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• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/14—Hydrolases (3)
  • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • 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)
  • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
• • 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)
  • A61K36/82—Theaceae (Tea family), e.g. camellia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/60—Sugars; Derivatives thereof
  • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9771—Ginkgophyta, e.g. Ginkgoaceae [Ginkgo family]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/74—Biological properties of particular ingredients
  • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
  • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/004—Aftersun preparations

Definitions

• the present invention generally relates to a method for treating inflammation and irritation of the skin by topical application.
• This composition is also useful in cosmetics for improving skin conditions related to damages produced by weather, sun, chemicals or aging.
• cyclic AMP or cyclic 3 '5' adenosine monophosphate (cAMP) as a second messenger and regulator of numerous cellular functions is now universally accepted. It has been established that the level of cAMP in the cell depends on the speed of its formation in the cell under the direction of adenyl cyclase and its hydrolysis by the enzyme phosphodiesterase (PDE) (R.W. Butcher and al. J. Biol. Chem. 241 , 1651 , 1966). Because all the earlier studies were conducted using saturating substrates, only later was it established that kinetically different forms of PDE activity were present in most tissues (VV.J. Thompson, Biochem. 10, 31 , 1 71 ).
• PDE phosphodiesterase
• the present invention relates to an improved composition based on the isolation of very active and specific inhibitors of iso PDEs from plants.
• the invention relates to compositions for the treatment of skin infllamation and prevention and improvement of skin conditions related to the damage produced by weather, chemicals or aging.
• the most active on human skin iso PDE were flavonoid extracts from Ginkgo Biloba namely Amentoflavone, Bilobetine and Ginkgo Biloba Biflavonoid, and also extracts from Green Tea and Orthosiphon or their active ingredient.
• the Bilobetine and Amentoflavone showed similar potency in inhibiting PDE as the crude Ginkgo Biloba extract.
• This Ginkgo Biloba extract was active in concentration of 1 - 10 ⁇ g/ml. This exceptionally high potency indicates the possibility of its use without further purification.
• this new human skin iso PDE belongs to the group No 4 or cAMP specific iso enzyme family.
• the present invention deals with composition for improving skin conditions containing as active ingredient a specific inhibitor of human skin iso PDE and a dermatological acceptable carrier and also with method for improving skin conditions comprising the appl ication of said composition.
• composition according to the invention can be under a form of an emulsion, a cream, a gel, a foam or a lotion.
• composition comprising specific inhibitor of female human skin iso PDE or male human skin iso PDE
• Said composition may also contain cyclic AMP or one of its analogs or derivatives as described in U.S. Patent 3 978 213 and U.S. Patent 4 208 406.
• cyclic AMP or one of its analogs or derivatives as described in U.S. Patent 3 978 213 and U.S. Patent 4 208 406.
• compositions are especially useful for treatment of inflammation of skin but also for improving skin conditions caused by wind, cold, chemicals, sunshine, insect bites or other irritating substances as poison oak or poison , air conditioning, polution and others (croton oil, mustard oil, etc ) Said compositions are also useful to improve normal physiological function in
• a topical application of a cream, gel, lotion, emulsion, foam or spray with Ginkgo Biloba extract or other specific inhibitors at the concentration of 0 01 % with O 1 % of cyclic AMP is recommended for mild skin inflammation or irritation produced b ⁇ cold, wind, sunshine, chemicals, air conditioning, polution and other skin stressing conditions and aging
• Tigure 1 show s the results of phosphodiesterase assav on Rotofor for fractions of female human skjn using the Thompson PDE assav method The x-avis gives the fraction number
• Figure 2 is analogous to figure 2 except that it corresponds to male human
• Figure 3 show s the inhibitory action of some plant extracts on iso PDE from human skin
• the extracts are the following I - Ginkgo Biloba biflavono ⁇ ds
• the x-axis gives the concentration of the extract ( ⁇ g/ml) .
• the y-axis gives the percentage of inhibition.
• Figure 4 shows the results of the study of UV induced Erythema in Guinea Pigs following topical application of creams with : - 0.1 % cAMP, (cAMP),
• the x-axis represents the time after the application, expressed in hour.
• the y-axis represents the ratio of erythema to corresponding 0-hour measurement, expressed in %.
• cyclic AMP cyclic AMP
• PDE phosphodiesierases
• the iso PDEs are relatively large protein molecules ( MW around 50 to 1 10 kD), they are not stable and lose their biological activity very quickly even when frozen at -20°C, also, many laboratories are using different methods of separation and isolation and it is still very difficult to make a clear classification of different iso PDEs obtained from various laboratories.
• a Rotofor apparatus there are twenty compartments separated by membranes. At the end of electrophoresis (2 - 3 hours) the solution in these 20 compartments are pumped (by vacuum) into 20 tubes. After measuring pH, obtained fractions are assayed for their hv drolysing activities on different substrates (cAMP, cGMP, in presence of CA+/Calmoduhn or cGMP) using the Thompson PDE assay method (W. J. Thompson, Biochem. 10, 3 1 , 1971 ) Usual.) 50 to 100 ⁇ l of obtained fractions are used for each assay. The total volume of each fraction varies from 1 9 to 3.0 ml The remaining solution is stored at -20'C or lyophilized in a l iophi zer freeze dryer 4.5 ( Labconco) .
• the Ginkgo Biloba Biflavonoid showed extremely high inhibitory activity on human skin iso PDE. It was active at the concentration of 0.001 mg/ml. Fifty percent (50 %) inhibition was obtained in vitro at the concentration of 10 ⁇ g/ml.
• the dorsal skin was covered with half cylindrical bakelite shield containing four holes ( 1.3 cm) in diameter symmetrically oriented.
• the administration of test articles was alternated on the test sites.
• the UN. lamp G. E. model RSK 6 was used immediately following the U.V. exposure, the creams were topically applied (0.1 ml/site) and gently dispersed by gloved fingers on the appropriate test sites. Sixty minutes following the application, the remaining cream was gently removed with a tissue. The cream application was repeated at 60, 120 and 180 minutes.
• the test sites were evaluated at 0, 60, 120, 180 and 240 minutes and 24 hours following topical application.
• a negative (placebo) control site was included for each animal.
• O no erythema
• 1 skin appears pink (barely perceptible)
• 2 red, well defined erythema
• 3 beet red, moderate to severe erythema
• 4 beet red, severe erythema to slight eschar formation. It was established in several experiments that cAMP alone reduced UN. erythema, Ginkgo Biloba had the same effect in the first 3 hours.
• the placebo consisted of a cream formulation, (table 2 for composition) which was used as the base for all other test articles.
• the 0.1 % cAMP cream alone reduced erythema after 3 hours of application (table 3 ), whereas the Ginkgo Biloba cream alone significantly decreased the erythema after 2 hours of application with enhanced activity over a period of 4 hours.
• Enhanced activity was evident with the combination of 0. 1 % cAMP and 0.01 % of Ginkgo Biloba. More important is the fact that the above results are obtained after acute administration of each cream while expected use of a product would be chronic.
• PEG-6 stearate (and glyceryl stearate and ceteth-20) 10.0 g

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• 1996
  • 1996-03-06 EP EP96903160A patent/EP0813418A2/de not_active Withdrawn
  • 1996-03-06 WO PCT/IB1996/000176 patent/WO1996027384A2/en not_active Ceased
  • 1996-03-06 JP JP8526738A patent/JPH11501311A/ja active Pending

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