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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• • 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
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• • 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
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/716—Glucans
  • A61K31/722—Chitin, chitosan
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/362—Polycarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/73—Polysaccharides
  • A61K8/736—Chitin; Chitosan; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • 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
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • 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
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • 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
• • 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
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

• the present invention relates to compositions containing chitosan, a chitosan derivative or a physiologically acceptable salt thereof, and a short-medium chain dicarboxylic acid amide, or a physiologically acceptable salt thereof, for the preparation of a medicament, or a medical device, or a sanitary product, or a cosmetic, forming a film after application onto the skin of the face and of other affected areas, useful for protecting skin in rosacea, a chronic inflammatory condition of the skin, and other skin conditions characterized by teleangectasia, like couperose and leg teleangectasia.
• Rosacea is a common but often misunderstood condition that is estimated to affect over 13 million people worldwide
• erythema flushing and redness, also called “couperose”
• rosacea As rosacea progresses, other symptoms can develop such as semi-permanent erythema, teleangiectasia
• rhinophyma red lobulated nose
• Rosacea affects both sexes, but is almost three times more common in women, is common in the third and fourth decade and peaks between the ages of 40 and 50 years.
• the presence of rash on the scalp or ears suggests a different or co-existing diagnosis, as rosacea is primarily a facial diagnosis.
• Microorganism also have been claimed to contribute to the development or complicate rosacea, like Demodex folliculorum, Helicobacter pylori or Propionibacterium acnes. Treatment of rosacea is inconclusive. Systemic or topical treatments include antibiotics, metronidazole and antifungals; retinoids, some beta blockers, spironolactone. No causal treatment has ever been proposed, and lifelong symptomatic treatment is often necessary, as just few cases may go into a permanent remission of the symptoms. Long term treatment of rosacea is limited by the intrinsic toxicity of drugs. Leg teleangectasia consists in very thin varicose capillaries, with calibre within 0,1 and 1 mm, that are classified as follows:
• Teleangectasia due to venous insufficiency due to venous insufficiency, accompanied by other clinical signs of venous insufficiency. They are localized at the foot back, retromalleolar region, legs, and at the medial thigh surface.
• Reticular varicous veins in most cases they represent the nourishing veins for the districts that are interested by telengectasia .
• Chitosan and its derivatives are amino-polysaccharides, derived from the chitin extracted from the exoskeleton of the crustaceans, known in the art for their use in different preparations.
• KR20020084672 discloses chitosan as an ingredient of microspheres, useful as a carrier for separation of proteins or peptides;
• KR20020048534 reports chitosan as an ingredient of a pack composition for skin massage, including paraffin wax as an effective component;
• JP2005306746 is teaching the use of chitosan to obtain a wrinkle therapeutic agent as an ingredient of gel-like or spongy preparations of botulinus toxin.
• WO2005055924 reports chitosan derivatives as ingredients of hydrogels useful for cavity-filling wound dressings.
• JP2004231604 teaches compositions of chitosans having a high deacetylation degree, as an ingredient of a carrier sheet with a porous spongy texture.
• WO03042251 discloses compositions comprising chitosan in the form of a network of nano-sized fibres.
• WO02057983 discloses a multi- layered, air gap sheet of chitosan with a regular lamellar structure which retains drugs for a prolonged period of time;
• JP11060605 teaches an amphiphilic chitosan derivative which can be used as dispersion stabilizer or emulsifier in a drug for application to skin.
• EP1303249 discloses a nail varnish composition containing at least one antimycotic agent and an hydroxyalkyl or a carboxyalkyl chitosan
• WO2004/112814 discloses a nail restructuring composition based on one herb extract from the genus Equisetum in combination with hydroxypropyl chitosan .
• preparations containing chitosan or its derivatives, and at least the amide of a short-medium chain (from 6 to 12 carbon atoms) aliphatic dicarboxylic acid may form an elastic film onto the skin, after application and drying, suitable to protect the skin from chemical or physical insults.
• the two components of the film, saccharidic and lipidic act in a synergistic way and have a protective activity superior to that of the two components alone.
• the film forming compositions according to the present invention may easily be sprayed onto the skin surface, by allowing quick drying and easy formation of an elastic film, that avoids bothersome sensation of oily skin.
• the film forming compositions according to the present invention may also be applied on the skin by gently massage.
• the film formed after drying protects the skin from the insult of both hot and cold temperature, decreases the inflammation due to ultraviolet radiation and prevents the growth of microorganisms by coating them and inhibiting their vital functions.
• the object of the present invention is thus represented by a pharmaceutical and/or cosmetic composition containing:
• Said composition is useful to form a film after application onto the skin and drying, that protects the skin of the face and the other areas affected byrosacea as well as by other skin conditions characterized by teleangectasia .
• water soluble chitosans are preferred; hydroxyalkyl chitosans, such as hydroxypropyl chitosan, being the most preferred water soluble chitosans derivatives .
• Cs-Cio-dicarboxylic acids are particularly preferred, Cg-dicarboxylic acids being the most preferred; according to additional preferred ambodiments, such dicarboxylic acids are linear and/or alkyl acids.
• the C6-Ci2-dicarboxylic acid amide which is used for the purposes of the present invention is preferably represented by the following formula:
• n is comprised between 4 and 10, preferably between 6 and 8 and, more preferably, it is 7 ;
• R is a -N (R' ) (R'') group, wherein: R' is H or a Ci-C 4 -alkyl group, and
• R'' is H, a Ci-C 4 -alkyl group or a Ci-C 4 -carboxy group.
• said Ci-C 4 -alkyl groups are methyl or ethyl whereas said Ci-C 4 -carboxy group is carboxy methyl .
• the preferred C6-Ci2-dicarboxylic acid is azelaic acid .
• azelaic acid amides such as azeloyl diglycine, are thus preferred, and may be in form of a salt, preferably a sodium or potassium salt, such as potassium azeloyl diglycinate.
• compositions according to the present invention may be applied by a gently massage on the skin, or may be sprayed by allowing the formation of an elastic film after drying.
• the composition according to the present invention allows a long lasting intimate contact and continuous protection of the skin for many hours after the application.
• Compositions according to the present invention are in the form are in the form of liquid, semiliquid or semisolid preparations, including solutions, suspensions, lotions, emulsions, colloids, creams, gels, with a content in component A from 0.1 to 10 wt . % (percentages by weight are given with respect to the whole preparation) , preferably from 0.2 to 5 wt.%, more preferably from 0.25 to 2.0 wt . % and with a content in component B from 0.1 to 30 wt.% (percentages by weight are given with respect to the whole preparation), preferably from 0.25 to 25 wt.%, more preferably from 0.5 to 20 wt.%.
• compositions according to the present invention are superior to the conventional formulations, in that they leave an uniform and invisible film. Moreover, compositions according to the present invention do not dirty, do not dry like gels and lotions do, and do not give bothersome sensation when applied, like other rigid film preparations do.
• compositions are prepared according to conventional technique, using compatible excipients, adjuvants and/or pharmaceutically or cosmetically acceptable carriers, and may contain, in combination, other active principles with complementary or, in any case, useful activity.
• compositions prepared according to the present invention include: solutions, emulsions, suspensions, colloids, creams, gels, for application to affected skin.
• compositions according to the present invention may contain one or more additional ingredients selected from solvents, sunscreens, skin-conditioning agents, emollients, moisturizers, emulsifying agents, viscosity- increasing agents, UV-A filters, plant extracts, antioxidants .
• Phase A Hydroxypropyl chitosan was dispersed in ca. 50%wt of total water until a clear solution was obtained. The solution was heated at 65°C ⁇ 2°C and Xanthan gum was added and stirred until a homogenous solution was obtained.
• Phase B Potassium palmitoyl, Glyceryl Stearate, Cetearyl
• Phase B was added to Phase A under agitation (turbo) to allow the emulsification .
• the resulting emulsion was cooled to 35°C ⁇ 2°C under continuous mixing.
• the formulation was prepared by using the same method described for Example 1.
• Phase A Hydroxypropyl chitosan was dispersed in ca. 50%wt of total water until a clear solution was obtained. The solution was heated at 65°C ⁇ 2°C and Xanthan gum was added and stirred until a homogenous solution was obtained.
• Phase B Potassium palmitoyl, Cetearyl Alcohol, Glyceryl
• Phase B was added to Phase A under agitation (turbo) to allow the emulsification .
• the resulting emulsion was cooled to 35°C ⁇ 2°C under continuous mixing.
• Phenethyl Alcohol, Potassium Azeloyl Diglycinate dissolved in the rest of purified water (50%wt) and Ethyl Alcohol were mixed into the emulsion at the end of preparation.
• the product was kept under gentle agitation until a homogenous oil in water cream was obtained.
• the preparation was made as in Example 1. A homogenous oil in water cream was obtained.
• VEGF Vascular Endothelial Growth Factor
• VEGF Vascular Endothelial Growth Factor
• keratinocytes i.e. the cells of the skin.
• soluble inflammation mediator like IL-I alpha
• epidermal keratinocytes increase the synthesis and release of VEGF.
• Epidermis units have been treated with IL-l ⁇ in the cell medium to induce an increase in the VEGF synthesis, and at the same time treated applying the investigated samples undiluted on the epidermis corneous layer. Following 24 h treatment, the cell culture medium below the epidermis units was collected and analyzed for the VEGF content through an ELISA assay.
• the tested samples were the preparation as per the Example 4 and the two comparative preparations LPOL2899A and LPOL2899B. Skin units treated with IL-l ⁇ only have been used as positive controls.
• the experiment was carried out in three replicas.
• In vitro test system employed consists of a tridimensional artificial system of human epidermis (Mattek, USA) i. e. a reconstructed artificial human skin model comprising normal human epidermal keratinocytes, growing as an integrated three-dimensional cell culture model, perfectly mimicking the human skin in vitro. The model exhibits normal barrier functions (presence of a differentiated stratum corneum) .
• VEGF release assay following IL-l ⁇ treatment 500 pg/ml, with and without treatment with the samples is reported in the following table.
• the effect of the preparation containing hydroxypropyl chitosan was 25.7% inhibition and that of the preparation containing potassium azeloyl diglycinate was 33.9% inhibition.
• the preparation as per the Example 4 had the strongest inhibitory effect (46.4% inhibition) confirming a synergistic activity of the two components on the protection of skin against the insult of IL-I ⁇ .

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• Molecular Biology (AREA)
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• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Diabetes (AREA)
• Cosmetics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Polysaccharides And Polysaccharide Derivatives (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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