WO2000074699A1 - Extracts of feverfew (tanacetum parthenium) against inflammatory disorders - Google Patents

Extracts of feverfew (tanacetum parthenium) against inflammatory disorders Download PDF

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Publication number
WO2000074699A1
WO2000074699A1 PCT/US2000/015125 US0015125W WO0074699A1 WO 2000074699 A1 WO2000074699 A1 WO 2000074699A1 US 0015125 W US0015125 W US 0015125W WO 0074699 A1 WO0074699 A1 WO 0074699A1
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Prior art keywords
feverfew
extract
inflammatory disorders
parthenolide
extracts
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PCT/US2000/015125
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French (fr)
Inventor
Theresa Callaghan
Thierry Oddos
Gerard J. Gendimenico
Katharine Martin
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Johnson and Johnson Consumer Holdings France SAS
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Johnson and Johnson Consumer France SAS
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Priority to MXPA01001327A priority Critical patent/MXPA01001327A/en
Priority to AT00938038T priority patent/ATE291433T1/en
Priority to DE60018881T priority patent/DE60018881T2/en
Priority to CA2339221A priority patent/CA2339221C/en
Priority to DK00938038T priority patent/DK1100516T3/en
Application filed by Johnson and Johnson Consumer France SAS filed Critical Johnson and Johnson Consumer France SAS
Priority to BRPI0006634A priority patent/BRPI0006634B8/en
Priority to AU53130/00A priority patent/AU778261B2/en
Priority to JP2001501233A priority patent/JP2004500329A/en
Priority to EP00938038A priority patent/EP1100516B1/en
Publication of WO2000074699A1 publication Critical patent/WO2000074699A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to the topical treatment and prevention of inflammatory disorders and related conditions using extracts of feverfew (Tanacetum parthenium).
  • Tanacetum parthenium a plant commonly known as Feverfew, has been recognized since the Middle Ages as having significant medicinal properties when taken orally - used as a general febrifuge, hence its common name. Many have isolated extracts of the plant and those extracts have been used to orally treat migraines, arthritis, and bronchial complaints.
  • Extracts of feverfew contain many components. Although not all components have been isolated and characterized, the known components of an extract of feverfew contain a significant number of biologically active components. To date, the chemical constituents of whole feverfew extract are as follows: apigenin-7-glucoside, apigenin-7-glucuronide, 1- ⁇ -hydroxyarbusculin, 6- hydroxykaempf erol-3 ,7-4 '-trimethylether (Tanetin) , 6-hy droxykaempferol-3 ,7- dimethyl ether, 8- ⁇ -reynosin, 10-epicanin, ascorbic acid, beta-carotene, calcium, chromium, chrysanthemolide, chrysanthemomin, chrysarten-A, chrsyart-c, chrysoeriol-7-glucuronide, cobalt, cosmosiin, epoxyartemorin, luteolin-7- glucoside, luteolin
  • This invention relates to a method of treating or preventing inflammatory disorders and related conditions using an extract of feverfew. More particularly, the invention includes a method of treating or preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient.
  • the method of this invention includes a method of treating or preventing inflammatory disorders and related conditions of the skin by applying a topical composition comprising an effective amount of an extract of feverfew to a patient.
  • the invention includes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient where said extract is substantially free of ⁇ -unsaturated ⁇ -lactone.
  • the invention includes a method of treating and preventing inflammatory disorders and related conditions of the skin by applying a topical composition containing an effective amount of an extract of feverfew to a patient where said extract is substantially free of ⁇ -unsaturated ⁇ -lactone.
  • This invention includes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient.
  • Inflammatory disorders and related conditions which may be treated or prevented by topical use of the compositions of this invention include, but are not limited to the following: arthritis, bronchitis, contact dermatitis, atophic dermatitis, psoriasis, seborrheic dermatitis, eczema, , allergic dermatitis, polymorphous light eruptions, inflammatory dermatoses, folliculitis, alopecia, poison ivy, insect bites, acne inflammation, irritation induced by extrinsic factors including, but not limited to, chemicals, trauma, pollutants (such as cigarette smoke) and sun exposure, secondary conditions resulting from inflammation including but not limited to xerosis, hyperkeratosis, pruritus, post-inflammatory hyperpigmentation, scarring and
  • the inflammatory disorders and related conditions which may be treated or prevented using the methods of the invention are arthritis, inflammatory dermatoses, contact dermatitis, allergic dermatitis, atopic dermatitis, polymorphous light eruptions, irritation, including erythema induced by extrinsic factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, poison ivy, insect bites, foUiculitus, alopecia, and secondary conditions and the like.
  • feverfew is a plant belonging to the family of Asteraceae/Composite which is technically known as, Tanacetum parthenium, Altamisa, Crisanthemum, Leucanthemum, or Pyrethrum parthenium.
  • effective amount refers to the percentage by weight of the feverfew extract in the topical composition which is needed to treat an inflammatory disorder or related condition in a patient.
  • the effective amount is between about 0.0005 to about 20% by weight of the composition. More preferably, the concentration should be less than about 10% by weight of the topical composition. Even more preferably between about 0.001% and about 10%, and most preferably between about 0.01% and about 2%.
  • the term "patient” refers to a mammal which is being treated prophylactically for an inflammatory condition and/or for an inflammatory condition with visible symptoms.
  • the patient is a human.
  • the invention includes a method of treating and preventing inflammatory disorders and related conditions of the skin by applying a topical composition containing an effective amount of an extract of feverfew to a patient.
  • the terms, inflammatory disorder and related condition, feverfew, effective amount, and patient have their aforementioned meanings.
  • skin includes all surfaces of a patient, such as the exposed hide or surfaces covered by hair.
  • the invention also includes a method of treating and preventing inflammatory disorders and related conditions which comprises applying a topical composition comprising an effective amount of an extract of feverfew to a patient where said extract is ⁇ -unsaturated ⁇ -lactone-deprived.
  • a topical composition comprising an effective amount of an extract of feverfew to a patient where said extract is ⁇ -unsaturated ⁇ -lactone-deprived.
  • substantially free of ⁇ -unsaturated ⁇ -lactone refers to an extract of feverfew having a weight content of the ⁇ -unsaturated ⁇ -lactones found in natural feverfew extracts of less than about 0.2% by weight.
  • ⁇ -unsaturated ⁇ -lactones include but are not limited to parthenolide ([l ⁇ R -(la R * , 4E,7a S * , 10a S * , 10b
  • the feverfew extract has a weight content of ⁇ -unsaturated ⁇ -lactone below about 0.2.
  • the ⁇ -unsaturated ⁇ -lactone is parthenolide. The method of preparing this parthenolide-deprived extract is described in an Italian patent application
  • This invention also includes a method of treating inflammatory disorders and related conditions of the skin by applying a topical composition comprising an effective amount of an extract of feverfew to a patient where said extract is substantially free of ⁇ -unsaturated ⁇ -lactone.
  • inflammatory disorders and related conditions feverfew, effective amount, patient, skin, and ⁇ -unsaturated ⁇ -lactone-deprived have their aforementioned meanings.
  • Biologically active agents may include, but are not limited to, flavanoid/flavone compounds which include but are not limited to tanetin, 3,7,3'- trimethoxyquercetagetin, apigenin and its derivatives.
  • flavanoid/flavone compounds When flavanoid/flavone compounds are present, they are present at a concentration of between about 0.001% to about 0.5% preferably, between about 0.005% and 0.2% based on the weight of the topical composition.
  • Additional biologically active agents include but are not limited to sunscreens, anti-wrinkling/antiaging agents, antifungal agents, antibiotic agents, anti-acne and antipsoriatic agents, depigmentating agents, where such agents may be utilized so long as they are physically and chemically compatible with the other components of the topical composition.
  • compositions of this invention may include additional skin actives.
  • Actives can be but not limited to vitamin compounds.
  • Skin lightening agents kojic acid, ascorbic acid and derivatives such as ascorbyl pamiltate, and the like
  • anti-oxidant agents such as tocopherol and esters
  • metal chelators, retinoids and derivatives moisturizing agents, hydroxy acids such as salicylic acid, sun screen such as octyl methoxycinnamate, oxybenzone, avobenzone, and the like, sun blocks such as titanium oxide and zinc oxide, and skin protectants.
  • Mixtures of above skin actives may be used.
  • Sunscreens which may be used in the compsoitions of this invention may include but are not limited to organic or inorganic sunscreens, such as, octylmethoxycinnamate and other cinnamate compounds, titanium dioxide, zinc oxide and the like.
  • Anti-wrinkling/anti-aging agents may include but are not limited to retinoids (for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate) alpha hydroxy acids, galactose sugars (for example, melibiose and lactose), antioxidants, including but not limited to water soluble antioxidants such as sulfhydryl compounds and their derivatives (for example, sodium metabisulfite and N-acetyl-cysteine, acetyl-cysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferin, ascorbic acid and ascorbic acid derivatives (for example ascorbyl palmitate and ascorbyl polypeptide).
  • retinoids for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate
  • alpha hydroxy acids for example, gal
  • Oil soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to tocopherols (for example, tocopheryl acetate, -tocopherol), tocotrienols and ubiquinone.
  • Natural extracts containing antioxidants suitable for use in the compositions of this invention include, but not limited to extracts containing flavonoids, phenolic compounds, flavones, flavanones, isoflavonoids, mono, di- and tri-terpenes, sterols and their derivatives. Examples of such natural extracts include grape seed, green tea, pine bark and propolis extracts and legume extracts and the like.
  • Antifungal agents include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts.
  • Antibiotic include but are not limited to but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, /-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetrachcycline hydrochoride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, benzoyl peroxide and their pharmaceutically acceptable salts.
  • Acne ingredients include but are not limited to agents that normalize epidermal differentiation (e.g. retinoids), keratolytic agents (e.g. salicylic acid and alpha hydroxy acids), benzoyl peroxide, antibiotics and compounds or plant extracts that regulate sebum.
  • agents that normalize epidermal differentiation e.g. retinoids
  • keratolytic agents e.g. salicylic acid and alpha hydroxy acids
  • benzoyl peroxide e.g. salicylic acid and alpha hydroxy acids
  • Antipsoriatic agents include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide, mometasone furoate, methylprednisolone acetate), Vitamin D and its analogues (e.g. calcipotriene), retinoids (e.g. Tazarotene) and anthraline.
  • corticosteroids e.g., betamethasone dipropionate, betamethasone valerate,
  • Cosmetic agents which may be used in the compositions of this invention may include, but are not limited to those agents which prevent potential skin irritation, such as emollients, vitamins and antioxidants (e.g., vitamin E) and herbal extracts (e.g., aloe vera). Further, the cosmetic agents may include humectants, antioxidants/preservatives, plant extracts, flavors, fragrances, surface active agents, and the like.
  • humectants include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA, hyaluronic acid and the like. They may be used either singly or in combination.
  • Cosmetic agents may also include substances which mask the symptoms of inflammatory disorders and related conditions; such substances include but are not limited to pigments, dyes, and other additives (e.g., silica, talk, zinc oxide, titanium oxide, clay powders).
  • the pharmaceutical excipients include but are not limited to pH modifying agents such as pH-modifying agents , organic solvents (e.g., propylene glycol, glycerol, etc.), cetyl alcohol, kaolin, talc, zinc oxide, titanium oxide, cornstarch, sodium gluconate, oils (e.g., mineral oil), ceteareth-20, ceteth-2, surfactants and emulsifiers, thickener (or binders), perfume, antioxidants, preservatives, and water.
  • pH modifying agents such as pH-modifying agents , organic solvents (e.g., propylene glycol, glycerol, etc.), cetyl alcohol, kaolin, talc, zinc oxide, titanium oxide, cornstarch, sodium
  • Binders or thickeners may be used in the compositions of this invention to provide substantivity and physical stability to the compositions.
  • Binders or thickeners suitable for use in the compositions of this invention include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone. Thickeners such as natural gums and synthetic polymers, as well as coloring agents and fragrances also are commonly included in such compositions.
  • preservatives which may be used in the compositions of this invention include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para- hydroxybenzoate and the like.
  • flavors and fragrances which may be used in the compositions of this invention include menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like.
  • compositions of the present invention may be prepared in a number of forms for topical application to a patient.
  • the composition may be applied in a gel, cream, ointment, shampoo, scalp conditioners, liquid, spray liquid, paint-/brush-on preparation, aerosol, powder or adhesive bandage.
  • the composition may be impregnated on a bandages, hydrocolloid dressing, treatment patch or on cloth wipe products, such as baby wipes or facial wipes.
  • compositions of this invention may be in the form of emulsions, such as creams, lotions and the like. Such compositions may have more than one phase and may include surface active agents which enable multiphase emulsions to be manufactured.
  • Examples of surface active agents which may be used in the compositions of this invention include sodium alkyl sufates, e.g., sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate and N-acyl glutamates, e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefin sulfonate and sodium dioctylsulfosuccinate; N- alkylaminoglycerols, e.g., N-lauryldiaminoethy
  • a dermatologically acceptable carrier is adequate for topical use. It is not only compatible with the active ingredients described herein, but will not introduce any toxicity and safety issues.
  • An effective and safe carrier varies from about 50% to about 99% by weight of the compositions of this invention, more preferably froma bouat 75% to about 99% of the compositions and most preferably from about 85% to about 95% by weight of the compositions.
  • compositions of this invention are often controlled or affected by the type of inflammatory disorder or related condition which is being treated. For example, if the compositions of this invention were used to treat a skin inflammation associated with athlete's foot, jock itch or diaper rash, talc would be a preferred pharmaceutical excipient and an antifungal agents would be preferred biological agents. If the compositions of this invention were to be used to treat eczema of the scalp, emulsifiers and oils would be preferred pharmaceutical excipients.
  • the condition of contact dermatitis may be treated by applying a topical composition comprising a feverfew extract where said extract has 1% of feverfew which is substantially free of parthenolides, i.e., the parthenolide concentration of said extract is ⁇ 0.1%. Due to the extremely low concentration of parthenolide in such a feverfew extract, a topical composition made from this extract will be non- irritating.
  • Tanacetum parthenium Two kilograms of Tanacetum parthenium are extracted at 50 - 60° C with 20 L of 70% aqueous methanol.
  • the extract is concentrated under vacuum to about 1 L and diluted with an equal volume of methanol.
  • the resulting solution is extracted with 3 x 2 liters of n-hexane.
  • the hexane extract is evaporated to dryness under vacuum to yield about 30 g of residue (extract H).
  • the water-methanolic solution is then extracted with 2 x 0.5 L of methylene chloride.
  • the organic phase are evaporated to dryness under vacuum to yield about 70 g of residues (extract DCM).
  • the water-methanolic phase (extract HM) is set aside.
  • the DCM extract is dissolved in 0.6 L of 90% methanol and treated under stirring with 0.6 L of strong basic resin (Relite 2A) for three-four hours.
  • the suspension is filtered under vacuum and the resin is washed with about 2 L of 90% methanol.
  • the methanolic solution, containing parthenolide and its congeners, is removed.
  • the basic resin is then treated under stirring for one hour with 0.6 L of methanol containing 65 mL of concentrated hydrochloric acid.
  • the resin is filtered under vacuum and washed with a further 2.5 L of methanol.
  • the filtrate and the washings are combined, concentrated under vacuum to about 200 mL and extracted with 3 x 200 mL of ethyl acetate.
  • the residues of the extracts H and E.A. are combined with the extract HM.
  • the resulting solution is evaporated to dryness under vacuum and the solid residue is dried under vacuum at 50°C to constant weight.
  • parthenium are obtained which shows, by HPLC analysis, (column Zorbax SB C18; eluent H 2 0 + 0.01% TFA; B:MeCN + 0.01% TFA; gradient A:B:90%- 10%:10%-90%; flow 1 ml/min), a parthenolide content below 0.07%.
  • feverfew and of parthenolide deprived feverfew were illustrated by its ability to reduce the production of lymphocyte function in the following assay.
  • the feverfew (“FFW”) used in this experiment was commercially obtained from Indena S.p.A.
  • the parthenolide free feverfew (“PFFW”) was obtained by using the method of Example 1.
  • Human leukocytes were collected from a healthy adult male via leukophoresis, and adjusted to a density of 1x10 cells/mL in serum free lymphocyte growth medium (LGM-2, Clonetics Corporation, San Diego, CA). PBLs were stimulated with lO ⁇ g/mL PHA in the presence or absence of test sample. Following a 48 hour incubation at 37°C with 5% C0 2 , supernatant was removed and evaluated for cytokine content using commercially available colorimetric ELISA kits. Proliferation was determined using alamarBlueTM (Alamar Biosciences, Sacramento, CA) after 96 hours. IL & Cytokine Release Inhibition Assays (IC 50 ⁇ g/mL)
  • FFW 50 40 30 10 10 30 ⁇ 10 30 30 30 30 25
  • PFFW 100 38 16 > 100 NT > 100 > 100 > 100 > 100 > 100 ⁇ 1.0 NT > 100
  • substantially parthenolide-free feverfew was able to modulate lymphocyte activation
  • Raw 264 murine macrophage cells were stimulated 24 hours by 1 ⁇ g/ml of LPS and 10 U/ml of IFN ⁇ in the presence or in the absence of the test products.
  • Nitrites the stable end product of nitric oxide, were assayed with the Griess reaction and PGE2 levels assessed by ELISA. Results are expressed as the percent inhibition of inflammatory mediator production compared to a stimulated control culture. Cell viability was checked with the MTT reduction test.
  • FFW fever ew having 0.7% parthenolide
  • PFFW parthenolide- deprived feverfew having less than 0.1% parthenolide
  • FLAV feverfew containing 3% parthenolide and 26% flavoids (where the individual flavenoids are tanetin and 3,7,3 '-trimethoxyquercetagetin comprising 7% and 22% of the flavenoid composition respectively)
  • PGE 2 prostaglandin E 2
  • NO nitric oxide
  • Epidermal equivalents (EPI 200 HCF) were purchased form MatTeK Corporation. Upon receipt, epidermal equivalents were incubated for 24 hours at 37°C in maintenance medium without hydrocortisone. Epidermal equivalents were pretreated for 2 hours with 50 ⁇ l of test product, washed and PMA (1 ⁇ g/ml) added to the culture medium. Equivalents were incubated for 24 hours at 37°C with maintenance medium, culture supernatant collected and evaluated for PGE 2 and by ELISA. Viability was assessed with the MTT assay.
  • Test compounds were applied to the left ear (20 ⁇ L) 1 hour after oxazolone challenge in a 70% ethanol/30% propylene glycol vehicle. The right ear was not treated. The mice were sacrificed by C0 2 inhalation 24 hours after the oxazolone challenge, the left and right ears were removed and a 7 mm biopsy was taken from each ear and weighed. The difference in biopsy weights between the right and left ear was calculated. Antiinflammatory effects of compounds are evident as an inhibition of the increase in ear weight.
  • FFW and PFFW are effective in inhibiting reaction to oxazolone.
  • mice were sacrificed by C0 2 inhalation (5.5 hours after TPA), the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ear was calculated. Antiinflammatory effects of compounds are demonstrated by the inhibition of the increase in ear weight.
  • mice were sacrificed by CO2 inhalation 1 hour after AA, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ear was calculated. Antiinflammatory effects of compounds are evident as an inhibition of the increase in ear weight. Inhibition of Arachidonic Acid Induced Ear Edema
  • PFFW Substantially parthenolide-free feverfew
  • Parthenolide deprived feverfew was evaluated for its ability to prevent skin inflammation in a controlled human study involving 10 volunteers.
  • PFFW was tested at 0.1 and 1% and compared to its vehicle and hydrocortisone also at 0J and 1%.
  • Test product was applied to 5 different locations on the volar forearm twice daily for 2 consecutive days (2mg/cm 2 ). The sites were exposed to 2MED UVB. Chromameter measurements were made prior to irradiation and at 18, 24, 42 and 48 hours post irradiation. The Colorimetric Erythema Index (CEI) was calculated for each time point. The following reductions in erythema were obtained:
  • Example 10 Treatment of Trauma Induced Inflammation Following Topical Application of Substantially Parthenolide Free Feverfew to Human Subjects
  • PFFW Substantially parthenolide-free feverfew
  • PFFW Substantially parthenolide-free feverfew
  • Examples 12 illustrates skin care composition according to the present invention.
  • the compositions can be processed in conventional manner. They are suitable for cosmetic use.
  • the compositions are suitable for applications to prevent and treat the inflammatory disorders and related conditions, such as but not limited to the conditions of contact dermatitis, edema, trauma induced inflammation, and UNB induced inflammation and thereof as well as for application to healthy skin to prevent or retard inflammation thereof.
  • This example illustrates an oil-in-water incorporating a composition of this invention.

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Abstract

This invention relates to a method of treating and preventing inflammatory disorders and related conditions using an extract of feverfew. Particularly, the invention includes a method of treating and preventing inflammatory disorders and related conditions which comprises applying a topical composition comprising an effective amount of an extract of feverfew to a patient and a method of treating and preventing inflammatory disorders and related conditions of the skin by applying a topical composition containing an effective amount of an extract of feverfew to a patient. In addition, the invention includes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient where said extract is substantially free of α-unsaturated η-lactone.

Description

EXTRACTS OF FEVERFEW (TANACETUM PARTHENIUM) AGAINST INFLAMMATORY DISORDERS
FIELD OF THE INVENTION
This invention relates to the topical treatment and prevention of inflammatory disorders and related conditions using extracts of feverfew (Tanacetum parthenium). BACKGROUND OF THE INVENTION Tanacetum parthenium, a plant commonly known as Feverfew, has been recognized since the Middle Ages as having significant medicinal properties when taken orally - used as a general febrifuge, hence its common name. Many have isolated extracts of the plant and those extracts have been used to orally treat migraines, arthritis, and bronchial complaints. (See Johnson et al, US Patent 4,758,433, discussing the treatment of a variety of diseases by oral, inhalation, injection or suppository administration of the extract and see WO 94 06800, discussing a extract of feverfew which contains parthenolide).
Extracts of feverfew contain many components. Although not all components have been isolated and characterized, the known components of an extract of feverfew contain a significant number of biologically active components. To date, the chemical constituents of whole feverfew extract are as follows: apigenin-7-glucoside, apigenin-7-glucuronide, 1-β-hydroxyarbusculin, 6- hydroxykaempf erol-3 ,7-4 '-trimethylether (Tanetin) , 6-hy droxykaempferol-3 ,7- dimethyl ether, 8-β-reynosin, 10-epicanin, ascorbic acid, beta-carotene, calcium, chromium, chrysanthemolide, chrysanthemomin, chrysarten-A, chrsyarten-c, chrysoeriol-7-glucuronide, cobalt, cosmosiin, epoxyartemorin, luteolin-7- glucoside, luteolin-7-glucuronide, mangnoliolide, parthenolide, quercetagentin-
3,7,3 '-trimethylether, quercetagetin-37-dimethylether, reynosin, tanaparthin, tanaparthin-lα,4α-epoxide, tanaparthin-lβ,4β-epoxide, β-costunolide, 3-β-hydroxy-parthenolide, and 3,7,3'-trimethoxyquercetagetin. The specific role that each of these component compounds plays in the biological activity of feverfew is to date unknown. However, some information is known about the allergic reactions to the extract. It is believed that many of these allergic reactions are caused by the α-unsaturated γ-lactones such as parthenolide. (See, Arch. Dermatol. Forsch. 1975, 251 (3):235-44; Arch. Dermatol. Forsch 1976, 255 (2):111- 21; Contact Dermatitis, 1988, 38 (4):207-8; Am. J. Contact Dermatol. 1998-9 (l):49-50; Br. J. Dermatol, 1995, 132 (4): 543-47).
Despite the existence of oral methods of using extracts of feverfew, there are no defined methods for topically using these extracts to treat or prevent inflammatory disorders and related conditions. In addition, there are no teachings which describe the use of an extract of feverfew which does not contain the allergy causing α-unsaturated γ-lactones. These are two areas which are addressed by this invention.
SUMMARY OF THE INVENTION
This invention relates to a method of treating or preventing inflammatory disorders and related conditions using an extract of feverfew. More particularly, the invention includes a method of treating or preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient. The method of this invention includes a method of treating or preventing inflammatory disorders and related conditions of the skin by applying a topical composition comprising an effective amount of an extract of feverfew to a patient. Still further, the invention includes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient where said extract is substantially free of α-unsaturated γ-lactone. Further, the invention includes a method of treating and preventing inflammatory disorders and related conditions of the skin by applying a topical composition containing an effective amount of an extract of feverfew to a patient where said extract is substantially free of α-unsaturated γ-lactone.
DETAILED DESCRIPTION OF THE INVENTION This invention includes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition containing an effective amount of an extract of feverfew to a patient. Inflammatory disorders and related conditions which may be treated or prevented by topical use of the compositions of this invention include, but are not limited to the following: arthritis, bronchitis, contact dermatitis, atophic dermatitis, psoriasis, seborrheic dermatitis, eczema, , allergic dermatitis, polymorphous light eruptions, inflammatory dermatoses, folliculitis, alopecia, poison ivy, insect bites, acne inflammation, irritation induced by extrinsic factors including, but not limited to, chemicals, trauma, pollutants (such as cigarette smoke) and sun exposure, secondary conditions resulting from inflammation including but not limited to xerosis, hyperkeratosis, pruritus, post-inflammatory hyperpigmentation, scarring and the like. Preferably, the inflammatory disorders and related conditions which may be treated or prevented using the methods of the invention are arthritis, inflammatory dermatoses, contact dermatitis, allergic dermatitis, atopic dermatitis, polymorphous light eruptions, irritation, including erythema induced by extrinsic factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, poison ivy, insect bites, foUiculitus, alopecia, and secondary conditions and the like.
"Feverfew" is a plant belonging to the family of Asteraceae/Composite which is technically known as, Tanacetum parthenium, Altamisa, Crisanthemum, Leucanthemum, or Pyrethrum parthenium. The term "effective amount" refers to the percentage by weight of the feverfew extract in the topical composition which is needed to treat an inflammatory disorder or related condition in a patient. Preferably the effective amount is between about 0.0005 to about 20% by weight of the composition. More preferably, the concentration should be less than about 10% by weight of the topical composition. Even more preferably between about 0.001% and about 10%, and most preferably between about 0.01% and about 2%.
The term "patient" refers to a mammal which is being treated prophylactically for an inflammatory condition and/or for an inflammatory condition with visible symptoms. Preferably the patient is a human. Further, the invention includes a method of treating and preventing inflammatory disorders and related conditions of the skin by applying a topical composition containing an effective amount of an extract of feverfew to a patient. The terms, inflammatory disorder and related condition, feverfew, effective amount, and patient, have their aforementioned meanings. The term "skin" includes all surfaces of a patient, such as the exposed hide or surfaces covered by hair.
The invention also includes a method of treating and preventing inflammatory disorders and related conditions which comprises applying a topical composition comprising an effective amount of an extract of feverfew to a patient where said extract is α-unsaturated γ-lactone-deprived. The terms, inflammatory disorders and related conditions, feverfew, effective amount, and patient have their aforementioned meanings. The term
"substantially free of α-unsaturated γ-lactone", refers to an extract of feverfew having a weight content of the α-unsaturated γ-lactones found in natural feverfew extracts of less than about 0.2% by weight.. These α-unsaturated γ-lactones include but are not limited to parthenolide ([lαR -(la R*, 4E,7a S*, 10a S*, 10b
R )]2J,4,7,7a,8J0a,10b-octahydro-la,5-dimethyl-8-4,5α-epoxy-6β-hydroxy- germacra-l(10),H(13)-dien-12-oic acid γ-lactone), 3-β-hydroxy-parthenolide, costunolide, 3-β-constunolide,artemorin, 8-α-hydroxy-estafiatin, chysanthemolide, magnoliolide, tanaparthin, tanaparthin-lα,4α-epoxide, tanaparthin-lβ,4β-epoxide, chrysanthemonin, and other sesquiterpenes. Preferably, the feverfew extract has a weight content of α-unsaturated γ-lactone below about 0.2. Preferably the α-unsaturated γ-lactone is parthenolide. The method of preparing this parthenolide-deprived extract is described in an Italian patent application
(MI99A001244, filed on June 3, 1999) which is hereby incorporated by reference. Since the α-unsaturated γ-lactones cause some of the allergic reactions to extracts of feverfew, topical compositions made from α-unsaturated γ-lactone-deprived extracts are expected to be non-irritating.
This invention also includes a method of treating inflammatory disorders and related conditions of the skin by applying a topical composition comprising an effective amount of an extract of feverfew to a patient where said extract is substantially free of α-unsaturated γ-lactone.
The terms inflammatory disorders and related conditions, feverfew, effective amount, patient, skin, and α-unsaturated γ-lactone-deprived have their aforementioned meanings.
In addition to the extracts of feverfew, other substances, such as biologically active agents, pharmaceutical excipients, and cosmetic agents may be included in the topical compositions of this invention.
Biologically active agents may include, but are not limited to, flavanoid/flavone compounds which include but are not limited to tanetin, 3,7,3'- trimethoxyquercetagetin, apigenin and its derivatives. When flavanoid/flavone compounds are present, they are present at a concentration of between about 0.001% to about 0.5% preferably, between about 0.005% and 0.2% based on the weight of the topical composition.
Additional biologically active agents include but are not limited to sunscreens, anti-wrinkling/antiaging agents, antifungal agents, antibiotic agents, anti-acne and antipsoriatic agents, depigmentating agents, where such agents may be utilized so long as they are physically and chemically compatible with the other components of the topical composition.
The compositions of this invention may include additional skin actives. Actives can be but not limited to vitamin compounds. Skin lightening agents (kojic acid, ascorbic acid and derivatives such as ascorbyl pamiltate, and the like); anti-oxidant agents such as tocopherol and esters; metal chelators, retinoids and derivatives, moisturizing agents, hydroxy acids such as salicylic acid, sun screen such as octyl methoxycinnamate, oxybenzone, avobenzone, and the like, sun blocks such as titanium oxide and zinc oxide, and skin protectants. Mixtures of above skin actives may be used. Sunscreens which may be used in the compsoitions of this invention may include but are not limited to organic or inorganic sunscreens, such as, octylmethoxycinnamate and other cinnamate compounds, titanium dioxide, zinc oxide and the like.
Anti-wrinkling/anti-aging agents may include but are not limited to retinoids (for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate) alpha hydroxy acids, galactose sugars (for example, melibiose and lactose), antioxidants, including but not limited to water soluble antioxidants such as sulfhydryl compounds and their derivatives (for example, sodium metabisulfite and N-acetyl-cysteine, acetyl-cysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferin, ascorbic acid and ascorbic acid derivatives (for example ascorbyl palmitate and ascorbyl polypeptide). Oil soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to tocopherols (for example, tocopheryl acetate, -tocopherol), tocotrienols and ubiquinone. Natural extracts containing antioxidants suitable for use in the compositions of this invention, include, but not limited to extracts containing flavonoids, phenolic compounds, flavones, flavanones, isoflavonoids, mono, di- and tri-terpenes, sterols and their derivatives. Examples of such natural extracts include grape seed, green tea, pine bark and propolis extracts and legume extracts and the like.
Antifungal agents include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts.
Antibiotic (or antiseptic agents) include but are not limited to but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, /-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetrachcycline hydrochoride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, benzoyl peroxide and their pharmaceutically acceptable salts.
Acne ingredients include but are not limited to agents that normalize epidermal differentiation (e.g. retinoids), keratolytic agents (e.g. salicylic acid and alpha hydroxy acids), benzoyl peroxide, antibiotics and compounds or plant extracts that regulate sebum.
Antipsoriatic agents include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide, mometasone furoate, methylprednisolone acetate), Vitamin D and its analogues (e.g. calcipotriene), retinoids (e.g. Tazarotene) and anthraline.
Cosmetic agents which may be used in the compositions of this invention may include, but are not limited to those agents which prevent potential skin irritation, such as emollients, vitamins and antioxidants (e.g., vitamin E) and herbal extracts (e.g., aloe vera). Further, the cosmetic agents may include humectants, antioxidants/preservatives, plant extracts, flavors, fragrances, surface active agents, and the like. Examples of humectants include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA, hyaluronic acid and the like. They may be used either singly or in combination.
Cosmetic agents may also include substances which mask the symptoms of inflammatory disorders and related conditions; such substances include but are not limited to pigments, dyes, and other additives (e.g., silica, talk, zinc oxide, titanium oxide, clay powders). The pharmaceutical excipients include but are not limited to pH modifying agents such as pH-modifying agents , organic solvents (e.g., propylene glycol, glycerol, etc.), cetyl alcohol, kaolin, talc, zinc oxide, titanium oxide, cornstarch, sodium gluconate, oils (e.g., mineral oil), ceteareth-20, ceteth-2, surfactants and emulsifiers, thickener (or binders), perfume, antioxidants, preservatives, and water. Binders or thickeners may be used in the compositions of this invention to provide substantivity and physical stability to the compositions. Binders or thickeners suitable for use in the compositions of this invention include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone. Thickeners such as natural gums and synthetic polymers, as well as coloring agents and fragrances also are commonly included in such compositions.
Examples of preservatives which may be used in the compositions of this invention include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para- hydroxybenzoate and the like.
Examples of flavors and fragrances which may be used in the compositions of this invention include menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like. The compositions of the present invention may be prepared in a number of forms for topical application to a patient. For example, the composition may be applied in a gel, cream, ointment, shampoo, scalp conditioners, liquid, spray liquid, paint-/brush-on preparation, aerosol, powder or adhesive bandage. In addition the composition may be impregnated on a bandages, hydrocolloid dressing, treatment patch or on cloth wipe products, such as baby wipes or facial wipes.
The compositions of this invention may be in the form of emulsions, such as creams, lotions and the like. Such compositions may have more than one phase and may include surface active agents which enable multiphase emulsions to be manufactured.
Examples of surface active agents which may be used in the compositions of this invention include sodium alkyl sufates, e.g., sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate and N-acyl glutamates, e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefin sulfonate and sodium dioctylsulfosuccinate; N- alkylaminoglycerols, e.g., N-lauryldiaminoethylglyecerol and N- myristyldiaminoethylglycerol, N-alkyl-N-carboxymethylammonium betaine and sodium 2-alkyl-l-hydroxyethylimidazoline betaine; polyoxyethylenealkyl ether, polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol, polyoxyethyleneglyceryl monoaliphatic acid ester, polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphatic acid ester, higher aliphatic acid glycerol ester, sorbitan aliphatic acid ester, Pluronic type surface active agent, and polyoxyethylenesorbitan aliphatic acid esters such as polyoxyethylenesorbitan monooleate and polyoxyethylenesorbitan monolaurate. Emulsifier-type surfactants know to those of skill in the art should be used in the compositions of this invention.
Another important ingredient of the present invention is a dermatologically acceptable carrier. Such a suitable carrier is adequate for topical use. It is not only compatible with the active ingredients described herein, but will not introduce any toxicity and safety issues. An effective and safe carrier varies from about 50% to about 99% by weight of the compositions of this invention, more preferably froma bouat 75% to about 99% of the compositions and most preferably from about 85% to about 95% by weight of the compositions.
The choice of which pharmaceutical excipient or biological agent, or cosmetic agent to use is often controlled or affected by the type of inflammatory disorder or related condition which is being treated. For example, if the compositions of this invention were used to treat a skin inflammation associated with athlete's foot, jock itch or diaper rash, talc would be a preferred pharmaceutical excipient and an antifungal agents would be preferred biological agents. If the compositions of this invention were to be used to treat eczema of the scalp, emulsifiers and oils would be preferred pharmaceutical excipients.
The condition of contact dermatitis may be treated by applying a topical composition comprising a feverfew extract where said extract has 1% of feverfew which is substantially free of parthenolides, i.e., the parthenolide concentration of said extract is < 0.1%. Due to the extremely low concentration of parthenolide in such a feverfew extract, a topical composition made from this extract will be non- irritating.
The following examples are illustrate, but do not serve to limit the scope of the invention described herein. They are meant only to suggest a method of practicing the invention. Those knowledgeable in the treatment and prevention of inflammatory disorders and related conditions as well as other specialties may find other methods of practicing the invention. However, those methods are deemed to be within the scope of this invention.
Example 1: Preparation of Feverfew Which is Substantially Free of Parthenolide
Two kilograms of Tanacetum parthenium are extracted at 50 - 60° C with 20 L of 70% aqueous methanol. The extract is concentrated under vacuum to about 1 L and diluted with an equal volume of methanol. The resulting solution is extracted with 3 x 2 liters of n-hexane. The hexane extract is evaporated to dryness under vacuum to yield about 30 g of residue (extract H). The water-methanolic solution is then extracted with 2 x 0.5 L of methylene chloride. The organic phase are evaporated to dryness under vacuum to yield about 70 g of residues (extract DCM). The water-methanolic phase (extract HM) is set aside. The DCM extract is dissolved in 0.6 L of 90% methanol and treated under stirring with 0.6 L of strong basic resin (Relite 2A) for three-four hours. The suspension is filtered under vacuum and the resin is washed with about 2 L of 90% methanol. The methanolic solution, containing parthenolide and its congeners, is removed. The basic resin is then treated under stirring for one hour with 0.6 L of methanol containing 65 mL of concentrated hydrochloric acid. The resin is filtered under vacuum and washed with a further 2.5 L of methanol. The filtrate and the washings are combined, concentrated under vacuum to about 200 mL and extracted with 3 x 200 mL of ethyl acetate. The resulting extract (E.A.), containing the flavone components tanetin and congeners, is evaporated to dryness under vacuum, to obtain about 4 g of residue. The residues of the extracts H and E.A. are combined with the extract HM. The resulting solution is evaporated to dryness under vacuum and the solid residue is dried under vacuum at 50°C to constant weight. About 490 g of extract of departhenolidized T. parthenium are obtained which shows, by HPLC analysis, (column Zorbax SB C18; eluent H20 + 0.01% TFA; B:MeCN + 0.01% TFA; gradient A:B:90%- 10%:10%-90%; flow 1 ml/min), a parthenolide content below 0.07%.
Example 2: Immunomodulation of Periperal Blood Leukocytes
The ability of feverfew and of parthenolide deprived feverfew to affect the inflammatory responses was illustrated by its ability to reduce the production of lymphocyte function in the following assay. The feverfew ("FFW") used in this experiment was commercially obtained from Indena S.p.A. The parthenolide free feverfew ("PFFW") was obtained by using the method of Example 1.
Human leukocytes were collected from a healthy adult male via leukophoresis, and adjusted to a density of 1x10 cells/mL in serum free lymphocyte growth medium (LGM-2, Clonetics Corporation, San Diego, CA). PBLs were stimulated with lOμg/mL PHA in the presence or absence of test sample. Following a 48 hour incubation at 37°C with 5% C02, supernatant was removed and evaluated for cytokine content using commercially available colorimetric ELISA kits. Proliferation was determined using alamarBlue™ (Alamar Biosciences, Sacramento, CA) after 96 hours. IL & Cytokine Release Inhibition Assays (IC50μg/mL)
IL-lα IL-lβ IL-2 I -4 IL-5 IL-6 IL-10 I -12 INFγ TNFα GMCSF Pro-lif
FFW 50 40 30 10 10 30 < 10 30 30 30 30 25
PFFW > 100 38 16 > 100 NT > 100 > 100 > 100 > 100 < 1.0 NT > 100
(where NE = not effective; NT= not tested; FFW = Feverfew; PFFW = substantially parthenolide-free feverfew, IL = Interleukin (Cytokine); IFN = interferon; TNF = tissue necrosis factor; GM-CSF = granulocyte macrophage stimulating factor).
Based on the foregoing, it can be seen that substantially parthenolide-free feverfew was able to modulate lymphocyte activation
Example 3: Evaluation on RAW 264 Macrophage Cell Line
Raw 264 murine macrophage cells were stimulated 24 hours by 1 μg/ml of LPS and 10 U/ml of IFNγ in the presence or in the absence of the test products. Nitrites, the stable end product of nitric oxide, were assayed with the Griess reaction and PGE2 levels assessed by ELISA. Results are expressed as the percent inhibition of inflammatory mediator production compared to a stimulated control culture. Cell viability was checked with the MTT reduction test.
RAW 264 Murine Marcophages Stimulate by LPS& IFNγ (% inhibition)
Figure imgf000014_0001
FFW = fever ew having 0.7% parthenolide, PFFW = parthenolide- deprived feverfew having less than 0.1% parthenolide, FLAV= feverfew containing 3% parthenolide and 26% flavoids (where the individual flavenoids are tanetin and 3,7,3 '-trimethoxyquercetagetin comprising 7% and 22% of the flavenoid composition respectively) ,PGE2 = prostaglandin E2, NO = nitric oxide Based on the foregoing, it can be seen that PFFW was able to down- regulate an immune response. Example 4: Evaluation on Reconstituted Epidermis
The effect of substantially parthenolide-free feverfew on PGE2 release from human epidermal equivalents was evaluated. Epidermal equivalents (EPI 200 HCF) were purchased form MatTeK Corporation. Upon receipt, epidermal equivalents were incubated for 24 hours at 37°C in maintenance medium without hydrocortisone. Epidermal equivalents were pretreated for 2 hours with 50 μl of test product, washed and PMA (1 μg/ml) added to the culture medium. Equivalents were incubated for 24 hours at 37°C with maintenance medium, culture supernatant collected and evaluated for PGE2 and by ELISA. Viability was assessed with the MTT assay.
Effect of Substantially Parthenolide-Free Feverfew on PGE2 production
Figure imgf000015_0001
Control Control + TPA <0J % PFFW 1 % PFFW
+TPA +TPA
Thus, it can be seen that both Feverfew extract and PFFW down-regulated the production of PGE2.
Example 5: Inhibition of Oxazolone Contact Hypersensitivity
The following experiments were carried out to test the effect of feverfew and substantially parthenolide-free feverfew in a contact hypersensitivity assay. In this assay, the compositions of the invention were evaluated against hydrocortisone, a steroid known to inhibit contact hypersensitivity. Albino male CD-I mice, 7-9 weeks old, were induce on the shaved abdomen with 50 μL of 3% oxazolone in acetone/corn oil (Day 0). On Day 5, a 20 μL volume of 2% oxazolone in acetone was appplied to the dorsal left ear of the mouse. Test compounds were applied to the left ear (20 μL) 1 hour after oxazolone challenge in a 70% ethanol/30% propylene glycol vehicle. The right ear was not treated. The mice were sacrificed by C02 inhalation 24 hours after the oxazolone challenge, the left and right ears were removed and a 7 mm biopsy was taken from each ear and weighed. The difference in biopsy weights between the right and left ear was calculated. Antiinflammatory effects of compounds are evident as an inhibition of the increase in ear weight.
Figure imgf000016_0001
NT = Not tested
Thus, it can be seen that FFW and PFFW are effective in inhibiting reaction to oxazolone.
Example 6: Mouse Ear Edema Inhibition Model
The following experiments were carried out to test the effect of feverfew and substantially parthenolide-free feverfew in a phorbol ester (TPA) induced edema assay. In this assay, the compositions of the invention were evaluated against hydrocortisone and dexamethasone, steroids which are known to show efficacy in this model. Albino male CD-lmice, 7-9 weeks old, were used. A 0.005% (w/v) TPA solution was made in acetone. A 20 μL volume of this TPA solution was applied to the dorsal left ear of the mouse. Test compounds were applied immediately to the left ear (20 μL) after TPA in a 70% ethanol/propylene glycol vehicle. The right ear was not treated. The mice were sacrificed by C02 inhalation (5.5 hours after TPA), the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ear was calculated. Antiinflammatory effects of compounds are demonstrated by the inhibition of the increase in ear weight.
Figure imgf000017_0001
Example 7: Inhibition of Arachidonic Acid Induced Ear Edema
In this in vivo model, feverfew's ability to reduce arachidonic acid induced edema was compared to the known cycloxygenase/lipoxgenase inhibitor tepoxalin. Albino male CD-I mice, 7-9 weeks old, were used. A 20% (w/v) arachidonic acid (AA) solution was made in acetone. A 20 μl volume of the AA was applied to the dorsal left ear of the mouse. Test compounds (20 μl) were applied immediately to the left ear after A A in a 70% ethanol/30% propylene glycol vehicle. The right ear was not treated. The mice were sacrificed by CO2 inhalation 1 hour after AA, the left and right ears were removed and a 7 mm biopsy was removed from each ear and weighed. The difference in biopsy weights between the right and left ear was calculated. Antiinflammatory effects of compounds are evident as an inhibition of the increase in ear weight. Inhibition of Arachidonic Acid Induced Ear Edema
Figure imgf000017_0002
Example 8: Prevention of Trauma Induced Inflammation Following Topical Application of Parthenolide Deprived Feverfew to Human Subjects
Substantially parthenolide-free feverfew (PFFW) was evaluated for its ability to prevent skin inflammation in a controlled human study involving 10 volunteers. In this study, parthenolide deprived everfew was tested at 0.1 and 1% and compared to its vehicle and hydrocortisone also at 0J and 1%. Test product was applied to the ventral side of the forearm twice daily for 2 consecutive days. Erythema was induced by 10 successive stratum corneum strippings. Chromameter measurements were made prior to stripping and at 0.5, 1, 1.5 and 2 hours post stripping. The Colorimetric Erythema Index (CEI) was calculated for each time point. For the total 2 hour period, and compared to the vehicle, the following reductions in erythema were obtained;
Figure imgf000018_0001
These results demonstrate that substantially parthenolide-free feverfew is effective at preventing trauma induced inflammation in humans and has activity comparable to equal concentrations of hydrocortisone.
Example 9: Prevention of UVB Induced Inflammation Following Topical Application of Parthenolide Deprived Feverfew to Human Subjects
Parthenolide deprived feverfew (PFFW) was evaluated for its ability to prevent skin inflammation in a controlled human study involving 10 volunteers. In this study, PFFW was tested at 0.1 and 1% and compared to its vehicle and hydrocortisone also at 0J and 1%. Test product was applied to 5 different locations on the volar forearm twice daily for 2 consecutive days (2mg/cm2). The sites were exposed to 2MED UVB. Chromameter measurements were made prior to irradiation and at 18, 24, 42 and 48 hours post irradiation. The Colorimetric Erythema Index (CEI) was calculated for each time point. The following reductions in erythema were obtained:
Figure imgf000019_0001
These results demonstrate that parthenolide deprived feverfew is effective at preventing UV induced inflammation in humans.
Example 10: Treatment of Trauma Induced Inflammation Following Topical Application of Substantially Parthenolide Free Feverfew to Human Subjects
Substantially parthenolide-free feverfew (PFFW) was evaluated for its ability to prevent skin inflammation in a controlled human study involving 10 volunteers. In this study, PFFW was tested at 0J and 1% and compared to its vehicle and hydrocortisone also at 0J and 1%. Erythema was induced by 10 successive stratum corneum strippings. Test product was applied to the ventral side of the forearm for 2 hours, immediately after stripping. Chromameter measurements were made prior to stripping and at 0.5, 1, 1.5 and 2 hours post stripping. The Colorimetric Erythema Index (CEI) was calculated for each time point. For the total 2 hour period, and compared to the vehicle, the following reductions in erythema were obtained:
Figure imgf000020_0001
These results demonstrate that higher doses of substantially parthenolide-free feverfew are moderately effective at preventing trauma induced inflammation in humans and has activity comparable to equal concentrations of hydrocortisone.
Example 11: Treatment of UVB Induced Inflammation Following Topical Application of Parthenolide Deprived Feverfew to Human Subjects
Substantially parthenolide-free feverfew (PFFW) was evaluated for its ability to treat skin inflammation in a controlled human study involving 10 volunteers. In this study, PFFW was tested at 0J and 1% and compared to its vehicle and hydrocortisone also at 0J and 1%. Ten healthy volunteers were irradiated with 2MED UV light on five distinct spots of the volar forearms. Test product was applied (2mg/cm on the irradiated sites immediately after irradiation , and 5 and 8 hours later. Erythema scores were measured before irradiation and 1, 4, 7 and 24 hours later. The following reductions in erythema were obtained:
Figure imgf000020_0002
These results demonstrate that Parthenolide deprived feverfew is effective at treating UN induced inflammation in humans.
Examples 12 illustrates skin care composition according to the present invention. The compositions can be processed in conventional manner. They are suitable for cosmetic use. In particular, the compositions are suitable for applications to prevent and treat the inflammatory disorders and related conditions, such as but not limited to the conditions of contact dermatitis, edema, trauma induced inflammation, and UNB induced inflammation and thereof as well as for application to healthy skin to prevent or retard inflammation thereof.
Example 12
This example illustrates an oil-in-water incorporating a composition of this invention.
Figure imgf000021_0001

Claims

What is claimed is:
1. A method of treating and preventing inflammatory disorders and related conditions which comprises applying a topical composition comprising an effective amount of an extract of feverfew to a patient.
2. The method of claim 1 where said inflammatory disorders or related condition is a disorder or related condition of the skin.
3. The method of claim 1 where said extract is substantially free of α-unsaturated γ-lactone.
4. The method of claim 1 where said extract is substantially free of α-unsaturated γ-lactone and said inflammatory disorder or related condition is a disorder or related condition of the skin.
5. The method of claim 3 where said α-unsaturated γ-lactone is parthenolide.
6. The method of claim 3 where said effective amount of said extract is from about 0.005% to about 10%.
7. The method of claim 6 where said extract has a parthenolide concentration of from about 0 to about 0.2%.
8. The method of claim 4 where said extract further comprises flavanoid compounds.
9. A topical composition useful in the treatment and prevention of inflammatory disorders or related conditions comprising an effective amount of an extract of feverfew and a pharmaceutically acceptable excipient.
0. The composition of claim 8 where said extract is substantially free of α-unsaturated γ-lactone.
PCT/US2000/015125 1999-06-03 2000-06-02 Extracts of feverfew (tanacetum parthenium) against inflammatory disorders Ceased WO2000074699A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP00938038A EP1100516B1 (en) 1999-06-03 2000-06-02 Extracts of feverfew (tanacetum parthenium) against inflammatory disorders
AT00938038T ATE291433T1 (en) 1999-06-03 2000-06-02 FEMALE EXTRACTS (TANACETUM PARTHENIUM) AGAINST INFLAMMATORY DISEASES
DE60018881T DE60018881T2 (en) 1999-06-03 2000-06-02 EXTRACTS FROM MOTHER HERB (TANACETUM PARTHENIUM) AGAINST INFLAMMATORY DISEASES
CA2339221A CA2339221C (en) 1999-06-03 2000-06-02 Extracts of feverfew (tanacetum parthenium) against inflammatory disorders
DK00938038T DK1100516T3 (en) 2000-06-02 2000-06-02 Extracts of matrem (Tanacetum parthenium) against inflammatory disorders
MXPA01001327A MXPA01001327A (en) 1999-06-03 2000-06-02 Extracts of feverfew (tanacetum parthenium) against inflammatory disorders.
BRPI0006634A BRPI0006634B8 (en) 1999-06-03 2000-06-02 topical composition comprising feverfew extract in the treatment and prevention of inflammatory disorders
AU53130/00A AU778261B2 (en) 1999-06-03 2000-06-02 Extracts of feverfew (tanacetum parthenium) against inflammatory disorders
JP2001501233A JP2004500329A (en) 1999-06-03 2000-06-02 Feverfew (Tanacetam-Palthenium) extract for inflammatory disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13733299P 1999-06-03 1999-06-03
US60/137,332 1999-06-03

Publications (1)

Publication Number Publication Date
WO2000074699A1 true WO2000074699A1 (en) 2000-12-14

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PCT/US2000/015125 Ceased WO2000074699A1 (en) 1999-06-03 2000-06-02 Extracts of feverfew (tanacetum parthenium) against inflammatory disorders

Country Status (14)

Country Link
US (1) US6410062B1 (en)
EP (1) EP1100516B1 (en)
JP (1) JP2004500329A (en)
KR (1) KR100755798B1 (en)
CN (1) CN1319020A (en)
AT (1) ATE291433T1 (en)
AU (1) AU778261B2 (en)
BR (1) BRPI0006634B8 (en)
CA (1) CA2339221C (en)
DE (1) DE60018881T2 (en)
ES (1) ES2239010T3 (en)
MX (1) MXPA01001327A (en)
PT (1) PT1100516E (en)
WO (1) WO2000074699A1 (en)

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CN1319020A (en) 2001-10-24
EP1100516A1 (en) 2001-05-23
BR0006634A (en) 2001-05-02
ES2239010T3 (en) 2005-09-16
BRPI0006634B8 (en) 2021-05-25
PT1100516E (en) 2005-07-29
CA2339221A1 (en) 2000-12-14
KR20010072221A (en) 2001-07-31
KR100755798B1 (en) 2007-09-07
EP1100516B1 (en) 2005-03-23
CA2339221C (en) 2013-09-10
AU778261B2 (en) 2004-11-25
MXPA01001327A (en) 2002-11-29
ATE291433T1 (en) 2005-04-15
DE60018881D1 (en) 2005-04-28
US6410062B1 (en) 2002-06-25
BRPI0006634B1 (en) 2015-06-02
DE60018881T2 (en) 2006-02-16
AU5313000A (en) 2000-12-28
JP2004500329A (en) 2004-01-08

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