15% by weight, relative to the total weight of the composition, and
  • At least one active agent chosen from anti-bacterials, anti-virals, anti-fungals, painkillers, anti-inflammatories, depigmenting agents, keratolytic agents, anesthetics, moisturizing agents, antidiabetics and vitamins.
  • Ingredients 2 to 5 are mixed with stirring at 700 rpm for 10 minutes with a propeller stirrer.
  • the nitrocellulose is then dispersed in the mixture with stirring, and the mixture is stirred successively for 20 minutes at 1100 rpm and for 30 minutes at 2000 rpm.
  • the films were prepared by pouring into a petri dish. The boxes are then placed for about 1 hour in an oven previously thermostated at 32 ° C for drying the film.
  • ⁇ fixed molar extinction coefficient for a molecule that depends on the wavelength.
  • L tank length (1cm).
  • the equation of the calibration line thus obtained for salicylic acid was used to determine its concentration during the kinetics of release. From these concentrations are determined the amount of salicylic acid per mg of film then the% released relative to the amount of salicylic acid used for the manufacture of these films.
  • the absorbances of the salicylic acid-free films were determined in order to compare them with the films containing it. They are very low ( ⁇ 0.01) and will therefore be neglected in the calculations.
  • Example 1 31.61+ 5.73 44.13 + 9.44 57.7 + 10.4 80.5 ⁇ 17.2
  • Example 4 37.48 ⁇ 0.68 46.01 ⁇ 0.78 68.4 + 1.2 84.0 + 1.4
  • Example 6 Example 7
  • Example 8 Example 9 According to the invention According to the invention According to the invention According to the invention According to the invention According to the invention According to the invention According to the invention
  • Ingredients 2-4 are mixed with stirring at 700 rpm for 10 minutes with a propeller stirrer.
  • the nitrocellulose is then dispersed in the mixture with stirring, and the mixture is stirred successively for 20 minutes at 1100 revolutions / min then 30 minutes at 2000 rev / min and finally 700 rev / min 60 minutes.
  • metformin is added after being dissolved in the amount of distilled water prescribed. The new mixture is stirred at 700 rpm for 120 minutes.
  • the films were prepared by pouring into a petri dish. The petri dishes are then placed, for 1 night, in an oven previously thermostated at 32 ° C for drying the film.
  • the release properties of metformin from the films at 3.7% plasticizer and 0.8% metformin were determined by means of a small vane dissolution apparatus (VanKel VK 6010) in physiological saline ( 100 ml) at a fixed temperature of 37 ° C, with an average rotation of 50 rpm.
  • VanKel VK 6010 a small vane dissolution apparatus
  • ⁇ fixed molar extinction coefficient for a molecule that depends on the wavelength.
  • L tank length (1cm).
  • PEG will preferably be used as plasticizer for intermediate release, glyceryl tributyrate and dibutyl sebacate, castor for a gradual release.

Abstract

The present invention relates to a film-forming liquid composition which can form a film on the skin, skin appendages or mucous membranes, allowing the controlled release of one or more active agents. In particular, the present invention relates to a film-forming liquid composition comprising at least one film-forming nitrocellulose polymer, at least one plasticiser, at least one volatile solvent and at least one active agent selected from among anti-bacterial agents, anti-viral agents, anti-fungal agents, painkillers, anti-inflammatories, depigmentation agents, keratolytic agents, anaesthetics, moisturising agents, anti-diabetic agents, and vitamins. The invention also relates to a method for producing a film from said liquid composition. The invention further relates to the use of a plasticiser selected from among castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol in order to control the release of active agent(s) from the film obtained from such a liquid composition.

Description

COMPOSITION CONTENANT DE LA NITROCELLULOSE, UN PLASTIFIANT, UN SOLVANT VOLATIL ET UN ACTIF, SES UTILISATIONS COMME PANSEMENT  COMPOSITION COMPRISING NITROCELLULOSE, PLASTIFIANT, VOLATILE SOLVENT AND ACTIVE INGREDIENT, ITS USES AS DRESSING
La présente invention a pour objet une composition liquide filmogène apte à former un film sur la peau, les phanères ou les muqueuses permettant la libération contrôlée d'actif(s). The subject of the present invention is a film-forming liquid composition capable of forming a film on the skin, superficial body growths or mucous membranes enabling the controlled release of active (s).
En particulier, la présente invention a pour objet une composition liquide filmogène comprenant au moins un polymère filmogène de nitrocellulose, au moins un plastifiant, au moins un solvant volatil et au moins un actif. L'invention a également pour objet un procédé d'obtention d'un film à partir de ladite composition liquide. L'invention se rapporte également à l'utilisation d'un plastifiant choisi parmi l'huile de ricin, le dibutyl sébacate, le glycéryl tributyrate et le polyéthylène glycol pour contrôler la libération d'actif(s) du film obtenu à partir d'une telle composition liquide. La cicatrisation d'une plaie est un phénomène biologique naturel, les tissus humains et animaux étant capables de réparer des lésions localisées par des processus de réparation et de régénération qui leur sont propres. In particular, the subject of the present invention is a film-forming liquid composition comprising at least one film-forming nitrocellulose polymer, at least one plasticizer, at least one volatile solvent and at least one active ingredient. The invention also relates to a process for obtaining a film from said liquid composition. The invention also relates to the use of a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol to control the release of active (s) film obtained from such a liquid composition. Wound healing is a natural biological phenomenon, with human and animal tissue capable of repairing localized lesions through their own repair and regeneration processes.
La cicatrisation naturelle d'une plaie se déroule principalement selon 3 phases successives possédant chacune une activité cellulaire et moléculaire propre. Ainsi, il est retrouvé successivement :  The natural healing of a wound occurs mainly in 3 successive phases each having a specific cellular and molecular activity. Thus, it is found successively:
La phase inflammatoire qui débute consécutivement au traumatisme par la mise en œuvre de phénomènes inflammatoires et vasculaires, telle la formation d'un caillot sanguin composé entre autres de fibrine, médiée par différents facteurs cellulaires et moléculaires, et formant une matrice provisoire appelée tissu « fibrineux » ou tissu «jaune ».  The inflammatory phase that begins following the trauma by the implementation of inflammatory and vascular phenomena, such as the formation of a blood clot composed among other fibrin, mediated by different cellular and molecular factors, and forming a temporary matrix called fibrinous tissue Or "yellow" fabric.
La phase de granulation qui est caractérisée par l'arrivée sur le site de la blessure des fibroblastes et de nouvelles cellules endothéliales nécessaires à la néovascularisation du tissu lésé. Une fois activés, les fibroblastes se transforment en myofibroblastes et participent ainsi à la maturation du tissu de granulation. The granulation phase which is characterized by the arrival at the site of the wound fibroblasts and new endothelial cells necessary for the neovascularization of the damaged tissue. Once activated, the fibroblasts turn into myofibroblasts and thus participate in the maturation of the granulation tissue.
La phase d'épithélialisation qui est caractérisée par la réorganisation de la matrice extra- cellulaire. Par exemple, le collagène de type 3 est remplacé par le collagène de type 1. On observe une prolifération de la plupart des cellules. Celles-ci ont un comportement invasif dans un premier temps, type les myofibroblastes, les fibroblastes et les cellules endothéliales, puis voient leur activité diminuer sensiblement. Cette phase permet d'aboutir à terme à une cicatrice remodelée, souple et ne provoquant plus de ressenti douloureux, dans le cadre toutefois d'un processus cicatriciel normal de la plaie. Il arrive cependant parfois qu'à cette étape des cicatrices pathologiques apparaissent, dues à une mauvaise réalisation des étapes terminales de la cicatrisation. The epithelialization phase which is characterized by the reorganization of the extracellular matrix. For example, type 3 collagen is replaced by type 1 collagen. Most cells proliferate. These have an invasive behavior at first, like myofibroblasts, fibroblasts and endothelial cells, and then see their activity decrease significantly. This phase eventually leads to a remodeled scar, flexible and no longer causing pain in the frame however, a normal scar process of the wound. However, sometimes, at this stage, pathological scars appear due to poor completion of the final stages of healing.
Pour favoriser la cicatrisation, il peut être avantageux de délivrer sur la plaie des actifs pharmaceutiques susceptibles d'intervenir à différents stades de la cicatrisation, tels de des agents antibactériens, des antiseptiques, des anti-inflammatoires ou des anti-douleurs par exemple.  To promote healing, it may be advantageous to deliver on the wound pharmaceutical active agents capable of intervening at different stages of healing, such as antibacterial agents, antiseptics, anti-inflammatories or painkillers, for example.
Différents systèmes ont été développés pour permettre le relargage contrôlé d'actifs. La demande FR 2 956 322 propose par exemple des pansements comprenant un composé choisi parmi le groupe constitué des oligosaccharides polysulfatés possédant de 1 à 4 oses, leurs sels ou leurs dérivés, compris dans la masse d'enduction ou d'imprégnation du pansement, afin de garantir une biodisponibilité efficace du principe actif sur le site cicatriciel du patient.  Different systems have been developed to allow the controlled release of assets. Application FR 2 956 322 proposes, for example, dressings comprising a compound chosen from the group consisting of polysulfated oligosaccharides having 1 to 4 monosaccharides, their salts or their derivatives, included in the coating or impregnation mass of the dressing, in order to to ensure effective bioavailability of the active ingredient on the patient's scar site.
La demande FR 2 993 182 propose quant à elle un pansement comprenant au moins une interface micro-adhérente, ladite interface micro-adhérente comprenant un actif, ledit pansement ayant subi un traitement par de l'oxyde d'éthylène pour permettre un relargage important et prolongé du principe actif contenu dans le pansement. The application FR 2 993 182 proposes a dressing comprising at least one micro-adherent interface, said microadherent interface comprising an active agent, said dressing having undergone treatment with ethylene oxide to allow significant release and extended active ingredient contained in the dressing.
Toutefois, les systèmes de type pansements comprenant des principes actifs susceptibles d'être libérés de manière contrôlée et progressive sont généralement des structures complexes comprenant au moins un support, un matériau absorbant, et une trame enduite comprenant le principe actif. Lorsque leur structure est très complexe, ces pansements peuvent s'avérer rigides et peu confortables pour les patients. Ils sont donc principalement réservés au traitement de plaies importantes mais moins adaptés aux petites plaies ou coupures.  However, the dressing-type systems comprising active principles that can be released in a controlled and progressive manner are generally complex structures comprising at least one support, an absorbent material, and a coated screen comprising the active ingredient. When their structure is very complex, these dressings can be rigid and uncomfortable for patients. They are therefore mainly reserved for the treatment of important wounds but less adapted to small wounds or cuts.
Pour les affections de la peau, comme par exemple les plaies de petites dimensions et superficielles, les crevasses, les cicatrices, les piqûres d'insectes, etc .. les pansements de types filmogènes, obtenus à partir de compositions filmogènes destinées à être appliquées, avec ou sans applicateur, sur des tissus tels que la peau, les phanères (les ongles ou les cheveux), les muqueuses, ont été développés. For skin conditions, such as small and superficial wounds, crevices, scars, insect bites, etc .. Dressings of film-forming types, obtained from film-forming compositions intended to be applied, with or without an applicator, on tissues such as skin, superficial body growths (nails or hair), mucous membranes, have been developed.
Ils sont généralement liquides à l'application et contiennent classiquement un polymère filmogène dissous dans un solvant volatil, typiquement de l'eau ou un alcool. L'évaporation du solvant permet alors la formation d'un film solide protecteur. Les polymères mis en œuvre pour la fabrication de ces films doivent être choisis de manière à ne pas être biodégradables au contact de l'eau de manière à assurer leur intégrité au contact des exsudais. Des polymères solubles dans l'eau tels que l'hydroxypropylcellulose sont donc à proscrire pour ces usages. Le document US 2007/004835 décrit par exemple un pansement liquide pour petites plaies ou petites coupures, dans lequel il est proposé de remplacer une partie des solvants irritants pour la peau (utilisés de façon classique dans les pansements liquides) par des alcanes volatils. Un des exemples proposés contient 3,85% en poids de nitrocellulose et 2% d'huile de ricin. Ce document mentionne que la quantité de nitrocellulose peut varier de 3 à 7% en poids sec. Les films obtenus sont toutefois trop fins pour protéger correctement les plaies. Les compositions ne sont ainsi pas adaptées pour véhiculer efficacement et libérer de manière contrôlée des actifs sur la plaie. Les documents de l'art antérieur identifiés ne décrivent pas comment contrôler ou moduler la libération d'actifs contenus dans des compositions filmogènes. They are generally liquid on application and typically contain a film-forming polymer dissolved in a volatile solvent, typically water or an alcohol. Evaporation of the solvent then allows the formation of a protective solid film. The polymers used for the manufacture of these films must be chosen so as not to be biodegradable in contact with water so as to ensure their integrity in contact with the exudates. Water-soluble polymers such as hydroxypropylcellulose should therefore be banned for these uses. Document US 2007/004835 for example describes a liquid dressing for small wounds or small cuts, in which it is proposed to replace some of the irritating solvents for the skin (conventionally used in liquid dressings) with volatile alkanes. One of the proposed examples contains 3.85% by weight of nitrocellulose and 2% of castor oil. This document mentions that the amount of nitrocellulose can vary from 3 to 7% by dry weight. The films obtained, however, are too thin to properly protect wounds. The compositions are thus not adapted to efficiently convey and release in a controlled manner active ingredients on the wound. The documents of the prior art identified do not describe how to control or modulate the release of assets contained in film-forming compositions.
Il existe donc un besoin pour des compositions filmogènes non cytotoxiques, capables de former in situ et rapidement des films homogènes et souples, permettant la libération contrôlée d'actif(s) sur la zone à traiter.  There is therefore a need for non-cytotoxic film-forming compositions capable of forming in situ and rapidly homogeneous and flexible films, allowing the controlled release of active (s) on the area to be treated.
La Demanderesse a donc cherché à développer un pansement liquide filmogène permettant une libération contrôlée, sur la peau, les phanères ou les muqueuses, des actifs qu'il contient. Le produit de l'invention peut être avantageusement appliqué sur une zone de la peau présentant des affections et pour laquelle une libération d'actif(s) est requise. The Applicant has therefore sought to develop a film-forming liquid dressing allowing controlled release, on the skin, integuments or mucous membranes, of the active ingredients it contains. The product of the invention may be advantageously applied to an area of the skin having affections and for which release of active (s) is required.
La Demanderesse a découvert que l'utilisation d'un plastifiant choisi parmi l'huile de ricin, le dibutyl sébacate, le glycéryl tributyrate et le polyéthylène glycol dans une composition filmogène à base de nitrocellulose, d'un solvant volatil et d'au moins un actif particulier permet d'obtenir un film dans lequel la libération de l'actif est contrôlée. The Applicant has discovered that the use of a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol in a film-forming composition based on nitrocellulose, a volatile solvent and at least one a particular active agent makes it possible to obtain a film in which the release of the asset is controlled.
En fonction du plastifiant choisi, on obtiendra un profil de libération déterminé. En effet, en fonction de l'actif choisi et de l'action pharmacologique désirée, on préférera, selon le cas une libération rapide ou au contraire, une libération progressive. Par exemple, lorsque l'on souhaite traiter la douleur, notamment avec un anesthésiant, une libération rapide de l'actif sera privilégiée. Pour favoriser la cicatrisation ou soulager une irritation, une libération sur le long terme se révélera plus appropriée. Depending on the chosen plasticizer, a specific release profile will be obtained. Indeed, depending on the chosen active ingredient and the desired pharmacological action, preference will be given, depending on the case, a rapid release or, on the contrary, a gradual release. For example, when one wishes to treat pain, especially with anesthetic, a quick release of the asset will be preferred. To promote healing or relieve irritation, long-term release will be more appropriate.
La présente invention a donc pour objet une composition liquide filmogène destinée à être appliquée sur la peau, les phanères ou les muqueuses comprenant un polymère filmogène de nitrocellulose, au moins un plastifiant, au moins un solvant volatil et au moins un actif choisi parmi les anti-bactériens, les anti-viraux, les anti-fongiques, les anti-douleurs, les antiinflammatoires, les agents dépigmentants, les agents kératolytiques, les anesthésiques, les agents hydratants, les antidiabétiques et les vitamines. Les profils de libération d'actifs optimisés ont été obtenus, dans le cadre de la présente invention, par la mise en œuvre d'un film à base de nitrocellulose. D'autres polymères de cellulose, tels que par exemple l'hydroxypropylcellulose, dont les propriétés de solubilité à l'eau et dans les solvants organiques diffèrent significativement de celles de la nitrocellulose, ne sauraient donner les mêmes profils de libération d'actifs compte tenu de leur caractère biodégradable. The subject of the present invention is therefore a film-forming liquid composition intended to be applied to the skin, superficial body growths or mucous membranes comprising a film-forming nitrocellulose polymer, at least one plasticizer, at least one volatile solvent and at least one active agent selected from the group consisting of -bacterial, anti-viral, anti-fungal, anti-pain, anti-inflammatory, depigmenting agents, keratolytic agents, anesthetics, moisturizers, antidiabetics and vitamins. Optimized active release profiles have been obtained, in the context of the present invention, by the implementation of a film based on nitrocellulose. Other cellulose polymers, such as, for example, hydroxypropylcellulose, whose properties of solubility in water and in organic solvents differ significantly from those of nitrocellulose, can not give the same profiles of release of assets taking into account of their biodegradable character.
Polymère filmogène de nitrocellulose Nitrocellulose film forming polymer
La composition selon l'invention comprend au moins un polymère filmogène de nitrocellulose.  The composition according to the invention comprises at least one film-forming nitrocellulose polymer.
En effet, les compositions à base de nitrocellulose permettent d'obtenir des films protecteurs, résistant à l'eau et qui présentent une bonne tenue dans le temps. La nitrocellulose est de préférence choisie parmi les nitrocelluloses de viscosité élevée, notamment les nitrocelluloses de qualité comprise entre S 1/2 et RS 20 secondes selon la norme américaine qui correspond à une qualité comprise entre 8E et 21E selon la norme européenne. On préfère par exemple la nitrocellulose de qualité 10E ou 11E selon la norme européenne correspondant à la qualité RS 15 secondes selon la norme américaine.  Indeed, the compositions based on nitrocellulose make it possible to obtain protective films that are water-resistant and have good durability over time. The nitrocellulose is preferably chosen from nitrocelluloses of high viscosity, in particular nitrocellulose of quality between S 1/2 and RS 20 seconds according to the American standard which corresponds to a quality of between 8E and 21E according to the European standard. For example, nitrocellulose grade 10E or 11E is preferred according to the European standard corresponding to the quality RS 15 seconds according to the American standard.
La nitrocellulose peut être choisie notamment parmi les nitrocelluloses RS 5 sec. et RS 15 sec. commercialisées par la société HERCULES, les produits DHL® 120/170, DHL® 25/45 ou DHX® 40/70 commercialisés par Nobel Entreprises, les nitrocelluloses E 840® et E 620® produites par Wolff Cellulosics, et les produits commercialisés sous les références E80®, E70®, E60® et E40® par SNPE-Bergerac.  The nitrocellulose may be chosen in particular from nitrocellulose RS 5 sec. and RS 15 sec. marketed by the company HERCULES, products DHL® 120/170, DHL® 25/45 or DHX® 40/70 marketed by Nobel Enterprises, nitrocellulose E 840® and E 620® produced by Wolff Cellulosics, and products marketed under the references E80®, E70®, E60® and E40® by SNPE-Bergerac.
La nitrocellulose peut être fournie sous forme sèche ou en solution dans un solvant tel que l'isopropanol ou l'éthanol.  The nitrocellulose may be provided in dry form or in solution in a solvent such as isopropanol or ethanol.
Le polymère filmogène de nitrocellulose, en particulier la nitrocellulose, est présent dans la composition liquide filmogène selon l'invention en une teneur allant de 5% à 20 % en poids sec, de préférence encore de 6% à 12 % en poids sec par rapport au poids total de la composition. The film-forming nitrocellulose polymer, in particular nitrocellulose, is present in the film-forming liquid composition according to the invention in a content ranging from 5% to 20% by dry weight, more preferably from 6% to 12% by dry weight relative to to the total weight of the composition.
La masse moléculaire Mn du polymère filmogène de nitrocellulose est avantageusement comprise entre 60 000 et 80 000.  The molecular weight Mn of the film-forming nitrocellulose polymer is advantageously between 60,000 and 80,000.
Le plastifiant The plasticizer
La composition selon l'invention comprend au moins un plastifiant choisi parmi l'huile de ricin, le dibutyl sébacate, le glycéryl tributyrate et le polyéthylène glycol. Le plastifiant est, de préférence, présent dans la composition en une teneur allant de 1% à 60% en poids sec, de préférence encore de 1% à 40 % en poids sec par rapport au poids total de la composition. Le solvant volatil The composition according to the invention comprises at least one plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol. The plasticizer is preferably present in the composition in a content ranging from 1% to 60% by dry weight, more preferably from 1% to 40% by dry weight relative to the total weight of the composition. The volatile solvent
Les compositions de l'invention contiennent également un solvant volatil, qui solubilise le polymère filmogène de nitrocellulose. Ce solvant permet de solubiliser une partie ou la totalité des ingrédients de la composition et participe à la formation d'un film uniforme sur la peau lors de l'application de la composition, de par son évaporation rapide.  The compositions of the invention also contain a volatile solvent, which solubilizes the film forming nitrocellulose polymer. This solvent makes it possible to solubilize some or all of the ingredients of the composition and participates in the formation of a uniform film on the skin during the application of the composition, by virtue of its rapid evaporation.
Dans le cadre de la présente invention, on entend par solvant volatil un solvant capable de s'évaporer rapidement au contact de la peau. En particulier, on entend par solvant volatil, un composé liquide à la température ambiante (20 °C) et à la pression atmosphérique présentant une pression de vapeur à 20 °C supérieure à 20 mmHg et de préférence comprise entre 20 et 300 mmHg, encore plus préférentiellement entre 30 et 200 mmHg. L'eau est exclue de cette définition. On préfère les solvants volatils ou les mélanges de solvant volatils dont la température d'ébullition est supérieure à 50°C (à pression atmosphérique). In the context of the present invention, the term "volatile solvent" means a solvent capable of evaporating rapidly on contact with the skin. In particular, volatile solvent is understood to mean a compound which is liquid at ambient temperature (20 ° C.) and at atmospheric pressure and has a vapor pressure at 20 ° C. of greater than 20 mmHg and preferably of between 20 and 300 mmHg. more preferably between 30 and 200 mmHg. Water is excluded from this definition. Volatile solvents or volatile solvent mixtures having a boiling point above 50 ° C (at atmospheric pressure) are preferred.
Comme solvant volatil utilisable dans le cadre de la présente invention, on peut citer : As volatile solvent that can be used in the context of the present invention, mention may be made of:
- les cétones telles que la méthyléthylcétone, la méthylisobutylcétone, la diisobutylcétone, l'isophorone, la cyclohexanone, l'acétone;  ketones such as methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, isophorone, cyclohexanone, acetone;
- les alcools tels que l'éthanol, l'isopropanol, le n-propanol, le n-butanol, le diacétone alcool, le 2-butoxyéthanol, le cyclohexanol; alcohols such as ethanol, isopropanol, n-propanol, n-butanol, diacetone alcohol, 2-butoxyethanol, cyclohexanol;
- les esters tels que l'acétate d'éthyle, l'acétate de méthyle, l'acétate de propyle, l'acétate de n- butyle, l'acétate d'isopentyle;  esters such as ethyl acetate, methyl acetate, propyl acetate, n-butyl acetate, isopentyl acetate;
- les éthers tels que le diéthyléther, le diméthyléther ou le dichlorodiéthyléther;  ethers such as diethyl ether, dimethyl ether or dichlorodiethyl ether;
et leurs mélanges. and their mixtures.
Le solvant volatil est choisi avantageusement parmi l'éthanol, l'acétate d'éthyle et leurs mélanges. Selon un mode de mise en œuvre particulier de l'invention, le solvant volatil est un mélange d'acétate d'éthyle et d'éthanol, préférentiellement dans des proportions massiques comprises entre 1/1 et 3/1, de préférence de l'ordre de 2/1.  The volatile solvent is advantageously chosen from ethanol, ethyl acetate and their mixtures. According to one particular embodiment of the invention, the volatile solvent is a mixture of ethyl acetate and ethanol, preferably in mass proportions of between 1/1 and 3/1, preferably of order of 2/1.
La quantité de solvant volatil représente par exemple de 60 à 90 % en poids par rapport au poids total de la composition, avantageusement de 70 à 90 % en poids par rapport au poids total de la composition. The amount of volatile solvent is for example 60 to 90% by weight relative to the total weight of the composition, preferably 70 to 90% by weight relative to the total weight of the composition.
La composition liquide filmogène selon l'invention est de préférence anhydre, c'est-à-dire essentiellement exempte d'eau. Elle en contient, de préférence, moins de 2% en poids d'eau. Actif(s) The film-forming liquid composition according to the invention is preferably anhydrous, that is to say substantially free of water. It preferably contains less than 2% by weight of water. Active (s)
La composition selon l'invention comprend également au moins un actif.  The composition according to the invention also comprises at least one active ingredient.
L'actif est de préférence choisi parmi les actifs pharmaceutiques choisis parmi : The active ingredient is preferably chosen from pharmaceutical active ingredients chosen from:
- les anti-bactériens tels que le Polymyxine B, les pénicillines (Amoxycilline), l'acide clavulanique, les tétracyclines, la Minocycline, la chlorotétracycline, les aminoglycosides, l'Amikacine, la Gentamicine, la Néomycine, l'argent et ses sels (Sulfadiazine argentique), les probiotiques ; anti-bacterials such as polymyxin B, penicillins (amoxycillin), clavulanic acid, tetracyclines, minocycline, chlorotetracycline, aminoglycosides, amikacin, gentamicin, neomycin, silver and its salts (Sulfadiazine argentic), probiotics;
- les anti-viraux tels que l'Acyclovir, le Famciclovir, le itonavir ;  anti-virals such as Acyclovir, Famciclovir, Itonavir;
- les anti-fongiques tels que les polyènes, le Nystatin, l'Amphotéricine B, la Natamycine, les imidazolés (Miconazole, Ketoconazole, Clotrimazole, Éconazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Thiabendazole, Tioconazole), les triazolés (Fluconazole, Itraconazole, Ravuconazole, Posaconazole, Voriconazole), les allylamines, la Terbinafine, l'Amorolfine, la Naftifine, la Buténafine ; - la Flucytosine (antimétabolite), la Griséofulvine, la Caspofungine, la Micafungine ; antifungal agents such as polyenes, Nystatin, Amphotericin B, Natamycin, imidazoles (Miconazole, Ketoconazole, Clotrimazole, Ecconazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Thiabendazole, Tioconazole) triazoles (Fluconazole, Itraconazole, Ravuconazole, Posaconazole, Voriconazole), allylamines, Terbinafine, Amorolfine, Naftifine, Butenafine; Flucytosine (antimetabolite), Griseofulvin, Caspofungin, Micafungin;
- les anti-douleurs tels que le Paracétamol, la Codéine, le Dextropropoxyphène, le Tramadol, la Morphine et ses dérivés, les Corticoïdes et dérivés ;  anti-pain agents such as paracetamol, codeine, dextropropoxyphene, tramadol, morphine and its derivatives, corticosteroids and derivatives;
- les anti-inflammatoires tels que les Glucocorticoïdes, les anti inflammatoires non stéroïdiens, l'Aspirine, l'Ibuprofène, le Kétoprofène, le Flurbiprofène, le Diclofénac, l'Acéclofénac, le Kétorolac, le Méloxicam, le Piroxicam, le Ténoxicam, le Naproxène, l'Indométacine, le Naproxcinod, le Nimésulide, le Célécoxib, l'Etoricoxib, le Parécoxib, le Rofécoxib, le Valdécoxib, la Phénylbutazone, l'acide niflumique, l'acide méfénamique, l'acide bêta-18-glycyrrhétinique ;  anti-inflammatories such as glucocorticoids, nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, ketoprofen, flurbiprofen, diclofenac, aceclofenac, ketorolac, meloxicam, piroxicam, tenoxicam, Naproxen, Indomethacin, Naproxcinod, Nimesulide, Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib, Phenylbutazone, Niflumic acid, Mefenamic acid, Beta-18-glycyrrhetinic acid;
- les agents dépigmentants tels que l'acide kojique (Kojic Acid SL® - Quimasso (Sino Lion)), l'Arbutine (Olevatin® - Quimasso (Sino Lion)), le mélange de palmitoylpropyl de sodium et d'extrait de nénuphar blanc (Sepicalm® - Seppic), l'undécylénoyl phénylalanine (Sepiwhite® - Seppic), l'extrait de réglisse obtenue par fermentation d'Aspergillus et éthoxydiglycol (Gatuline Whitening® - Gattefossé), l'acide octadécènedioïque (ODA White® depigmenting agents such as kojic acid (Kojic Acid SL®-Quimasso (Sino Lion)), Arbutin (Olevatin® - Quimasso (Sino Lion)), the mixture of palmitoylpropyl of sodium and white water lily extract (Sepicalm® - Seppic), undecylenoyl phenylalanine (Sepiwhite® - Seppic), licorice extract obtained by fermentation of Aspergillus and ethoxydiglycol (Gatuline Whitening® - Gattefossé), octadecenedioic acid (ODA White®
- Sederma), l'alpha-arbutin (Alpha-arbutin®, SACI-CFPA (Pentapharm)), l'extrait aqueux de feuilles Arctophylos Uva Ursi (Melfade-J® - SACI-CFPA (Pentapharm)), le mélange de plante complexe Gigawhite® (SACI-CFPA (Alpaflor)), la diacétyl boldine (Lumiskin® - Sederma), l'extrait de mandarine du Japon (Melaslow® - Sederma), le mélange d'extrait de citron enrichi en acide citrique et d'extrait de concombre (Uninontan®U-34 - Unipex), le mélange d'extrait de Rumex occidentalis et de vitamine C (Tyrostat® 11 - Unipex), des oligopeptides (Mélanostatine 5® - Unipex), le dipalmitate kojique (KAD-15® - Quimasso (Sino Lion)), le complexe d'origine naturelle Vegewhite® de LCW, des extraits de germe de blé (Clariskin® II - Silab), l'éthyldiamine triacetate (EDTA); - Sederma), alpha-arbutin (Alpha-arbutin®, SACI-CFPA (Pentapharm)), the aqueous leaf extract Arctophylos Uva Ursi (Melfade-J® - SACI-CFPA (Pentapharm)), the plant mixture Gigawhite® complex (SACI-CFPA (Alpaflor)), diacetyl boldine (Lumiskin® - Sederma), mandarin extract from Japan (Melaslow® - Sederma), lemon extract mixture enriched with citric acid and cucumber extract (Uninontan®U-34 - Unipex), Rumex occidentalis extract and vitamin C extract (Tyrostat® 11 - Unipex), oligopeptides (Melanostatin 5® - Unipex), kojic dipalmitate (KAD-15® - Quimasso (Sino Lion)), LCW Vegewhite® natural origin complex, wheat germ extracts (Clariskin® II - Silab), ethyldiamine triacetate (EDTA);
- les agents kératolytiques tels que l'acide salicylique, le salicylate de zinc, l'acide ascorbique, les acides alpha hydroxylés (acide glycolique, lactique, malique, citrique, tartrique), les extraits d'Erable argenté, de Griottier, de Tamarinier, l'urée, le rétinoïde topique Kératoline® (Sederma), les protéases obtenues par fermentation de Bacillus Subtilis, le produit Linked- Papain® (SACI-CFPA), la papaïne (enzyme protéolytique issue du fruit de papaye) ;  keratolytic agents such as salicylic acid, zinc salicylate, ascorbic acid, alpha hydroxylated acids (glycolic acid, lactic acid, malic acid, citric acid, tartaric acid), extracts of silver maple, Griottier, tamarind urea, topical retinoid Keratoline® (Sederma), proteases obtained by fermentation of Bacillus Subtilis, the product Linked-Papain® (SACI-CFPA), papain (proteolytic enzyme from papaya fruit);
- les actifs restructurants (par exemple resctructurants des phanères) tels que les dérivés de silice, la vitamine E, la camomille, le calcium, l'extrait de prêle, le Lip ester de soie ;  - Restructuring assets (for example, resuscitators of dander) such as silica derivatives, vitamin E, chamomile, calcium, horsetail extract, silk ester lip;
- les anesthésiques tels que la benzocaïne, la lidocaïne, la dibucaïne, le chlorhydrate de pramoxine, la bupivacaïne, la mepivacaïne, la prilocaïne, l'étidocaïne,  anesthetics such as benzocaine, lidocaine, dibucaine, pramoxine hydrochloride, bupivacaine, mepivacaine, prilocaine, etidocaine,
- les agents hydratants tels que la glycérine,  moisturizing agents such as glycerine,
- les antidiabétiques tels que la metformine,  antidiabetic agents such as metformin,
- les vitamines. - vitamins.
Le ou les actifs est (sont) présent(s) dans la composition selon l'invention en une teneur allant par exemple de 0,01 à 50 % en poids par rapport au poids total de la composition, avantageusement de 0,1 à 20 % en poids par rapport au poids total de la composition. The active agent (s) is (are) present in the composition according to the invention in a content ranging, for example, from 0.01% to 50% by weight relative to the total weight of the composition, advantageously from 0.1% to 20% by weight. % by weight relative to the total weight of the composition.
La composition selon l'invention peut également contenir des arômes ou des agents d'amertume (tels que le benzoate de dénatonium), des parfums, ou des conservateurs. The composition according to the invention may also contain flavors or bitterness agents (such as denatonium benzoate), perfumes, or preservatives.
Agent auxiliaire de filmification Auxiliary filming agent
Pour améliorer les propriétés filmogènes de la composition, un agent auxiliaire de filmification peut avantageusement être ajouté. To improve the film-forming properties of the composition, an auxiliary film-forming agent may advantageously be added.
L'agent auxiliaire de filmification est, bien évidemment, différent du solvant organique présent dans la composition liquide filmogène selon l'invention.  The auxiliary film-forming agent is, of course, different from the organic solvent present in the film-forming liquid composition according to the invention.
Un tel agent auxiliaire de filmification peut être choisi parmi tous les composés connus de l'homme du métier, comme étant susceptibles de remplir la fonction recherchée, et être notamment choisi parmi les agents plastifiants autres que l'huile de ricin, le polyéthylène glycol, le dibutyl sébacate et le glycéryl tributyrate, et les agents de coalescence du ou des polymère(s) filmogène(s). Ainsi, la composition peut comprendre, en outre, au moins un autre agent plastifiant et/ou un agent de coalescence. En particulier, on peut citer, seuls ou en mélange, les plastifiants et agents de coalescence usuels, tels que : Such an auxiliary film-forming agent may be chosen from all the compounds known to those skilled in the art, as being capable of fulfilling the desired function, and in particular be chosen from plasticizers other than castor oil, polyethylene glycol, dibutyl sebacate and glyceryl tributyrate, and the coalescing agents of the film-forming polymer (s). Thus, the composition may further comprise at least one other plasticizer and / or a coalescing agent. In particular, mention may be made, alone or as a mixture, of the usual plasticizers and coalescence agents, such as:
les alcools gras comme l'octyldodécanol, le 2-butyloctanol, le 2-hexyl décanol, le 2- undécylpentadécanol, l'alcool oléique ;  fatty alcohols such as octyldodecanol, 2-butyloctanol, 2-hexyl decanol, 2-undecylpentadecanol, oleyl alcohol;
les acides gras tels que l'acide oléique, l'acide linoléique, l'acide linolénique ;  fatty acids such as oleic acid, linoleic acid, linolenic acid;
les esters de glycol tels que la triacétine (ou triacétate de glycéryle) ;  glycol esters such as triacetin (or glyceryl triacetate);
les dérivés de propylène glycol et en particulier le propylène glycol phényléther, le propylène glycol diacétate, le dipropylène glycol éthyléther, le tripropylène glycol méthyléther, le propylène glycol butyléther ;  propylene glycol derivatives and in particular propylene glycol phenyl ether, propylene glycol diacetate, dipropylene glycol ethyl ether, tripropylene glycol methyl ether, propylene glycol butyl ether;
les esters d'acides, notamment carboxyliques, tels que les citrates, les phtalates, les adipates, les carbonates, les tartrates, les phosphates,  esters of acids, especially carboxylic acids, such as citrates, phthalates, adipates, carbonates, tartrates, phosphates,
les dérivés oxyéthylénés, tels que les huiles oxyéthylénées, notamment les huiles végétales, telles que l'huile de sésame, l'huile de ricin, l'huile d'amande, l'huile de canola, l'huile de noisette, l'huile de pistache, l'huile de lin, l'huile de bourrache, l'huile de chanvre, l'huile de jojoba, l'huile de tournesol, l'huile de germe de blé, l'huile de maïs et/ou de germe de maïs, l'huile d'arachide, l'huile d'avocat, l'huile de carthame, l'huile de colza, l'huile d'olive, l'huile d'argan, l'huile de tournesol, l'huile de pépin de raisin, l'huile de soja, l'huile de noix, l'huile de pépin de de courge, l'huile de palme, l'huile de coprah, et leurs mélanges. L'huile peut également être un dérivé d'une des huiles végétales citées précédemment. Il peut s'agir d'huile hydrogénée ou non, peroxydée ou non.  oxyethylenated derivatives, such as oxyethylenated oils, especially vegetable oils, such as sesame oil, castor oil, almond oil, canola oil, hazelnut oil, Pistachio oil, linseed oil, borage oil, hemp oil, jojoba oil, sunflower oil, wheat germ oil, corn oil and / or corn germ, peanut oil, avocado oil, safflower oil, rapeseed oil, olive oil, argan oil, sunflower oil , grape seed oil, soybean oil, walnut oil, pumpkin seed oil, palm oil, coconut oil, and mixtures thereof. The oil can also be a derivative of one of the vegetable oils mentioned above. It may be hydrogenated oil or not, peroxidized or not.
et leurs mélanges. and their mixtures.
Par exemple, la teneur en agent auxiliaire de filmification peut aller de 0,5 à 15% en poids, et en particulier de 1 à 10%> en poids par rapport au poids total de la composition.  For example, the content of auxiliary film-forming agent may range from 0.5 to 15% by weight, and in particular from 1 to 10% by weight relative to the total weight of the composition.
Polymère filmogène secondaire Secondary film forming polymer
La composition selon l'invention peut comprendre, outre la nitrocellulose précédemment décrite, un polymère filmogène secondaire.  The composition according to the invention may comprise, in addition to the nitrocellulose previously described, a secondary film-forming polymer.
Parmi les polymères filmogènes utilisables dans la composition de la présente invention, on peut citer les polymères synthétiques, de type radicalaire ou de type polycondensat, les polymères d'origine naturelle et leurs mélanges. Le polymère filmogène peut être choisi en particulier parmi les polyuréthanes, les polymères acryliques, les polymères vinyliques, les polyvinylbutyrals, les résines alkydes, les résines issues des produits de condensation d'aldéhyde tels que les résines arylsulfonamide formaldéhyde comme la résine toluène sulfonamide formaldéhyde, les résines aryl- sulfonamide époxy ou encore les résines éthyl tosylamide, le copolymère de PolyVinylMéthyl éther et de Maleic Anhydride (PVM/MA). Among the film-forming polymers that can be used in the composition of the present invention, mention may be made of synthetic polymers, of free radical type or of polycondensate type, polymers of natural origin, and mixtures thereof. The film-forming polymer may be chosen in particular from polyurethanes, acrylic polymers, vinyl polymers, polyvinylbutyrals, alkyd resins, resins derived from aldehyde condensation products, such as arylsulfonamide formaldehyde resins such as toluene sulfonamide formaldehyde resin, epoxy arylsulfonamide resins or ethyl tosylamide resins, the copolymer of polyvinyl methyl ether and maleic anhydride (PVM / MA).
Comme polymère filmogène, on peut notamment utiliser les résine toluène sulfonamide formaldéhyde "Ketjentflex MS80" de la société AKZO ou "Santolite MHP", "Santolite MS 80" de la société FAÇONNIER ou "RESIMPOL 80" de la société PAN AMERICANA, la résine alkyde "BECKOSOL ODE 230-70-E" de la société DAINIPPON, la résine acrylique "ACRYLOID B66" de la société ROHM & HAAS, la résine polyuréthane "TRIXENE PR 4127" de la société BAXENDEN.  As film-forming polymer, use may especially be made of toluene sulfonamide formaldehyde resin "Ketjentflex MS80" from the company Akzo or "Santolite MHP", "Santolite MS 80" from the company Fonsonnier or "Resimpol 80" from the company PAN AMERICANA, the alkyd resin "BECKOSOL ODE 230-70-E" from the company DAINIPPON, the acrylic resin "ACRYLOID B66" of the company ROHM & HAAS, the polyurethane resin "TRIXENE PR 4127" from the company BAXENDEN.
Le polymère filmogène secondaire peut être présent dans la composition selon l'invention en une teneur en matières sèches allant de 1 à 15% en poids, de préférence allant de 1 à 10% en poids, par rapport au poids total de la composition.  The secondary film-forming polymer may be present in the composition according to the invention in a solids content ranging from 1 to 15% by weight, preferably ranging from 1 to 10% by weight, relative to the total weight of the composition.
Comme indiqué précédemment, la composition selon la présente invention se présente sous forme d'un liquide destiné à être appliqué à l'aide d'un applicateur approprié, tel qu'un pinceau ou une palette. As indicated above, the composition according to the present invention is in the form of a liquid intended to be applied using a suitable applicator, such as a brush or a palette.
Les compositions selon la présente invention sont destinées à être appliquées sur des plaies ou des cicatrices, qu'elles soient liées à un accident, une maladie ou les suites d'une intervention chirurgicale, ou des brûlures. Ces compositions peuvent également être appliquées à toutes affections de la peau. On peut citer, à titre d'exemple, l'acné, la varicelle, le zona, la couperose, les brûlures au premier degré, l'eczéma, l'hyperpigmentation, la lucite, le vitiligo, la xérose, la porphyrie, les vergetures, le psoriasis, les piqûres d'insectes. The compositions according to the present invention are intended to be applied to wounds or scars, whether they are related to an accident, a disease or the consequences of a surgical procedure, or burns. These compositions can also be applied to all skin conditions. Examples include acne, chickenpox, shingles, rosacea, first-degree burns, eczema, hyperpigmentation, lucite, vitiligo, xerosis, porphyria, stretch marks, psoriasis, insect bites.
L'invention a donc pour objet la composition telle que définie ci-dessus pour son utilisation dans la protection des brûlures, en particulier les brûlures légères, des plaies cutanées superficielles, ou des cicatrices. Les compositions selon l'invention sont également utiles pour les traitements des ampoules, des gerçures, ou des crevasses. La composition selon la présente invention peut aussi être appliquée sur des blessures non totalement cicatrisées à condition qu'elles ne soient pas suintantes et qu'elles aient été préalablement décontaminées.  The invention therefore relates to the composition as defined above for its use in the protection of burns, in particular light burns, superficial skin wounds, or scars. The compositions according to the invention are also useful for the treatment of ampoules, cracks, or crevices. The composition according to the present invention can also be applied to wounds not totally healed provided that they are not oozing and that they have been previously decontaminated.
L'invention concerne également l'utilisation d'une composition telle que définie ci-dessus pour la préparation d'un pansement destiné à protéger les brûlures, les plaies cutanées superficielles ou les cicatrices. Préparation d'un film The invention also relates to the use of a composition as defined above for the preparation of a dressing intended to protect burns, superficial skin wounds or scars. Preparation of a film
Selon un mode particulier de réalisation, l'invention a pour objet un procédé d'obtention d'un film à partir d'une composition filmogène telle que décrite précédemment, caractérisé en ce que :  According to a particular embodiment, the subject of the invention is a process for obtaining a film from a film-forming composition as described above, characterized in that:
i. on applique une composition telle que décrite précédemment sur les tissus tels que la peau, les phanères ou les muqueuses de manière à former un film liquide uniforme,  i. a composition as described above is applied to the tissues such as the skin, the superficial body growths or the mucous membranes so as to form a uniform liquid film,
ii. on laisse sécher pendant 1 à 5 minutes.  ii. let it dry for 1 to 5 minutes.
L'épaisseur des films obtenus est par exemple supérieure à 500 nm, de préférence comprise entre 1 et 300 μιη, plus préférentiellement comprise entre 2 et 200 μιη.  The thickness of the films obtained is for example greater than 500 nm, preferably between 1 and 300 μιη, more preferably between 2 and 200 μιη.
L'invention a aussi pour objet un film susceptible d'être obtenu à partir d'un tel procédé.  The invention also relates to a film that can be obtained from such a process.
Utilisation d'huile de ricin, de polyéthylène glycol, de dibutyl sébacate et de glycéryl tributyrate Use of castor oil, polyethylene glycol, dibutyl sebacate and glyceryl tributyrate
Selon un mode particulier de réalisation, l'invention a pour objet l'utilisation d'un plastifiant choisi parmi l'huile de ricin, le dibutyl sébacate, le glycéryl tributyrate et le polyéthylène glycol, de préférence choisi parmi le glycéryl tributyrate et le polyéthylène glycol, préférentiellement le polyéthylène glycol pour contrôler la libération d'actif(s) d'un film obtenu à partir de la composition précédemment décrite. According to a particular embodiment, the subject of the invention is the use of a plasticizer chosen from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol, preferably chosen from glyceryl tributyrate and polyethylene. glycol, preferably polyethylene glycol to control the release of active (s) a film obtained from the previously described composition.
En particulier, l'invention a pour objet l'utilisation de polyéthylène glycol, de dibutyl sébacate et de glycéryl tributyrate pour pour contrôler la libération d'actif(s) du film obtenu à partir de la composition comprenant In particular, the subject of the invention is the use of polyethylene glycol, dibutyl sebacate and glyceryl tributyrate for controlling the release of active substance (s) from the film obtained from the composition comprising
- au moins un polymère filmogène de nitrocellulose présent dans la composition en une teneur en matières sèches allant de 5 % à 20 % en poids, de préférence allant de 6 % à 15 % en poids, par rapport au poids total de la composition, et  at least one nitrocellulose film-forming polymer present in the composition in a solids content ranging from 5% to 20% by weight, preferably ranging from 6% to 15% by weight, relative to the total weight of the composition, and
- au moins un solvant volatil présent en une quantité de 60 à 90 % en poids par rapport au poids total de la composition, avantageusement de 70 à 90 % en poids par rapport au poids total de la composition,  at least one volatile solvent present in an amount of 60 to 90% by weight relative to the total weight of the composition, advantageously 70 to 90% by weight relative to the total weight of the composition,
- au moins un actif choisi parmi les anti-bactériens, les anti-viraux, les anti-fongiques, les anti-douleurs, les anti-inflammatoires, les agents dépigmentants, les agents kératolytiques, les anesthésiques, les agents hydratants, les antidiabétiques et les vitamines.  at least one active agent chosen from anti-bacterials, anti-virals, anti-fungals, painkillers, anti-inflammatories, depigmenting agents, keratolytic agents, anesthetics, moisturizing agents, antidiabetics and vitamins.
Les exemples suivants illustrent l'invention, sans en limiter la portée. Exemples 1 à 4 : The following examples illustrate the invention without limiting its scope. Examples 1 to 4:
On prépare les compositions du tableau 1 suivantes :  The following compositions of Table 1 are prepared:
Figure imgf000013_0001
Figure imgf000013_0001
Mode opératoire:  Operating mode:
On mélange les ingrédients 2 à 5 sous agitation à 700 tours/min pendant 10 minutes avec un agitateur à hélice. La nitrocellulose est ensuite dispersée dans le mélange sous agitation, et le mélange est agité successivement pendant 20 minutes à 1100 tours/min et pendant 30 minutes à 2000 tours/min.  Ingredients 2 to 5 are mixed with stirring at 700 rpm for 10 minutes with a propeller stirrer. The nitrocellulose is then dispersed in the mixture with stirring, and the mixture is stirred successively for 20 minutes at 1100 rpm and for 30 minutes at 2000 rpm.
Les films ont été préparés par coulage dans une boite de Pétri. Les boites sont ensuite placées pendant lh environ dans une étuve préalablement thermostatée à 32°C pour séchage du film.  The films were prepared by pouring into a petri dish. The boxes are then placed for about 1 hour in an oven previously thermostated at 32 ° C for drying the film.
Exemple 5 : évaluation de la quantité d'actif libéré dans le temps à partir des films obtenus des compositions des exemples 1 à 4 EXAMPLE 5 Evaluation of the Amount of Asset Released in Time from the Films Obtained from the Compositions of Examples 1 to 4
Les propriétés de libération de l'acide salicylique à partir des films à 4,5 % de plastifiants et à 1% d'acide salicylique ont été déterminées au moyen d'un appareil de dissolution à petites palettes (VanKel VK 6010) dans du sérum physiologique (70 ml) à une température fixe de 32°C, avec une rotation moyenne de 50 rpm. Pour ce test, trois cercles d'échantillons du film de 2,5 cm de diamètre ont été préparés, pesés et placés dans des cellules de diffusion (surface de contact = 2 cm2, Enhancer cells®), introduites par la suite dans des béchers à (T=0). Ces béchers remplis de sérum physiologique sont placés dans le bain thermostaté et le liquide est agité régulièrement grâce aux petites palettes. Pendant le test (24heures), 2 ml du milieu ont été prélevés périodiquement et placés dans une cuve en quartz pour mesurer la concentration en acide salicylique (mg/ml) par spectrophotométrie UV-vis (Biochrom Libra S22). Cet échantillon a été réintroduit après lecture optique dans le milieu de libération pour garantir un volume constant (70 ml) sur toute la durée de test. La longueur d'onde d'absorption maximale (λ max) de l'acide salicylique a été initialement déterminée à partir du spectre d'absorption d'une solution d'acide salicylique dans le sérum physiologique. La longueur d'onde λ max était 296 nm. La courbe d'étalonnage a été réalisée grâce à une série de solutions d'étalons de concentration 4, 8, 20, 40, 64 et 80 mg/1 en acide salicylique en appliquant la loi de Beer- Lambert : The release properties of salicylic acid from the 4.5% plasticizer and 1% salicylic acid films were determined using a small dissolution apparatus. pallets (VanKel VK 6010) in physiological saline (70 ml) at a fixed temperature of 32 ° C, with an average rotation of 50 rpm. For this test, three circles of samples of the 2.5 cm diameter film were prepared, weighed and placed in diffusion cells (contact area = 2 cm 2 , Enhancer cells®), subsequently introduced into beakers at (T = 0). These beakers filled with physiological saline are placed in the thermostatic bath and the liquid is agitated regularly thanks to the small pallets. During the test (24 hours), 2 ml of the medium were taken periodically and placed in a quartz vat to measure the concentration of salicylic acid (mg / ml) by UV-vis spectrophotometry (Biochrom Libra S22). This sample was reintroduced after optical reading in the release medium to ensure a constant volume (70 ml) over the entire test period. The maximum absorption wavelength (λ max) of salicylic acid was initially determined from the absorption spectrum of a salicylic acid solution in physiological saline. The wavelength λ max was 296 nm. The calibration curve was carried out using a series of solutions of standards of concentration 4, 8, 20, 40, 64 and 80 mg / l in salicylic acid by applying the Beer-Lambert law:
A= s.L.C A = s.L.C
Avec With
ε: coefficient d'extinction molaire fixe pour une molécule qui dépend de la longueur d'onde. L : longueur de cuve (1cm). ε: fixed molar extinction coefficient for a molecule that depends on the wavelength. L: tank length (1cm).
C : concentration de la solution (mg/L). C: concentration of the solution (mg / L).
L'équation de la droite d'étalonnage ainsi obtenue pour l'acide salicylique a servi à la détermination de sa concentration lors de la cinétique de libération. De ces concentrations sont déterminées la quantité d'acide salicylique par mg de film puis le % libéré par rapport à la quantité d'acide salicylique utilisée pour la fabrication de ces films. Les absorbances des films sans acide salicylique ont été déterminées pour pouvoir les comparer avec les films le contenant. Elles sont très faibles (< 0,01) et seront donc négligées dans les calculs.  The equation of the calibration line thus obtained for salicylic acid was used to determine its concentration during the kinetics of release. From these concentrations are determined the amount of salicylic acid per mg of film then the% released relative to the amount of salicylic acid used for the manufacture of these films. The absorbances of the salicylic acid-free films were determined in order to compare them with the films containing it. They are very low (<0.01) and will therefore be neglected in the calculations.
Les résultats sont regroupés dans le tableau ci-dessous : Quantité d'acide Quantité d'acide Pourcentage Pourcentage salicylique libérée salicylique libérée d'acide d'acide The results are summarized in the table below: Amount of acid Amount of acid Percent Salicylic acid released salicylic acid released from acid
^g) en 8 h / mg ^g) en 24 h / mg salicylique libéré salicylique libéré de film de film en 8 h par rapport en 24 h par à la quantité rapport à la théorique dans le quantité théorique film dans le film g) in 8 hr / mg / g) in 24 hr / mg salicylic released salicylic released from film film in 8 hr versus 24 hr by the amount ratio to the theoretical in the theoretical amount film in the film
Exemple 1 31,61+ 5,73 44,13 + 9,44 57,7 + 10,4 80,5 ± 17,2Example 1 31.61+ 5.73 44.13 + 9.44 57.7 + 10.4 80.5 ± 17.2
Exemple 2 40,07 ± 5,62 55,53 + 6,11 73,1 ± 10,3 101,3 ± 11,2Example 2 40.07 ± 5.62 55.53 + 6.11 73.1 ± 10.3 101.3 ± 11.2
Exemple 3 23,33 + 4,80 29,63 ± 4,36 42,6 ± 8,8 54,1 ± 8,0Example 3 23.33 ± 4.80 29.63 ± 4.36 42.6 ± 8.8 54.1 ± 8.0
Exemple 4 37,48 ± 0,68 46,01 ± 0,78 68,4 + 1,2 84,0 + 1,4 Example 4 37.48 ± 0.68 46.01 ± 0.78 68.4 + 1.2 84.0 + 1.4
Des cinétiques de libération en fonction du temps sont également présentées sur la figure 1. Pour une libération rapide de l'actif, on utilisera préférentiellement comme plastifiant le dibutyl sebacate, pour une libération intermédiaire, l'huile de ricin et le PEG, pour une libération progressive, le glyceryl tributyrate. Release kinetics as a function of time are also presented in FIG. 1. For rapid release of the active agent, dibutyl sebacate will preferably be used as plasticizer, for intermediate release, castor oil and PEG for a second time. progressive release, glyceryl tributyrate.
Exemples 6 à 9 : Examples 6 to 9:
On prépare les compositions du tableau 2 suivantes  The following Table 2 compositions are prepared
Ëxemple6 Exemple 7 Ëxemple8 Exemple 9 Selon l'invention Selon l'invention Selon l'invention Selon l'inventionExample 6 Example 7 Example 8 Example 9 According to the invention According to the invention According to the invention According to the invention
Nom Nom INCI % massique % massique % massique % massique commercial Name INCI name% mass% mass% mass% commercial mass
l .DHL® Nitrocellulose 11,1 11,1 11,1 11,1l .DHL® Nitrocellulose 11.1 11.1 11.1 11.1
120/170 IPA 120/170 IPA
Nobel  Nobel
Nitrocellulose  nitrocellulose
Ricinus 3,7  Ricinus 3.7
2. Huile de ricin  2. Castor oil
Communis  communis
Prod'hyg  Prod'Hyg
(Castor) Seed  (Beaver) Seed
Laboratoire Laboratory
Oil  Oil
2. dibutyl Dibutyl 3,7  2. dibutyl Dibutyl 3,7
sébacate Sebacate sebacate sebacate
2.glycéryl 3,7  2.glyceryl 3,7
tributyrate tributyrate
2.polyéthylène PEG 200 3,7 glycol 2.Polyethylene PEG 200 3.7 glycol
3.Ethanol Alcohol 22,2 22,2 22,2 22,2 absolu  3.Ethanol Alcohol 22.2 22.2 22.2 22.2 absolute
Charbonneau  Charbonneau
Brabant  Brabant
4.Acétate Ethylacetate 44,4 44,4 44,4 44,4 d'éthyle  4.Acetate Ethylacetate 44.4 44.4 44.4 44.4 ethyl
Darfeuille Darfeuille
5. Eau Eau distillée 17,8 17,8 17,8 17,8 5. Water Distilled water 17.8 17.8 17.8 17.8
6. Metformine 0,8 0,8 0,8 0,8 6. Metformin 0.8 0.8 0.8 0.8
Mode opératoire: Operating mode:
On mélange les ingrédients 2 à 4 sous agitation à 700 tours/min pendant 10 minutes avec un agitateur à hélice. La nitrocellulose est ensuite dispersée dans le mélange sous agitation, et le mélange est agité successivement pendant 20 minutes à 1100 tours/min puis 30 minutes à 2000 tours/min et enfin 700 tours /min 60 minutes. Enfin la metformine est ajoutée après avoir été dissoute dans la quantité d'eau distillée prescrite. Le nouveau mélange est agité à 700 tours / min pendant 120 minutes.  Ingredients 2-4 are mixed with stirring at 700 rpm for 10 minutes with a propeller stirrer. The nitrocellulose is then dispersed in the mixture with stirring, and the mixture is stirred successively for 20 minutes at 1100 revolutions / min then 30 minutes at 2000 rev / min and finally 700 rev / min 60 minutes. Finally metformin is added after being dissolved in the amount of distilled water prescribed. The new mixture is stirred at 700 rpm for 120 minutes.
Les films ont été préparés par coulage dans une boite de Pétri. Les boites de Pétri sont ensuite placées, pendant 1 nuit, dans une étuve préalablement thermostatée à 32°C pour séchage du film.  The films were prepared by pouring into a petri dish. The petri dishes are then placed, for 1 night, in an oven previously thermostated at 32 ° C for drying the film.
Exemple 10 : évaluation de la quantité d'actif libéré dans le temps à partir des films obtenus des compositions des exemples 6 à 9  EXAMPLE 10 Evaluation of the Amount of Asset Released in Time from the Films Obtained from the Compositions of Examples 6 to 9
Les propriétés de libération de la metformine à partir des films à 3,7 % de plastifiants et à 0,8 % de metformine ont été déterminées au moyen d'un appareil de dissolution à petites palettes (VanKel VK 6010) dans du sérum physiologique (100 ml) à une température fixe de 37°C, avec une rotation moyenne de 50 rpm. Pour ce test, trois cercles d'échantillons du film de 2,5 cm de diamètre ont été préparés, pesés et placés dans des cellules de diffusion (surface de contact = 2 cm2, Enhancer cells®), introduites par la suite dans des béchers à (T=0). Ces béchers remplis de sérum physiologique sont placés dans le bain thermostaté et le liquide est agité régulièrement grâce aux petites palettes. Pendant le test (24heures), 2 ml du milieu ont été prélevés périodiquement et placés dans une cuve en quartz pour mesurer la concentration en metformine (mg/ml) par spectrophotométrie UV-vis (Biochrom Libra S22). Cet échantillon a été réintroduit après lecture optique dans le milieu de libération pour garantir un volume constant (100 ml) sur toute la durée de test. La longueur d'onde d'absorption maximale (λ max) de la metformine a été initialement déterminée à partir du spectre d'absorption d'une solution de metformine dans le sérum physiologique. La longueur d'onde λ max était 230 nm. La courbe d'étalonnage a été réalisée grâce à une série de solutions d'étalons de concentration 1, 5, 10, 20 et 40 mg/1 en metformine en appliquant la loi de Beer- Lambert : The release properties of metformin from the films at 3.7% plasticizer and 0.8% metformin were determined by means of a small vane dissolution apparatus (VanKel VK 6010) in physiological saline ( 100 ml) at a fixed temperature of 37 ° C, with an average rotation of 50 rpm. For this test, three circles of samples of the 2.5 cm diameter film were prepared, weighed and placed in diffusion cells (contact area = 2 cm 2 , Enhancer cells®), subsequently introduced into beakers at (T = 0). These beakers filled with physiological saline are placed in the thermostatic bath and the liquid is agitated regularly thanks to the small pallets. During the test (24 hours), 2 ml of the medium was taken periodically and placed in a quartz vat to measure the concentration of metformin (mg / ml) by UV-vis spectrophotometry (Biochrom Libra S22). This sample was reintroduced after optical reading in the release medium to ensure a constant volume (100 ml) over the entire test period. The maximum absorption wavelength (λ max) of metformin was initially determined from the absorption spectrum of a metformin solution in saline. The wavelength λ max was 230 nm. The calibration curve was achieved through a series of solutions of standards of concentration 1, 5, 10, 20 and 40 mg / l in metformin by applying the Beer-Lambert law:
A= s.L.C  A = s.L.C
Avec  With
ε: coefficient d'extinction molaire fixe pour une molécule qui dépend de la longueur d'onde. L : longueur de cuve (1cm).  ε: fixed molar extinction coefficient for a molecule that depends on the wavelength. L: tank length (1cm).
C : concentration de la solution (mg/L).  C: concentration of the solution (mg / L).
L'équation de la droite d'étalonnage ainsi obtenue pour la metformine a servi à la détermination de sa concentration lors de la cinétique de libération. De ces concentrations sont déterminées la quantité de metformine par mg de film puis le % libéré par rapport à la quantité de metformine utilisée pour la fabrication de ces films. Les absorbances des films sans metformine ont été déterminées pour pouvoir les comparer avec les films le contenant. Elles sont très faibles (< 0,01) et seront donc négligées dans les calculs. Les résultats sont regroupés dans le tableau ci-dessous :  The equation of the calibration line thus obtained for metformin was used to determine its concentration during the kinetics of release. From these concentrations are determined the amount of metformin per mg of film and the% released relative to the amount of metformin used for the manufacture of these films. The absorbances of the films without metformin were determined in order to compare them with the films containing it. They are very low (<0.01) and will therefore be neglected in the calculations. The results are summarized in the table below:
Figure imgf000017_0001
Figure imgf000017_0001
Des cinétiques de libération en fonction du temps sont également présentées sur la figure 2. Pour une libération rapide de l'actif, on utilisera préférentiellement comme plastifiant le PEG, pour une libération intermédiaire, le glyceryl tributyrate et le dibutyl sebaçate, l'huile de ricin pour une libération progressive. Release kinetics as a function of time are also presented in FIG. 2. For quick release of the active agent, PEG will preferably be used as plasticizer for intermediate release, glyceryl tributyrate and dibutyl sebacate, castor for a gradual release.

Claims

Revendications claims
1. Composition liquide filmogène caractérisée en ce qu'elle comprend : 1. film-forming liquid composition characterized in that it comprises:
- au moins un polymère filmogène de nitrocellulose présent dans la composition en une teneur en matières sèches allant de 5 % à 20% en poids, de préférence allant de 6 % à 12% en poids, par rapport au poids total de la composition,  at least one film-forming nitrocellulose polymer present in the composition in a solids content ranging from 5% to 20% by weight, preferably ranging from 6% to 12% by weight, relative to the total weight of the composition;
- au moins un solvant volatil,  at least one volatile solvent,
- au moins un actif choisi parmi les anti-bactériens, les anti-viraux, les anti-fongiques, les anti-douleurs, les anti-inflammatoires, les agents dépigmentants, les agents kératolytiques, les anesthésiques, les actifs restructurants, les agents hydratants, les antidiabétiques, et les vitamines, et  at least one active agent chosen from anti-bacterials, anti-virals, anti-fungals, anti-pain agents, anti-inflammatory agents, depigmenting agents, keratolytic agents, anesthetics, restructuring agents and moisturizing agents , antidiabetics, and vitamins, and
- au moins un plastifiant choisi parmi l'huile de ricin, le polyéthylène glycol, le dibutyl sébacate et le glycéryl tributyrate.  at least one plasticizer chosen from castor oil, polyethylene glycol, dibutyl sebacate and glyceryl tributyrate.
2. Composition filmogène selon la revendication 1, caractérisée en ce que le plastifiant est présent en une teneur allant de là 60% en poids, de préférence de 1 à 40 %>en poids, par rapport au poids total de la composition.  2. Film-forming composition according to claim 1, characterized in that the plasticizer is present in a content ranging from 60% by weight, preferably from 1 to 40% by weight, relative to the total weight of the composition.
3. Procédé d'obtention d'un film à partir d'une composition filmogène selon l'une quelconque des revendications 1 ou 2, caractérisé en ce que :  3. Process for obtaining a film from a film-forming composition according to any one of claims 1 or 2, characterized in that:
i. on applique une composition selon l'une quelconque des revendications 1 ou 2 sur les tissus tels que la peau, les phanères ou les muqueuses de manière à former un film liquide uniforme,  i. a composition according to any one of claims 1 or 2 is applied to the tissues such as the skin, the superficial body growths or the mucous membranes so as to form a uniform liquid film,
ii. on laisse sécher pendant 1 à 5 minutes.  ii. let it dry for 1 to 5 minutes.
4. Procédé selon la revendication 3, caractérisé en ce que l'épaisseur du film obtenu à l'étape ii. est supérieure à 500 nm, de préférence comprise entre 1 et 300 μιη, plus préférentiellement comprise entre 2 et 200 μιη.  4. Method according to claim 3, characterized in that the thickness of the film obtained in step ii. is greater than 500 nm, preferably between 1 and 300 μιη, more preferably between 2 and 200 μιη.
5. Film susceptible d'être obtenu à partir du procédé selon l'une des revendications 3 ou 4. 5. Film obtainable from the process according to one of claims 3 or 4.
6. Utilisation d'un plastifiant choisi parmi l'huile de ricin, le dibutyl sébacate, le glycéryl tributyrate et le polyéthylène glycol pour contrôler la libération d'actif(s) d'un film obtenu à partir d'une composition selon l'une des revendications 1 ou 2. 6. Use of a plasticizer selected from castor oil, dibutyl sebacate, glyceryl tributyrate and polyethylene glycol to control the release of active (s) a film obtained from a composition according to the one of claims 1 or 2.
PCT/FR2018/050798 2017-03-31 2018-03-30 Composition containing nitrocellulose, a plasticiser, a volatile solvent and an active agent, uses thereof as a dressing WO2018178596A1 (en)

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