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EP2167072A1 - Use of oleocanthal for treatment of cutaneous inflammation - Google Patents

Use of oleocanthal for treatment of cutaneous inflammation

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Publication number
EP2167072A1
EP2167072A1 EP08827837A EP08827837A EP2167072A1 EP 2167072 A1 EP2167072 A1 EP 2167072A1 EP 08827837 A EP08827837 A EP 08827837A EP 08827837 A EP08827837 A EP 08827837A EP 2167072 A1 EP2167072 A1 EP 2167072A1
Authority
EP
European Patent Office
Prior art keywords
oleocanthal
treatment
use according
olive oil
cutaneous
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08827837A
Other languages
German (de)
French (fr)
Inventor
Cyril Estanove
François PRUVOST
Jean-Claude Allart
Frédéric SALDMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bc Development Sa
Sprim
Original Assignee
Bc Development Sa
Sprim
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Filing date
Publication date
Application filed by Bc Development Sa, Sprim filed Critical Bc Development Sa
Publication of EP2167072A1 publication Critical patent/EP2167072A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation

Definitions

  • the present invention relates to a new use of derivatives extracted from olive oil, and more particularly from oleocanthal and oleocanthal derivatives in the pharmaceutical and dermatological field, in particular for the preparation of medicaments for the treatment of skin inflammation.
  • the skin is an essential organ of life, which fulfills several functions whose quality has a decisive influence on the health of every individual.
  • the skin is a real barrier to the environment and is subject to incessant aggression.
  • the quality of its defenses is therefore a major element for the effectiveness of its protection.
  • the skin constitutes a living anatomical barrier between the body and its environment, and it comprises several integrated layers, namely a superficial layer constituted by the epidermis, and deeper layers forming the dermis and hypodermis, and each of these layers has specific properties allowing the whole to react and adapt to the conditions of its environment.
  • the epidermis is mainly composed of keratinocytes (90% of epidermal cells), melanocytes (2 to 3% of epidermal cells) and Langerhans cells. Its thickness is variable according to the different parts of the body.
  • the dermis is thicker, and consists mainly of collagen, elastin and proteoglycans. These three types of molecules are synthesized by dermal fibroblasts. Collagen fibers provide the strength and texture of the skin, elastin is responsible for elasticity, and proteoglycans play a major role in the structure and hydration of the skin. Other cells such as macrophages and leukocytes are also present in the layer of the dermis.
  • the hypodermis is the deepest layer of the skin, and contains lipid-producing adipocytes so that the subcutaneous tissue can make a fat layer that protects muscles, bones, and internal organs from shock.
  • the cutaneous immune system includes a large number of cellular actors such as keratinocytes, Langerhans cells, fibroblasts, mast cells, macrophages and endothelial cells, as well as leukocytes, and various soluble inflammatory mediators such as cytokines. and chemokines.
  • This cutaneous immune system ensures the maintenance of cutaneous homeostasis. It is also responsible for the activation and regulation of normal and pathological inflammatory reactions. Inflammation is a defense response of the body in response to an aggression that can be microbial, viral, physical (for example, a prolonged exposure injury or burn to ultraviolet light) or chemical. This reaction results in the arrival in the dermis and epidermis of inflammatory cells that oppose aggression.
  • T lymphocytes are activated and secrete substances such as cytokines, for example TNF ⁇ (tumor necrosis factor) and IL-I (interleukin-1), which accelerate the proliferation of keratinocytes.
  • cytokines for example TNF ⁇ (tumor necrosis factor) and IL-I (interleukin-1), which accelerate the proliferation of keratinocytes.
  • IL- ⁇ interleukin- ⁇
  • IL- ⁇ is another cytokine released by most cells in response to stimulation and is also a good marker of inflammation.
  • the reaction of the cutaneous immune system first has the effect of helping to eliminate the inflammatory agent and to promote the recovery and healing of tissue affected by inflammation.
  • tissue damage may become chronic.
  • the inflammatory response may be the consequence of innate immune activation, resulting in irritation of the skin, or specific immune activation, for example in the form of allergic eczema. It is therefore desirable to be able to rapidly treat the inflammatory response of the innate immune response because it can induce not only the maintenance of primary inflammation but also a specific inflammatory reaction whose consequences are sometimes serious.
  • Olive oil contains in particular monounsaturated fatty acids (oleic acid) as well as phenolic compounds with antioxidant properties which have the effect of retarding the oxidation of LDL lipoproteins.
  • phenolic compounds there are phenolic alcohols such as tyrosol and hydroxytyrosol, benzoic acids, caffeic and elenolic acids esterified with tyrosol and hydroxy-tyrosol, as well as flavonoids such as flavones and flavonols.
  • Epidemiological studies have shown the health benefits of Mediterranean diets including a high intake of fiber, fruit, vegetables, and olive oil which is the main source of fat. For example, RW Owen et al., Lancet Oncol. (Oct. 2000) 107-12.
  • compositions containing polyphenols of olive oil with antioxidant activity and free radical scavenger, such as hydroxy-tyrosol and oleuropein can be applied on the skin.
  • WO 03/068171 teaches that hydroxytyrosol and oleuropein may be useful in the treatment of certain neurological disorders and inflammations.
  • the application WO 2007/012057 describes the treatment of certain cutaneous inflammations by compositions containing hydroxytyrosol obtained from the olive treatment water.
  • oleochalhal properties of oleochalhal are also described in WO 2006/122128. These properties show that oleocanthal could be considered in the indications of ibuprofen, that is to say as general antiinflammatory, oral, likely to be useful in rheumatology and not for the treatment of cutaneous inflammation. which is specific as indicated above.
  • Oleocanthal or deacetoxy-ligstroside aglycone, has been detected in olive oils of various origins, especially in virgin olive oil obtained by first cold pressing, at very low concentrations which generally vary from at 200 ppm (mass), ie from 0.002 to 0.02% by weight, depending on the source of the olive oil.
  • Oleocanthal may be represented by the following general formula (I): Oleuropein, found in fruits and mainly in olive leaves, is a glycoside represented by the general formula (II) below:
  • oleuropein in food or pharmaceutical compositions for stimulating bone mineralization in humans or animals has been proposed in WO 2004091591.
  • the antiviral activity of certain oleuropein derivatives has also been described in US Pat. US Patent 6,455,580.
  • Derivatives such as oleuropein aglycone, having antioxidant properties, and its dialdehyde form may be extracted from olive oil.
  • R is a hydrogen atom or a hydroxy group
  • the dialdehyde form of decarboxymethyl oleuropein aglycon represented by formula (IV).
  • oleocanthal is a very fragile product, easily destroyed by heat and oxidation, as are most of the other polyphenolic compounds naturally present in vegetable oils.
  • the subject of the present invention is therefore the use of olive oil extracts containing oleocanthal and / or derivatives of general formula (A) below.
  • the invention more particularly relates to the use of olive oil extracts containing oleocanthal and / or derivatives, for the preparation of a topically administrable medicament for external use for the treatment skin inflammation.
  • the invention also relates to the combined use of oleocanthal, and / or derivatives of formula (A) above, and oleuropein and a pharmaceutical composition associating them, useful in particular for the treatment of the skin inflammation.
  • compositions based on olive oil extracts containing oleocanthal and / or derivatives of formula (A) above, such as decarboxymethyl dialdehyde Oleurospine aglycone in the local treatment of cutaneous inflammation results from a mechanism of action clearly different from that of general anti-inflammatories such as ibuprofen, which is explained in more detail below.
  • This study has revealed a novel mechanism of action of oleocanthal that represses the activation of alert messages or sensitivity of the inflammatory messenger receptors (PGE-2 and IL- ⁇ ) by decreasing the anti-radical defense systems induced by inflammation, which reflects a decrease in innate inflammation.
  • the study also revealed a decrease in IL-6 receptor induction and the repression of ENA-78 which is the chemotactic factor for neutrophils. This This mechanism is important because the recruitment pathway of polynuclear lymphocytes and macrophages is a fundamental pathway in the primary inflammatory response. Thus oleocanthal can be effectively used for the local treatment of skin inflammation.
  • These derivatives are particularly useful in the treatment of primary burns, sunburns, insect bites, radiodermites following radiotherapy, superficial wounds and cutaneous irritations caused by chemicals or substances. stinging. They also have the advantage of treating inflammation and having a pain relieving analgesic effect possibly associated with inflammation.
  • the oleocanthal as well as the derivatives described above, can be used in the form of olive oil extract more or less enriched with oleocanthal.
  • the oleocanthal concentration, and the case derivatives greater than or equal to 10% by weight relative to the total weight of the extract.
  • the extract it is advantageous for the extract to contain at least 10% by weight of oleocanthal and at least 10% by weight of derivative.
  • the amounts used per unit dose may range from 0.1 mg to 500 mg for Oleocanthal and the derivative used alone or, preferably, in combination with oleocanthal.
  • the composition comprises in combination 1 to 100 mg of oleocanthal and 0.5 to 100 mg of derivative per 100 g of total composition.
  • compositions according to the invention combining oleocanthal and oleuropein have the advantage of providing an inflammatory action complementary to that of oleocanthal improving the effectiveness of the treatment.
  • compositions that may be used in the present invention may be in any of the usual dosage forms suitable for topical local administration.
  • compositions for topical application may be in the form of oily or aqueous-alcoholic solutions, spraying solutions, dispersions, serums, gels or lipogels, suspensions, liquid or semi-liquid emulsions (eg milk), solid or semi-solid, shampoo or spot-on formulation.
  • the emulsions may be of the oil-in-water (O / W) type or water in oil (W / O), for example gels or creams.
  • a lipid medium is preferably used, for example a lipophilic solvent such as 1,2-O-isopropylideneglycerol.
  • an olive oil extract of the invention containing about 30% oleocanthal, in impregnated form in tissues to be applied to the skin.
  • Such a form is well suited to the treatment of trauma, the resorption of fibrous nodules on the fasciae and the reduction of bruises.
  • the encapsulated extract can be used in tissue bandages such that the release of the extract is caused by the movements.
  • a form adapted to a sports activity likely to cause trauma may be formed by microcapsules impregnated in clothing worn by sportsmen such as jerseys and socks.
  • composition dosed at 20 or 50 mg of oleochalhal for two daily applications for a duration of two or three days for curative treatment or about 3 to 15 days for preventive treatment or maintenance.
  • a lipogel at 0.5% 30% oleocanthal solution was administered to 5 patients who received a 30% trichloroacetic acid peel. The erythema, swelling and tingling sensations and burns resulting from the peeling are very clearly attenuated from the first application of the composition of the invention.
  • Example 1 oleocanthal-based pharmaceutical compositions are given below. In these examples all parts and percentages are by weight unless otherwise indicated. Example 1
  • a tulle composition on a cotton support is prepared according to the formulation below.
  • This composition is impregnated on a tulle with a cotton support to constitute a tulle gras intended for the treatment of cutaneous inflammations related to primary burns and seborrheic keratoses.
  • a fluid cream for external application is prepared according to conventional techniques and its formulation is as follows.
  • Cyclopentasiloxane 8.0 Cyclopentasiloxane (and) crosslinked dimethicone (and) cyclohexasiloxane 2.0
  • An oil paste having the weight composition indicated below (in g) is prepared.
  • Extract of olive oil with 30% oleocanthal 0.5 This paste can be used more particularly for the treatment of inflammatory dermatitis linked to repeated frictions during sports practice.
  • Phase A Phase A:
  • Phase B C10-30 Acrylate / Alkyl Acrylate Crosslinked Copolymer (Pemulen®) 0.2
  • Phase A is prepared conventionally by mixing the components in a tank.
  • Phase D is prepared and carefully homogenized in another tank.
  • Phase D and the previously dispersed phases B and C are then added separately, the addition being carried out slowly with stirring. It is then neutralized by adding phase E and the previously dissolved F phase is added.
  • the pH of the composition is about 5.6, and the viscosity is 2000 mPas (Brookfield RVT MOB 3, 20 rpm, 1 min.).
  • a gel of the type described above can be advantageously impregnated in applied to the skin to treat various trauma, or to reduce bruising.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

The invention relates to a novel use of oleocanthal. oleocanthal and/or a derivative thereof of general formula (A), where R is H or OH is used for the production of a medicament for topical cutaneous administration for treatment of cutaneous inflammation.

Description

UTILISATION DE L ' OLEOCANTHAL DANS LE TRAITEMENT DE L'INFLAMMATION CUTANEE USE OF OLEOCANTHAL IN THE TREATMENT OF SKIN INFLAMMATION
La présente invention concerne une nouvelle utilisation de dérivés extraits de l'huile d'olive, et plus particulièrement de 1 ' oléocanthal et de dérivés d'oléocanthal dans le domaine pharmaceutique et dermatologique, notamment pour la préparation de médicaments pour le traitement de l'inflammation cutanée.The present invention relates to a new use of derivatives extracted from olive oil, and more particularly from oleocanthal and oleocanthal derivatives in the pharmaceutical and dermatological field, in particular for the preparation of medicaments for the treatment of skin inflammation.
La peau constitue un organe essentiel à la vie, qui remplit plusieurs fonctions dont la qualité a une influence déterminante sur la santé de tout individu. Plus particulière- ment, la peau constitue une véritable barrière vis-à-vis de l'environnement et elle est soumise à des agressions incessantes. La qualité de ses défenses est donc un élément majeur pour l'efficacité de sa protection.The skin is an essential organ of life, which fulfills several functions whose quality has a decisive influence on the health of every individual. In particular, the skin is a real barrier to the environment and is subject to incessant aggression. The quality of its defenses is therefore a major element for the effectiveness of its protection.
La peau constitue une barrière anatomique vivante entre le corps et son environnement, et elle comprend plusieurs couches intégrées, à savoir une couche superficielle constituée par l'épiderme, et des couches plus profondes formant le derme et l'hypoderme, et chacune de ces couches possède des propriétés spécifiques permettant à l'ensemble de réagir et de s'adapter aux conditions de son environnement.The skin constitutes a living anatomical barrier between the body and its environment, and it comprises several integrated layers, namely a superficial layer constituted by the epidermis, and deeper layers forming the dermis and hypodermis, and each of these layers has specific properties allowing the whole to react and adapt to the conditions of its environment.
L'épiderme est principalement composé de kératinocytes (90% des cellules épidermiques) , de mélanocytes (2 à 3% des cellules épidermiques) et des cellules de Langerhans. Son épaisseur est variable selon les différentes parties du corps. Le derme est plus épais, et se compose principalement de collagène, d'élastine et de protéoglycanes . Ces trois types de molécules sont synthétisés par les fibroblastes dermiques. Les fibres de collagène assurent la résistance mécanique et la texture de la peau, l'élastine est responsable de l'élasti- cité, et les protéoglycanes jouent un rôle majeur de structure et d'hydratation de la peau. D'autres cellules comme les macrophages et les leucocytes sont également présentes dans la couche du derme. L ' hypoderme est la couche la plus profonde de la peau, et contient les adipocytes qui produisent des lipides afin que le tissu sous-cutané puisse fabriquer une couche grasse protégeant les muscles, les os et les organes internes contre les chocs .The epidermis is mainly composed of keratinocytes (90% of epidermal cells), melanocytes (2 to 3% of epidermal cells) and Langerhans cells. Its thickness is variable according to the different parts of the body. The dermis is thicker, and consists mainly of collagen, elastin and proteoglycans. These three types of molecules are synthesized by dermal fibroblasts. Collagen fibers provide the strength and texture of the skin, elastin is responsible for elasticity, and proteoglycans play a major role in the structure and hydration of the skin. Other cells such as macrophages and leukocytes are also present in the layer of the dermis. The hypodermis is the deepest layer of the skin, and contains lipid-producing adipocytes so that the subcutaneous tissue can make a fat layer that protects muscles, bones, and internal organs from shock.
Le système immunitaire cutané regroupe un grand nombre d'acteurs cellulaires tels que les kératinocytes, les cellules de Langerhans, les fibroblastes, les mastocytes, les macrophages et les cellules endothéliales, ainsi que des leuco- cytes, et divers médiateurs inflammatoires solubles tels que cytokines et chimiokines. Ce système immunitaire cutané assure le maintien de l 'homéostasie cutanée. Il est aussi responsable de l'activation et de la régulation des réactions inflammatoires normales et pathologiques. L'inflammation est une réaction de défense de l'organisme en réponse à une agression qui peut être microbienne, virale, physique (par exemple une blessure ou une brûlure par exposition prolongée aux rayons ultraviolets) ou chimique. Cette réaction se traduit par l'arrivée dans le derme et l'épiderme de cellules inflammatoires qui s'opposent à l'agression. Ainsi les lymphocytes T sont activés et sécrètent des substances telles que des cytokines, par exemple TNFα (facteur de nécrose tumorale) et IL-I (interleukine-1) , qui accélèrent la prolifération des kératinocytes. L'IL-β (interleukine-β) est une autre cytokine relarguée par la plupart des cellules en réponse à une stimulation et constitue également un bon marqueur de l'inflammation.The cutaneous immune system includes a large number of cellular actors such as keratinocytes, Langerhans cells, fibroblasts, mast cells, macrophages and endothelial cells, as well as leukocytes, and various soluble inflammatory mediators such as cytokines. and chemokines. This cutaneous immune system ensures the maintenance of cutaneous homeostasis. It is also responsible for the activation and regulation of normal and pathological inflammatory reactions. Inflammation is a defense response of the body in response to an aggression that can be microbial, viral, physical (for example, a prolonged exposure injury or burn to ultraviolet light) or chemical. This reaction results in the arrival in the dermis and epidermis of inflammatory cells that oppose aggression. Thus T lymphocytes are activated and secrete substances such as cytokines, for example TNFα (tumor necrosis factor) and IL-I (interleukin-1), which accelerate the proliferation of keratinocytes. IL-β (interleukin-β) is another cytokine released by most cells in response to stimulation and is also a good marker of inflammation.
La réaction du système immunitaire cutané a d'abord pour effet de contribuer à éliminer l'agent inflammatoire et de favoriser le rétablissement et la cicatrisation du tissu atteint par l'inflammation. Cependant, lorsque la réponse inflammatoire est excessive en raison d'une altération très importante du tissu, les lésions tissulaires peuvent devenir chroniques. La réponse inflammatoire peut être la conséquence d'une activâtion immunitaire innée, se traduisant par une irritation de la peau, ou d'une activation immunitaire spécifique, par exemple sous forme d'eczéma allergique. Il est donc souhaitable de pouvoir traiter rapidement la réaction inflammatoire de la réponse immunitaire innée car elle peut induire non seulement l'entretien de l'inflammation primaire mais aussi une réaction inflammatoire spécifique dont les conséquences sont parfois graves.The reaction of the cutaneous immune system first has the effect of helping to eliminate the inflammatory agent and to promote the recovery and healing of tissue affected by inflammation. However, when the inflammatory response is excessive due to very large tissue damage, tissue damage may become chronic. The inflammatory response may be the consequence of innate immune activation, resulting in irritation of the skin, or specific immune activation, for example in the form of allergic eczema. It is therefore desirable to be able to rapidly treat the inflammatory response of the innate immune response because it can induce not only the maintenance of primary inflammation but also a specific inflammatory reaction whose consequences are sometimes serious.
De nombreux traitements ont été proposés contre l'inflammation, mais dans le cas de l'inflammation cutanée leur efficacité est généralement médiocre. De plus, ils entraînent souvent des effets secondaires, des effets d'intolérance ou des risques d'accoutumance ou de dépendance. Ainsi les corticoïdes locaux, qui sont les anti-inflammatoires topiques les plus utilisés, présentent des effets secondaires tels qu'une atrophie cutanée ou un développement d'infection microbienne et virale, qui limitent leur utilisation.Many treatments have been proposed against inflammation, but in the case of skin inflammation their effectiveness is generally poor. In addition, they often cause side effects, intolerance effects or risks of addiction or dependence. Thus, local steroids, which are the most used topical anti-inflammatories, have side effects such as cutaneous atrophy or development of microbial and viral infection, which limit their use.
L'huile d'olive, et en particulier l'huile d'olive vierge, contient notamment des acides gras mono-insaturés (acide oléique) ainsi que des composés phénoliques à propriétés anti-oxydantes qui ont pour effet de retarder l'oxydation des lipoprotéines LDL. Parmi ces composés phénoliques, on distingue des alcools phénoliques tels que le tyrosol et l 'hydroxytyrosol, des acides benzoïques, des acides caféique et élénolique estérifiés par le tyrosol et l'hydroxy- tyrosol, ainsi que des flavonoïdes tels que des flavones et flavonols. Des études épidémiologiques ont montré les effets bénéfiques pour la santé des régimes diététiques méditerranéens comprenant un apport élevé en fibres, fruits, légumes, et en huile d'olive qui constitue la source principale de matière grasse. On peut se référer par exemple à RW Owen et al., Lancet Oncol. (Oct. 2000) 107-12.Olive oil, and in particular virgin olive oil, contains in particular monounsaturated fatty acids (oleic acid) as well as phenolic compounds with antioxidant properties which have the effect of retarding the oxidation of LDL lipoproteins. Among these phenolic compounds, there are phenolic alcohols such as tyrosol and hydroxytyrosol, benzoic acids, caffeic and elenolic acids esterified with tyrosol and hydroxy-tyrosol, as well as flavonoids such as flavones and flavonols. Epidemiological studies have shown the health benefits of Mediterranean diets including a high intake of fiber, fruit, vegetables, and olive oil which is the main source of fat. For example, RW Owen et al., Lancet Oncol. (Oct. 2000) 107-12.
La demande internationale WO 01/76579 décrit des compositions contenant des polyphénols d'huile d'olive à activité anti-oxydante et piège à radicaux libres, tels que l'hydroxy- tyrosol et l 'oleuropéine. De telles compositions peuvent être appliquées sur la peau. La demande WO 03/068171 enseigne que l ' hydroxytyrosol et l 'oleuropéine peuvent être utiles dans le traitement de certains troubles neurologiques et inflammations. La demande WO 2007/012057 décrit le traitement de certaines inflammations cutanées par des compositions contenant de l' hydroxytyrosol obtenues à partir de l'eau de traitement des olives.International application WO 01/76579 describes compositions containing polyphenols of olive oil with antioxidant activity and free radical scavenger, such as hydroxy-tyrosol and oleuropein. Such compositions can be applied on the skin. WO 03/068171 teaches that hydroxytyrosol and oleuropein may be useful in the treatment of certain neurological disorders and inflammations. The application WO 2007/012057 describes the treatment of certain cutaneous inflammations by compositions containing hydroxytyrosol obtained from the olive treatment water.
P. Andrewes et al., J. Agric. Food Chem. 51:5, 1415-1420 (2003), ont montré que l'huile d'olive contient un dérivé phénolique particulier, à savoir la deacetoxy ligstroside aglycone, qui est responsable de son goût typique. G. K. Beauchamp et al. Nature, vol. 437, 45-46 (Sept. 2005), ont montré que la deacetoxy ligstroside aglycone, aussi dénommée oléocanthal, contenue dans l'huile d'olive vierge obtenue par première pression à froid, présente des propriétés inhibi- trices des enzymes COXl et COX2, c'est-à-dire des propriétés anti-inflammatoires voisines de celles de l' ibuprofène, molécule utilisée depuis de nombreuses années comme médicament anti-inflammatoire non-stéroidien. Ces propriétés de l'oléo- canthal sont aussi décrites dans WO 2006/122128. Ces propriétés montrent que l ' oléocanthal pourrait être envisagé dans les indications de l ' ibuprofène, c'est-à-dire comme antiinflammatoire général, par voie orale, susceptible d'être utile en rhumatologie et non pour le traitement de l'inflammation cutanée, qui est spécifique comme indiqué ci- dessus.P. Andrewes et al., J. Agric. Food Chem. 51: 5, 1415-1420 (2003), have shown that olive oil contains a particular phenolic derivative, namely deacetoxy ligstroside aglycone, which is responsible for its typical taste. G. K. Beauchamp et al. Nature, vol. 437, 45-46 (Sept. 2005), have shown that deacetoxy ligstroside aglycone, also called oleocanthal, contained in virgin olive oil obtained by first cold pressing, has inhibitory properties of COX1 and COX2 enzymes. , that is to say anti-inflammatory properties similar to those of ibuprofen, a molecule used for many years as a non-steroidal anti-inflammatory drug. These properties of oleochalhal are also described in WO 2006/122128. These properties show that oleocanthal could be considered in the indications of ibuprofen, that is to say as general antiinflammatory, oral, likely to be useful in rheumatology and not for the treatment of cutaneous inflammation. which is specific as indicated above.
L 'oléocanthal, ou deacetoxy-ligstroside aglycone, a été détecté dans des huiles d'olive de diverses provenances, plus particulièrement dans l'huile d'olive vierge obtenue par première pression à froid, à des concentrations très faibles qui varient généralement de 20 à 200 ppm (masse) , soit de 0,002 à 0,02% en poids, en fonction de la provenance de l'huile d'olive.Oleocanthal, or deacetoxy-ligstroside aglycone, has been detected in olive oils of various origins, especially in virgin olive oil obtained by first cold pressing, at very low concentrations which generally vary from at 200 ppm (mass), ie from 0.002 to 0.02% by weight, depending on the source of the olive oil.
L 'oléocanthal peut être représenté par la formule générale (I) suivante : L'oleuropéine, que l'on trouve dans les fruits et principalement dans les feuilles de l'olivier, est un glyco- side représenté par la formule générale (II) ci-dessous :Oleocanthal may be represented by the following general formula (I): Oleuropein, found in fruits and mainly in olive leaves, is a glycoside represented by the general formula (II) below:
( H ) (H)
L'utilisation de l'oleuropéine dans des compositions alimentaires ou pharmaceutiques afin de stimuler la minéralisation osseuse chez l'homme ou l'animal a été proposée dans WO 2004091591. L'activité antivirale de certains dérivés d' oleuropéine a aussi été décrite dans le brevet US 6.455.580. Des dérivés tels que l'oleuropéine aglycone, présentant des propriétés anti-oxydantes, et sa forme dialdéhydique peuvent αuGoi être extraite de l'huile d'olive.The use of oleuropein in food or pharmaceutical compositions for stimulating bone mineralization in humans or animals has been proposed in WO 2004091591. The antiviral activity of certain oleuropein derivatives has also been described in US Pat. US Patent 6,455,580. Derivatives such as oleuropein aglycone, having antioxidant properties, and its dialdehyde form may be extracted from olive oil.
Parmi les autres dérivés d'intérêt que contient l'huile d'olive, on peut citer les formes aldéhyde de l'oleuropéine aglycone et du ligstroside aglycone, représentées par la formule (III) ci-dessous,Among the other derivatives of interest contained in olive oil, mention may be made of the aldehyde forms of oleuropein aglycone and ligstroside aglycone, represented by formula (III) below,
dans laquelle R est un atome d'hydrogène ou un groupe hydroxy, et la forme dialdéhyde de la décarboxyméthyl oleuropéine agly- cone représentée par la formule (IV) . in which R is a hydrogen atom or a hydroxy group, and the dialdehyde form of decarboxymethyl oleuropein aglycon represented by formula (IV).
Une utilisation pharmaceutique de ces composés requiert l'obtention de fractions relativement concentrées. De plus, l'oléocanthal est un produit très fragile, facilement détruit par la chaleur et par oxydation, comme le sont d'ailleurs la plupart des autres composés polyphénoliques naturellement présents dans les huiles végétales.Pharmaceutical use of these compounds requires the production of relatively concentrated fractions. In addition, oleocanthal is a very fragile product, easily destroyed by heat and oxidation, as are most of the other polyphenolic compounds naturally present in vegetable oils.
Ces dérivés, ainsi que l'oléocanthal, participent aux propriétés utiles de l'huile d'olive et pour cette raison divers procédés d'extraction ont été mis au point pour les isoler ou pour produire des extraits enrichis en l'un ou l'autre ou plusieurs de ces dérivés.These derivatives, as well as oleocanthal, participate in the useful properties of olive oil and for this reason various extraction processes have been developed to isolate them or to produce enriched extracts in one or the other. other one or more of these derivatives.
Les études effectuées par la demanderesse ont montré de manière étonnante que des extraits contenant ces dérivés, et tout particulièrement l'oléocanthal et certains dérivés, présentent en outre des propriétés intéressantes permettant de les utiliser dans les domaines cosméceutique et dermatologique en raison de leur action anti-inflammatoire cutanée et de leur bonne stabilité.The studies carried out by the Applicant have surprisingly shown that extracts containing these derivatives, and especially oleocanthal and certain derivatives, also have advantageous properties for use in the cosmeceutical and dermatological fields because of their anti-aging action. -Inflammatory skin and their good stability.
La présente invention a donc pour objet l'utilisation d'extraits d'huile d'olive contenant de l'oléocanthal et/ou des dérivés de formule générale (A) ci-aprèsThe subject of the present invention is therefore the use of olive oil extracts containing oleocanthal and / or derivatives of general formula (A) below.
(A) dans laquelle R représente un atome d'hydrogène ou un groupe hydroxy, pour la préparation d'un médicament destiné au traitement de l'inflammation cutanée. (AT) wherein R represents a hydrogen atom or a hydroxy group, for the preparation of a medicament for the treatment of cutaneous inflammation.
L'invention a plus particulièrement pour objet l'utili- sation d'extraits d'huile d'olive contenant de l'oléocanthal et/ou des dérivés, pour la préparation d'un médicament administrable par voie topique à usage externe pour le traitement de l'inflammation cutanée.The invention more particularly relates to the use of olive oil extracts containing oleocanthal and / or derivatives, for the preparation of a topically administrable medicament for external use for the treatment skin inflammation.
L'invention a encore pour objet l'utilisation combinée d'oléocanthal, et/ou de dérivés de formule (A) ci-dessus, et d'oleuropéine ainsi qu'une composition pharmaceutique les associant, utile notamment pour le traitement de l'inflammation cutanée.The invention also relates to the combined use of oleocanthal, and / or derivatives of formula (A) above, and oleuropein and a pharmaceutical composition associating them, useful in particular for the treatment of the skin inflammation.
Les études effectuées par la demanderesse ont montré que l'efficacité de compositions à base d'extraits d'huile d'olive contenant de l'oléocanthal et/ou des dérivés de formule (A) ci-dessus, tels que le dialdéhyde de décarboxyméthyl oleuro- péine aglycone, dans le traitement local de l'inflammation cutanée résulte d'un mécanisme d'action clairement différent de celui des anti-inflammatoires généraux comme l ' ibuprofène, qui est expliqué plus en détail ci-après.The studies carried out by the applicant have shown that the effectiveness of compositions based on olive oil extracts containing oleocanthal and / or derivatives of formula (A) above, such as decarboxymethyl dialdehyde Oleurospine aglycone, in the local treatment of cutaneous inflammation results from a mechanism of action clearly different from that of general anti-inflammatories such as ibuprofen, which is explained in more detail below.
Une étude de l'effet de l'oléocanthal et de dérivés suivant l'invention sur les kératinocytes humains a été faite par la technique des gènes "microarray" dédiés, permettant de préciser l'action thérapeutique par rapport à celle de la dexaméthasone .A study of the effect of oleocanthal and derivatives according to the invention on human keratinocytes was made by the technique of "microarray" genes dedicated to clarify the therapeutic action compared to that of dexamethasone.
Cette étude a permis de mettre en évidence un mécanisme d'action inédit de l'oléocanthal qui réprime l'activation des messages d'alerte ou de sensibilité des récepteurs de messagers d'inflammation (PGE-2 et IL-β) en diminuant les systèmes de défense antiradicalaires induits par l'inflammation, ce qui traduit une diminution de l'inflammation innée. L'étude a aussi mis en évidence une diminution de l'induction du récepteur IL-6 et la répression de l'ENA-78 qui est le facteur chimiotactique pour les neutrophiles . Ce mécanisme est important car la voie de recrutement des lymphocytes et des macrophages polynucléaires est une voie fondamentale dans la réaction inflammatoire primitive. Ainsi l'oléocanthal peut être efficacement utilisé pour le traitement local de l'inflammation cutanée.This study has revealed a novel mechanism of action of oleocanthal that represses the activation of alert messages or sensitivity of the inflammatory messenger receptors (PGE-2 and IL-β) by decreasing the anti-radical defense systems induced by inflammation, which reflects a decrease in innate inflammation. The study also revealed a decrease in IL-6 receptor induction and the repression of ENA-78 which is the chemotactic factor for neutrophils. This This mechanism is important because the recruitment pathway of polynuclear lymphocytes and macrophages is a fundamental pathway in the primary inflammatory response. Thus oleocanthal can be effectively used for the local treatment of skin inflammation.
De plus, l'étude a montré que l'action de l'oléocanthal sur les défenses antiradicalaires est tout à fait originale car elle a pour effet de limiter l'induction de l'inflammation par le PMA (phorbol-12 myristate-13 acétate) et diminue ainsi la nécessité de renforcer les défenses antiradicalaires pour combattre l'inflammation.In addition, the study showed that the action of oleocanthal on the antiradical defenses is quite original because it has the effect of limiting the induction of inflammation by PMA (phorbol-12 myristate-13 acetate ) and thus decreases the need to strengthen the antiradical defenses to combat inflammation.
Ces actions mettent en évidence les différences avec un anti-inflammatoire général comme la dexaméthasone et expliquent que l'oléocanthal, et ses dérivés, puissent être efficacement utilisés dans le traitement de l'inflammation cutanée primaire, contrairement à la dexaméthasone.These actions highlight the differences with a general anti-inflammatory such as dexamethasone and explain that oleocanthal, and its derivatives, can be effectively used in the treatment of primary cutaneous inflammation, unlike dexamethasone.
Une autre étude sur le profil d'expression du génome entier par la technique "microarray" a mis en évidence d'autres effets inattendus de l'oléocanthal sur les kérati- nocytes humains traités par le PMA dont l'action est proinflammatoire. L'effet sur l'expression des gènes régulés directement ou indirectement par la protéine kinase C en réponse au PMA permet de conclure à une modulation de l'action du TNFα directement impliqué dans la réaction inflammatoire primaire.Another study of the whole genome expression profile by the "microarray" technique revealed other unexpected effects of oleocanthal on PMA-treated human keratinocytes with proinflammatory action. The effect on the expression of genes regulated directly or indirectly by protein kinase C in response to PMA makes it possible to conclude that the TNFα action directly involved in the primary inflammatory reaction is modulated.
Ainsi ces résultats confirment que des compositions à base d'extraits contenant l'oléocanthal et les dérivés de l'invention permettent de contrôler les actions pro-inflam- matoires d'haptènes et peuvent donc être utilisés efficacement dans le traitement local de l'inflammation primaire cutanée.Thus these results confirm that extracts-based compositions containing oleocanthal and the derivatives of the invention make it possible to control the pro-inflammatory actions of haptens and can therefore be used effectively in the local treatment of inflammation. primary skin.
Ces dérivés sont tout particulièrement utiles dans le traitement des brûlures primaires, des coups de soleil, de piqûres d'insectes, des radiodermites consécutives à une radiothérapie, des plaies superficielles et des irritations cutanées provoquées par des agents chimiques ou des substances urticantes. Ils présentent en outre l'avantage de traiter l'inflammation et d'avoir un effet antalgique calmant la douleur éventuellement associée à l'inflammation.These derivatives are particularly useful in the treatment of primary burns, sunburns, insect bites, radiodermites following radiotherapy, superficial wounds and cutaneous irritations caused by chemicals or substances. stinging. They also have the advantage of treating inflammation and having a pain relieving analgesic effect possibly associated with inflammation.
L' oléocanthal, ainsi que les dérivés décrits ci-dessus, peuvent être utilisés sous forme d'extrait d'huile d'olive plus ou moins enrichis en oléocanthal.The oleocanthal, as well as the derivatives described above, can be used in the form of olive oil extract more or less enriched with oleocanthal.
Les études effectuées par la méthode ELISA et le dosage du récepteur d'IL-6 ont montré que dans le cas de l'utilisation d'un extrait d'huile d'olive, il est préférable que la concentration en oléocanthal, et le cas échéant en dérivés, soit supérieure ou égale à 10% en poids par rapport au poids total de l'extrait. Ainsi il est avantageux que l'extrait contienne au moins 10% en poids d Oléocanthal et au moins 10% en poids de dérivé. Les quantités utilisées par dose unitaire peuvent être comprises entre 0,1 mg et 500 mg pour 1 Oléocanthal et pour le dérivé utilisé isolément ou, de préférence, en association avec l ' oléocanthal . Suivant une forme préférentielle de réalisation de l'invention, la composition comprend en association 1 à 100 mg d'oléocanthal et 0,5 à 100 mg de dérivé pour 100 g de composition totale.Studies using the ELISA method and the IL-6 receptor assay have shown that in the case of using an olive oil extract, it is preferable that the oleocanthal concentration, and the case derivatives, greater than or equal to 10% by weight relative to the total weight of the extract. Thus, it is advantageous for the extract to contain at least 10% by weight of oleocanthal and at least 10% by weight of derivative. The amounts used per unit dose may range from 0.1 mg to 500 mg for Oleocanthal and the derivative used alone or, preferably, in combination with oleocanthal. According to a preferred embodiment of the invention, the composition comprises in combination 1 to 100 mg of oleocanthal and 0.5 to 100 mg of derivative per 100 g of total composition.
Les compositions suivant l'invention associant l' oléocanthal et l ' oleuropéine présentent l'avantage de procurer un action inflammatoire complémentaire de celle de l ' oléocanthal améliorant l'efficacité du traitement.The compositions according to the invention combining oleocanthal and oleuropein have the advantage of providing an inflammatory action complementary to that of oleocanthal improving the effectiveness of the treatment.
Les compositions utilisables dans la présente invention peuvent se présenter sous toutes les formes galéniques usuelles adaptées à une administration locale topique.The compositions that may be used in the present invention may be in any of the usual dosage forms suitable for topical local administration.
Ainsi, les compositions pour application topique peuvent se présenter sous forme de solutions huileuses ou hydroalcooliques, de solutions pour pulvérisation, de dispersions, de sérums, de gels ou de lipo-gels, de suspensions, d'émul- sions liquides ou semi-liquides (par exemple un lait) , solide ou semi-solide, de shampooing ou de formulation de type spot- on. Les émulsions peuvent être du type huile dans eau (H/E) ou eau dans huile (E/H) , par exemple des gels ou des crèmes. On utilise de préférence un milieu lipidique, par exemple un solvant lipophile tel que le 1, 2-O-isopropylidèneglycérolThus, compositions for topical application may be in the form of oily or aqueous-alcoholic solutions, spraying solutions, dispersions, serums, gels or lipogels, suspensions, liquid or semi-liquid emulsions (eg milk), solid or semi-solid, shampoo or spot-on formulation. The emulsions may be of the oil-in-water (O / W) type or water in oil (W / O), for example gels or creams. A lipid medium is preferably used, for example a lipophilic solvent such as 1,2-O-isopropylideneglycerol.
(Solketal) et le mono-éthyléther de diéthylène glycol (Trans- cutol) , plus compatible en particulier avec l'utilisation d'un extrait d'huile d'olive.(Solketal) and diethylene glycol mono-ethyl ether (Transcutol), more compatible in particular with the use of an olive oil extract.
Il peut être particulièrement avantageux d'utiliser un extrait d'huile d'olive de l'invention, contenant environ 30% d'oléocanthal, sous forme imprégnée dans des tissus destinés à être appliqués sur la peau. Une telle forme est bien adaptée au traitement de traumatismes, à la résorption des nodules fibreux sur les aponévroses et à la réduction des contusions. On peut utiliser l'extrait sous forme encapsulée dans des bandages en tissus de telle sorte que la libération de l'extrait soit provoquée par les mouvements. Par exemple, une forme adaptée à une activité sportive susceptible d'entraîner des traumatismes peut être constituée par des microcapsules imprégnées dans des vêtements portés par les sportifs tels que maillots et chaussettes. Le choix de la dose utilisée et de la durée du traitement est déterminé par le praticien, mais d'une manière générale on peut utiliser une composition dosée à 20 ou 50 mg d'oléo- canthal à raison de deux applications quotidiennes pendant une durée de deux ou trois jours pour un traitement curatif ou d'environ 3 à 15 jours pour un traitement préventif ou d' entretien.It may be particularly advantageous to use an olive oil extract of the invention, containing about 30% oleocanthal, in impregnated form in tissues to be applied to the skin. Such a form is well suited to the treatment of trauma, the resorption of fibrous nodules on the fasciae and the reduction of bruises. The encapsulated extract can be used in tissue bandages such that the release of the extract is caused by the movements. For example, a form adapted to a sports activity likely to cause trauma may be formed by microcapsules impregnated in clothing worn by sportsmen such as jerseys and socks. The choice of the dose used and the duration of the treatment is determined by the practitioner, but in general one can use a composition dosed at 20 or 50 mg of oleochalhal for two daily applications for a duration of two or three days for curative treatment or about 3 to 15 days for preventive treatment or maintenance.
Une étude clinique multicentrique a été réalisée sur 50 patients présentant une inflammation cutanée primaire.A multicenter clinical study was performed on 50 patients with primary cutaneous inflammation.
Un tulle gras identique à celui de l'Exemple 1 ci-après mais contenant un extrait d'huile d'olive à 30% d'oléocanthal, est utilisé pour traiter 5 patients préalablement traités par dermabrasion pour kératoses séborrhéiques du tronc et du visage. On constate alors une résorption du gonflement, de la rougeur et de la douleur résultant de la dermabrasion. Un lipogel à 0,5% de solution à 30% d'oléocanthal est administré à 5 patients ayant reçu un peeling à l'acide tri- chloracétique à 30%. L'érythème, le gonflement et les sensations de picotement et brûlures résultant du peeling sont très nettement atténués dès la première application de la composition de l'invention.A tulle fat identical to that of Example 1 below but containing an olive oil extract 30% oleocanthal, is used to treat 5 patients previously treated with dermabrasion for seborrheic keratosis of the trunk and face. There is a resorption of swelling, redness and pain resulting from dermabrasion. A lipogel at 0.5% 30% oleocanthal solution was administered to 5 patients who received a 30% trichloroacetic acid peel. The erythema, swelling and tingling sensations and burns resulting from the peeling are very clearly attenuated from the first application of the composition of the invention.
5 patientes présentant une radiodermite aiguë de stade 1 consécutive à une radiothérapie pour cancer du sein sont traitées par une crème conforme à l'Exemple 2. On observe un soulagement rapide des patientes par contrôle de l'érythème présent .5 patients with stage 1 acute radiodermatitis following radiotherapy for breast cancer are treated with a cream according to Example 2. Rapid relief of patients is observed by control of the erythema present.
Un gel-spray à 0,3% d'une solution à 40% d'oléocanthal et 40% de dialdéhyde de décarboxyméthyl oleuropéine aglycone de formule (A) ou R est OH, est appliqué à 5 patients présentant un érythème actinique primaire après photothérapie UV-B pour psoriasis. On observe une réduction rapide de la symptoma- tologie fonctionnelle.A gel-spray containing 0.3% of a 40% oleocanthal solution and 40% of decarboxymethyl oleuropein aglycone dialdehyde of formula (A) or R is OH, is applied to 5 patients presenting a primary actinic erythema after phototherapy. UV-B for psoriasis. There is a rapid reduction in functional symptomology.
20 patients (sportifs de haut niveau) présentant des dermites inflammatoires liées à des frictions répétées lors de la pratique sportive dans les zones préthoraciques, les plis interfessiers, le tendon d'Achille, la pulpe des orteils et des talons ainsi que l'intérieur des cuisses, ont été traités par une pâte à l'huile conforme à celle de l'Exemple 3. Une amélioration rapide de l'état des patients a été observée. 6 patients présentant une peau réactive sensible et irritable et 4 patients affectés d'acné rosacée irritée, ont été traités en deux applications quotidiennes d'une crème fluide conforme à l'Exemple 2. On a constaté chez tous les patients un soulagement rapide et en particulier un contrôle de l'érythème.20 patients (high-level athletes) with inflammatory dermatitis associated with repeated frictions during sports practice in the pre-rhoenic areas, the intergluteal folds, the Achilles tendon, the pulp of the toes and heels and the interior of the muscles. thighs, were treated with an oil paste according to that of Example 3. A rapid improvement in the condition of the patients was observed. 6 patients with sensitive and irritable reactive skin and 4 patients with irritated rosacea acne were treated in two daily applications of a fluid cream according to Example 2. All patients were found to have rapid relief and particular control of erythema.
Des exemples de compositions pharmaceutiques à base d'oléocanthal sont donnés ci-après. Dans ces exemples toutes les parties et pourcentages sont indiqués en poids, sauf indication contraire. Exemple 1Examples of oleocanthal-based pharmaceutical compositions are given below. In these examples all parts and percentages are by weight unless otherwise indicated. Example 1
Une composition pour tulle gras sur support en coton est préparée suivant la formulation ci-dessous.A tulle composition on a cotton support is prepared according to the formulation below.
Vaseline 30,0 Glycérine 25,0Vaseline 30.0 Glycerin 25.0
Cyclomethicone 5,0Cyclomethicone 5.0
Copolymère éthylène / propylène 12,0Ethylene / propylene copolymer 12.0
Perfluorodiméthylcyclohexane 15, 0Perfluorodimethylcyclohexane 15.0
Lauroyl lysine 5,0 Polysaccharides 7,0Lauroyl lysine 5.0 Polysaccharides 7.0
Extrait d'huile d'olive à 10% d'oléocanthal 0,5 Conservateur 0,5Olive oil extract with 10% oleocanthal 0.5 preservative 0.5
Cette composition est imprégnée sur un tulle à support en coton pour constituer un tulle gras destiné au traitement des inflammations cutanées liées aux brûlures primaires et des kératoses séborrhéiques.This composition is impregnated on a tulle with a cotton support to constitute a tulle gras intended for the treatment of cutaneous inflammations related to primary burns and seborrheic keratoses.
Exemple 2Example 2
Une crème fluide pour application externe est préparée suivant les techniques classiques et sa formulation est la suivante.A fluid cream for external application is prepared according to conventional techniques and its formulation is as follows.
Cyclopentasiloxane (and) PEG/PPG 18/18 diméthicone 10,0Cyclopentasiloxane (and) PEG / PPG 18/18 Dimethicone 10.0
Cyclopentasiloxane 8,0 Cyclopentasiloxane (and) diméthicone réticulée (and) cyclohexasiloxane 2,0Cyclopentasiloxane 8.0 Cyclopentasiloxane (and) crosslinked dimethicone (and) cyclohexasiloxane 2.0
Benzoate d'alkyle C12/15 8,0C12 / 15 alkyl benzoate 8.0
Acétate de tocophéryle 0,5Tocopheryl acetate 0.5
Chlorure de sodium 1,0Sodium chloride 1.0
Chlorphénésine 0,3 Gomme de xanthane 0,2Chlorphenesin 0.3 Xanthan gum 0.2
Butylène glycol 3,0Butylene glycol 3.0
Imidazolidinyl urée 0,2Imidazolidinyl urea 0.2
Extrait d'huile d'olive à 80% d'oléocanthal 0,1Olive oil extract with 80% oléocanthal 0,1
Eau q.s.p. 100,0 Cette crème peut être appliquée sur les zones de la peau présentant une inflammation cutanée consécutive à un érythème ou coup de soleil, une ou deux fois par jour pendant 2 à 3 jours.Water qs 100.0 This cream can be applied to areas of skin with skin inflammation following erythema or sunburn, once or twice daily for 2 to 3 days.
Exemple 3Example 3
On prépare une pâte à l'huile ayant la composition pondérale indiquée ci-après (en g) .An oil paste having the weight composition indicated below (in g) is prepared.
Oxyde de zinc 12,0Zinc oxide 12.0
Talc 13,0 Lanoline 35,0Talc 13.0 Lanolin 35.0
Vaseline 35,0Vaseline 35.0
Glycérine 4,5Glycerin 4,5
Extrait d'huile d'olive à 30% d' oléocanthal 0,5 Cette pâte peut être utilisée plus particulièrement pour le traitement de dermites inflammatoires liées à des frictions répétées lors de la pratique sportive.Extract of olive oil with 30% oleocanthal 0.5 This paste can be used more particularly for the treatment of inflammatory dermatitis linked to repeated frictions during sports practice.
Exemple 4Example 4
On prépare un gel ayant la composition pondérale indiquée ci-après : Phase A :A gel having the weight composition indicated below is prepared: Phase A:
Glycérine 4,5Glycerin 4,5
Sorbitol 70% 4,0Sorbitol 70% 4.0
Polysorbate 80 0,1Polysorbate 80 0.1
Gomme xanthane 0,1 Pentylène glycol 2,0Xanthan Gum 0.1 Pentylene Glycol 2.0
EDTA disodique 0,10.1 disodium EDTA
Eau q.s.p.Water q.s.
Phase B : Copolymère réticulé acrylate / alkyl acrylate C10-30 (Pemulen®) 0,2Phase B: C10-30 Acrylate / Alkyl Acrylate Crosslinked Copolymer (Pemulen®) 0.2
Phase C :Phase C:
Copolymère acrylate d'hydroxyéthyle / acryloyl diméthyl taurate de sodium et Polysorbate 60 1,5 Phase D :Hydroxyethyl acrylate / sodium acryloyl dimethyl taurate copolymer and Polysorbate 60 1.5 Phase D:
Octyldodécanol 2,0Octyldodecanol 2.0
Cyclométhicone 4,0Cyclomethicone 4.0
Ethanol 96° 2,0 Extrait d'huile d'olive à 30% d'oléocanthal 1,6Ethanol 96 ° 2.0 Olive oil extract with 30% oleocanthal 1.6
Phase E :Phase E:
Hydroxyde de sodium 30% 0,2Sodium hydroxide 30% 0.2
Phase F :Phase F:
Tetrahydropiperine (Sabinsa) 0,5 La phase A est préparée de manière classique par mélange des composants dans une cuve. La phase D est préparée et homogénéisée soigneusement dans une autre cuve. Puis on ajoute la phase D ainsi que les phases B et C préalablement dispersées séparément, l'ajout étant effectué lentement sous agita- tion. On neutralise ensuite en ajoutant la phase E et on ajoute la phase F préalablement dissoute.Tetrahydropiperine (Sabinsa) 0.5 Phase A is prepared conventionally by mixing the components in a tank. Phase D is prepared and carefully homogenized in another tank. Phase D and the previously dispersed phases B and C are then added separately, the addition being carried out slowly with stirring. It is then neutralized by adding phase E and the previously dissolved F phase is added.
Le pH de la composition est d'environ 5,6, et la viscosité de 2000 mPas (Brookfield RVT MOB 3, 20 trs/min, 1 min. ) Un gel du type de celui décrit ci-dessus peut être avantageusement imprégné dans des tissus appliqués sur la peau afin de traiter divers traumatismes, ou pour réduire des contusions . The pH of the composition is about 5.6, and the viscosity is 2000 mPas (Brookfield RVT MOB 3, 20 rpm, 1 min.). A gel of the type described above can be advantageously impregnated in applied to the skin to treat various trauma, or to reduce bruising.

Claims

REVENDICATIONS
1. Utilisation d'extraits d'huile d'olive contenant de l'oléocanthal et/ou des dérivés de formule générale (A) ci- après1. Use of olive oil extracts containing oleocanthal and / or derivatives of general formula (A) below
dans laquelle R représente un atome d'hydrogène ou un groupe hydroxy, dans la préparation d'un médicament pour le traitement de l'inflammation cutanée. wherein R represents a hydrogen atom or a hydroxy group, in the preparation of a medicament for the treatment of cutaneous inflammation.
2. Utilisation selon la revendication 1, caractérisée en ce que le médicament est administrable par voie topique cutanée.2. Use according to claim 1, characterized in that the medicament is administrable topically cutaneous.
3. Utilisation selon l'une quelconque des revendications 1 et 2, caractérisée en ce que l'extrait d'huile d'olive contient au moins 10% en poids d'oléocanthal.3. Use according to any one of claims 1 and 2, characterized in that the olive oil extract contains at least 10% by weight of oleocanthal.
4. Utilisation selon la revendication 3, caractérisée en ce que l'extrait d'huile d'olive contient au moins 30% en poids d'oléocanthal .4. Use according to claim 3, characterized in that the olive oil extract contains at least 30% by weight of oleocanthal.
5. Utilisation selon la revendication 4, caractérisée en ce que l'extrait contient en outre au moins 10% en poids de dérivé. 5. Use according to claim 4, characterized in that the extract further contains at least 10% by weight of derivative.
6. Utilisation selon l'une quelconque des revendications 1 à 4, caractérisée en ce la composition contient entre 1 et 100 mg d'oléocanthal par dose unitaire.6. Use according to any one of claims 1 to 4, characterized in that the composition contains between 1 and 100 mg of oleocanthal unit dose.
7. Utilisation selon la revendication 6, caractérisée en ce que la composition contient en outre entre 0,5 et 100 mg de dérivé de formule (A) où R est un groupe hydroxy.7. Use according to claim 6, characterized in that the composition further contains between 0.5 and 100 mg of derivative of formula (A) where R is a hydroxy group.
8. Utilisation selon l'une quelconque des revendications précédentes, caractérisée en ce que la composition contient en outre de l ' oleuropéine. 8. Use according to any one of the preceding claims, characterized in that the composition further contains oleuropein.
9. Utilisation selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle est destinée au traitement des brûlures primaires, des coups de soleil, de piqûres d'insectes, des radiodermites consécutives à une radiothérapie, des plaies superficielles et des irritations cutanées provoquées par des agents chimiques ou des substances urticantes .9. Use according to any one of the preceding claims, characterized in that it is intended for the treatment of primary burns, sunburn, insect bites, radiodermites following radiotherapy, superficial wounds and irritation. cutaneous caused by chemicals or stinging substances.
10. Composition pharmaceutique utile pour le traitement de l'inflammation cutanée, caractérisée en ce qu'elle comprend en combinaison un dérivé de formule générale (A) de la revendication 1 et de l ' oleuropéine. 10. Pharmaceutical composition useful for the treatment of cutaneous inflammation, characterized in that it comprises in combination a derivative of general formula (A) of claim 1 and oleuropein.
EP08827837A 2007-07-04 2008-07-04 Use of oleocanthal for treatment of cutaneous inflammation Withdrawn EP2167072A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0704825A FR2918278B1 (en) 2007-07-04 2007-07-04 USE OF OLEOCANTHAL IN THE TREATMENT OF SKIN INFLAMMATION.
PCT/FR2008/000964 WO2009024680A1 (en) 2007-07-04 2008-07-04 Use of oleocanthal for treatment of cutaneous inflammation

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EP2167072A1 true EP2167072A1 (en) 2010-03-31

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ES2769901A1 (en) * 2018-12-28 2020-06-29 Consejo Superior Investigacion Use of secoiridoids for the treatment or prevention of immune mediated inflammatory diseases.

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RO113113B1 (en) * 1997-05-07 1999-04-30 Felician Titus Stoica Ointment for treating burns and other skin affections
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FR2918278A1 (en) 2009-01-09
WO2009024680A1 (en) 2009-02-26

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