Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
• • 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
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/748—Cyanobacteria, i.e. blue-green bacteria or blue-green algae, e.g. spirulina
• • 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
  • A61K36/09—Lichens
• • 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)
  • A61K36/52—Juglandaceae (Walnut 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)
  • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
• • 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
  • A61K8/9728—Fungi, e.g. yeasts
• • 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
  • A61K8/9733—Lichens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations

Definitions

• This invention relates to natural extracts, novel compounds obtained therefrom and their use for medical and cosmetic sun-protection agents.
• UVR ultraviolet radiation
• sunscreens raises several concerns: Most sunscreens do not effectively filter out all the detrimental wavelengths of sun light. Second, even though sunscreens prevent sunburn, little is known regarding the threshold or dose-response for UVR-induced effects on other endpoints such as immune suppression and DNA damage. Finally, there is increasing body of evidence that presently used topical sunscreens might undergo UV-induced photooxidation and form potentially toxic metabolites.
• Commercial sunscreen formulations make use of both organic and inorganic agents as the components of the formulation. Organic sunscreens have been the mainstay of sunscreen formulation for decades.
• UV filters in the form of pigments are abundant and might constitute attractive candidates for new effective and nontoxic sunscreens.
• melanin and flavonoides they include scytonemins found in cyanobacteria with a recently elucidated structure (Proteau et al (1993) Experimentia 49:825-829).
• This pigment the first shown to be an effective photostable UV shield in prokaryotes, is a dimeric molecule of indole and phenol subunits.
• the scytonemin absorbs strongly and broadly in the spectral region of 325-425 nm (UVA) but also has an absorption in the UVB (280-320 nm) and UVC ( ⁇ 250 nm) regions (US patent No. 5,461,070).
• Mycosporine is another family of water-soluble, ultra violet-absorbing metabolites found in cyanobacteria with an UV absorption peak in the UVB range.
• the elucidated structure of mycosporine is cyclohexenone chromophore conjugated with the nitrogen of an amino acid or an amino alcohol.
• a variety of specific mycosporin amino acids were identified and their distribution in various groups has been described (Karentz et al. (1991) Marine Biology 108, 157-166).
• the present invention is based on the fact that extracts from various natural sources and novel compounds obtained therefrom and their derivatives, absorb efficiently ultra violet radiation and thus may be used as effective sun-protection agents.
• the present invention relates to novel natural extracts isolated from fungus, cyanobacteria, plants, lichens or a mixture thereof having ultra violet absorbency in the range between 220 nm and 425 nm.
• the extraction is done by contacting said fungus, cyanobacteria, plants, lichens or a mixture thereof with a C ⁇ -7 -alcoholic solution.
• the alcoholic solution may be an aqueous solution or comprise a hydrophobic organic solvent.
• the fungus is Collema associated fungus, the plant is chosen from the group comprising of Pecan nut, Cichorium endivia, Eriobotrya nut or mixtures thereof, the lichen is Xanthoria and the cyanobacteria is chosen from the group consisting of Spirulina or Aphanizomeno or mixture thereof.
• the invention further relates to a compound extracted and isolated from Collema lichens and its derivatives of formula (I):
• R J -R 8 which may be the same or different are selected from the
• R 9 10 group comprising of hydrogen, a C ⁇ -C ⁇ o-alkyl or acyl group
• R and R which may be the same or different are selected from the group comprising of Ci-Cio-alkyl, aryl, hydrogen or an acyl group
• X is NR, oxygen or sulfur, wherein R is hydrogen, alkyl or aryl.
• the invention further relates to cosmetic formulations providing protection for skin from the hazardous effects of ultra violet (UVA and UVB) irradiation, comprising an effective amount of an alcoholic extract from fungus, cyanobacteria, plant, lichen, a mixture thereof or an effective amount of a compound of formula (I).
• Such cosmetic formulations may further comprise at least one additional sun-protecting agent.
• the invention still further relates to the use of an effective amount of the extract of the present invention or of a compound of formula I, optionally together with at least one additional sun-protecting agent for the preparation of a sunscreen formulation providing protection from ultra violet (UVA and UVB) irradiation.
• UVA and UVB ultra violet
• Figs. 1 A and IB show the ultra violet spectrum of extracts from the fungus
• Figs. 2A and 2B show the ultra violet spectrum of extracts from Pecan nut (2 A) and from Cichorium endivia subsp. Divaricatum (2B).
• Figs. 3A, 3B and 3C show the ultra violet spectrum of extracts from Eriobotrya nuts (3 A), from Spirulina (3B) and from Xanthoria (3C).
• Fig. 4 shows results from in vivo testing of the efficacy of protection of skin of an arm exposed to U. irradiation when covered with lotion comprising of (1) Collema associated fungus; (2) Cichorium; (3) Eriobotrya; (4) Pecan; and (5) olive oil (serving as control).
• Figs 5A and 5B show the ultra violet spectrum in the range of 290 nm to 400 nm taken in increments of 5 nm of extracts Spirulina (5A) and from Aphanizomenonflos aquae (5B) showing the UVA UVB ratio.
• Figs 6A and 6B show the ultra violet spectrum in the range of 290 nm to 400 nm taken in increments of 5 nm of two comparative samples "nivea 3 star” (6A) and “boots soltan 4 star” showing the UVA/UVB ratio.
• Fig. 7 shows the ultra violet spectrum of the purified compound (compound I) isolated from the extract of Collema lichens.
• Fig 8 is a 1 -Dimensional NMR spectrum of the purified compound I together with its chemical formula.
• Figs. 9A and 9B show the Mass Spectrum of the purified compound I.
• Fig. 9A shows the Time of Flight Electron Spray Ionization (TOF ESI).
• Fig. 9B is a simulation of the proposed molecular peak at 497.026 corresponding to Figs 10A and 10B show the in vitro ultra violet (UVB) protection obtained by the compound of formula I in terms of survival of cultured human keratinocytes (10A) and the protection in terms of pyrimidine dimer formation in cultured human keratinocytes (10B).
• UVB in vitro ultra violet
• Figs. HA i ) ⁇ ) m)-D i ) ⁇ ) ⁇ ) ⁇ ) show the in vitro ultra violet protection in terms of survival of cultured human keratinocytes (I), the protection in terms of immunosuppression as measured by expression of IL-6 mRNA (II) and the protection in terms of pyrimidine dimer formation in cultured human keratinocytes (III) after ultraviolet (UVB) radiation. Protection was measured with the natural extracts of: CAF (11A), Cichorium (11B), Pecan (11C) and Eriobotrya (11D).
• Figs. 1A and IB show the ultra violet spectrum of the extracts obtained from the cyanobacteria Aphanizomenon flos aquae and from the fungal part of the Collema, hereinafter termed Collema associated fungus (CAF). These two extracts posses a strong absorption in the ultra violet region, the former at 336 nm and the latter at 250nm and 311 nm.
• CAF Collema associated fungus
• Figs 2A and 2B show the ultra violet spectrum of the extracts obtained from the plants pecan and Cichorium endivia showing an ultra violet absorption at 306 nm and 283 nm, respectively.
• Figs 3A, 3B and 3C show the ultra violet spectrum of the extracts obtained from Eriobotrya nuts, from the cyanobacteria Spirulina and from lichen Xanthoria showing ultra violet absorption at 306 nm, 422 nm and 319 nm, respectively.
• Figs 5A and 5B show the UVA/UVB ratio of the extracts obtained from the two cyanobacteria, Spirulina and Aphanizomenon. The figures clearly show that the UVA/UVB ratio of the two cyanobacteria extracts is 0.9-0.95.
• Figs 6A and 6B show the UVA/UVB ratio of two commercial sun-protecting lotions (used herein as control) demonstrating a lower UVA/UVB ratio of 0.7 in figure 6A and 0.88 in figure 6B.
• Fig. 7 shows the ultra violet spectrum of a purified compound isolated from Collema lichens.
• Figs 11A-D further show the effective in vitro activity against ultra violet irradiation (UVB) of the extracts obtained from CAF, Eriobotrya, Pecan and Cichorium.
• UVB ultra violet irradiation
• the activity is demonstrated by means of survival of cultured human keratinocytes coated by each of these extracts and irradiated by ultraviolet radiation, the protection in terms of pyrimidine dimer formation in cultured human keratinocytes after ultraviolet radiation and by measuring immunosuppression as indicated by the expression of IL-6 mRNA.
• the present invention relates to extracts from natural species wherein the extracts have an ultra violet absorbency both in the UVA and UVB regions and their use in cosmetic preparations providing effective sun protection activity.
• the extracts of the present invention are from microorganisms such as fungus, cyanobacteria, plants, lichens or mixtures thereof. Such microorganisms, plants and lichens live in an environment exposed to strong solar radiation and have developed an effective ultra violet protection system enabling them to be exposed for long periods to sunlight that comprises ultra violet irradiation, with no apparent damage in their function.
• the present invention concerns C ⁇ - 7 -alcoholic extracts from the fungal part of the Collema which is termed collema associated fungus (CAF), from the cyanobacteria Aphanizomenon and Spirulina, from the plants Pecan nuts, Cichorium endivia subsp. Divaricatum - a wild plant, Eriobotrya nuts and from the lichen Xanthoria.
• CAF collema associated fungus
• the CAF after isolation from the Collema may easily be grown on PDA medium.
• the naturally occurring material used as source for the isolation of the extracts of the present invention were grounded and the active material extracted with a C ⁇ _ 7 -alcoholic solution.
• the alcoholic solution may be an aqueous solution or a solution comprising a mixture of alcohol and a hydrophobic organic solvent.
• the C ⁇ -7 -alcohol used in the present invention are straight or branched C ⁇ -7 -alcohols.
• the aqueous alcoholic solution comprises H 2 0:ROH in a ratio from 50:50 (%) to 5:95 (%).
• Particular non-limiting examples of the organic solvent used in the present invention are selected from the group consisting of alkyls, chlorinated alkyls, esters, ketones, aldehydes and aromatics.
• the UV absorbency of each extract is determined.
• the extracted compounds are very strong UV absorbers that absorb strongly in the spectral region from 220 to 425 nm.
• the two extracts from cyanobacteria, Spirulina and Aphanizomenon display UVA/UVB ratios of 0.9 to 0.95.
• Such a UVA/UVB ratio which is close to unity, reveals that these extracts are materials having effective absorbance activity in the UVA region.
• R lichens may easily be derivatized to yield compounds of formula (I) where R -R which may be the same or different selected from the group consisting of hydrogen, a Ci-Cio-alkyl or acyl group; R 9 and R 10 which may be the same or different are selected from the group consisting of Ci-Cio-alkyl, aryl, hydrogen or an acyl group; and X is NR, oxygen or sulfur, wherein R is hydrogen, alkyl or aryl.
• R -R which may be the same or different selected from the group consisting of hydrogen, a Ci-Cio-alkyl or acyl group
• R 9 and R 10 which may be the same or different are selected from the group consisting of Ci-Cio-alkyl, aryl, hydrogen or an acyl group
• X is NR, oxygen or sulfur, wherein R is hydrogen, alkyl or aryl.
• the rational of derivatization of the isolated natural compound is that the naturally occurring compound of formula I
• the use of the extracts or the purified compound or its derivatives of formula I as effective sun protection lotions may also be by encapsulating them in appropriate encapsulating agent thus rendering their environment hydrophobic and aiding in dispersion.
• they may be used together with at least one additional organic or inorganic sun protecting agent.
• the at least one additional sun protecting agent are derivatives of anthranilates, benzophenones, camphors, cinnamates, dibenzoylmethanes, p-aminobenzoates, salicylates, zinc oxide, titanium dioxide and mixtures thereof.
• Example 1 Aphanizomenon flos aquae (Upper Klamath Lake,USA). 10gr. of green powder (capsules comprising of Aphanizomenon Flos Aquae made by SOLGAR, IL) was transferred into a 500 ml flask connected to a condenser. 250 ml of 75% aqueous Methanol were added, and the solution was boiled for one hour. After reaching room temperature the extract was filtered through a Bichner funnel (Schleicher & Schuell 595 filter papers). The extract (intense green color) was transferred into a 500ml separatory funnel. A mixture of 100 ml CH 2 C1 2 and H 2 0 was added. The layers separated, where the organic phase remains as an emulsion (green) and transferred into flask I.
• green powder capsules comprising of Aphanizomenon Flos Aquae made by SOLGAR, IL
• the upper aqueous layer (clear and yellow) was transferred to a second separatory funnel and the extraction procedure was repeated again with the same solvent mixture in the presence of NaCl. After separation, the organic layer was transferred into flask II. The aqueous layer appeared as clear and yellow, and transferred into flask III. The organic solvent's residues from flask III were evaporated, and the water was lyophilized till dryness. 4.326gr. of a pale yellow powder was obtained. A sample of the powder was redissolved in methanol and checked for its UV absorbance. A UVA peak is observed at 336 nm (Fig. 1A).
• Example 2 Collema associated fungus (CAF) (one out of four fungus which exist in a Lichen known as Collema sp.) The CAF was isolated and easily grown on PDA medium.
• CAF Collema associated fungus
• the powder was dissolved in 100ml H 2 0, filtered through cotton and transferred into a separatory funnel.
• the upper organic phase is colorless, while the lower aqueous phase appears as clear yellow.
• the aqueous layer was lyophilized to dryness, and 28mg of pale yellow powder were obtained.
• Example 3 Pecan. lOOgr of Pecan nuts (purchased on local market in Jerusalem, IL) were homogenized in a high-speed unit and transferred into a 500ml flask connected to a condenser. A mixture of 100 ml of methanol and 100 ml CH 2 CI 2 were added, and solution was boiled for 1 h. After reaching to room temperature the extract was filtered through a Bichner filter. The extract (green-brown) was transferred into a 500 ml separatory funnel. A mixture of 100 ml C 2 H 2 and 200ml cold H 2 0 (with ice) was added. The layers were separated. The organic phase (yellow-bright) was transferred into flask. The organic layer was dried over MgS0 4 . The lipid-soluble extract has UV absorbance 294 and 302 nm (Fig. 2A).
• Cichorium endivia subsp. Divaricatum The wild plant Cichorium endivia L. subsp. divaricatum (Schousb.) P.D. Sell was collected at Sedot Micha, IL) stalks, inflorescences, and roots were separately homogenized in a high-speed unit. Homogenized roots were transferred into a 2000ml flask connected to a condenser. A mixture of 500ml of ethanol and 300ml water were added, the solution was boiled for 6 hrs. After reaching to room temperature the extract was filtered through a Bichner filter. The ethanol-water extract (yellow-brown) was transferred into a 1500ml separatory funnel.
• Example 5 Eriobotrya nuts. lOOgr of fresh Eriobotrya nuts (purchased on local market in Jerusalem) were homogenized in a high-speed unit and transferred into a 500ml flask connected to a condenser. A mixture of 100 ml of methanol and 100 ml CH 2 C1 2 were added, and the solution was boiled for lhr. After reaching room temperature the extract was filtered through a Bichner filter. The green-brown extract was transferred into a 500ml separatory funnel. A mixture of 100ml C 2 H 2 and 200ml cold H 2 0 (with ice) was added. The layers were separated. The organic phase (green-brown) was transferred into flask. The organic layer was dried over MgS0 . The lipid-soluble extract has a UV absorbency at 298 nm and 306 nm (Fig. 3A).
• Example 9 Determining the chemical structure of the extracted compound of formula I.
• the second system is a four protons, named as Xa, Xb, Ya, Yb having the following interactions:
• Fig. 8 Analysis of the various ID and 2D NMR experiments give rise to a chemical structure as shown in Fig. 8. Such a compound has a chemical formula of C ⁇ H 32 N 2 Oi3 and its molecular weight is 496. Confirmation for such a chemical structure and formula was obtained from the Mass Spectrum of purified material. The mass spectrum is shown in Fig. 9A as the Time of Flight Electron Spray Ionization (TOF ESI) reveals a molecular peak of 497.026 corresponding to the MH+. Fig. 9B further shows a simulation of the proposed molecular peak at 497.198 corresponding to C ⁇ H 32 N 2 0 ⁇ 3 .
• TOF ESI Time of Flight Electron Spray Ionization
• CAF Collema associated fungus
• Pecan extracts totally prevented UVB induced erythema 11C(I) and partially prevented UVB induced cell death, IL-6 expression HC( ⁇ ) and cyclobutane pyrimidine dimer formation 1 l rrn.
• Example 12 Detenriining UVA/UVB ratio of extracts. Determining the UVA/UVB ratio is intended to give an indication of the scope of the UV absorbence properties of a test product as part of a "broad spectrum” claim (HW Lim et al. (2001) JAAD 44:505-508).
• UV transmittance spectrophotometry UV radiation was directed onto the surface of a smooth quartz glass plate and the quantity of radiation transmitted through the plate was measured. UV transmission through the plate was measured at 5nm increments throughout the UVB and UVA regions (290nm to 400nm) at single discrete regions of the plate to determine 100% transmission.
• a roughened quartz glass plate was coated with the appropriate natural extract whose UV absorbency was measured. Coating was done in the following manner. The natural extract was dissolved in water at a concentration of lOmg/mL and the solution was applied in a series of small dots to the roughened quartz glass plate using a micro-pipette and then spread evenly using a gloved finger to achieve a typical uniform application rate of 0.75mg/cm 2 of product. Care was taken to ensure the formation of a uniform film. The coating was allowed to dry for ca. 10 minutes. Radiation from a U.V. source was directed onto the surface of the coated plate and the quantity of radiation transmitted through the coated plate was measured.
• UV transmission was measured at 5nm increments from 290nm to 400nm at 6 discrete regions of the plate. This procedure was carried out 3 times for each of the extracts whose ultra violet absorbency was measured.
• Two internal control containing commercial sun-protecting products agents were tested prior, and after the irradiation extract, for validation purposes.
• the two internal control products are hereinafter termed “nivea 3 star” (SPF 12) and “boots soltan 4 star” (SPF 4).
• SPF 12 noa 3 star
• SPF 4 boots soltan 4 star
• Example 13 In vitro activity of the compound of formula I (purified from Collema lichens).
• a compound of formula I at a concentration between 0.5 to 3 mg/cm was spread on a quartz plate, which covered the dish, containing the cultured cells.
• Four FS-40 fluorescent lights radiating at wavelengths between 280 and 320 nanometers served as the source of UVB. These lamps were placed at a distance of 20 cm from the quartz plate. Under the same conditions of irradiation a cultured cell preparation was irradiated with no protection, i.e. naked quartz plate.
• Fig. 10A shows the cell survival after 200mJ/cm 2 UVB irradiation. UVB protection was offered in a dose-dependent manner, since 74 % of the cells survived when cells were protected with 3 mg/cm 2 of the compound whereas only
• Fig. 10B shows generation of pyrimidine dimers after 60 mJ/cm UVB irradiation through quartz plates covered with 6 mg/cm of the formula (I) compound, commercial sunscreen or naked quartz plate. Non-irradiated cells showed a low background of pyrimidine dimers. Plates covered with the formula (I) compound offered around 80 % protection compared to cells irradiated through the naked quartz plate.

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