Classifications

• • 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
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
  • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
• • 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
  • A61K31/12—Ketones
• • 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
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
• • 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
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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

• the present invention relates to the use of equol, dehydroequol and isoflav-3-ene and isoflavan compounds in promoting repair of DNA mutagenic damage.
• Metallothioneins are proteins synthesised or over expressed in response to DNA damaging agents e.g. UNR (Hansen et al 1997).
• UNR DNA damaging agents
• Induced synthesis of MT is considered as one of the mechanisms involved in the adaptive response to low dose UNR exposure, and increased levels of MT appear to be associated with protection from UNR, possibly mediated through scavenging of ROS in the skin (Hanada, et al 1992).
• UNR induces immunohistochemically detectable MT in keratinocytes and dermal fibroblasts concurrently with the photoconduction of p53, which suggests the these protein systems are protective and complimentary in function.
• MT is detectable in dermal fibroblasts from 2 hours post-UN (Anstey, et al l996).
• Equol, dehydroequol, isofla-3-ene and isoflavan compounds and methods for producing the same are described in copending International Patent Application PCT/AU03/00427 and WO 98/08503 which are incorporated herein by reference.
• BCC basal cell carcinoma
• SCC squamous cell carcinoma
• a method for protecting skin from UN induced D ⁇ A mutagenic damage which comprises applying to skin a composition containing one or more of equol, dehydroequol, isoflav-3-ene, or isoflavan compounds in admixture with a dermally acceptable carrier.
• Isoflav-3-ene and isoflavan compounds may be represented by the general formula (II)
• Ri, R 2 , R 3 and R4 are independently hydrogen, hydroxy, OR 9 , OC(O)R ⁇ 0 , OS(O)R ⁇ o,
• Ri and R 4 are as previously defined, and R 2 and R 3 taken together with the carbon atoms to which they are attached form a five-membered ring selected from
• Ri and R 2 are as previously defined, and R 3 and R 4 taken together with the carbon atoms to which they are attached form a five-membered ring selected from
• R 5 , R 6 and R 7 are independently hydrogen, hydroxy, OR 9 , OC(O)R ⁇ o, OS(O)R ⁇ 0 , CHO,
• R g is hydrogen, hydroxy, alkyl, aryl, amino, thio, NRnR ⁇ , CONR1 1 R 12 , C(O)R 13 where
• R ⁇ 3 is hydrogen, alkyl, aryl, arylalkyl or an amino acid, or CO 2 R ⁇ 4 where R ⁇ 4 is hydrogen, alkyl, haloalkyl, aryl or arylalkyl, R 9 is alkyl, haloalkyl, aryl, arylalkyl, C(O)R ⁇ 3 where R ⁇ 3 is as previously defined, or
• R ⁇ 5 is independently hydrogen, alkyl or aryl
• R 10 is hydrogen, alkyl, haloalkyl, amino, aryl, arylalkyl, an amino acid, alkylamino or dialkylamino
• R ⁇ is hydrogen, alkyl, arylalkyl, alkenyl, aryl, an amino acid, C(O)R ⁇ 3 where R 13 is as previously defined, or CO 2 R ⁇ 4 where R ⁇ 4 is as previously defined
• R 12 is hydrogen, alkyl or aryl, or R ⁇ and R ⁇ 2 taken together with the nitrogen to which they are attached comprise pyrrolidinyl or piperidinyl, the drawing "— " represents either a single bond or a double bond, preferably a double bond
• T is independently hydrogen, alkyl or aryl
• X is O, NR ⁇ 2 or S, preferably O, including pharmaceutically acceptable salts and derivatives thereof.
• Equol corresponds to the formula (II) when Ri, R 2 , R , R 4 , R 6 , R 7 and R 8 are hydrogen, R 5 is hydroxy, X is O, and "TM" is a single bond.
• Dehydroequol corresponds to formula (II) when Ri, R 2 , R 3 , R , Re, R 7 and R 8 are hydrogen, R 5 is hydroxy, X is O and "— " is a double bond.
• Dermally acceptable carriers and lotions are well known in the art, and are described for example in Remington's Pharmaceutical Sciences, Gennaro A. 18th Ed., Mack Publishing Co., Easton, PA, 1990, pp. 1492-1517.
• Any derrnatologically acceptable carrier can be used in the compositions of the invention.
• "derrnatologically acceptable carrier” refers to vehicles, diluents, carriers, which can include adjuvants, additives, or excipients, known for use in dermatological compositions.
• the compositions of the invention include, but are not limited to, creams, ointments, solutions, sticks, wipes, cleansers and/or gels.
• the compounds of the present invention may be simply mixed, admixed or blended with suitable carriers to give compositions suitable for application to the skin.
• Dermally acceptable carriers may include one or more sunscreen agents.
• Sunscreens include those materials commonly used to block ultraviolet light.
• Illustrative compounds include the derivatives of cinnamate, PABA, and salicylate.
• octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone also known as oxybenzone
• Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are commercially available under the trademarks, Parsol MCX and Benzophenone-3, respectively.
• the exact amount of sunscreen employed can vary depending upon the degree of protection desired from the sun's UN irradiation.
• one or more compounds of the formula (II) are formulated into cosmetic preparations.
• cosmetic formulations include creams, gels, powders, pastes, cakes and the like.
• make-up typically used to provide a smooth, even appearance to skin and as a base for coloured cosmetics.
• compositions may be used in the compositions in an amount from 0.001% to 100%, preferably from 0.1% to 20%, most preferably from 0.1% to 10% w/w.
• compositions may comprise 1 ⁇ m to 500 mmol equol or other compounds of the formula (II), such as 20 ⁇ m to 400 ⁇ m.
• the remainder of the composition will comprise one or more derrnatologically acceptable carriers and excipients as are well known in the art.
• One or more compounds may be utilised in the compositions, with equol and dehydroequol being particularly preferred.
• Compositions may be administered topically to the skin before, during and/or after sun exposure. Typically, doses of between about 1 to 500 mg per day, with doses between 2 to 100 mg per day being preferred.
• a method for the treatment, or amelioration or preventing the formation of skin cancer such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma, which comprises applying to the skin of a subject a composition containing one or more of equol, dehydroequol, or an isoflav-3-ene or isoflavan compounds of the general formula (II).
• BCC basal cell carcinoma
• SCC squamous cell carcinoma
• malignant melanoma which comprises applying to the skin of a subject a composition containing one or more of equol, dehydroequol, or an isoflav-3-ene or isoflavan compounds of the general formula (II).
• a method for increasing metallothionein production in the skin such as the basal layer of skin, which comprises applying to skin one or more of equol, dehydroequol, isoflav-3-ene or isoflavan compound in association with a dermally acceptable carrier.
• the applicant has further found that the compounds according to this invention promote DNA repair.
• the promotion of DNA repair may be by one or more of increasing the rate of repair of cyclobutane pyrimidine dimers (CPDs), promoting DNA repair by decreasing P53 expression, and/or by promoting the formation of metallothionein (MT).
• CPDs cyclobutane pyrimidine dimers
• MT metallothionein
• CPD CPD-derived neuropeptide
• TP53 P53 protein
• the P53 protein is expressed after D ⁇ A damage by UN irradiation.
• P53 is a transcription factor which blocks cellular progression from Gl to S phase, thus preventing replication of damaged D ⁇ A (Campbell et al, 1993).
• the P53 protein may act as a tumour promoting agent (Murphey et al, 2001).
• Example 1 The effect of equol on the induction of CPD was examined in the skin of hairless mice (a standard model for human dermatological investigations) exposed to solar simulated ultraviolet radiation (SSUN).
• SSUN solar simulated ultraviolet radiation
• dorsal skin was excised, fixed for 6hr in a standard fixing medium (HistoChoice , Amersco Inc, Solon, Ohio, USA), processed and paraffin-embedded.
• Pyrimidine dimers were detected immunohistochemically using citric acid antigen retrieval and the H3 anti-pyrimidine dimer antibody. The number of dimer-positive cells was counted manually in 30 fields per mouse, at 40x magnification.
• Equol was applied to the skin of five human volunteers immediately after, and at 4 hours and 6 hours post-UN irradiation. A control lotion was also used containing no equol. Twenty-four hours after UN irradiation, skin biopsies were taken and MT production was measured using immunohistochemistry.
• Table 2 shows the counts of cells in the basal epidermis and superficial dermis that demonstrated positive staining for MT. Approximately half of the cells in the basal epidermis constitutively expressed MT at baseline, whereas almost none of the cells in the more superficial layers of the epidermis expressed MT. At 24 hrs after exposure to 2.5 MED SSUN, there were apparent differences in the expression of MT in the basal layers of the epidermis between sections treated with equol and those treated with DMSO in base lotion (vehicle). In all 5 participants, the expression of MT was higher in the skin treated with equol, with the magnitude of the difference ranging from +4% to +21%.
• Table 2 Proportion of cells staining positively for MT in the epidermis of five human volunteers, by treatment group Total epidermis Upper epidermis Basal epidermis
• N14GBO Baseline 270 127 32 113 0 0 157 127 45 lO mins 381 242 39 247 0 0 134 242 64
• Baseline refers to the skin sections from the punch biopsy taken prior to exposure to 2.5 MED SSUN.
• DMSO refers to the skin sections from the punch biopsy taken 24 hrs after exposure to
• the skin biopsies from the five human volunteers from Example 2 were tested for cyclobutane pyrimidine dimer formation using immunohistochemistry.
• Table 3 presents the counts and percentages of cells staining positively with an antibody directed against CPD.
• Table 3 Proportion of cells staining positively for CPDs in the epidermis of five human volunteers, by treatment group Total epidermis Upper epidermis Basal epidermis
• NO1DWH Baseline 345 0 0 134 0 0 211 0 0
• NO3PPA Baseline 309 0 0 104 0 0 205 0 0
• N13PDO Baseline 205 0 0 60 0 0 145 0 0
• Baseline refers to the skin sections from the punch biopsy taken prior to exposure to 2.5 MED SSUN.
• 10 mins refers to the skin sections from the punch biopsy taken 10 mins after exposure to 2.5 MED SSUN.
• the skin was not treated with either DMSO in base lotion (vehicle) or equol at 200 ⁇ M.
• DMSO refers to the skin sections from the punch biopsy taken 24 hrs after exposure to 2.5 MED SSUN. The skin was from the grid treated with DMSO in base lotion (vehicle).
• Equol refers to the skin sections from the punch biopsy taken 24 hrs after exposure to 2.5 MED SSUN. The skin was from the grid treated with lotion containing equol at 200 ⁇ M.
• N13PDO Baseline 325 0 0 141 0 0 184 0 0 lO mins 304 0 0 140 0 0 164 0 0
• Baseline refers to the skin sections from the punc ;h biops ⁇ y taken j . rior to expos ure to 2.5 MED SSUN.
• 10 mins refers to the skin sections from the punch biopsy taken 10 mins after exposure to 2.5 MED SSUN. The skin was not treated with either DMSO in base lotion (vehicle) or equol at 200 ⁇ M.
• DMSO refers to the skin sections from the punch biopsy taken 24 hrs after exposure to 2.5 MED SSUN. The skin was from the grid treated with DMSO in base lotion (vehicle).
• Equol refers to the skin sections from the punch biopsy taken 24 hrs after exposure to 2.5 MED SSUN. The skin was from the grid treated with equol at 200 ⁇ M.
• biomarkers assessed in these experiments were selected based on their biological associations with skin cancer (which is directly associated with UV-induced DNA mutagenic damage).
• MTs are molecules with anti-oxidant properties that are specifically induced in response to UN exposure. This study found consistent evidence that human skin treated with equol, and it is believed other compounds of the formula (II), induce more MT than skin treated with base lotion.
• CPDs are the earliest indicator of molecular damage following exposure to UN radiation, and if not repaired, lead to fixed mutations in the D ⁇ A of skin cells. Thus one mechanism of action of a post-exposure treatment would be to increase the rate of repair of these lesions.
• the experiments conducted here suggest that CPD repair may be enhanced by topical equol compositions, and other compositions containing one or more compounds of the formula (II).
• P53 is clearly an important regulatory gene that is commonly mutated in epidermal skin cancers. Moreover, in normal skin cells, p53 is up-regulated following UN exposure to prevent mitosis until D ⁇ A damage is repaired. Equol modulated the expression of p53 in this study causing a reduction in the number of cells in the upper or basal epidermis expressing p53 for four of five subjects.

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• 2002
  • 2002-09-06 AU AU2002951271A patent/AU2002951271A0/en not_active Abandoned
• 2003
  • 2003-09-05 EP EP03793484A patent/EP1534232A4/en not_active Withdrawn
  • 2003-09-05 JP JP2004533066A patent/JP2006501252A/ja active Pending
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