Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-11-04
2003-03-04
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S038000, C514S738000, C514S185000, C536S004100, C424S059000, C424S195110
Reexamination Certificate
active
06528490
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of compositions and methods for treatment of inflammation, irritation and the effects of free radicals, using oenothein ellagitannins.
BACKGROUND OF THE INVENTION
Ellagitannins are a diverse family of naturally-occurring compounds consisting of a central core of glucose esterified with hexahydroxydiphenic acid. Ellagitannins are known as active constituents of a variety of medicinal plants (Okuda and Hotano, 1989
, Planta Med
. 55(2):117). For example, U.S. Pat. No. 5,843,911 issued Dec. 1, 1998 discloses the use of ellagitannins having galloyl and hexahydroxydiphenoyl substituents as hyaluronidase enzyme inhibitors for topical application, to enhance water retention in skin by preventing the hydrolysis of hyaluronic acid. The ellagitannins disclosed in U.S. Pat. No. 5,843,911 are identified as “GOD-type” ellagitannins, extractable from a variety of plants.
U.S. Pat. No. 5,525,594 issued Jun. 11, 1996 discloses the use of the ellagitannin oenothein-B (which is not a “GOD-type” ellagitannin as defined in U.S. Pat. No. 5,843,911) for the treatment of hyperandrogenic disorders by oral, rectal or parenteral administration (also reported in Lesuisse et al., 1996
, J. Nat. Prod
. 59(5):490). In this treatment, the mechanism of action of oenothein-B is taught to be the inhibition of 5-reductase, an enzyme responsible for the conversion of testosterone to dihydrotestosterone. Both oenothein-A and oenothein-B from Epilobium species have been shown to have similar pharmocologic activity, evidenced by 5-reductase and aromatase inhibition (Ducrey et al., 1996
, Planta Medica
63:111). It is disclosed in U.S. Pat. No. 5,525,594 that oenothein-B may be extracted from various Onagraceae plants (evening-primrose family), including
Epilobium parviflorum
. Ducrey et al., 1996, supra, disclose the extraction of oenotheins-A and B from
E. capense
, and the quantitation of oenothein-B in a variety of old world Epilobium species, including Old World
E. angustifolium
L (Rosebay Willowherb). The apparent antiviral and antitumour activities of oenothein-B are also discussed by Ducrey et al., 1996, supra, and in U.S. Pat. No. 5,525,594.
Aqueous extracts of Old World
Epilobium angustifolium
have been suggested for use as oral anti-inflammatories (German Patent No. 3,605,250 of Jul. 16, 1987), and the active ingredient in such extracts has been identified as the flavonoid compound myricetin glucuronide (3,3′4′,5,5′,7-hexahydroxyflavone-3-O-glucuronide; see Hiermann et al., 1991
, Planta Medica
57:357 and German Patent 3,900,023 of Jul. 12, 1990).
It has previously been disclosed, by the present inventors, that crude aqueous extracts of New World
Epilobium angustifolium
(Canadian Willowherb) have anti-irritant and anti-inflammatory properties when applied to human skin.
Exposure of skin to sunlight can cause inflammation directly as a result of the harmful effects of ultraviolet light. In the presence of atmospheric oxygen, sun-exposed skin may also be indirectly damaged by exposure to free radicals of oxygen generated by solar radiation. There remains a need in the art for compounds that may be used to treat inflammation, irritation and exposure to free radicals.
SUMMARY OF THE INVENTION
It has surprisingly been discovered that oenotheins are potent topical anti-inflammatories, anti-irritants and free radical scavengers (useful for treating exposure to free radicals). These activities provide unexpected advantages in topical formulations or medicaments, for example to ameliorate the effects of sunlight on skin. Accordingly, the invention provides formulations comprising an oenothein, including formulations for topical use as free-radical-scavengers or as a prophylactic against damage caused by sunlight or other ionizing radiation, or to treat irritation and inflammation (including irritation and inflammation caused by exposure to sunlight or other agents). The oenothein for use in such formulations may for example be oenothein-A or oenothein-B. The oenothein may be purified from natural sources, such as plant material, or it may be prepared synthetically.
Other aspects of the invention include methods of formulating topical medications for treatment of inflammation, irritations or exposure to free radicals, comprising adding a known amount of an oenothein to such compositions (prior to the present invention, there was no motivation to determine the amount of oenothein being administered in herbal remedies, such as
Epilobium angustifolium
extracts). In light of the present invention, plant extracts for use in such formulations may now be assayed to determine the concentration of oenothein in the extracts so that dosages may be formulated more reliably. For example, New World
Epilobium angustifolium
extracts may be assayed for oenothein-B content. Packaging for formulations of the invention may include text that indicates that the formulations are useful for prophylaxis of sunlight induced damage, as free radical scavengers for treating exposure to free radicals, or for treating inflammation or irritation, such text may optionally disclose that the formulations contain an oenothein.
In another aspect of the invention, new plant extracts found to contain an oenothein may be used topically to ameliorate the effects of sunlight, as anti-irritants, as anti-inflammatories, or for treating exposure to free radicals. For example, Epilobium spp. other than
Epilobium angustifolium
may be used for making such extracts where they contain oenothein-A or oenothein-B or mixtures thereof.
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Hendry et al. “Iron-induced oxygen radical metabolism in waterlogged plants”. HCAPLUS 103:211253, New Phytol. (1985), 101(1), 199-206.*
Juan et al. “Anti-inflammatory effects of a substance extracted fromEpilobium angustifolium”. Medline: 88180554 Agents and Actions, (1988 Feb.) 23 (1-2), 106-107.*
Ducrey et al. “Inhibition of 5-alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species.” Planta Med. (1977), 63(2), 111-114.*
Dijkstra et al. (1996). “Repertorium 96/97”SDU Service-centrum Uitgeveverijen.
Ducrey et al. (1997). “Inhibition of 5-alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species”Planta Medica, vol. 63(2): 111-114.
Hiermann (1987). “The investigation of active compounds from Epilobium species. 4thCommunication. The anti-inflammatory effect of different Epilobium species and their influence on prostaglandin”Scientia Pharamaceutica, vol. 55(2): 111-116.
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Luepke, N. P. & Kemper, F. H., (1986), The HETCAM Test: An Alternative to the Draize Eye Test, Food and Chemical Toxicology, 24:495-496.
Spielmann et al., (1997), CAM-based Assays, Food and Chemical Toxicology, 35:39-66.
Okuda, T., Yoshida, T. & Hatano, T. (1989), Ellagitannins as Ative Constituents of Medicinal Plants, Planta Med, 55(2):117-22.
Miyamoto, K., et al. (1993), Jpn J Cancer Res, Antitumor Activity of Oenothein B., a Unique Macroyclic Ellagitannin, 84(1):99-103.
Aoki, K. et al. (1995), Biochem Biophys Res Commun, A Macrocircular Ellagitannin, Oenothein B., Suppresses Mouse Mammary Tumor Gene Expression via Inhibition of Poly(ADP-ribose) Glycohydrolase, 210(2): 329-37.
Lesuisse, D. et al. (1996), J Nat Prod, Determination of Oenothein B as the Active 5-Alpha-Reductase-In
Hetherington Mark
Steck Warren
Barts Samuel
Bozicevic, Field & Francis
Fields Bret E.
Fytoken Products, Inc.
Khare Devesh
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