WO1996012504A1 - Oil-in-water formulation for topical application - Google Patents

Oil-in-water formulation for topical application Download PDF

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Publication number
WO1996012504A1
WO1996012504A1 PCT/DE1994/001238 DE9401238W WO9612504A1 WO 1996012504 A1 WO1996012504 A1 WO 1996012504A1 DE 9401238 W DE9401238 W DE 9401238W WO 9612504 A1 WO9612504 A1 WO 9612504A1
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WIPO (PCT)
Prior art keywords
formulation
formulation according
oil
oil phase
water
Prior art date
Application number
PCT/DE1994/001238
Other languages
German (de)
French (fr)
Inventor
Martin Schmitt
Hans Burgschat
Original Assignee
Martin Schmitt
Hans Burgschat
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to DE9320586U priority Critical patent/DE9320586U1/en
Priority to DE4334600A priority patent/DE4334600C2/en
Application filed by Martin Schmitt, Hans Burgschat filed Critical Martin Schmitt
Priority to AU79894/94A priority patent/AU7989494A/en
Priority to PCT/DE1994/001238 priority patent/WO1996012504A1/en
Publication of WO1996012504A1 publication Critical patent/WO1996012504A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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)
    • A61K36/49—Fagaceae (Beech family), e.g. oak or chestnut
    • 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)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • 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)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • 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
    • A61K47/06—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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the invention relates to a topical oil-in-water formulation with an inner dispersed oil phase and an outer coherent water phase and with a ravon glycoside extract solubilized in the water phase, and to the use of such a formulation.
  • Ginkgo biloba extract contains ravones and ravone glycosides as the quantitatively most important fraction of the value-determining ingredients. Both antioxidative and anti-inflammatory as well as bactericidal and antiviral properties are described in the literature for ravones and ravone glycosides (Duduk et al, Arch. Exp. Veterinärmed. 26, 285 [19721; Bauman et al, Prostglandins 20, 627 [1080]; Takahama et al, Phytochemistry 24, 1443 [1985]; Alcaraz et al, Pharmazie 41, 299 [1986]; Ho et al, Agric. Biol. Chem. 49. 2173 [1985]; Waage et al, Phytochemistry 23, 2509 [1984] ; Vrijsen et al, Antiviral Res. 7, 35 [1987]).
  • Other plant extracts that contain ravone glycosides are, for example, leaf extracts from buckwheat, butcher's broom or holm oak.
  • the solvent-containing extracts are usually treated according to known processes for enriching the ravon glycosides and processed into dry extracts. Because of the rapid metabolism of the flavone glycosides in the intestine or in the liver, their beneficial properties, if at all, only have a short-term effect when used orally or parenterally. A meaningful therapeutic use of the properties mentioned above can therefore not be undertaken in this way. Oral use of flavone glycosides to treat inflammation and skin infections is also not possible. Topical application is therefore desirable to combat infections and inflammation of the skin, but this brings with it galenic problems.
  • Flavone glycosides have the disadvantage that they are very sparingly soluble in water and most of the solvents permitted for use in pharmaceuticals and cosmetics. It is therefore extremely difficult to prepare a topical formulation which contains a sufficiently dissolved concentration of the flavone glycosides in order to achieve a clear effect.
  • the galenical formulation must be demonstrably stable and free from loss of activity over a defined period. No crystal growth or precipitation of the flavone glycosides may occur during storage, nor should the topical formulation cause skin irritation.
  • the active ingredient in topical formulations is usually suspended in the oil phase in order to achieve good transdermal absorption.
  • Such formulations are described in French Patents 2,207,692 and 2,316,946 and in US Pat. No. 3,934,013.
  • German Offenlegungsschrift 3 840 832 describes preparations to be used externally, inter alia in the form of oil-in-water formulations which contain a liquid, ie. H. Ginkgo biloba extract containing solvents and also contain propylene glycol.
  • solvent-containing liquid extracts are undesirable because, on the one hand, they introduce undesirable solvent components into the formulation and, on the other hand, they have a volume that is undesirably large for transport and handling compared to dry extracts.
  • simple liquid extracts of Ginkgo biloba leaves contain undesired alk ⁇ lphenol derivatives for regular use.
  • the object on which the invention is based was therefore to obtain topical formulations using flavone glycoside dry extracts which, due to solubilization of the flavone glycosides, have good transdermal absorption and penetration and also have adequate shelf life.
  • this object is achieved with oil-in-water formulations which can be used in the middle with an inner dispersed oil phase and an outer coherent water phase and dissolved with flavone glycoside extract solubilized in the water phase, this formulation being characterized in that the aqueous phase is a combination of at least one water-miscible polyalcohol with dimethyl isosorbide (DMI) in a weight ratio of polyalcohol to DMS of 3: 1 to 1 : 1 and contains a solubilized dry extract as a flavone glycoside extract.
  • DMI dimethyl isosorbide
  • the invention is based on the synergistic effect of the water-miscible polyalcohols on the one hand and the dimethyl isosorbide on the other hand for solubilizing the flavone glycosides in dry extract form. If one tries to solubilize flavone glycoside extracts either with polyalcohol alone or with dimethylisosorbide alone, this fails or the preparation is not sufficiently stable. Surprisingly, however, the combination of both components brings the flavone glycoside dry extract in solution in the outer water phase, which results in high transdermal absorption and penetration and at the same time high storage stability of the formulation.
  • the formulation is usually in the form of an ointment or cream.
  • any extracts which contain flavone glycosides can be used as the flavone glycoside dry extracts.
  • Dry extracts are usually used in which undesired constituents have been removed by known processes and the flavone glycosides have been enriched, for example, up to 25% of the dry matter.
  • the formulation according to the invention can contain one or more water-miscible polyalcohols, ie. H. Alcohols with at least two hydroxyl groups.
  • polyalcohols are, for example and preferably, propylene glycols, polyethylene glycol, glycerol, sorbitol and mixtures thereof.
  • the formulations according to the invention can be applied topically for the treatment of bacterial and viral infections of the skin and mucosa and for the anti-inflammatory and antipruritic treatment of allergic and atopic eczema and other irritation conditions of the skin, such as, for. B. occupational dermatoses or prosthetic care. It can be used as a medicine or as a care product.
  • the formulations according to the invention for the treatment of various skin imperfections, such as acne vulgaris, for eliminating allergies and skin infections in areas of long-term contact of the skin with inanimate surfaces, such as in contact with hearing aids, epitheses, etc., as a deodorant for regulating the Skin flora and to remove hand and foot sweat or against mycotic infections.
  • the weight ratio of polyalcohol to DMI should be in the range from 3: 1 to 1: 1, although exceeding and falling below this weight ratio is not outside the scope of the invention, since then only one of the components is partially ineffective in the formulation.
  • the preferred weight ratio of polyalcohol to DMI is in the range from 2.5: 1 to 1.2: 1, the particularly preferred weight ratio in the range from 2: 1 to 1.5: 1. Weight ratios in these ranges solubilize a sufficient amount of dry flavone glycoside extract in the aqueous phase to give sufficiently effective formulations. The optimal release behavior with regard to the flavonyl glycosides is achieved by solubilizing them in the aqueous phase.
  • the total amount of polyalcohol (s) and dimethyl isosorbide is preferably in the range from 12 to 35% by weight, preferably in the range from 15 to 30% by weight and particularly preferably in the range from 19 to 27% by weight of the finished formulation. It is further preferred that the formulation according to the invention 0.05 to 2.5, preferably 0.1 to 2.0 and particularly preferably 0.2 to 1.2% by weight of the flavone glycoside extract, based on the total weight of the formulation including the oil phase. If we are talking about a flavone glycoside extract, this can of course consist of a mixture of different sources, such as a mixture of ginkgo biloba extract and buckwheat extract.
  • the weight percentage of dimethyl isosorbide in the formulation is expediently in the range from 1 to 20% by weight (w / w) and the content of polyalcohols in the range from 5 to 30% by weight (w / w), in each case based on the total weight the formulation including the oil phase.
  • the formulation can contain customary formulation auxiliaries in customary concentrations, such as emulsifiers for the oil phase, e.g. B. stearyl alcohol, cetostearyl alcohol, glyceryl monostearate or polyoxyethylene glycerol stearate or mixtures thereof.
  • the oil phase is expediently a fat and / or oil, such as liquid paraffin or mineral oil.
  • the Ginkgo biloba extract (1) is dissolved in a mixture of polyethylene glycol (2) and dimethylisorbide (3) at 70 ° C.
  • the mixture of glycerol (9) and water (1 1) is mixed in at 70 ° C.
  • the medium-chain triglycerides (4), liquid paraffin (8) and the emulsifiers (5, 6, 7) are mixed homogeneously at 70 ° C and homogenized at the same temperature with the water phase under vacuum. It is filled in glass or porcelain pots or aluminum tubes.
  • Sorbitol solution 70% 50.0 g 10. Purified water to 1000.0 g
  • the Ginkgo biloba extract (1) is dissolved in a mixture of polyethylene glycol (2) and dimethylisorbide (3) at 70 ° C.
  • the mixture of sorbitol solution 70% (9) and water (10) is mixed in at 70 ° C.
  • the medium-chain triglycerides (4), liquid paraffin (8) and the emulsifiers (5, 6, 7) are mixed homogeneously at 70 ° C and homogenized at the same temperature with the water phase under vacuum. The filling takes place in glass or porcelain pots or aluminum tubes.
  • the cream was also produced analogously to the production process described in Example 2.

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Abstract

Disclosed is an oil-in-water formulation for topical application, with an inner dispersed oil phase and an outer cohesive water phase, and with flavon glycoside extract solubilized in the water phase. The proposed formulation is characterized by the fact that the water phase contains a combination of at least one water-miscible polyalcohol with dimethyl isosorbide (DMI) in a weight ratio of between three and one parts polyalcohol to one part DMI, and the flavon glycoside extract is a solubilized dry extract.

Description

Topisch anzuwendende ÖI-in-Wasser-Formulierung Topical oil-in-water formulation
Die Erfindung betrifft eine topisch anzuwendende ÖI-in-Wasser-Formulierung mit einer inneren dispergierten Ölphase und einer äußeren zusammenhängenden Wasserphase und mit einem in der Wasserphase solubilisierten Ravonglykosid-Extrakt sowie eine Verwendung einer solchen Formulierung.The invention relates to a topical oil-in-water formulation with an inner dispersed oil phase and an outer coherent water phase and with a ravon glycoside extract solubilized in the water phase, and to the use of such a formulation.
Ginkgo-biloba-Extrakt enthält als quantitativ wichtigste Fraktion der wertbestimmenden Iπhaltsstofe Ravone und Ravonglykoside. Für Ravone und Ravonglykoside werden in der Literatur sowohl antioxidative und antiinflammatorische als auch bakterizide und antivirale Eigenschaften beschrieben (Duduk et al, Arch. Exp. Veterinärmed. 26, 285 [19721; Bauman et al, Prostglandins 20, 627 [1080]; Takahama et al, Phytochemistry 24, 1443 [1985]; Alcaraz et al, Pharmazie 41 , 299 [1986]; Ho et al, Agric. Biol. Chem. 49. 2173 [1985]; Waage et al, Phytochemistry 23, 2509 [1984]; Vrijsen et al, Antiviral Res. 7, 35 [1987]).Ginkgo biloba extract contains ravones and ravone glycosides as the quantitatively most important fraction of the value-determining ingredients. Both antioxidative and anti-inflammatory as well as bactericidal and antiviral properties are described in the literature for ravones and ravone glycosides (Duduk et al, Arch. Exp. Veterinärmed. 26, 285 [19721; Bauman et al, Prostglandins 20, 627 [1080]; Takahama et al, Phytochemistry 24, 1443 [1985]; Alcaraz et al, Pharmazie 41, 299 [1986]; Ho et al, Agric. Biol. Chem. 49. 2173 [1985]; Waage et al, Phytochemistry 23, 2509 [1984] ; Vrijsen et al, Antiviral Res. 7, 35 [1987]).
Andere Pfianzenextrakte, die Ravonglykoside enthalten, sind beispielsweise Blattextrakte von Buchweizen, Mäusedorn oder Steineichen. Die lösungsmittelhaltigen Extrakte werden üblicher¬ weise nach bekannten Verfahren zur Anreicherung der Ravonglykoside behandelt und zu Trockeπextrakteπ verarbeitet. Wegen der raschen Verstoffwechselung der Flavonglykoside im Darm bzw. in der Leber kommen bei oraler oder parenteraler Anwendung ihre günstigen Eigenschaften, wenn über¬ haupt, nur kurzfristig zur Wirkung. Eine sinnvolle therapeutische Nutzungder oben angegebenen Eigenaschaften kann daher auf diese Weise nicht vorgenommen werden. Auch eine orale Anwendung von Flavonglykosiden zur Behandlung von Entzündungen und Infektionen der Haut ist nicht möglich. Eine topische Anwendung ist daher zur Bekämpfung von Infektionen und Entzündungen der Haut erwünscht, was aber galenische Probleme mit sich bringt.Other plant extracts that contain ravone glycosides are, for example, leaf extracts from buckwheat, butcher's broom or holm oak. The solvent-containing extracts are usually treated according to known processes for enriching the ravon glycosides and processed into dry extracts. Because of the rapid metabolism of the flavone glycosides in the intestine or in the liver, their beneficial properties, if at all, only have a short-term effect when used orally or parenterally. A meaningful therapeutic use of the properties mentioned above can therefore not be undertaken in this way. Oral use of flavone glycosides to treat inflammation and skin infections is also not possible. Topical application is therefore desirable to combat infections and inflammation of the skin, but this brings with it galenic problems.
Flavonglykoside haben den Nachteil, daß sie in Wasser und den meisten für die Verwendung in Arzneimitteln und Kosmetika erlaubten Lösungsmitteln sehr schwer löslich sind. Es gestaltet sich daher äußerst schwierig, eine topische Formulierung herzustellen, die eine ausreichend gelöste Konzentration der Flavonglykoside enthält, um einen deutlichen Wirkeffekt zu erzielen. Darüber hinaus muß die galenische Formulierung über einen definierten Zeitraum nachweislich stabil und frei von Wirkverlust sein. Im Laufe der Lagerung darf kein Kristallwachstum oder Ausfällen der Flavonglykoside auftreten, noch darf die topische Formulierung zu Hautreizungen führen.Flavone glycosides have the disadvantage that they are very sparingly soluble in water and most of the solvents permitted for use in pharmaceuticals and cosmetics. It is therefore extremely difficult to prepare a topical formulation which contains a sufficiently dissolved concentration of the flavone glycosides in order to achieve a clear effect. In addition, the galenical formulation must be demonstrably stable and free from loss of activity over a defined period. No crystal growth or precipitation of the flavone glycosides may occur during storage, nor should the topical formulation cause skin irritation.
In Anbetracht der Lipidstruktur der Hautoberfläche, besonders des Stratum corneum, wird, um eine gute transdermale Resorption zu erreichen, der Wirkstoff bei topischen Formulierungen meistens in der Ölphase suspendiert. Solche Formulierungen sind in den französischen Patentschriften 2 207 692 und 2 316 946 sowie in der US-Patentschrift 3 934 013 be¬ schrieben. Darüber hinaus beschreibt die deutsche Offenlegungsschrift 3 840 832 äußerlich anzuwendende Präparate unter anderen in der Form von ÖI-in-Wasser-Formulierungen, die einen flüssigen, d. h. lösungsmittelhaltigen Extrakt von Ginkgo biloba und außerdem Propγlenglykol enthalten. Die Verwendung lösungsmittelhaltiger flüssiger Extrakte ist jedoch unerwünscht, da sie einerseits in die Formulierung unerwünschte Lösungsmittelanteile einführen und andererseits gegenüber Trockenextrakten ein für den Transport und die Handhabung unerwünscht großes Volumen besitzen. Außerdem enthalten solche einfachen Flüssigextrakte von Blättern vom Ginkgo biloba für regelmäßige Anwendung unerwünschte Alkγlphenolderivate.In view of the lipid structure of the skin surface, especially the stratum corneum, the active ingredient in topical formulations is usually suspended in the oil phase in order to achieve good transdermal absorption. Such formulations are described in French Patents 2,207,692 and 2,316,946 and in US Pat. No. 3,934,013. In addition, German Offenlegungsschrift 3 840 832 describes preparations to be used externally, inter alia in the form of oil-in-water formulations which contain a liquid, ie. H. Ginkgo biloba extract containing solvents and also contain propylene glycol. However, the use of solvent-containing liquid extracts is undesirable because, on the one hand, they introduce undesirable solvent components into the formulation and, on the other hand, they have a volume that is undesirably large for transport and handling compared to dry extracts. In addition, such simple liquid extracts of Ginkgo biloba leaves contain undesired alkγlphenol derivatives for regular use.
Die der Erfindung zugrundeliegende Aufgabe bestand daher darin, unter Verwendung von Flavonglykosid-Trockenextrakten topisch anzuwendende Formulierungen zu bekommen, die aufgrund einer Solubilisierung der Flavonglykoside eine gute transdermale Resorption und Penetration und außerdem ausreichende Lagerbeständigkeit besitzen.The object on which the invention is based was therefore to obtain topical formulations using flavone glycoside dry extracts which, due to solubilization of the flavone glycosides, have good transdermal absorption and penetration and also have adequate shelf life.
Erfindungsgemäß wird diese Aufgabe mittopisch anzuwendenden ÖI-in-Wasser-Formulierungen mit einer inneren dispergierten Ölphase und einer äußeren zusammenhängenden Wasserphase und mit in der Wasserphase solubilisiertem Flavonglykosid-Extrakt gelöst, wobei diese Formulierung dadurch gekennzeichnet ist, daß die wäßrige Phase eine Kombination wenigstens eines mit Wasser mischbaren Polyalkohols mit Dimethylisosorbid (DMI) in einem Gewichts¬ verhältnis von Polyalkohoi zu DMS von 3 : 1 bis 1 : 1 und als Flavonglykosid-Extrakt einen solubilisierten Trockenextrakt enthält.According to the invention, this object is achieved with oil-in-water formulations which can be used in the middle with an inner dispersed oil phase and an outer coherent water phase and dissolved with flavone glycoside extract solubilized in the water phase, this formulation being characterized in that the aqueous phase is a combination of at least one water-miscible polyalcohol with dimethyl isosorbide (DMI) in a weight ratio of polyalcohol to DMS of 3: 1 to 1 : 1 and contains a solubilized dry extract as a flavone glycoside extract.
Die Erfindung beruht auf der synergistischen Wirkung des oder der mit Wasser mischbaren Polγalkohole einerseits und des Dimethylisosorbids andererseits zur Solubilisierung der Flavonglykoside in Trockenextraktform. Versucht man, Flavonglykosid-Trockenextrakte entweder mit Polyalkohoi allein oder mit Dimethylisosorbid allein löslich zu machen, so mißlingt dies bzw. man erhält unzureichende Stabilität der Zubereitung. Überraschenderweise bringt die Kombination beider Komponenten jedoch den Flavonglykosid-Trockenextrakt in Lösung in der äußeren Wasserphase, was eine hohe transdermale Resorption und Penetration und gleichzeitig hohe Lagerbeständigkeit der Formulierung ergibt. Die Formulierung liegt gewöhnlich in Form einer Salbe oder Creme vor.The invention is based on the synergistic effect of the water-miscible polyalcohols on the one hand and the dimethyl isosorbide on the other hand for solubilizing the flavone glycosides in dry extract form. If one tries to solubilize flavone glycoside extracts either with polyalcohol alone or with dimethylisosorbide alone, this fails or the preparation is not sufficiently stable. Surprisingly, however, the combination of both components brings the flavone glycoside dry extract in solution in the outer water phase, which results in high transdermal absorption and penetration and at the same time high storage stability of the formulation. The formulation is usually in the form of an ointment or cream.
Als Flavonglykosid-Trockenextrakte können beliebige Extrakte verwendet werden, die Flavonglykoside enthalten, wie Buchweizenextrakte, Mäusedornextrakte und Steineichen¬ extrakte. Dabei verwendet man gewöhnlich Trockenextrakte, in denen unerwünschte Bestand¬ teile nach bekannten Verfahren entfernt und die Flavonglykoside beispielsweise bis zu 25 % der Trockensubstanz angereichert wurden.Any extracts which contain flavone glycosides, such as buckwheat extracts, butcher's broom extracts and holm oak extracts, can be used as the flavone glycoside dry extracts. Dry extracts are usually used in which undesired constituents have been removed by known processes and the flavone glycosides have been enriched, for example, up to 25% of the dry matter.
Die erfindungsgemäße Formulierung kann einen oder mehrere mit Wasser mischbare Poly- alkohole enthalten, d. h. Alkohole mit mindestens zwei Hydroxylgruppen. Solche Polyalkohole sind beispielsweise und bevorzugt Propylenglykole, Polyethylenglykol, Glycerol, Sorbitol und Mischungen hiervon.The formulation according to the invention can contain one or more water-miscible polyalcohols, ie. H. Alcohols with at least two hydroxyl groups. Such polyalcohols are, for example and preferably, propylene glycols, polyethylene glycol, glycerol, sorbitol and mixtures thereof.
Die erfindungsgemäßen Formulierungen sind topisch anwendbar zur Behandlung von bakteriel¬ len und viralen Infektionen der Haut und Mukosa und zur entzündungshemmenden und juckreizstillenden Behandlung von allergischen und atopischen Ekzemen und anderen Reizzuständen der Haut, wie z. B. Berufsdermatosen oder bei prothetischer Versorgung. Die Verwendung kann als Arzneimittel oder als Pflegemittel erfolgen. So können die erfindungs¬ gemäßen Formulierungen zur Behandlung diverser Hautunreinheiten, wie Akne vulgaris, zur Beseitigung von Allergien und Infektionen der Haut in Bereichen langzeitigen Kontaktes der Haut mit unbelebten Oberflächen, wie bei Kontakt mit Hörgeräten, Epithesen usw., als Desodorans, zur Regulierung der Hautflora und zur Beseitigung von Hand- und Fußschweiß oder gegen mycotische Infektionen eingesetzt werden. Wie angegeben, sollte das Gewichtsverhältnis von Polyalkohoi zu DMI im Bereich von 3 : 1 bis 1 : 1 liegen, obwohl ein Über- und Unterschreiten dieses Gewichtsverhältnisses nicht außerhalb des Erfindungsgedankens liegt, da dann lediglich einer der Bestandteile teilweise unwirksam in der Formulierung vorliegt. Das bevorzugte Gewichtsverhältnis von Polyalkohoi zu DMI liegt im Bereich von 2,5 : 1 bis 1 ,2 : 1 , das besonders bevorzugte Gewichtsverhältnis im Bereich von 2 : 1 bis 1 ,5 : 1 . Gewichtsverhältnisse in diesen Bereichen solubilisieren eine ausreichende Menge an Flavonglykosid-Trockenextrakt in der wäßrigen Phase, um ausreichend wirksame Formulierungen zu ergeben. Das optimale Freigabeverhalten bezüglich der Flavonylglykoside erreicht man durch die Solubilisierung derselben in der wäßrigen Phase.The formulations according to the invention can be applied topically for the treatment of bacterial and viral infections of the skin and mucosa and for the anti-inflammatory and antipruritic treatment of allergic and atopic eczema and other irritation conditions of the skin, such as, for. B. occupational dermatoses or prosthetic care. It can be used as a medicine or as a care product. Thus, the formulations according to the invention for the treatment of various skin imperfections, such as acne vulgaris, for eliminating allergies and skin infections in areas of long-term contact of the skin with inanimate surfaces, such as in contact with hearing aids, epitheses, etc., as a deodorant for regulating the Skin flora and to remove hand and foot sweat or against mycotic infections. As stated, the weight ratio of polyalcohol to DMI should be in the range from 3: 1 to 1: 1, although exceeding and falling below this weight ratio is not outside the scope of the invention, since then only one of the components is partially ineffective in the formulation. The preferred weight ratio of polyalcohol to DMI is in the range from 2.5: 1 to 1.2: 1, the particularly preferred weight ratio in the range from 2: 1 to 1.5: 1. Weight ratios in these ranges solubilize a sufficient amount of dry flavone glycoside extract in the aqueous phase to give sufficiently effective formulations. The optimal release behavior with regard to the flavonyl glycosides is achieved by solubilizing them in the aqueous phase.
Bevorzugt liegt die Gesamtmenge von Polyalkohol(en) und Dimethylisosorbid im Bereich von 12 bis 35 Gew.-%, bevorzugt im Bereich von 15 bis 30 Gew.-% und besonders bevorzugt im Bereich von 19 bis 27 Gew.-% der fertigen Formulierung. Weiterhin ist es bevorzugt, daß die erfindungsgemäße Formulierung 0,05 bis 2,5, vorzugsweise 0, 1 bis 2,0 und besonders bevorzugt 0,2 bis 1 ,2 Gew.-% des Flavonglykosid-Extraktes, bezogen auf das Gesamtgewicht der Formulierung einschließlich der Ölphase, enthält. Wenn hier von einem Flavonglykosid- Extrakt die Rede ist, kann dieser selbstverständlich aus einem Gemisch aus unterschiedlichen Quellen bestehen, wie aus einem Gemisch von Ginkgo-biloba-Extrakt und Buchweizen-Extrakt.The total amount of polyalcohol (s) and dimethyl isosorbide is preferably in the range from 12 to 35% by weight, preferably in the range from 15 to 30% by weight and particularly preferably in the range from 19 to 27% by weight of the finished formulation. It is further preferred that the formulation according to the invention 0.05 to 2.5, preferably 0.1 to 2.0 and particularly preferably 0.2 to 1.2% by weight of the flavone glycoside extract, based on the total weight of the formulation including the oil phase. If we are talking about a flavone glycoside extract, this can of course consist of a mixture of different sources, such as a mixture of ginkgo biloba extract and buckwheat extract.
Der Gewichtsprozentsatz von Dimethylisosorbid in der Formulierung liegt zweckmäßig im Bereich von 1 bis 20 Gew.-% (w/w) und der Gehalt an Polyalkohoi im Bereich von 5 bis 30 Gew.-% (w/w), jeweils bezogen auf das Gesamtgewicht der Formulierung einschließlich der Ölphase.The weight percentage of dimethyl isosorbide in the formulation is expediently in the range from 1 to 20% by weight (w / w) and the content of polyalcohols in the range from 5 to 30% by weight (w / w), in each case based on the total weight the formulation including the oil phase.
Zusätzlich zu den erfindungswesentlichen Bestandteilen, die oben angegeben sind, kann die Formulierung übliche Formulierungshilfsstoffe in üblichen Konzentrationen enthalten, wie Emulgatoren für die Ölphase, z. B. Stearylalkohol, Cetostearylalkohol, Glycerylmonostearat oder Polyoxyethylenglycerolstearat oder Mischungen hiervon. Die Ölphase ist zweckmäßig ein Fett und/oder Öl, wie flüssiges Paraffin oder Mineralöl.In addition to the constituents essential to the invention, which are given above, the formulation can contain customary formulation auxiliaries in customary concentrations, such as emulsifiers for the oil phase, e.g. B. stearyl alcohol, cetostearyl alcohol, glyceryl monostearate or polyoxyethylene glycerol stearate or mixtures thereof. The oil phase is expediently a fat and / or oil, such as liquid paraffin or mineral oil.
BeispieleExamples
Beispiel 1example 1
0,25 % (w/w) Ginkgo-biloba-Creme0.25% (w / w) ginkgo biloba cream
1 . Ginkgo-biloba-Trockenextrat 2,5 g1 . Ginkgo biloba dry extract 2.5 g
2. Polyethylenglykol 120,0 g 3. Dimethylisosorbid 70,0 g2. Polyethylene glycol 120.0 g 3. Dimethyl isosorbide 70.0 g
4. Mittelkettige Triglyceride 45,0 g4. Medium chain triglycerides 45.0 g
5. Polyoxyethylenglycerolstearat 50,0 g5. Polyoxyethylene glycerol stearate 50.0 g
6. Cetostearylalkohol 40,0 g6. Cetostearyl alcohol 40.0 g
7. Glycerylmonostearat 30,0 g7. Glyceryl monostearate 30.0 g
8. Flüssiges Paraffin 60,0 g8. Liquid paraffin 60.0 g
9. Glycerol 35,0 g 10. Gereinigtes Wasser zu 1000,0 g9. Glycerol 35.0 g 10. Purified water to 1000.0 g
Der Ginkgo-biloba-Extrakt (1 ) wird in einer Mischung aus Polyethylenglykol (2) und Dimethyliso¬ sorbid (3) bei 70 °C gelöst. Hierzu wird die Mischung aus Glycerol (9) und Wasser ( 1 1 ) bei 70 °C untergemischt. Die mittelkettigen Triglyceride (4), flüssiges Paraffin (8) und die Emulgatoren (5, 6, 7) werden bei 70 °C homogen gemischt und bei der gleichen Temperatur mit der Wasserphase unter Vakuum homogenisiert. Die Abfüllung erfolgt in Glas- oder Porzellantiegel oder Aluminiumtuben.The Ginkgo biloba extract (1) is dissolved in a mixture of polyethylene glycol (2) and dimethylisorbide (3) at 70 ° C. For this purpose, the mixture of glycerol (9) and water (1 1) is mixed in at 70 ° C. The medium-chain triglycerides (4), liquid paraffin (8) and the emulsifiers (5, 6, 7) are mixed homogeneously at 70 ° C and homogenized at the same temperature with the water phase under vacuum. It is filled in glass or porcelain pots or aluminum tubes.
Beispiel 2Example 2
0,75 % (w/w) Ginkgo-biloba-Creme0.75% (w / w) ginkgo biloba cream
1 . Ginkgo-biloba-Trockenextrat 7,5 g1 . Ginkgo biloba dry extract 7.5 g
2. Polyethylenglykol 120,0 g2. Polyethylene glycol 120.0 g
3. Dimethylisosorbid 70,0 g3. Dimethyl isosorbide 70.0 g
4. Mittelkettige Triglyceride 50,0 g4. Medium chain triglycerides 50.0 g
5. Polyoxyethylenglycerolstearat 80,0 g5. Polyoxyethylene glycerol stearate 80.0 g
6. Stearylalkohol 40,0 g6. Stearyl alcohol 40.0 g
7. Glycerylmonostearat 40,0 g7. Glyceryl monostearate 40.0 g
8. Flüssiges Paraffin 60,0 g8. Liquid paraffin 60.0 g
9. Sorbitol-Lösung 70 % 50,0 g 10. Gereinigtes Wasser zu 1000,0 g9. Sorbitol solution 70% 50.0 g 10. Purified water to 1000.0 g
Der Ginkgo-biloba-Extrakt (1) wird in einer Mischung aus Polyethylenglykol (2) und Dimethyliso¬ sorbid (3) bei 70 °C gelöst. Hierzu wird die Mischung aus Sorbitol-Lösung 70 % (9) und Wasser (10) bei 70 °C untergemischt. Die mittelkettigen Triglyceride (4), flüssiges Paraffin (8) und die Emulgatoren (5, 6, 7) werden bei 70 °C homogen gemischt und bei der gleichen Temperatur mit der Wasserphase unter Vakuum homogenisiert. Die Abfüllung erfolgt in Glas¬ oder Porzellantiegel oder Aluminiumtuben. Beispiel 3The Ginkgo biloba extract (1) is dissolved in a mixture of polyethylene glycol (2) and dimethylisorbide (3) at 70 ° C. For this purpose, the mixture of sorbitol solution 70% (9) and water (10) is mixed in at 70 ° C. The medium-chain triglycerides (4), liquid paraffin (8) and the emulsifiers (5, 6, 7) are mixed homogeneously at 70 ° C and homogenized at the same temperature with the water phase under vacuum. The filling takes place in glass or porcelain pots or aluminum tubes. Example 3
1 % (w/w) Buchweizen-Creme1% (w / w) buckwheat cream
1 . Buchweizen-Trockenextrat 10,0 g1 . Buckwheat dry extract 10.0 g
2. Polyethylenglykol 1 60,0 g2. Polyethylene glycol 1 60.0 g
3. Dimethylisosorbid 100,0 g3. Dimethyl isosorbide 100.0 g
4. Mittelkettige Triglyceride 75,0 g4. Medium chain triglycerides 75.0 g
5. Polyoxyethylenglycerolstearat 80,0 g5. Polyoxyethylene glycerol stearate 80.0 g
6. Stearylalkohol 77,5 g6. Stearyl alcohol 77.5 g
7. Glycerylmonostearat 40,0 g7. Glyceryl monostearate 40.0 g
8. Flüssiges Paraffin 80,0 g8. Liquid paraffin 80.0 g
9. Weiße Vaseline 75,0 g 10. Gereinigtes Wasser zu 1000,0 g9. White petroleum jelly 75.0 g 10. Purified water to 1000.0 g
Die Creme wurde ebenfalls analog dem in Beispiel 2 beschriebenen Herstellverfahren herge¬ stellt.The cream was also produced analogously to the production process described in Example 2.
Anwendungsbeobachtungen bei Patienten mit Akne und Herpes sowie bei Patienten mit atopischen und allergisch bedingten Ekzemen haben zu folgenden Ergebnissen geführt:Observations of use in patients with acne and herpes as well as in patients with atopic and allergic eczema have led to the following results:
An einer Gruppe von 20 Ekzem-Patienten (Patienten mit Neurodermatitis bzw. allergisch bedingten Ekzemen, u. a. berufsbedingten Kontaktekzemen) mit ausgeprägtem Juckreiz war bei topischer Anwendung einer Creme nach Beispiel 2 eine überraschend schnelle Juckreiz¬ stillung zu beobachten. Eine mit der Dauer der Anwendung einsetzende entzündungshemmende Wirkung führte über einen Zeitraum von 7 bis 14 Tagen zu einer deutlichen Linderung der Symptome der Entzündung. Die wirkstofffreie Formulierung (Placebo-Creme) dagegen führte zu keiner Verbesserung des Zustandes. Die überraschend schnelle Juckreizstillung ließ sich unter anderem auch bei Insektenstichen sehr deutlich demonstrieren. Die entzündungshem¬ mende Wirkung konnte auch bei kleineren Brandwunden sehr gut beobachtet werden.In a group of 20 eczema patients (patients with neurodermatitis or allergy-related eczema, including occupational contact eczema) with pronounced itching, surprisingly fast itching was observed when a cream according to Example 2 was applied topically. An anti-inflammatory effect that started with the duration of the application led to a significant relief of the symptoms of the inflammation over a period of 7 to 14 days. The drug-free formulation (placebo cream), however, did not improve the condition. The surprisingly quick itching relief was demonstrated very clearly, among other things, by insect bites. The anti-inflammatory effect could also be observed very well in the case of minor burns.
Bei Patienten mit Akne vulgaris war ebenfalls eine ausgeprägte entzündungshemmende und juckreizstillende Wirkung festzustellen. Akne-Pusteln heilten unter regelmäßiger Anwendung der erfindungsgemäßen Formulierung deutlich schneller ab als ohne Behandlung. Insbesondere war eine rasche Eintrocknung und Verschorfung der Pusteln zu verzeichnen. Der gleiche Effekt konnte neben der Juckreizstillung auch bei Patienten mit Herpes labialis beobachtet werden. Da unter der Entwicklung der erfindungsgemäßen Ginkgo-biloba-Zubereitung kleine Schnitt¬ wunden praktisch infektionsfrei abheilen, ist der erfindungsgemäßen Zubereitung neben der beobachteten entzündungshemmenden Wirkung auch eine direkte antibakterielle sowie eine gewisse antivirale Wirkung zuzuordnen. A pronounced anti-inflammatory and antipruritic effect was also found in patients with acne vulgaris. Acne pustules healed significantly faster with regular use of the formulation according to the invention than without treatment. In particular, there was rapid drying and scabbing of the pustules. The same effect was observed in addition to the itching relief in patients with herpes labialis. Since small incised wounds heal practically free of infection during the development of the ginkgo biloba preparation according to the invention, the preparation according to the invention can be assigned not only the observed anti-inflammatory effect but also a direct antibacterial and a certain antiviral effect.

Claims

P a t e n t a n s p r ü c h e Patent claims
1 . Topisch anzuwendende ÖI-in-Wasser-Formulierung mit einer inneren dispergierten Ölphase und einer äußeren zusammenhängenden Wasserphase und mit in der Wasser¬ phase solubilisiertem Flavonglykosid-Extrakt, dadurch gekennzeichnet, daß die wäßrige Phase eine Kombination wenigstens eines mit Wasser mischbaren Polyalkohols mit Dimethylisosorbid (DMI) in einem Gewichtsverhältnis von Polyalkohoi zu DMI von 3 : 1 bis 1 : 1 und als Flavonglykosid-Extrakt einen solubilisierten Trockenextrakt enthält.1 . Topical oil-in-water formulation with an inner dispersed oil phase and an outer coherent water phase and with flavone glycoside extract solubilized in the water phase, characterized in that the aqueous phase is a combination of at least one water-miscible polyalcohol with dimethyl isosorbide (DMI ) in a weight ratio of polyalcohol to DMI of 3: 1 to 1: 1 and as a flavone glycoside extract contains a solubilized dry extract.
2. Formulierung nach Anspruch 1 , dadurch gekennzeichnet, daß sie als Flavonglykosid- Extrakt Ginkgo-biloba-Trockenextrakt enthält.2. Formulation according to claim 1, characterized in that it contains ginkgo biloba dry extract as flavone glycoside extract.
3. Formulierung nach Anspruch 1 oder 2, dadurch gekennzeichnet , daß sie ein Gewichts¬ verhältnis von Polyalkohoi zu DMI von 2,5 : 1 bis 1 ,2 : 1 , vorzugsweise von 2 : 1 bis 1 ,5 : 1 enthält.3. Formulation according to claim 1 or 2, characterized in that it contains a weight ratio of polyalcohol to DMI of 2.5: 1 to 1.2: 1, preferably from 2: 1 to 1.5: 1.
4. Formulierung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet , daß sie, bezogen auf das Gesamtgewicht der Formulierung einschließlich der Ölphase, 1 2 bis 35, vorzugsweise 1 5 bis 30, besonders 19 bis 27 Gew.-% von Polyalkohoi und DMI zusammen enthält.4. Formulation according to one of claims 1 to 3, characterized in that, based on the total weight of the formulation including the oil phase, 1 2 to 35, preferably 1 5 to 30, particularly 19 to 27 wt .-% of polyalcohols and DMI together contains.
5. Formulierung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet , daß sie. bezogen auf das Gesamtgewicht der Fomulierung einschließlich der Ölphase, 0,05 bis 2,5, vorzugsweise 0, 1 bis 2,0, besonders 0,2 bis 1 ,2 Gew.-% des Flavonglykosid- Trockenextraktes enthält.5. Formulation according to one of claims 1 to 4, characterized in that it. based on the total weight of the formulation including the oil phase, 0.05 to 2.5, preferably 0.1 to 2.0, particularly 0.2 to 1.2% by weight of the flavone glycoside dry extract.
6. Formulierung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet , daß sie, bezogen auf das Gesamtgewicht der Formulierung einschließlich der Ölphase, 1 bis 20 Gew.-% Dimethylisosorbid enthält.6. Formulation according to one of claims 1 to 5, characterized in that it contains, based on the total weight of the formulation including the oil phase, 1 to 20 wt .-% dimethyl isosorbide.
7. Formulierung nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß sie, bezogen auf das Gesamtgewicht der Formulierung einschließlich der ölphase, 5 bis 30 Gew.-% Polyalkohoi enthält. 7. Formulation according to one of claims 1 to 6, characterized in that it contains, based on the total weight of the formulation including the oil phase, 5 to 30 wt .-% polyalcohols.
8. Formulierung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, daß sie als Polyalkohoi Propylenglykol, Polyethylenglykol, Glycerol, Sorbitol oder eine Mischung hiervon enthält.8. Formulation according to one of claims 1 to 7, characterized in that it contains as polyalcohol propylene glycol, polyethylene glycol, glycerol, sorbitol or a mixture thereof.
9. Formulierung nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, daß sie zusätzlich einen Emulgator für die Ölphase, vorzugsweise Stearylalkohol, Cetostearyl- alkohol, Glycerylmonostearat und/oder Polyoxyethylenglycerolstearat enthält.9. Formulation according to one of claims 1 to 8, characterized in that it additionally contains an emulsifier for the oil phase, preferably stearyl alcohol, cetostearyl alcohol, glyceryl monostearate and / or polyoxyethylene glycerol stearate.
10. Formulierung nach einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, daß die Ölphase ein Fett und/oder Öl enthält.10. Formulation according to one of claims 1 to 9, characterized in that the oil phase contains a fat and / or oil.
1 1 . Formulierung nach Anspruch 10, dadurch gekennzeichnet , daß die ölphase als Fett und/oder Öl flüssiges Paraffin und/oder ein Mineralöl enthält.1 1. Formulation according to Claim 10, characterized in that the oil phase contains liquid paraffin and / or a mineral oil as fat and / or oil.
12. Formulierung nach einem der Ansprüche 1 bis 1 1 zur Behandlung von mikrobiellen und viralen Infektionen der Haut und Mukosa und/oder zur entzündungshemmenden und juckreizstillenden Behandlung von allergischen und atopischen Ekzemen und anderen Reizzusständen der Haut. 12. Formulation according to one of claims 1 to 1 1 for the treatment of microbial and viral infections of the skin and mucosa and / or for the anti-inflammatory and antipruritic treatment of allergic and atopic eczema and other irritant conditions of the skin.
PCT/DE1994/001238 1993-10-11 1994-10-21 Oil-in-water formulation for topical application WO1996012504A1 (en)

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DE9320586U DE9320586U1 (en) 1993-10-11 1993-10-11 Topical formulation of a solubilized ginkgo biloba extract
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AU79894/94A AU7989494A (en) 1993-10-11 1994-10-21 Oil-in-water formulation for topical application
PCT/DE1994/001238 WO1996012504A1 (en) 1993-10-11 1994-10-21 Oil-in-water formulation for topical application

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DE9320586U1 (en) * 1993-10-11 1994-10-13 Hgb Pharma Service Gmbh Topical formulation of a solubilized ginkgo biloba extract
FR2755015B1 (en) * 1996-10-25 1998-12-24 Sod Conseils Rech Applic USE OF A FLAVONOID EXTRACT OF GINKGO BILOBA SUBSTANTIALLY FREE OF TERPENES, IN THE ORAL FIELD, AND COMPOSITION CONTAINING SUCH EXTRACT
DE19829516B4 (en) * 1998-07-02 2004-08-26 Dr. Willmar Schwabe Gmbh & Co. Kg Water-soluble native dry extract from Gingko biloba with a high content of terpenoids and flavone glycosides
RU2172322C1 (en) 1999-12-27 2001-08-20 Энтофарм Ко., Лтд. Allopherones as immunomodulating peptides
IT201700104536A1 (en) 2017-09-19 2019-03-19 Cmed Aesthetics Srl Topical products with two-phase system

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FR2613223B1 (en) * 1987-04-03 1991-09-13 Biogalenique Laboratoires GALENIC FORM PRESENTING IN THE FORM OF WATER-SOLUBLE GRAINS, PARTICULARLY BASED ON A DRY GINKGO BILOBA EXTRACT, AND ITS PREPARATION METHOD
DE3840832A1 (en) * 1988-12-03 1990-06-07 Mueller Robert Dr Product for external use
DE3940092A1 (en) * 1989-12-04 1991-06-06 Schwabe Willmar Gmbh & Co EXTRACT OF BLACKERS OF GINKGO BILOBA, METHOD FOR THE PRODUCTION THEREOF AND THE EXTRACT CONTAINING MEDICAMENT
FR2668063A1 (en) * 1990-10-17 1992-04-24 Fabre Pierre Cosmetique LIPOSOMES OF THERMAL WATER STABILIZED IN A DNA GEL.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

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