WO2004022034A1 - Preparation dermatologique pour le traitement de lesions cutanees - Google Patents

Preparation dermatologique pour le traitement de lesions cutanees Download PDF

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Publication number
WO2004022034A1
WO2004022034A1 PCT/PL2002/000105 PL0200105W WO2004022034A1 WO 2004022034 A1 WO2004022034 A1 WO 2004022034A1 PL 0200105 W PL0200105 W PL 0200105W WO 2004022034 A1 WO2004022034 A1 WO 2004022034A1
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weight
parts
grams
extract
preparation
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PCT/PL2002/000105
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English (en)
Inventor
Jerzy Maslanky
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Dermaphyt Ltd.
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Priority to AU2002368219A priority Critical patent/AU2002368219A1/en
Publication of WO2004022034A1 publication Critical patent/WO2004022034A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A61K35/644—Beeswax; Propolis; Royal jelly; Honey
    • 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
    • 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)
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • 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)
    • A61K36/55—Linaceae (Flax family), e.g. Linum
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/886—Aloeaceae (Aloe family), e.g. aloe vera
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • 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
    • 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
    • A61K47/44—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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the object of the present invention is a dermatological preparation for the treatment of skin lesions, particularly burns, thermal or chemical, and a method of preparing the preparation.
  • Known dermatological preparations for treating skin lesions, particularly burns usually have the form of creams or ointments, of solid or semisolid consistency.
  • Known preparations are most often based on biologically active substances contained in the extract of one kind of natural raw material, mainly a plant extract, particularly from a medicinal plant.
  • Biologically active substances contained in onion extracts form the basis of such preparations as (trade names) Contractubex Compositum, Cepan and Alcepal.
  • Polish patent application P.324236 describes an onion preparation for treating open wounds and burns and some forms of cutaneous carcinoma.
  • the preparation consists of at least 22 parts by weight of onion extract and ointment base in an amount making up to 100 parts or the same amount of oil- water type emulsion.
  • Biologically active substances of standardized marigold (Calendula of ⁇ cinalis) extract are part of the composition of known dermatological preparations such as
  • Standardized extract from Arnica montana or Arnica chamissonis having anti- inflammatory and antioedematous activities associated with a group of flavonoids (also contained in marigold extract) and sesquiterpene lactones, is part of such preparations as
  • the international patent application WO 91/15218 discloses a therapeutic composition for treatment of psoriasis, containing in its composition plant extracts of camomile, celandine, achillea, St. John's wort and marigold.
  • the vehicle of the composition comprises a mixture of cholesterol, petrolatum, anhydrous lanolin, linseed oil and distilled water.
  • dermatological preparations containing the extracts of both marigold and arnica such as (trade names) Ceffawell or Cesrasonal.
  • an antibiotic is used, most often bacitracin, e.g. in such drugs as (trade names) Batrax, Neobac, Nebacetin.
  • Bacitracin is most often combined with neomycin, an aminoglycoside antibiotic, and with polymyxin B, a peptide antibiotic, e.g. in Polyspectran HC.
  • the vehicle for the biologically active substances is a neutral one, such as paraffin, soft white paraffin, cholesterol ointment or vegetable oil.
  • an ointment for treatment of burns contains such active ingredients as aloe extract, vitamins A and E and levomicetine antibiotic.
  • a preparation protected by patent DE-19904801, designed for topical application in treatment of skin diseases, has a composition that varies depending on application and includes marigold extract, tincture of propolis/juniper, aloe, vitamins A and E and gentamicin anitbiotic.
  • the method of introducing active ingredients into ointment vehicle obtained by melting lipophilic vehicle components on a water bath and then cooling it in order to avoid overheating is known. The mixture is cooled and stirred until a homogenous mass is obtained. Then the medicinal compound is introduced and the mixture is stirred until an ointment of homogenous consistency is obtained.
  • Dense consistency of the dermatological preparations mentioned above is one of the factors that considerably limit their penetration and efficacy.
  • their active part is most often the bottom layer that directly acts on the skin, whereas the other part acts like a barrier obturating skin pores and impairing free air circulation within the skin lesion.
  • the barrier inhibits transpiration through the skin, which may result in considerable inhibition of tissue restoration and cell breakdown within the lesion. Additionally, transpiration is reduced by the necessity of bandaging.
  • the aim of the invention is to provide a dermatological preparation designed for application in the treatment of skin lesions, particularly burns, that preparation having the following properties: 1) antiseptic, 2) anti-inflammatory, 3) analgesic, 4) fast wound healing, 5) preventing against formation of hypertrophied scars.
  • the preparation should display desired activity independent of the type of burn, acting effectively in the case of both thermal and chemical burns.
  • the desirable preparation should be easily applicable and ready for immediate use after injury, particularly a burn.
  • the object of the present invention is a dermatological preparation for the treatment of skin lesions, particularly burns, the said preparation containing extract of propolis, a plant extract, a vegetable oil, antibiotics and vitamins forming a mixture with pharmaceutically admissible vehicle, characterized in that it contains 1 to 10 parts by weight of standardized extract of propolis with at least 4% ' of quercetin-equivalent flavonoids, 0.1 to 5 parts by weight of standardized plant extract, a small amount of 0 to 0.1 parts by weight of vitamin supplement, evenly dispersed in a neutral vehicle making up to 100 parts by weight, the said vehicle preferably comprising 0-30 parts by weight of liquid paraffin, 0-30 parts by weight of solid paraffin, 0-30 parts by weight of white petrolatum, 0-10 parts by weight of cholesterol, 0-70 parts by weight of untreated vegetable oil and 0-80 parts by weight of anhydrous lanolin.
  • the dermatological preparation according to the invention is advantageously characterized in that the untreated vegetable oil contained therein is linseed oil and/or sesame oil.
  • the dermatological preparation according to the invention is advantageously characterized in that the vehicle comprises a mixture consisting of 30-80 parts by weight of anhydrous lanolin, 10-30 parts by weight of white petrolatum, 10-30 parts by weight of solid paraffin and 1-8 parts by weight of cholesterol.
  • the dermatological preparation according to the invention is advantageously characterized in that the vehicle comprises a mixture consisting of 64 parts by weight of anhydrous lanolin, 18 parts by weight of white petrolatum, 15 parts by weight of solid paraffin and 3 parts by weight of cholesterol.
  • the dermatological preparation according to the invention is advantageously characterized in that the plant extract contained therein comprises a standardized extract of marigold, standardized extract of mountain and/or meadow arnica, standardized extract of St. John's wort, standardized extract of aloe or a combination thereof.
  • the dermatological preparation according to the invention is advantageously characterized in that the dermatological antibiotic contained therein comprises bacitracin, neomycin, polymyxin B, gentamycin, oxyteracin, erythromycin or staphylomycin or a combination thereof.
  • the dermatological preparation according to the invention is advantageously characterized in that the vitamin supplement contained therein comprises vitamin A, C or E or a combination thereof.
  • the dermatological preparation according to the invention is advantageously characterized in that it contains 50.06-54.28 parts by weight of untreated vegetable oil and anhydrous lanolin.
  • a beneficial variation of the dermatological preparation according to the invention is characterized in that 100 grams of it contain 5-10 grams of a standardized extract of marigold flowers, 1-5 grams of propolis extract, 0.1-2 grams of bacitracin, 0.01-0.1 gram of vitamin A made up to 100 grams with vehicle, whereas the vehicle comprises 20-25 grams of liquid paraffin, 2-8 grams of solid paraffin, 1-10 grams of white petrolatum, 0.2-2 grams of cholesterol, 30-70 grams of linseed oil.
  • 100 grams of the preparation contain 9 grams of standardized extract of marigold flowers, 3 grams of propolis extract, 1 gram of bacitracin, 0.03 gram of vitamin A made up to 100 grams with vehicle, whereas the vehicle comprises 22 grams of liquid paraffin, 5 grams of solid paraffin, 6 grams of white petrolatum, 1 gram of cholesterol and 51 grams of linseed oil.
  • Another beneficial variation of the dermatological preparation according to the invention is characterized in that 100 grams of it contain 5-10 grams of a standardized extract of marigold flowers, 1-5 grams of propolis extract, 0.1-2 grams of bacitracin, 0.01- 0.1 gram of vitamin A made up to 100 grams with vehicle, whereas the vehicle comprises 10-40 parts by weight of solid paraffin, 5-30 parts by weight of white petrolatum, 0.2-5 parts by weight of cholesterol, 20-80 parts by weight of linseed oil, 30-80 parts by weight of anhydrous lanolin.
  • the preparation Preferably 100 grams of the preparation contain 9 grams of standardized extract of marigold flowers, 3 grams of propolis extract, 1 gram of bacitracin, 0.03 gram of vitamin A made up to 100 grams with vehicle, whereas the vehicle comprises 10 parts by weight of solid paraffin, 12 parts by weight of white petrolatum, 2 parts by weight of cholesterol, 42 parts by weight of anhydrous lanolin and 43 parts by weight of linseed oil.
  • the preparation preferably has the form of an ointment.
  • Another beneficial variation of the dermatological preparation according to the invention is characterized in that 100 grams of it contain 5-20 grams of a standardized extract of marigold flowers, 1-5 grams of propolis extract, 0.1-2 grams of bacitracin, 30-70 grams of linseed oil and 10-50 grams of anhydrous lanolin.
  • 100 grams of the preparation contain 9 grams of standardized extract of marigold flowers, 3 grams of propolis extract, 1 gram of bacitracin, 0.03 gram of vitamin A, 52-53 grams of linseed oil and 33 grams of anl ydrous lanolin.
  • the preparation preferably has the form of an aerosol.
  • One of the described methods of preparing the dermatological preparation according to the invention consists in introducing into 53.50 - 56.50 parts by weight of neutral vehicle of 30.06 - 34.28 parts by weight of untreated vegetable oil at 40°C with preferably 0.02 - 0.04 parts by weight of vitamin dissolved in it beforehand and the entire mixture is stirred until homogenised.
  • a solution is added obtained by dissolving 0.5 - 1.3 part by weight of antibiotic in 5.20 - 10.20 parts by weight of standardized extract of vegetable raw material containing not more than 1.5% quercetin-equivalent flavonoids, adding 3.5 - 4.9 parts by weight of propolis extract containing not more than 6% quercetin-equivalent flavonoids and heating to 40°C, stirring and homogenising, afterwards the whole preparation is stirred and homogenised under reduced pressure and cooled.
  • One implementation of the described method of preparing the dermatological preparation of the invention consists in introducing into 33.50 - 36.50 parts by weight of neutral vehicle of 50.06 - 54.28 parts by weight of untreated vegetable oil at 40°C with preferably 0.02 - 0.04 parts by weight of vitamin dissolved in it beforehand and the entire mixture is stirred until homogenised. Then a solution is added obtained by dissolving 0.5 -
  • the neutral vehicle is formed by a mixture comprising 64 parts by weight of anhydrous lanolin, 18 parts by weight of white petrolatum, 15 parts by weight of solid paraffin and 3 parts by weight of cholesterol.
  • the neutral vehicle preferably contains anhydrous lanolin.
  • linseed oil and/or sesame oil is used as the untreated vegetable oil, extract of marigold, extract of mountain and/or meadow arnica, aloe extract, extract of St. John's wort or any combination thereof is used as the standardized plant extract, bacitracin, neomycin, polymyxin B, gentamycin, oxyteracin, erythromycin, staphylomycin or any combination of two or three of these antibiotics is used as the antibiotic, and vitamin A, C or E or any combination thereof is used as the vitamin component.
  • the preparation obtained has the form of a soft ointment with a characteristic propolis scent and yellow to brown colour.
  • the dermatological preparation of the invention is an agent of very advantageous medicinal properties.
  • the present composition provided a preparation having the following properties: 1) antiseptic, 2) anti-inflammatory, 3) analgesic, 4) fast wound healing, 5) preventing against formation of hypertrophied scars.
  • the present preparation inhibits development and growth of bacteria and viruses giving rise to inflammatory condition.
  • the rich set of flavonoids contained in it in conjunction with other biologically active substances, provides it with very effective anti-inflammatory and antibacterial activity and speeds up the healing of burn wounds.
  • An exceptional antiseptic effect has been produced by the incorporation of propolis, which has strong antibacterial properties, and an unexpected beneficial 2-3 -fold intensification of the antibacterial effect has been attained by adding bacitracin.
  • the neutral vehicle consists of a modified cholesterol ointment, where instead of liquid paraffin anhydrous lanolin has been used.
  • the latter significantly strengthens the gel structure, thereby improving the cohesiveness of the ointment, which prevents the tendency of liquid ingredients to separate.
  • High water number of anhydrous lanolin, ca. 200 makes the ointment capable of absorbing large amounts of water and aqueous solutions and, when applied to burned skin or a wound that heals with difficulty, it absorbs exudates forming a water/oil system.
  • lanolin enhances resorption of medicinal substances through skin, which is of great advantage in case of burns and wounds that heal with difficulty.
  • changing linseed oil content has provided further improvement in the spreadability of the ointment.
  • Soft consistency of the preparation in the form of ointment and/or aerosol enables its fast and easy application directly onto the skin, particularly onto burns, which in the first place reduces the pain suffered by the patient, and at the same time enables immediate commencement of treatment, particularly in the case of grade I and II burns. Immediate application of the medication prevents the formation of blisters, which can reduce the healing time even by several days. In case of severe and extensive burns classified as grade II or III burns, when skin grafting is necessary, it has been unexpectedly observed that the preparation had a beneficial effect in postponed treatment of residual wounds and autogenic graft donor sites.
  • the preparation according to the invention makes it unnecessary to dress the wound and reduces or even eliminates the hospitalisation period, because the patient can apply the preparation on his own or with the help of persons attending. It has unexpectedly been observed that the preparation according to the invention reduces the risk of scar formation and speeds up regression of skin discolouration after burns. The preparation also protects against plasma loss, which makes it possible to avoid the necessity of administering infusions.
  • the preparation of the invention speeds up and regulates healing processes (granulation tissue growth, angiogenesis and epithelialization) and epidermis and derma regeneration by intensifying the enzymatic activity of glucose-6- phosphate dehydrogenase (G6PD), c cytochrome oxidase (OCC) and electron transport enzyme dehydrogenase (NADHD), increasing RNA concentration in fibroblasts, intensifying collagen generation and accelerating transformation of fibroblasts into fobrocytes.
  • G6PD glucose-6- phosphate dehydrogenase
  • OCC c cytochrome oxidase
  • NADHD electron transport enzyme dehydrogenase
  • Figure 2 depicts a sagittal section of a specimen of Di group rat skin. 21 -days series. Response to RNA.
  • dynamic progression of regeneration of burn- affected skin is conspicuous evidenced by growth of fresh regenerative epidermis (NR)-
  • NR fresh regenerative epidermis
  • the area not covered by this fresh epidermis indicates the presence of protective leucocytal layer on skin surface.
  • Strong response to RNA in epidermis (N) and hair follicles is evident in skin of proper structure on both sides of the area shown.
  • Reaction in regenerative epidermis (NR) is evidently strong. Signs of poor, although distinct response to RNA occur in the granulation tissue (Z) under the NR epidermis.
  • the arrow points to the fragment of the image shown in Figure 3.
  • Figure 4 depicts a sagittal section of a specimen of D group rat skin. 21 -days series. Response to RNA. Skin of proper structure can be seen on both sides of the image with some mastocytes (m). The remaining part of the image presents skin in an advanced stage of regeneration. The arrow points to a fragment shown in Fig. 5.
  • Figure 5 depicts a fragment of the image shown in Figure 4.
  • Figure 6. Sagittal section of a specimen of K 2 group rat skin. 21 -days series. Evident strong
  • Figure 7 depicts a sagittal section of a specimen of Di group rat skin. 21 -days series.
  • NADH dehydrogenase is evident over the entire area. Early healing stage showing lack of occlusion by regenerative epidermis (NR) of poor enzymatic activity. Skin of proper structure and enzymatic activity can be seen to the left. Epidermis with significant
  • Figure 8 depicts a sagittal section of a specimen of D 2 group rat skin. 21 -days series.
  • NADH dehydrogenase is evident over the entire area.
  • the central area of the image shows indications of the final stage of healing of the entire wound.
  • Still some fresh epidermis (NR) is observed, however underneath it is a fresh loose connective tissue proper (TL) of low NADHD activity of fibroblasts transforming into f ⁇ brocytes.
  • NR fresh epidermis
  • TL fresh loose connective tissue proper
  • Figure 9 shows the average percentage of regenerative epidermis within the burn wound.
  • Example 1 Composition of the preparation and list of auxiliary substances
  • 100 parts by weight of the preparation contain, according to a general formula: - Standardized propolis extract: 1 to 10 parts by wt. (adjusted to 100% extract basis)
  • Vehicle make up to 100 parts by wt.
  • the composition of the vehicle is as follows (in parts by its weight):
  • Liquid paraffin 0-30 parts by wt.
  • the "standardized plant extract” is an extract of a plant, such as marigold, mountain and/or meadow arnica, St. John's wort or aloe or a combination thereof, with the content of flavonoids (in terms of quercetin) not less than 0.4%.
  • the "standardized propolis extract” is an extract that contains not less than 4% flavonoids (in terms of quercetin) and meets the antibacterial activity standard (not less than 3,300 AU in 1 gram of extract, determined against standard strain, e.g. Staphylococcus aureus FDA 209 P).
  • the "dermatological antibiotic” means bacitracin, neomycin, polymyxin B, gentamycin, oxyteracin, erythromycin or staphylomycin or a combination thereof.
  • the "vitamin” is vitamin A, C or E or a combination thereof.
  • the "untreated vegetable oil” means linseed oil or sesame oil or a combination thereof. All ingredients should meet the respective pharmacopeal standards.
  • the preparation formulated should have the form of an ointment or an aerosol. In the case of aerosol the composition may be supplemented with appropriate propellant gas. Variant 1 100 grams of preparation contain:
  • the "standardized extract of marigold flowers” is an extract containing not less than 0.4% flavonoids (in terms of quercetin), which may be obtained by extracting herbal raw material with 70% (v/v) aqueous solution of ethanol at a ratio of 1:3 at 60°C, pressing the material and filtering the product (P ⁇ -84/R-87013).
  • the "standardized propolis extract” with the characteristics described above may be obtained by extracting propolis with 70% (v/v) aqueous solution of ethanol at a ratio of 1:10 at room temperature, filtering and concentrating under reduced pressure until 67% dry matter content is attained (PN-A-77626). The preparation obtained is used in the form of an ointment.
  • the preparation is obtained from ingredients that meet the standards specified above.
  • the composition of 100.00 g of the preparation is as follows:
  • Marigold extract 9.0 g 3.
  • Bacitracin 1.0 g
  • Vitamin A 0.03g (adjusted to 0.055 g retinol palmitate)
  • the preparation is obtained from ingredients that meet the standards specified above.
  • the composition of 100.00 g of the preparation is as follows:
  • Marigold extract 9.0 g 3.
  • Bacitracin 1.0 g
  • Vitamin A 0.03g (adjusted to 0.055 g retinol palmitate)
  • Variant 4 The preparation is obtained from ingredients that meet the standards specified above.
  • the composition of 100.00 g of the preparation is as follows: Marigold extract 9.0 g
  • the preparation obtained is designed for use in the form of an aerosol.
  • a propellant gas preferably tetrafluoroethane, is introduced under pressure into the emulsion. obtained (see also example 9).
  • 33.60 parts by weight of lanolin are introduced into a mixing vessel and heated at 90°C under reduced pressure for 1 hour, then cooled to 40°C. Afterwards 52.60 parts by weight of linseed oil at 40°C with 0.04 parts by weight of vitamin C dissolved in it beforehand are added followed by 5.10 parts by weight of standardized extract of mountain arnica and 2.20 parts by weight of aloe extract with 1.16 part by weight of polymyxin B dissolved in it beforehand and 4.50 parts by weight of standardized propolis extract. The entire mixture is homogenised at 40°C under reduced pressure until homogenous emulsion is obtained, then cooled to room temperature.
  • a propellant gas preferably tetrafluoroethane
  • a propellant gas is introduced under pressure into the emulsion obtained in order to formulate an aerosol preparation.
  • Example 9. 33.60 parts by weight of lanolin are introduced into a mixing vessel and heated at 90°C under reduced pressure for 1 hour, then cooled to 40°C. Afterwards 50.80 parts by weight of sesame oil at 40°C with 0.02 parts by weight of vitamin A and 0.02 parts by weight of vitamin E dissolved in it beforehand are added followed by 6.20 parts by weight of standardized extract of marigold, 2.95 parts by weight of standardized extract of mountain arnica and 1.15 part by weight of aloe extract with 0.15 part by weight of neomycin dissolved in it beforehand and 4.80 parts by weight of standardized propolis extract.
  • the entire mixture is homogenised at 40°C under reduced pressure until homogenous emulsion is obtained, then cooled to room temperature.
  • a propellant gas preferably tetrafluoroethane, is introduced under pressure into the emulsion obtained in order to formulate an aerosol preparation.
  • Example 10 Physicochemical properties of ointments obtained. Selection of vehicle. a. Testing of spreadability of ointment vehicle and preparations obtained with its use
  • the extensometer applied consisted of the following parts: base plate (glass plate 200mm x 200mm with millimetre ruler), cover plate (glass plate with centre point), dispenser, weights.
  • base plate glass plate 200mm x 200mm with millimetre ruler
  • cover plate glass plate with centre point
  • dispenser weights.
  • a layer of vehicle about 10 mm was placed by means of the dispenser on the marked surface of base plate.
  • cover plate was placed over the vehicle so that the centre point was located in the centre of the vehicle layer.
  • mean radius ( r ) and area obtained were calculated.
  • the upper plate was further subjected to load increased in equal time intervals by placing subsequent weights and the surface area of the layer was calculated.
  • i(P) index which is equal to the quotient of surface areas expressed in conventional units of the preparation and the vehicle, enables assessment of the effect of biologically active ingredients on the internal structure of the preparation. It was observed that the content of linseed oil, apart form the presence of lanolin, had the decisive effect on the physical properties of the ointment.
  • sample "P" The composition of the preparation used in the test, designated as sample "P", corresponded to that of variant II preparation in example 1.
  • Linseed oil was added to that preparation in order to obtain a composition containing 20% (sample “P+20%”), 25% (sample “P+25%”) or 30% (sample “P+30%”) by weight of linseed oil, the mixture was homogenised and measurements were carried out.
  • 2-propanol solutions of ethanol extract of propolis with marigold extract were prepared and spectrophotometric analysis was carried out. Ethanol extracts were used in the same quantitative ratios as in the preparations. The results obtained were used to plot standard curves. To this end 0.2463 g of ethanol extract of propolis and 0.5154 g of ethanol extract of 0 marigold were weighed, transferred quantitatively to a 50 cm 3 measuring flask and made up to the mark with 2-propanol. Then 1 cm 3 of the solution obtained was taken and diluted with solvent to 50 cm 3 .
  • ointment obtained ( ⁇ 5 g) was introduced into a plastic container that performed the role of a therapeutic system.
  • the composition of test preparations was identical with that of the previous experiment.
  • the outer surface was covered with hydrated cellophane with pores of statistical size of 25 A.
  • the container was placed in a beaker containing 0.5 dm 3 solvent, the latter being water in the first series of tests and 2-propanol in the second series.
  • 5 ml of the solution was sampled and its absorbance was measured directly. Results are presented in Table 2 (designations identical to those in table 1).
  • Ointment with its composition defined as variant 1 showed insufficient physicochemical stability, high tendency to separate out liquid constituents, affecting thereby its homogeneity. After a certain period, inadequate consistency of the ointment made its application on skin difficult (when the tube was pressed, liquid ingredients of brown colour splashed in every direction) and its appearance unpleasant.
  • the ointment described as valiant 3 was diametrically opposed to that of variant 1. The experiments carried out unexpectedly indicated that replacing liquid paraffin with anhydrous lanolin and experimental determination of proper amount of linseed oil are of key significance to the physical properties of the ointment obtained. Good spreadability of vehicle and high homogeneity and stability of the ointment were attained.
  • preparation A containing 1% ethanol extract of propolis
  • preparation B containing 3% standardized ethanol extract of propolis, standardized extract of marigold and vehicle comprising cholesterol ointment and linseed oil.
  • Bee venom at a concentration of 10 ⁇ g/ml was used as the irritant.
  • the preparation contained 1% ethanol extract of propolis ** The preparation contained 3% concentrated extract of propolis
  • the effect of the preparations of the invention on micro-organisms that cause wound infections was also investigated.
  • An extract of the tested preparation B containing bacitracin was made.
  • the extract obtained was diluted in Penassay (Difco) liquid vehicle to concentrations ranging from 10 to 600 ⁇ g/ml.
  • the strains used in the test were of the type that cause wound infections, including burn infections.
  • the tests included 5 Gram-positive coccus strains and 5 Gram-negative bacillus strains.
  • Liquid 18-hour cultures of the tested strains were diluted in Penassay vehicle to a concentration of 10 -10 5 bacteria in 1 ml. Then 0.1 -ml samples of the diluted culture were introduced into each of the series of diluted preparations. The lowest concentrations of biologically active substances in the preparation B ointment that affected the growth of wound-infecting micro-organisms (MIC) were determined after 18 hours of sample incubation at 37°C.
  • MIC wound-infecting micro-organisms
  • preparation B concentration of biologically active substances contained in preparation B (30,000 ⁇ g/ml) is 70 to 1500 times higher in comparison with the lowest concentrations (20-420 ⁇ g/ml) of this preparation that affect the growth of the tested micro-organisms.
  • preparation A showed low microbiological activity (40 AU/g), whereas microbiological activity of preparation B without bacitracin was 15 times stronger, and the same preparation containing bacitracin had 38 times stronger microbiological activity as compared to preparation A.
  • Microbiological activity of ointment B containing bacitracin was 2.5 times stronger than that of the same preparation containing no antibiotic. It must be stressed that the tests described proved that propolis shows strong antibacterial activity, and the addition of bacitracin enhances that activity 2-3 times, showing evidence of an unexpected advantageous strengthening of the antibacterial effect and justifying the proposed composition of the preparation. Further tests were carried out with preparation B containing bacitracin of the highest microbiological acivity.
  • Test results have proven strong effect of the tested preparation on wound-infecting micro-organisms.
  • MIC was within 20 to 100 ⁇ g/ml
  • Gram-negative bacillus strains it was within 60 to 420 ⁇ g/ml. It may therefore be acknowledged that the concentration of biologically active substances contained in preparation B (30,000 ⁇ g/ml) is 70 to 1,500 times higher in comparison with the lowest concentrations (20-420 ⁇ g/ml) of this preparation that affect the growth of the tested micro-organisms. It has also been confirmed that the addition of bacitracin to preparation B clearly enhances its microbiological activity and that the preparation of the invention effectively destroys wound-infecting bacteria.
  • Example 12 Pharmacological, cytomorphological and histoenzymatic assessment of the preperation of the invention on a rat model of burn wound.
  • Preparation as described in example 1 as variant 1 was subject to the assessment. Test were performed on white Wistar rats and white guinea pigs, to which the tested preparation was always administered in the form of skin application. 1. Assessment of the primary irritating action of the preparation.
  • Tests of irritating action of the preparation were carried out on white male guinea pigs weighing 250-300 g. The animals were given a standard diet and water without restrictions. Experiments were performed on two groups of animals: the studied group (15 animals) and the control group with vehicle (10 animals). Every day, for a period of 10 subsequent days, 0.5 g of the preparation or the vehicle was spread (not rubbed in) on the shaved and degreased with ethyl alcohol and ether skin of the right flank of each guinea pig. Reaction was evoked on a surface 5 x 5 cm under a loose dressing of sterile gauze and cellophane. Results were checked every day for a period of 10 days.
  • Tests were carried out on white male guinea pigs weighing 250-300 g in two groups: control group (vehicle per se - 10 animals) and studied group (preparation - 15 animals). The animals were given a standard diet and free access to water. The tested compound preparation (as the potential contact allergen) and the vehicle were used in the skin (contact) tests. For 8 subsequent days, 0.1 g of the preparation (ointment) or the vehicle was spread on a surface of ca. 2 cm of the skin (5 x 5 cm) shaved and degreased with ethyl alcohol and ether on the right flank of each guinea pig (induction phase).
  • the aim of the test was to determine whether: a) the tested preparation may be an antigen that induces a delayed hypersensitivity reaction in healthy guinea pigs; b) the vehicle of the preparation produces a delayed skin reaction. 3. Cytomorphological and histoenzymatic assessment of burn wound healing in rats.
  • Tests were carried out on adult male white Wistar rats weighing 170-210 g. Experiments consisted in inducing a burn on shaved skin of the right flank on an area of 2 cm 2 by means of copper bar heated to 100°C and contacted with the skin for 12 seconds. Experiments were performed on four groups of animals.
  • control group Kj consisted of rats not subjected to any procedures.
  • Control group K skin of animals with burns, no treatment provided.
  • Skin specimens were always taken with a wide margin of healthy skin (ca. 0.5 cm). Average dimensions of the specimens taken were 2 cm x 2 cm. Each specimen was cut into halves, set on cryostatic table, with the cross section facing upwards, and immediately frozen with dry ice. The specimens were cut on a cryostatic microtome into 6 ⁇ m thick slices representing sagittal sections of the skin together with subcutaneous muscle layer.
  • Tissue sections were subjected to histochemical tests for assessing activity of selected oxidative enzymes:
  • G6PD glucose-6-phosphate dehydrogenase
  • RNA - c cytochrome oxidase (OCC) respiratory chain enzyme as an indicator of highly energetically efficient aerobic metabolism in cells [ Romeis B.R. ibid., Maibach H.J. ibid.].
  • OCC cytochrome oxidase
  • Response to RNA was also tested in tissue sections to determine intensity of RNA biosynthesis and also, indirectly, of protein biosynthesis [Maibach H.J. , ibid.].
  • Pappenheim staining [Romeis B.R., ibid.] was applied to detect defensive cells (mastocytes in particular) and reconstructive cells (fibroblasts). Van Gieson staining was applied to observe the growth of fibres of the connective tissue [ Maibach H.J., ibid.].
  • mice Microscopic specimens containing tissue sections on which tests had been performed were subjected to microdensitometric analysis (in order to determine precisely the activities of the enzymes studied and RNA content) and to histomorphometric analysis (in order to calculate areas of tissue regeneration and the count of some defensive cells [Bagi ⁇ ski S.,technika mikroskopowa (Microscopic technique), PWN, Warsaw, 1965]. The important results are supported by photographic and graphical documentation.
  • the ointment was administered every day in the form of skin application onto the burn wound, starting from the first day after inducing the burn, throughout the 21 -days period of the experiment. RESULTS 1. Assessment of the primary irritating action.
  • Dermotoxic reaction erythema, increase of the thickness of the skin fold
  • cytomorphological tests are presented in Fig. 1-8, and detailed results of histoenzymatic and histochemical tests are summarized in tables 6-8.
  • the sagittal sections of normal skin specimens not subjected to burns present a typical morphological structure of integument hair-bearing skin consisting of thin epidermis and thick derma.
  • Other integument components can also be seen in the specimens: subcutaneous tissue, muscle layer and fascia (loose connective tissue proper covered by peritoneal epithelium on the abdominal cavity side).
  • the derma contains very dense entangled bundles of collagen fibres with hair between them, sebaceous glands, quite numerous connective tissue cells of various types (fibrocytes, mast cells, single histocytes and fibroblasts) and blood vessels, ranging from capillaries, located mainly near the epidermis, to arteries and veins located near the subcutaneous tissue.
  • the subcutaneous tissue contains much less collagen fibres than the derma.
  • the muscle layer consists of muscle fibres with a limited number of connective tissue collagen fibres entwining the muscular tissue.
  • the epidermis-generating layer is characterised by distinctly strong activity of reduced NAD dehydrogenase (NADHD) and cytochrome oxidase (OCC) and moderate activity of glucose-6-phosphate dehydrogenase (G6PD).
  • NADHD reduced NAD dehydrogenase
  • OOC cytochrome oxidase
  • G6PD glucose-6-phosphate dehydrogenase
  • Table 8 Mean intensity of activity of oxidative enzymes and RNA response (in units of optical density) in selected components of skin specimens of group D 2 rats
  • the preparation and its vehicle do not produce any primary irritating action and do not induce an inflammatory condition of skin. No toxico-allergic reactions of the skin have been observed in any of the tested animals, both after first contact with the skin as well as after repeated application of the preparation and the vehicle.
  • the ointment and its vehicle do not cause irritating action and display no tendency to induce contact-type allergic reactions.
  • the tests performed indicate that the vehicle and the preparation, as well as possible products of their catabolism, are not capable of inducing contact-type immunological reaction of the skin in guinea pigs.
  • the regenerative epidermis in the burn wound area was highly developed in the skin of animals of the group treated with the preparation (group D 2 ) and it displayed higher intensity of activity of the tested enzymes and higher content of RNA (Tables 4-7).
  • the growth of the regenerative epidermis was enhanced by intensified cellular metabolism. This was manifested by intensified activity of OCC and NADHD in the regenerative epidermis and in hair follicles in the burn wound area after both 7 as well as 21 days after inducing the burns.
  • Tests on the irritating (dermatotoxic) effect of the preparations were based on the carrageenan method of assessing antiedematous effect of biologically active substances. The basis adopted for these tests was the effect of enhancing carrageenan-induced oedema in rats in the presence of irritating (toxic) substances.
  • preparation A containing 1% ethanol extract of propolis
  • preparation B containing 3% standardized ethanol extract of propolis, standardized extract of marigold and vehicle comprising cholesterol ointment and linseed oil.
  • Aqueous solution of bee venom at a concentration of 10 ⁇ g/ml was used as the irritant.
  • Wistar rats weighing 250-300 g were used in the tests, without restricting access to water and food. The number of animals in each studied and control group was 6. The tests followed the methodology described by Winter C.A., Risley E.A., Nuss G.W.: Carrageenan - induced oedema in hind paw of the rat as an assay for anti- inflammatory drugs . Proc. Soc. Exp. Biol. Med. 1962 ; 111 : 544 - 547.
  • Measurement results presented in table 9 indicate that the tested ointments of preparation A and preparation B, as well as semi-products used for the formulation of the ointment of preparation B, reduced the swelling of the rat's paw induced by carrageenan. This means that the tested products have no irritating effect.
  • Bee venom used as a control substance for increasing the carrageenan-induced oedema of rat's paw, had an irritating effect. Therefore a conclusion may be inferred that the tested ointments and semi-products used for their formulation are non-toxic when applied topically.
  • Toxicological tests which included tests of the irritating effect of the preparation of the invention, were carried out on rats according to the carrageenan method, applied to assess the antiedematous effect of biologically active substances.
  • Aqueous solution of bee venom which at a concentration of 10 ⁇ g/ml is an irritating (toxic) substance, was used as positive control substance.
  • the preparation of the invention does not show any primary irritating, allergic or allergenic effects on skin.
  • Example 14 Assessment of allergenic action of the preparation.
  • Preparations and vehicles of the invention were assessed using patch tests on 30 patients suffering from chronic allergic illnesses, including contact eczema and atopic skin inflammation.
  • the tested preparations and vehicles of the invention do not display any allergenic effect.
  • Example 15 Assessment of the primary irritating action of the preparation
  • the preparations and vehicles of the invention were applied to 30 healthy persons. Paper discs soaked with the tested preparations were applied in occlusive dressing for 48 hours. Results were noted immediately after removing the occlusive dressing and after 72 and 96 hours.
  • the preparations of the invention may have a primary irritating effect under occlusion conditions. Therefore we recommend including in the information materials a warning against complications that may arise when applying the preparation under an occlusive dressing.
  • Example 16 Assessment of phototoxic action of the tested aerosol preparation and vehicle.
  • Tests were carried out on 30 healthy persons of both sexes aged 20 to 44.
  • UVB ultraviolet light
  • MED 0.25 minimum erythema dose
  • Example 17 Use of the preparation for treating burns in children
  • Preparation of the invention (example 1, variant 3) was applied in the treatment of 45 children, aged 4 weeks to 15 years, suffering mainly grade Ila burns with an extent not exceeding 15% TBS A.
  • the medication was administered in various clinical situations, for instance: 1) first intention, onto minor burn wounds (Ila, up to 10% TBS A) after first change of occlusive dressing, on the second or third day after primary debridement of the burn wound on the admission day (Ila, up to 15% TBS A), or 2) on residual wounds after taking and implanting autogenic skin grafts on wounds of delayed healing.
  • the preparation was applied to wounds in the following manner: during the first 3 days the preparation was applied to the wounds every 2-3 hours, during the next 3-10 days the preparation was applied 3 times a day, afterwards the child had an overall bath made every 12 hours in lukewarm water with a small amount of Betadine added.
  • the principle of treating burn wounds using the preparation of the invention is that after initial debridement of the wound, further treatment is carried out in "open" conditions, without the use of occlusive dressings.
  • Patients were placed without clothes, gauze or dressings under a scaffold covered with sterile bed sheets protecting them against heat loss and reduced skin evaporation.
  • a clear advantage of such treatment is the ease of continuous control of the depth and cleanliness of the burn wounds and ease of swabbing the wound in order to make bacteriological tests.
  • the main positive surprise in the treatment performed using the preparation of the invention is the time after which the different wounds, caused by or associated with burns, heal.
  • the time taken by grade Ila burn wounds to heal ranged from 4 days (minor wounds) to 12 days (large wounds).
  • Complete healing of residual wounds described above took 3 to 6 days, whereas the healing of wounds that were difficult to heal before lasted 5 to 10 days.
  • Change in the reaction (appearance of the surface) within the area of fresh burn wound was observed after just 24 hours.
  • the appearance of the wound changes - within the first dozen to 24 hours it takes on a bright red colour, which is emphasized by the yellowish colour of the ointment, which in conjunction with the unavoidable covering of the surrounding healthy skin by the ointment may at first create a misguiding disconcerting impression.
  • the advance of the healing process of the wound can be easily seen.
  • the inflammatory reaction and congestion, natural for this type of wounds, start to weaken.
  • a thin, initially translucent pseudo-crust is formed, which at the beginning is firmly attached to the substrate. Its brownish colour may also be misleading to an inexperienced person.

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Abstract

Préparation dermatologique pour le traitement de lésions cutanées, en particulier de brûlures, contenant de l'extrait de propolis, de l'extrait de matière végétale, de l'huile végétale, des antibiotiques et des vitamines, ainsi qu'un excipient acceptable sur le plan pharmaceutique. Ladite préparation possède les propriétés suivantes : 1) antiseptique, 2) anti-inflammatoire, 3) analgésique, 4) favorise une cicatrisation rapide, 5) prévient la formation de cicatrices hypertrophiées.
PCT/PL2002/000105 2002-08-01 2002-12-18 Preparation dermatologique pour le traitement de lesions cutanees WO2004022034A1 (fr)

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PL02355298A PL355298A1 (en) 2002-08-01 2002-08-01 Dermatological preparation for curing skin defects
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EP1917072A2 (fr) * 2005-06-01 2008-05-07 Stiefel Research Australia Pty Ltd Preparation vitaminee
ITTO20080584A1 (it) * 2008-07-29 2010-01-30 Chiara Cesano Composizione per la rigenerazione di tessuto cutaneo e sottocutaneo senescente, relativi prodotti ed usi
WO2010089566A2 (fr) 2009-02-06 2010-08-12 Seeds Lp Composition destinée au traitement de la peau
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
WO2016088093A1 (fr) * 2014-12-06 2016-06-09 Peszke Jerzy Przemysław Préparation à base de propolis et d'argent accélérant la régénération de tissus mous, et son procédé d'obtention
GR1009068B (el) * 2016-05-09 2017-07-05 Πετρος Παναγιωτη Παναγιωτου Θεραπευτικο σκευασμα για πληγες κατακλισεων που, ψεκαζομενο επανω στην πληγη, δημιουργει επουλωτικη κρουστα - επιδεσμο
WO2017146603A1 (fr) * 2016-02-24 2017-08-31 Arcasiu Nicolae Composition pharmaceutique pour le traitement de brûlures, utilisation, et méthode de traitement
US20190022149A1 (en) * 2017-07-21 2019-01-24 MatrixMed Inc. Medicated Propolis Oil Composition
WO2021203704A1 (fr) * 2020-04-07 2021-10-14 中国科学院深圳先进技术研究院 Utilisation de bacitracine a dans la préparation de médicaments pour la prévention et le traitement de coronavirus
US11253467B2 (en) * 2018-12-03 2022-02-22 Slc Skin Llc. Wrinkle treatment
US11951199B1 (en) 2020-08-25 2024-04-09 Rivercrest, LLC Personal skincare product

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
EP1917072A4 (fr) * 2005-06-01 2010-10-13 Stiefel Res Australia Pty Ltd Preparation vitaminee
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
US8629128B2 (en) 2005-06-01 2014-01-14 Stiefel West Coast, Llc Vitamin formulation
EP1917072A2 (fr) * 2005-06-01 2008-05-07 Stiefel Research Australia Pty Ltd Preparation vitaminee
ITTO20080584A1 (it) * 2008-07-29 2010-01-30 Chiara Cesano Composizione per la rigenerazione di tessuto cutaneo e sottocutaneo senescente, relativi prodotti ed usi
WO2010013204A1 (fr) * 2008-07-29 2010-02-04 Luisa Gennero Composition pour régénérer des tissus cutanés et sous-cutanés sénescents, et produits et utilisations associés
US9403042B2 (en) 2009-02-06 2016-08-02 Seeds Group, Lp Composition for treatment of skin
WO2010089566A2 (fr) 2009-02-06 2010-08-12 Seeds Lp Composition destinée au traitement de la peau
WO2016088093A1 (fr) * 2014-12-06 2016-06-09 Peszke Jerzy Przemysław Préparation à base de propolis et d'argent accélérant la régénération de tissus mous, et son procédé d'obtention
WO2017146603A1 (fr) * 2016-02-24 2017-08-31 Arcasiu Nicolae Composition pharmaceutique pour le traitement de brûlures, utilisation, et méthode de traitement
GR1009068B (el) * 2016-05-09 2017-07-05 Πετρος Παναγιωτη Παναγιωτου Θεραπευτικο σκευασμα για πληγες κατακλισεων που, ψεκαζομενο επανω στην πληγη, δημιουργει επουλωτικη κρουστα - επιδεσμο
US20190022149A1 (en) * 2017-07-21 2019-01-24 MatrixMed Inc. Medicated Propolis Oil Composition
US10888590B2 (en) * 2017-07-21 2021-01-12 MatrixMed Inc. Medicated propolis oil composition
US11253467B2 (en) * 2018-12-03 2022-02-22 Slc Skin Llc. Wrinkle treatment
WO2021203704A1 (fr) * 2020-04-07 2021-10-14 中国科学院深圳先进技术研究院 Utilisation de bacitracine a dans la préparation de médicaments pour la prévention et le traitement de coronavirus
US11951199B1 (en) 2020-08-25 2024-04-09 Rivercrest, LLC Personal skincare product

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