EP1804787A2 - Flavonoid composition for treating oral diseases - Google Patents
Flavonoid composition for treating oral diseasesInfo
- Publication number
- EP1804787A2 EP1804787A2 EP05810437A EP05810437A EP1804787A2 EP 1804787 A2 EP1804787 A2 EP 1804787A2 EP 05810437 A EP05810437 A EP 05810437A EP 05810437 A EP05810437 A EP 05810437A EP 1804787 A2 EP1804787 A2 EP 1804787A2
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- EP
- European Patent Office
- Prior art keywords
- free
- group
- composition
- flavan
- isolated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
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Definitions
- This invention relates generally to a novel composition of matter comprised of a mixture of a blend of two specific classes of compounds -Free-B-Ring flavonoids and flavans — which target the eicosanoid and cytokine pathways for use in the prevention and treatment of diseases and conditions of the mouth, teeth and gums.
- the diseases and conditions of the mouth, teeth and gums include but not limited to periodontal diseases, such as gingivitis, periodontitis, pulpitis, periodontal conditions caused by the physical implantation of oral dentures, trauma, injuries, bruxism, neoplastic and other degenerative processes; material alba, pellicles, dental plagues, calculus, and stains.
- composition described herein also affords the benefit of maintaining optimum saliva production and pH, minimizing bacterial growth, reducing the formation of pellicles and plague, inhibiting tooth decalcification and tooth caries (decay), promoting remineralization, yielding healthy gums, whitening teeth, maintaining healthy oral hygiene and reducing oral malodour (halitosis).
- Periodontal disease is a combination of inflammation and infection of some or all of the tooth support structures (gingiva, cementum, periodontal ligament, alveolar bone and other tissues surrounding the teeth). Gingivitis (gums) and periodontitis (gums and bone) are the two main forms of periodontal disease. According to National Oral Information distributed by the National Institute of Dental and Craniofacial Research, an estimated 80 percent of American adults currently have some form of periodontal disease. Periodontal disease is initiated when a pellicle fo ⁇ ns on a clean tooth or teeth. This pellicle attracts aerobic gram-positive bacteria (mostly actinomyces and streptococci), which adhere to the tooth forming plaque.
- the inflammation resulting from periodontal disease is mainly related to two biological systems: —the eicosanoid system and the cytokine system.
- the release and metabolism of arachidonic acid (AA) from the cell membrane results in the generation of pro ⁇ inflammatory metabolites by several different pathways.
- Two of the most important pathways to inflammation are mediated by the enzymes lipoxygenase (LOX) and cyclooxygenase (COX). These are parallel pathways that result in the generation of leukotrienes and prostaglandins, respectively, which play important roles in the initiation and progression of the inflammatory response.
- LOX lipoxygenase
- COX cyclooxygenase
- TNF ⁇ induces the secretion of collagenase by fibroblasts, resorption of cartilage and bone, and has been implicated in the destruction of periodontal tissue in periodontitis (Elias et al. (1987) J. Immunol. 138:3812; Meikle et al. (1989) J Periodontal Res. 24:207-13; Chaudhary et al. (1992) Endocrinology 130:2528).
- TNF ⁇ induces the synthesis of IL-I ⁇ and prostaglandin E2.
- TNF- ⁇ also activates osteoclasts and thus induces bone resorption.
- COX-I is a constitutive form of the enzyme that has been linked to the production of physiologically important prostaglandins, which help regulate normal physiological functions, such as platelet aggregation, protection of cell function in the stomach and maintenance of normal kidney function.
- the second isoform, COX-2 is a form of the enzyme that is inducible by pro-inflammatory cytokines, such as interleukin-1 ⁇ (IL-I ⁇ ) and other growth factors.
- IL-I ⁇ interleukin-1 ⁇
- This isoform catalyzes the production of prostaglandin E 2 (PGE2) from arachidonic acid (AA). Inhibition of COX is responsible for the anti- inflammatory activity of conventional NSAIDs.
- Inhibitors that demonstrate dual specificity for COX and LOX would have the obvious benefit of inhibiting multiple pathways of arachidonic acid metabolism. Such inhibitors would block the inflammatory effects of prostaglandins (PG), as well as, those of multiple leukotrienes (LT) by limiting their production. This includes the vasodilation, vasopermeability and chemotactic effects of PGE2, LTB4, LTD4 and LTE4, also known as the slow reacting substance of anaphalaxis. Of these, LTB4 has the most potent chemotactic and chemokinetic effects. (Moore (1985) in Prostanoids: pharmacological, physiological and clinical relevance, Cambridge University Press, N. Y., pp. 229-230).
- COX inhibitors are used to treat many of the same symptoms, including pain and swelling associated with inflammation in transient conditions and chronic diseases in which inflammation plays a critical role.
- most of the known NSAIDs are not suitable for periodontal diseases due to their poor solubility and bioavailability.
- Current methods for treating periodontal disease are limited with control of the infection being the primary goal (Genco et al (1990) in Contenporary Periodontics. The CV. Mosby Company, St. Louis, pp. 361 -370).
- Common anti-microbial or anti-plaque agents include chlorhexidine, Triclosan, stannous fluoride, Listerine, hydrogen peroxide, cetylpyridimiun chloride and sanguinarine alkaloids.
- Prescription anti-microbial mouth rinse, antiseptic chip, antibiotic gel/micro-sphercs and enzyme suppressant-doxycycline are the preferred non-mechanical/physical options to treat and control periodontal disease. Applicant is unaware of any reports of a formulation combining Free-B-Ring-Flavonoids and flavans as the primary biologically active components targeting the eicosanoid and cytokine pathways for the treatment of oral diseases and conditions.
- Flavonoids or bioflavonoids are a widely distributed group of natural products, which have been reported to have antibacterial, anti-inflammatory, antiallergic, antimutagenic, antiviral, antineoplastic, anti-thrombic and vasodilatory activity.
- the structural unit common to this group of compounds includes two benzene rings on either side of a 3-carbon ring as illustrated by the following general structural formula:
- flavonoids include flavanols, flavones, flavan-3-ols (catechins), anthocyanins and isofiavones.
- Free-B-Ring flavones and flavonols are a specific class of flavonoids, which have no substituent groups on the aromatic B ring (referred to herein as Free-B-Ring flavonoids), as illustrated by the following general structure:
- R is an alkyl group having between 1-10 carbon atoms
- Flavans include compounds illustrated by the following general structure:
- (+)-catechin from red wine results from the antioxidant properties of catechin, rather than inhibitory effects on intracellular enzymes, such as cyclooxygenase, lipoxygenase, or nitric oxide synthase (Bastianctto et al. (2000) Br. J. Pharmacol. 131 :71 1 -720).
- Catechin derivatives purified from green and black tea such as epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and theaflavins showed inhibition of cyclooxygenase and lipoxygenase dependent metabolism of AA in human colon mucosa and colon tumor tissues (Hong et al. (2001 ) Biochem. Pharmacol. 62: 1 175-1 183) and induce cox-2 expression and PGE 2 production (Park et al. (2001 ) Biochem. Biophys. Res. Commun. 286:721 -725).
- Acacia is a genus of leguminous trees and shrubs.
- the genus Acacia includes more than 1000 species belonging to the family of Leguminosae and the subfamily of Mimosoideae.
- Acacias are distributed worldwide in tropical and subtropical areas of Central and South America, Africa, parts of Asia, as well as, Australia, which has the largest number of endemic species. To date, approximately 330 compounds have been isolated from various Acacia species.
- Flavonoids are the major class of compounds isolated from Acacias. Approximately 180 different tlavonoids have been identified, 1 1 1 of which are flavans. Terpenoids are second largest class of compounds isolated from species of the Acacia genus, with 48 compounds having been identified.
- Uncaria genus includes 34 species many of which are well known as medicinal plants. Uncaria plants have been utilized by different cultures for treatment of wounds, and ulcers, fevers, headaches, gastrointestinal illnesses and microbial/gungal infections. Uncaria plants contain significant amounts of catechin and other flavones. Other components that have been reported in Uncaria genus include alkaloids, terpenes, quinovic acid glycosides, coumarins, and flavonoids. Uncaria gambir is a species common in Malaysia, Singapore, India and other South East Asian countries. Catechins are major components in the whole plant of Uncaria gambir.
- the present invention includes methods that are effective in simultaneously inhibiting both the eicosanoid system and the cytokine system for use in the prevention and treatment of diseases and conditions related to the mouth, teeth and gums.
- the method for the simultaneous dual modulation of both the eicosanoid system and the cytokine system is comprised of administering, systemically or locally, a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
- This composition of matter is referred to herein as UP676.
- the efficacy and safety of this method is demonstrated with purified enzymes, in different cell lines, in multiple animal models and eventually in a human clinical study.
- the ratio of the Free-B-Ring flavonoids to flavans in the composition is in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1 :99.9 Free-B-Ring fiavonoids:flavans.
- the ratio of Free-B-Ring flavonoids to flavans is selected from the group consisting of approximately 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B- Ring flavonoids:flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia or Uncaria genus of plants.
- the ratio of Free-B-Ring flavonoids to flavans is selected from the group consisting of approximately 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B- Ring flavonoids: flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia or Uncaria genus of plants.
- Free-B-Ring flavonoids also referred to herein as Free-B-Ring flavones and flavonols, that can be used in accordance with the following invention include compounds illustrated by the following general structure: wherein
- R is selected from an alkyl group having between 1 -10 carbon atoms
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- the Free-B-Ring flavonoids of this invention may be obtained by synthetic methods or extracted from the family of plants including, but not limited to Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lauranceae, Leguminosae, Moraceae, Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae and Zingiberacea.
- the Free-B-Ring flavonoids can be extracted, concentrated, and purified from the following genus of high plants, including but not limited to Desmos, Achyrocline, Oroxylum, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatot ⁇ um, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Denis, Glycyrrhi ⁇ a, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholacna, Pinus, Ulmus and Alpinia. [0030
- the flavans that can be used in accordance with the following invention include compounds illustrated by the following general structure: wherein
- Ri, R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of H, -OH, -SH, -OCH 3 , -SCH 3 , -OR, -SR, -NH 2 , -NRH, -NR 2 , -NR 3 + X " , esters of the mentioned substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl- cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters, and their chemical derivatives thereof; a glycoside of a single or combination of multiple sugars, wherein said glycoside is linked to the 7-hydroxy chromone by a carbon, oxygen, nitrogen or sulfur, and wherein said single or combination of multiple sugars include, but are not limited to aldopentoses, methyl- aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof and other polymerized flavans
- Uncaria gambir Uncaria lanosa, Uncaria hirsute, Uncaria africana, Uncaria elliptica, Uncaria orientalis, Uncaria attenuate, Uncaria acida, Uncaria homomalla, Uncaria sessilifructus, Uncaria sterrophylla, Uncaria bernaysii, Uncaria sinensis, Uncaria callophylla, Uncaria rhychophylla, Uncaria tomentosa, Uncaria longiflora, Uncaria hirsute, Uncaria cordata, and Uncaria borneensis.
- the present invention further includes therapeutic compositions comprising the therapeutic agents of the present invention.
- the therapeutic compositions described herein can also be useful for maintaining optimum saliva production, saliva pH value, minimizing bacterial growth, reducing the formation of plague acids, inhibiting mineral loss, promoting remineralization, reducing the prevalence of caries, yielding a healthy gums, whitening teeth, maintaining healthy oral hygiene and reducing oral malodour (halitosis).
- the method of prevention and treatment according to this invention comprises administering systemically or topically to a host in need thereof a therapeutically effective amount of the formulated Free-B-Ring flavonoids and flavans isolated from a single source or multiple sources.
- the purity of the individual and/or a mixture of multiple Free-B-Ring flavonoids and flavans includes, but is not limited to 0.01% to 100%, depending on the methodology used to obtain the compound(s).
- doses of the mixture of Free-B-Ring flavonoids and flavans containing the same are an efficacious, nontoxic quantity generally selected from the range of 0.001 % to 100% based on total weight of the topical fo ⁇ nulation. Persons skilled in the art using routine clinical testing arc able to determine optimum doses for the particular ailment being treated.
- Free-B-Ring-Flavonoids As the primary biologically active components for the treatment of diseases and conditions related to the mouth, teeth and gums.
- the lack of substitution of one of the aromatic rings of the Free-B-Ring flavonoid plays very important role in making these compounds efficacious for use in oral care.
- Free-B-Ring flavonoids such as baicalin, has a low polarity aromatic ring on one side of the molecule and high polarity glucuronide and two hydroxyl groups on the other side. This structural arrangement allows these compounds to easily penetrate and remain in gum tissue.
- the combination of Free-B-Ring- flavonoids with flavans to produce the composition of matter referred to herein as UP676, offers a synergistic and potent modulator of both the cicosanoid system and the cytokine system that will help to control inflammation of the periodontal tissues, including inflammation in all four stages of periodontal disease. Additionally, due to the different biological availability, i.e. rate and percentage of biologically active compounds penetrating the epithelial cell membrane and the local concentrations of biologically active compounds in periodontal tissues, the combination of the two different type of compounds (higher polarity flavans vs.
- Figure 3 depicts graphically a profile of the inhibition of COX-I and COX-2 by the purified component baicalein isolated from S. baicalensis.
- the compound was examined for its inhibition of the peroxidase activity of recombinant ovine COX-I ( ⁇ ) and ovine COX-2 ( ⁇ ).
- the data is presented as percent inhibition vs. inhibitor concentration ( ⁇ g/mL).
- the IC 50 for COX-I was determined to be 0.18 ⁇ g/mL/unit of enzyme and the IC 50 for COX-2 was determined to be 0.28 ⁇ g/mL/unit.
- Figure 8 depicts graphically a profile of the inhibition of COX-I and COX-2 by a formulation produced by combining an extract of Free-B-Ring flavonoids isolated from the roots of S. baicalensis and an extract of flavans isolated from the bark of A. catechu in a ratio of about 20:80. The composition was examined for its inhibition of the peroxidase activity of recombinant ovine COX-I ( ⁇ ) and ovine COX-2 ( ⁇ ). The data is presented as percent inhibition vs.
- FIG. 9 depicts graphically a profile of the inhibition of 5-LO by the flavan extract from A. catechu. The composition was examined for its inhibition of recombinant potato 5- lipoxygenase activity ( ⁇ ) as described in Example 4. The data is presented as percent inhibition of assays without inhibitor. The IC 50 for 5-LO was 1.38 ⁇ g/mL/unit of enzyme.
- Figure 10 illustrates the High Pressure Liquid Chromatography (HPLC) chromatogram of a typical formulation comprised of a mixture of Free-B-Ring flavonoids isolated from the roots of S. baicalensis and flavans isolated from the bark of A. catechu in a ratio of 80:20 carried out under the conditions as described in Example 9.
- Figure 1 1 depicts graphically the effect of increasing concentrations of UP676 on the amount of LPS-induced newly synthesized LTB 4 ( ⁇ ) as dete ⁇ nined by ELISA in THP-I or 'HT-29 cells (ATCC) as " descnbed"in Example 10.
- the UP676 was produced through the combination of standardized extracts of Free-B-Ring flavonoids isolated from the roots of 5. baicalensis and flavans isolated from the bark of A. catechu in a ratio of 80:20.
- the activity of the UP676 formulation is expressed as % inhibition of induced LTB 4 synthesis.
- Figure 12 compares the LTB 4 levels as determined by ELISA that remain in HT-29 cells after treatment with 3 ⁇ g/mL UP676 in non-induced cells to treatment with 3 ⁇ g/mL ibuprofen as described in Example 10.
- the UP676 formulation demonstrated 80% inhibition of LTB4 production in the HT-29 cells after two days of treatment.
- Free-B-Ring Flavonoids as used herein are a specific class of flavonoids, which have no substitute groups on the aromatic B-ring, as illustrated by the following general structure:
- Ri, R 2 , R 3 , R 4 , and R 5 are independently selected from the group consisting of -H, - OH, -SH, OR, -SR, -NH 2 , -NHR, -NR 2 , -NR 3 + X " , a glycoside of a single or combination of multiple sugars, wherein said glycoside is linked to the 7-hydroxy chromone by a carbon, oxygen, nitrogen or sulfur, and wherein said single or combination of multiple sugars include, but are not limited to aldopentoses, methyl-aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof; wherein
- X is selected from the group of pharmaceutically acceptable counter anions including, but not limited to hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, carbonate, etc.
- Ri, R 2 , R 3 , R 4 and R 5 are independently selected from the group consisting of H, -OH, -SH, -OCH 3 , -SCH 3 , -OR, -SR, -NH 2 , -NRH, -NR 2 , -NR 3 + X " , esters of the mentioned substitution groups, including, but not limited to, gallate, acetate, cinnamoyl and hydroxyl- cinnamoyl esters, trihydroxybenzoyl esters and caffeoyl esters, and their chemical derivatives thereof; a glycoside of a single or combination of multiple sugars, wherein said glycoside is linked to the 7-hydroxy chromone by a carbon, oxygen, nitrogen or sulfur, and wherein said single or combination of multiple sugars include, but are not limited to aldopentoses, methyl- aldopentose, aldohexoses, ketohexose and their chemical derivatives thereof and other polymerized flavans
- a “pharmaceutically acceptable carrier” refers to any carrier, which does not interfere with effectiveness of the biological activity of the active ingredient and which is not toxic to the host to which it is administered.
- pharmaceutically acceptable carriers include, but are not limited to, any of the standard pharmaceutical carriers such as a saline solution, i.e. Ringer's solution, a buffered saline solution, water, a dextrose solution, serum albumin and other excipients and preservatives for tableting and capsulating formulations.
- RT-qPCR refers to a method for reverse transcribing (RT) an mRNA molecule into a cDNA molecule and then quantitatively evaluating the level of gene expression using a polymerase chain reaction (PCR) coupled with a fluorescent reporter.
- the current invention provides methods for the extraction (Example 1 , Table 1 ) of plants that contain Free-B-Ring flavonoids, including three species from the Scutellaria genus and Oroxulum indicum and plants that contain flavans, including Acacia catechu and three species from the Uncaria genus with organic and aqueous solvents.
- the crude extracts were assayed for cyclooxygenase inhibitory activity (Example 2, Tables 2 and 3).
- Purified Free-B-Ring flavonoids and flavans demonstrated inhibitory activity against cyclooxygenase (COX) and lipoxygenase (LOX), respectively, as shown in Examples 3 and 4 and Table 4.
- Methods for analyzing and quantifying the extracts are described in Examples 5 and 6 and the procedures to generate standardized Free-B-Ring flavonoids and flavans from botanical origins are provided in Examples 7 and 8.
- the standardized flavan extract is comprised of the active compounds having a purity of between 1 -99% (by weight) total flavans as defined in Examples 1 , 4, 6 and 7.
- Catechin is the major active component in the extracts derived from both Acacia catechu and Uncaria gambir that accounts for 30-95% (by weight) of the total flavans.
- the standardized flavan extract derived from Acacia catechu contains >80% of catechins.
- UF676 is produced by mixing the above two extracts or synthetic compounds in a ratio from 99: 1 to 1 :99.
- the preferred weight by weight ratios of Free-B-Ring flavonoids to flavans are 80:20 as defined in Example 9 and Table 1 1.
- the concentration of Free-B-Ring flavonoids in UP676 can be from about 1 % to 99% and the concentration of flavans in UP676 can be from 99% to 1 %.
- the concentration of total Free-B-Ring flavonoids in UP676 is approximately 75% with a baicalin content of approximately 60% of total weight of the UP676; and the concentration of total flavans in UP676 is approximately 10% with a catechin content of approximately 9.9%.
- the total active components (Free-B-Ring flavonoids plus flavans) in UP676 are >85% of the total weight.
- the present invention includes methods that are effective in simultaneously inhibiting both the eicosanoid and cytokine pathways, for use in the prevention and treatment of periodontal diseases and gingival conditions.
- the method for the dual modulation of the eicosanoid and cytokine pathways is comprised of administering, systemically or topically a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
- This composition of matter is referred to herein as UP676.
- the efficacy of this method is demonstrated with purified enzymes, in different cell lines, in multiple animal models and eventually in a human clinical study.
- the ratio of the Free-B-Ring flavonoids to flavans in the composition is in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1 :99.9 Free-B-Ring flavonoids:flavans.
- the ratio of Free-B-Ring flavonoids to flavans is selected from the group consisting of approximately 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the present invention also includes methods that simultaneously inhibit cycloxygenase (COX) and lipoxygenase (LOX) enzymatic activity.
- the method for simultaneously inhibititing cycloxygenase (COX) and lipoxygenase (LOX) enzymatic activity is comprised of administering, systemically or topically, to a host in need thereof an effective amount of a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants and a pharmaceutically acceptable earner.
- the ratio of the Free-B-Ring flavonoids to flavans in the composition can be in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1 :99.9 Free-B-Ring flavonoids:flavans.
- the ratio of Free-B-ring flavonoids to flavans is selected from the group consisting of approximately 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 80:20.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- Also included in the present invention is a method for the simultaneous reduction of IL-I ⁇ , TNF ⁇ and IL-6, as well as, other proteins related to inflammation for use in the prevention and treatment of diseases and conditions related to the mouth, gums and teeth. While not limited by theory it is believed that the mechanism for reducing these proteins is the result of the down regulation of their gene expression by the composition of matter of the instant invention.
- the pro-inflammatory cytokines especially IL- l ⁇ , TNF ⁇ and IL-6, play key roles in the chronic infections in the periodontium. Induction of the synthesis of the pro ⁇ inflammatory cytokines affects PDL cell phenotype and function.
- the method for the simultaneous suppression of the pro ⁇ inflammatory cytokine gene expression, especially of IL-I ⁇ , TNF ⁇ and IL-6, is comprised of administering, systemically or topically to a host in need thereof a composition comprised of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants to a host in need thereof.
- This composition of matter is referred to herein as UP676.
- the ratio of the Free-B-Ring flavonoids to flavans in the composition is in the range of 99.9:0.1 of Free-B-Ring flavonoids:flavans to 0.1 :99.9 Free-B-Ring flavonoids:flavans.
- the ratio of Free-B- Ring flavonoids to flavans is selected from the group consisting of approximately 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80 and 10:90.
- the ratio of Free-B-Ring flavonoids:flavans in the composition of matter is 20:80.
- the Free-B-Ring flavonoids are isolated from a plant or plants in the Scutellaria genus of plants and the flavans are isolated from a plant or plants in the Acacia genus of plants.
- the present invention includes a method for preventing and treating a number of diseases and conditions related to the mouth, gums and teeth including, but not limited to periodontal (gum; diseases including gingivitis, aggressive periodontitis, chronic periodontitis, periapical periodontitis, periodontitis as a manifestation of systemic diseases, and necrotizing periodontal disease, wherein the causes of said periodontal diseases include, but are not limited to chronic bacterial infection, plaque accumulation, tobacco usage by smoking and/or chewing, genetically susceptible, caused by pregnancy and puberty, stress, medications, and diabetes, poor nutrition and other systemic diseases.
- periodontal gingivitis, aggressive periodontitis, chronic periodontitis, periapical periodontitis, periodontitis as a manifestation of systemic diseases, and necrotizing periodontal disease
- the causes of said periodontal diseases include, but are not limited to chronic bacterial infection, plaque accumulation, tobacco usage by smoking and/or chewing, genetically susceptible, caused by pregnancy and puberty,
- the present invention further includes therapeutic compositions comprising the therapeutic agents of the present invention.
- the therapeutic compositions described herein can also be useful for maintaining optimum saliva production, saliva pH value, minimizing bacterial growth, reducing the formation of plague acids, inhibiting mineral loss, promoting remineralization, reducing the prevalence of caries, yielding a healthy gums, whitening teeth, maintaining healthy oral hygiene and reducing oral malodour (halitosis).
- the Free-B-Ring flavonoids that can be used in accordance with the instant invention include compounds illustrated by the general structure set forth above.
- the Free-B- Ring flavonoids of this invention may be obtained by synthetic methods or may be isolated from the family of plants including, but not limited to Annonaceae, Asteraceae, Bignoniaceae, Combretaceae, Compositae, Euphorbiaceae, Labiatae, Lawanceae, Leguminosae, Moraceae, Pinaceae, Pteridaceae, Sinopteridaceae, Ulmaceae, and Zingiberacea.
- the Free-B-Ring flavonoids can be extracted, concentrated, and purified from the following genus of high plants, including but not limited to Desmos, Achyrocline, Oroxyhim, Buchenavia, Anaphalis, Cotula, Gnaphalium, Helichrysum, Centaurea, Eupatorium, Baccharis, Sapium, Scutellaria, Molsa, Colebrookea, Stachys, Origanum, Ziziphora, Lindera, Actinodaphne, Acacia, Denis, Glycyrrhi ⁇ a, Millettia, Pongamia, Tephrosia, Artocarpus, Ficus, Pityrogramma, Notholaena, Pimts, Ulmns and Alpinia.
- the present invention implements a strategy that combines a series of in vivo inflammation and toxicity studies as well as in vitro biochemical, cellular, and gene expression screens to identify active plant extracts that specifically inhibit COX and LOX enzymatic activity, impact mRNA gene expression and reduce inflammation.
- the methods used herein to identify active plant extracts that specifically inhibit COX and LOX are described in Examples 1 and 2, as well as in U.S. Application Serial No. 10/091 ,362, filed March 1 , 2002, entitled "Identification of Free-B-Ring Flavonoids as Potent Cox-2 Inhibitors;" U.S. Application Serial No.
- the biochemical assay used to measure inhibition of COX, relies on the protein's peroxidase activity in the presence of heme and arachidonic acid.
- This study which is described in Example 3 shows that the purified Free-B-Ring flavonoids, baicalin and baicalein isolated from S. baicalensis and the flavan extract isolated from A. catechu, and each individual standardized extract containing high concentrations of Free-B-Ring flavonoids and flavans inhibited COX activity ( Figures 1 -5).
- the pro-inflammatory cytokines especially IL-I ⁇ , TNF ⁇ and IL-6, play key roles in chronic infections in the periodontium. They not only activate and recruit immune cells to the site ot infection, but also induce Toss of supporting bone and ligamentous attachment. It is well established that the mRNA levels of these cytokine genes are elevated in the diseased periodontium and the synthesis of the pro-inflammatory cytokines affects PDL cell phenotype and function. Since UP676 simultaneously suppresses pro-inflammatory cytokines dramatically, including IL-I ⁇ , TNF ⁇ and IL-6, at the mRNA level, it offers an effective way of treating periodontal diseases.
- excipients include, but are not limited to water, aicot ⁇ ois (ethanoi Or etftyiene glycol, propylene glycol), buffers, saline, hydratcd silica, dextrose solution, cellulose gum, sorbitol, mannitol, preservatives and other aqueous physiologically balanced salt solutions.
- the therapeutic composition can also contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability.
- compositions include suspensions containing viscosity enhancing agents, such as sodium carboxymethylcellulose, sorbitol, xanthan gum, methyl cellulose, or dextran.
- buffers include phosphate buffer, bicarbonate buffer, tris buffer, histidine, citrate, and glycine, or mixtures thereof, while examples of preservatives include, but are not limited to thimerosal, m- or o-cresol, formalin and benzyl alcohol.
- Standard formulations can either be liquid or gel or paste, or solids, which can be taken up in a suitable format as a suspension or solution for administration.
- the composition is prepared as a controlled release formulation, which slowly releases the composition of the present invention into the host.
- a controlled release formulation comprises a composition of the present invention in a controlled release vehicle.
- Suitable controlled release vehicles will be known to those skilled in the art.
- Preferred controlled release formulations are biodegradable (i.e., bioerodible).
- Example 15 illustrates the stability of catechin in solution varying both pH and preservatives.
- Catechin contains four phenolic hydroxyl groups which makes this compound more acidic and sensitive to oxidative stress.
- the extremely high Oxygen Radical Absorption Capacity (ORAC at 20,000) of catechin demonstrates its antioxidant properties.
- Table 14 shows the maximal values found for baicalein concentration (C max , ⁇ g/mL) and time (T max , hour) at which they were observed for each subject.
- C max baicalein concentration
- T max time
- Table 14 shows the maximal values found for baicalein concentration (C max , ⁇ g/mL) and time (T max , hour) at which they were observed for each subject.
- the data shows that for most subjects, the maximum concentration was achieved between 4 and 8 hours after the initial dose.
- the average time for absorption and clearance was calculated and plotted for the entire study group (Figure 17). Since the IC 50 values of COX inhibition from UP676 are between 0.2-0.4 ⁇ g/mL as shown in the Figure 6, it takes about two hours after oral administration for UP676 to reach efficacious concentrations.
- compositions of this invention can be administered by any method known to one of ordinary skill in the art.
- the modes of administration include, but are not limited to, enteral (oral) administration, parenteral (intravenous, subcutaneous, and intramuscular) administration and topical application.
- the method of treatment according to this invention comprises administering internally or topically to a patient in need thereof a therapeutically effective amount of a mixture of Free-B-Ring flavonoids and flavans synthesized and/or isolated from a single plant or multiple plants. In a one embodiment the composition is administered topically.
- the therapeutic agents of the instant invention are administered topically by any suitable means, known to those of skill in the art for topically administering therapeutic compositions including, but not limited to as a paste, ointment, gel, lotion, or mouse rinse liquid, or cream base or as an emulsion, as a patch, dressing or mask, a nonsticking gauze, a bandage, a swab or a cloth wipe.
- Such topical application can be locally administered to any affected area, using any standard means known for topical administration, such as brushing with a toothbrush, coated on dental floss, or applying with a swab or rinsing with the liquid or gel.
- a therapeutic composition can be administered in a variety of unit dosage forms depending upon the method of administration.
- a suitable ointment is comprised of the desired concentration of the mixture of Free-B-Ring flavonoids and flavans, that is an efficacious, nontoxic quantity generally selectecffr ⁇ 'ftf the " r"ange'"6f 0.001% to 100% based on total weight of the topical formulation, from 0.05 to 5% (preferably 0.1 to 0.5%) of toothpaste, from 0.01 to 5% of mouse washing liquid (preferably 0.2 to 1 %), and from 0.1 to 25% (preferably 0.5 to 5%) of emulsion gel or cream.
- Table 2 sets forth the inhibition of the COX-2 enzyme by the organic (20 ⁇ g/mL) and aqueous (20 ⁇ g/mL) extracts obtained from three plant species, including the bark of A catechu, roots of two Scutellaria species, which are comprised of structurally similar Free-B- Ring flavonoids. Data is presented as the percent of peroxidase activity relative to the recombinant ovine COX-2 enzyme and substrate alone. The percent inhibition by the organic extract ranged from 30% to 90%.
- Each inhibitor taken from a 10 mg/mL stock solution in 100% DMSO, was tested in triplicate at room temperature using the following range of concentrations: 0, 0.1, 1, 5, 10, 20, 50, 100, and 500 ⁇ g/mL.
- 150 ⁇ L of 100 mM Tris-HCl, pH 7.5 was added along with 10 ⁇ L of 22 ⁇ M Hematin diluted in tris buffer, 10 ⁇ L of inhibitor diluted in DMSO and 25 units of either the COX-I or COX-2 enzyme.
- the test article was applied to a naive site on the opposite side of the body and discarded by the subjects approximately 24 or 48 hours later.
- Skin responses to each patch application were examined and graded under light supplied by a 100-watt incandescent blue bulb according to the designated scoring scale. In instances where a strong irritation reaction warranted application of the test article to the move-site, residual scores were be recorded through the end of induction (or until resolved if reactions persist after induction is completed) for all previously exposed sites. All skin reactions were recorded.
- skin responses were evaluated approximately 48 and 72 or 96 hours after patch application. Conclusions, with regard to induced sensitivity, were derived primarily from the challenge evaluations.
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Abstract
Description
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CN107648111A (en) * | 2017-10-30 | 2018-02-02 | 刘俊君 | A kind of Chinese herbal toothpaste |
KR20200041659A (en) | 2018-10-12 | 2020-04-22 | 주식회사 엘지생활건강 | Composition for prevention or treatment of oral disease |
JP7448122B2 (en) * | 2020-09-10 | 2024-03-12 | 株式会社アカシアの樹 | Oral flora improvement and maintenance agent, plaque/plaque removal and tartar formation prevention agent |
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JPH0662408B2 (en) * | 1987-10-01 | 1994-08-17 | 太陽化学株式会社 | Anti-caries and anti-periodontal composition |
US6264926B1 (en) * | 1999-02-12 | 2001-07-24 | Council Of Scientific And Industrial Research | Formulation useful as a natural herbal tooth powder |
US6319523B1 (en) * | 2000-06-29 | 2001-11-20 | James H. Zhou | Composition and method for inhibiting oral bacteria |
AU7958701A (en) * | 2000-07-28 | 2002-02-13 | Immupharm Aps | Method of treating symptoms of common cold, allergic rhinitis and infections relating to the respiratory tract |
AU2002231030A1 (en) * | 2000-12-13 | 2002-06-24 | Universidade Estadual De Campinas | Oral compositions and use thereof |
JP2003212771A (en) * | 2002-01-23 | 2003-07-30 | Taiyo Kagaku Co Ltd | Anti-neissria bacterium composition |
ES2330097T3 (en) * | 2002-04-30 | 2009-12-04 | Unigen Pharmaceuticals, Inc. | FORMULATION OF A MIXTURE OF FLAVANS AND FLAVONOIDS OF FREE B RING AS A THERAPEUTIC AGENT. |
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2005
- 2005-10-18 TW TW094136336A patent/TW200630102A/en unknown
- 2005-10-19 NZ NZ554517A patent/NZ554517A/en not_active IP Right Cessation
- 2005-10-19 BR BRPI0518218-2A patent/BRPI0518218A/en not_active Application Discontinuation
- 2005-10-19 KR KR1020077011409A patent/KR20070073921A/en not_active Application Discontinuation
- 2005-10-19 RU RU2007118535/14A patent/RU2007118535A/en not_active Application Discontinuation
- 2005-10-19 JP JP2007538073A patent/JP2008517069A/en active Pending
- 2005-10-19 EP EP05810437A patent/EP1804787A4/en not_active Withdrawn
- 2005-10-19 WO PCT/US2005/037936 patent/WO2006045056A2/en active Application Filing
- 2005-10-19 CN CN2005800436448A patent/CN101083981B/en not_active Expired - Fee Related
- 2005-10-19 AU AU2005295190A patent/AU2005295190A1/en not_active Abandoned
- 2005-10-19 MX MX2007004471A patent/MX2007004471A/en not_active Application Discontinuation
- 2005-10-19 CA CA002584124A patent/CA2584124A1/en not_active Abandoned
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RU2007118535A (en) | 2008-11-27 |
BRPI0518218A (en) | 2008-11-04 |
WO2006045056A2 (en) | 2006-04-27 |
CN101083981B (en) | 2013-03-27 |
EP1804787A4 (en) | 2009-01-14 |
WO2006045056A3 (en) | 2007-02-01 |
NZ554517A (en) | 2011-02-25 |
TW200630102A (en) | 2006-09-01 |
AU2005295190A1 (en) | 2006-04-27 |
JP2008517069A (en) | 2008-05-22 |
CA2584124A1 (en) | 2006-04-27 |
MX2007004471A (en) | 2007-06-18 |
CN101083981A (en) | 2007-12-05 |
KR20070073921A (en) | 2007-07-10 |
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