(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2006/0013905 A1
`(43) Pub. Date:
`Jan. 19, 2006
`Tchoharidcs
`
`US 20060013905A1
`
`(54)
`
`ANTI-INFLAMMATORY COMPOSITIONS
`FOR TREATING MULTIPLE SCLEROSIS
`
`(76)
`
`Inventor:
`
`Theoharis C. Tehoharides, Brookline,
`MA (US)
`
`(21)
`(22)
`
`(63)
`
`Correspondence Address:
`DR. MELVIN BLECHER
`4329 VAN NESS ST., NW
`WASHINGTON, DC 20016 (US)
`
`Appl. No.:
`
`11/214,831
`
`Filed:
`
`Aug. 31, 2005
`
`Related US. Application Data
`
`Continuation-in-part of application No. 10/811,826,
`?led on Mar. 30, 2004.
`Continuation-in-part of application No. PCT/US02/
`00476, ?led on Jan. 3, 2002.
`Continuation-in-part of application No. 09/771,669,
`?led on Jan. 30, 2001.
`Continuation-in-part of application No. 09/056,707,
`?led on Apr. 8, 1998, noW Pat. No. 6,689,748.
`
`Publication Classi?cation
`
`(51) Im. c1.
`(2006.01)
`A61K 35/73
`(2006.01)
`A61K 31/7043
`(2006.01)
`A61K 31/737
`(2006.01)
`A61K 31/685
`(2006.01)
`A61K 31/225
`(52) US. Cl. ............................ .. 424/769; 514/27; 514/54;
`514/78; 514/547
`
`ABSTRACT
`(57)
`Compositions With synergistic anti-in?ammatory effects in
`in?ammatory diseases resulting from activation and conse
`quent degranulation of mast cells and folloWed by secretion
`of in?ammatory biochemicals from the activated mast cells,
`the compositions containg one or more of a ?avone or
`?avonoid glycoside a heavily sulfated, non-bovine pro
`teoglycan, an unre?ned olive kernel extract that increases
`absorption of these compositions in various routes of admin
`istration, a heXosamine sulfate such as D-glucosamine sul
`fate, S-adenosylmethionine, a histamine-1 receptor antago
`nist, a histamine-3 receptor agonist, an antagonist of the
`actions of CRH, a long-chain unsaturated fatty acid, a
`phospholipid, Krill oil, a polyamine, glutiramer acetate and
`interferon. Certain of the present compositions are useful in
`protecting against the neuropathological components of
`multiple sclerosis and similar in?ammatory neurological
`diseases.
`
`RIMFROST EXHIBIT 1030 page 0000
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`ANTI-INFLAMMATORY COMPOSITIONS FOR
`TREATING MULTIPLE SCLEROSIS
`[0001] This Continuation-in-Part application takes its pri
`ority from copending Ser. No. 10/811,826, ?led Mar. 13,
`2004, PCT/US02/00476, ?led Jan. 3, 2002, US. Ser. No.
`09/771,669, ?led Jan. 30, 2001, and US. Ser. No. 09/056,
`707, ?led Apr. 8, 1998, now US. Pat. No. 6,689,748.
`BACKGROUND OF THE INVENTION
`[0002] The invention is generally related to the treatment
`of in?ammatory conditions. More speci?cally, the invention
`is related to compositions containing inhibitors of mast cell
`activation and secretion such as a proteoglycan and a
`?avonoid compound that are designed to be used as dietary
`supplements or adjuvants to conventional approved medi
`cations for the relief of in?ammatory conditions, e.g., in the
`brain as in multiple sclerosis.
`
`[0003] There have been a number of mostly anecdotal
`reports that the proteoglycan chondroitin sulfate, as Well as
`glucosamine sulfate, a product of the intestinal breakdown
`of proteoglycans, may be helpful in relieving the pain of
`osteoarthritis:—Shute N. Aching for an arthritis cure. US
`News and World Report, Feb. 10, 1997.—CoWley G. The
`arthritis cure?Newsweek, Feb. 17, 1997; Foreman J ., People,
`and their pets, tout arthritis remedy. The Boston Globe, Apr.
`7, 1997; Tye L. Treatment gains scienti?c attention. The
`Boston Globe, Sep. 25, 2000.
`[0004] A meta-analysis shoWed potential therapeutic ben
`e?t of chondroitin sulfate and/or glucosamine in osteoar
`thritis [McAlindon et al. J Am Med Assn. 283:1469 (2000)],
`While a double-blind clinical trial With glucosamine shoWed
`de?nite bene?ts in osteoarthritis With respect to both pain
`and radiographic joint appearance [Reginster et al., Lancet
`337:252 (2001)]. HoWever, less than 5% of the chondroitin
`sulfate in commercially available preparations is absorbed
`orally, because the siZe of the molecule and the degree of
`sulfation impede its absorption from the gastrointestinal
`tract. Furthermore, such commercial preparations use chon
`droitin sulfate obtained from coW trachea, With the possible
`danger of contracting spongioform encephalopathy or “mad
`coW disease”. In fact, the European Union has banned even
`cosmetics that contain bovine-derived products.
`
`[0005] Theoharides et al. British Journal ofPharmacology
`131:1039 (2000) indicated for the ?rst time hoW proteogly
`cans, such as chondroitin sulfate, may Work. This paper
`reported that chondroitin sulfate and, to a lesser degree,
`glucosamine sulfate, inhibit activation of mast cells that are
`knoWn to trigger allergy and asthma. This discovery is the
`basis for Theoharides, T C, U.S. Pat. No. 6,689,748 and Ser.
`No. 09/773,576, ?led Feb. 2, 2001.
`
`[0006] Mast cells are also noW recogniZed as important
`causative intermediaries in many pain?ul in?ammatory con
`ditions [Galli, N Eng J. Med. 328:257 (1993); Theoharides,
`Int J Tissue Reactions 18:1 (1996)], such as insterstitial
`cystitis and irritable boWel syndrome [Theoharides, T C,
`Ann NYAcad, Sci. 840:619 (1998)], as Well as in migraines
`[Theoharides, T C, Brain Res. Rev. 49:65 (2005) and pos
`sibly multiple sclerosis [Theoharides, T C Persp Biol Med.
`26:672 (1983), Theoharides, Life Sci 46:607 (1996), and J.
`Neuroimmunol. 146:1 (2004
`[0007] Mast cells are increasingly implicated in conditions
`involving in?amed joints, such as in osteoarthritis and
`
`rheumatoid arthritis, through activation of local mast cells
`by, for eXample, neuropeptides, such as Substance P. Addi
`tional indirect evidence also supports the involvement of
`mast cells in bone resorption: (a) systemic mastocytosis is
`invariably associated With osteoporosis; (b) inhibition of
`mast cell mediator release reversed lytic bone changes; (c)
`depletion of mast cells inhibited bone resorption in organ
`culture; (d) human synovial mast cells Were shoWn to secrete
`in response to allergic and non-immunologic stimuli; (e)
`human mast cells release the cytokine IL-6 and
`IL-6 has
`been de?nitively linked to bone resorption and osteoporosis.
`
`[0008] It Was shoWn that chondroitin sulfate’s ability to
`inhibit the activation of mast cells compliments the inhibi
`tory effects on mast cell activation of another class of
`naturally occurring compounds, the ?avonoids [Middleton
`et al. Pharm Rev 52:1 (2000)]. Certain plant ?avones (in
`citrus fruit pulp, seeds, sea Weed) are noW recogniZed as
`anti-allergic, anti-in?ammatory, anti-oxidant and cytopro
`tective With possible anti-cancer properties. Only some
`?avonoids, especially those belonging to the subclass of
`?avonols, e.g., quercetin, inhibit mast cell activation.
`[0009] Quercetin inhibits secretion from human activated
`mast cells [Kimata et al. Allergy 30:501(2000)], and has also
`been used effectively for the treatment of chronic prostatitis
`[Shoskes et al., Urology 54:960 (1999)]. HoWever, other
`?avonoids may have opposite effects. Use of the term
`“bio?avonoids” or “citrus ?avonoids” in certain commercial
`products, therefore, provides little information, and may
`include molecules that have detrimental effects; for
`example, soy contains iso?avones that have estrogen-like
`activity that Worsens in?ammatory conditions.
`
`[0010] US. Pat. No. 6,689,748, and divisional application
`Ser. No. 09/773,576 claim the oral use of proteoglycans,
`Without and With ?avonoids, for the treatment of mast cell
`activation-induced diseases. Absorption of these composi
`tions from the gastrointestinal tract and synergism With other
`treatment modalities Were not addressed in these applica
`tions.
`
`[0011] Applicant has described the use of antagonists of
`the action of Corticotropin Releasing Hormone (“CRH”)
`(also knoWn as Corticotropin Releasing Factor) in inhibiting
`myocardial mast cell activation in myocardial ischemia, in
`treating stress-induced skin disease (US. Pat. No. 6,020,
`305) and stress-induced migraine headaches (US. Pat. No.
`5,855,884), the contents of Which are incorporated herein by
`reference. The synergistic effects of the compositions of the
`present invention that include antagonists of the actions of
`CRH on mast cells Were not recogniZed at the time of the
`previous studies. The Word “antagonists” in connection With
`CRH is intended herein to include any molecule that pre
`vents the actions of CRH on target cells, and includes, but
`is not limited to, anti-CRH neutraliZing antibodies or bind
`ing proteins, or molecules preventing the release of CRH at
`local sites (see beloW for details).
`[0012] Applicant has also described a method for treating
`patients With mast cell derived molecules-induced intersti
`tial cystitis With certain histamine-I receptor antagonists
`(Theoharides, U.S. Pat. No. 5,994,357). Treatment of mast
`cell molecules-induced migraines With histamine-3 receptor
`agonists is the subject of Theoharides US. Pat. No. 5,855,
`884. Histamine-3 receptor agonists as pharmaceutical agents
`in mast cell-involved diseases are described in Theoharides
`
`RIMFROST EXHIBIT 1030 page 0001
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`US. Pat. No. 5,831,259. The contents of these three patents
`are incorporated herein by reference. At the time of this
`invention the synergistic effects of the present compositions
`With such antagonists had not yet been recognized.
`[0013] An important need therefore eXists for composi
`tions for administration to human patients being treated for
`mast cell-induced in?ammatory diseases by various modali
`ties, that are synergistic in that they have stronger effects
`than the sum of the effects of the individual components, and
`also synergistic With conventional clinical treatments of
`in?ammatory conditions. “Synergistic” is also intended to
`mean: “coordinated or correlated action by tWo or more
`structures or drugs”[Stedman’s Medical Dictionary, 23rd
`edition, Williams & Wilkins, Baltimore, 1976]. An impor
`tant need also exists for formulations that increase the
`absorption from the gastrointestinal tract, nasal passages and
`skin surface of the compositions of the invention. Such
`formulations have been discovered, and are described beloW.
`
`SUMMARY OF THE INVENTION
`
`[0014] The invention comprises compositions for human
`use containing one or more of a ?avonoid compound, a
`non-bovine heavily sulfated proteoglycan, an unre?ned
`olive kernel eXtract, a sulfated heXosamine, S-adenosylme
`thionine (“SAM”), histamine-1 receptor antagonists, hista
`mine-3 receptor agonists, antagonists of the actions of CRH,
`folic acid, a straight chain polyunsaturated fatty acid, a
`phospholipid, a polyamine, an interferon and glutiramer
`acetate, together With appropriate eXcipients and carriers,
`said compositions having improved absorption from the
`gastrointestinal tract, skin surface, and nasal and pulmonary
`surfaces, and anti-in?ammatory effects synergistic With each
`other and synergistic With available conventional clinical
`treatment modalities.
`
`[0015] In one embodiment, the sulfated glucosamine is
`D-glucosamine sulfate, the proteoglycan is non-bovine
`chondroitin sulfate, and the ?avonoid is quercetin (3,3‘,4‘,
`5,7-pentahydroXy ?avone), the quercetin glycoside rutin,
`myricetin, genistein, kaempferol, luteolin, apigenin, (—)
`epigallocatechin-3 gallate, kaempferol or the kaempferol
`glycoside astragaline, or hesperitin or its glycoside hespe
`ridin.
`
`[0016] In another embodiment, compositions may also
`contain antagonists of the effects of CRH on mast cells or
`other target cells of the myocardium, gastric mucosa, urinary
`bladder, skin, meningeal membranes, blood-brain barrier,
`and brain structures.
`
`[0017] In still another embodiment, the inventive compo
`sitions are used against super?cial vasodilator ?ush syn
`dromes.
`
`[0018] In still another embodiment, the inventive compo
`sitions may be used as coatings on medical devices, not only
`to protect surrounding tissues from in?ammation due to the
`devices, but also to treat innate in?ammation in surrounding
`tissues.
`
`[0019] In another embodiment, the inventive composi
`tions are used against the in?ammatory processes of
`endometriosis.
`
`[0020] In yet another embodiment, the inventive compo
`sitions are used against the in?ammatory components of
`
`hormonally-related cancers, such as breast, ovarian, uterine,
`prostate and testicular cancers, and When supplemented With
`chemotherapeutic agents are used against the cancer itself.
`
`[0021] In still another embodiment, the inventive compo
`sitions may be used in the treatment of the neuroin?amma
`tory aspects of multiple sclerosis.
`
`[0022] In another embodiment, the inventive olive kernel
`eXtract is used to improve the absorption of biochemicals
`across membrane barriers in the body, such as those of the
`intestine, skin, oral mucosa, blood-brain barrier, and pulmo
`nary alveoli.
`
`[0023] In yet another embodiment, the inventive compo
`sitions may be used in the treatment of ?bromyalgia or
`chronic fatigue syndrome.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS OF THE
`INVENTION
`
`[0024] It has been discovered that various combinations of
`a sulfated proteoglycan, unre?ned olive kernel eXtract, a
`?avone (a.k.a. ?avonoid compound), a sulfated D-heXose
`amine, a phospholipid, a long chain unsaturated fatty acid,
`a CRH antagonist, a histamine-1 receptor antagonist, a
`histamine-3 receptor agonist, glutiramer acetate, an inter
`feron, and a polyamine have synergistic anti-in?ammatory
`effects When used as a dietary supplement, a topical product
`or an aerosol for nasal or pulmonary administration, Without
`or With a conventional clinical treatment for in?ammatory
`diseases. Within the present conteXt, such in?ammatory
`diseases result from the activation, degranulation and con
`sequent secretion of in?ammatory biochemicals from mast
`cells, and the resultant in?ammatory diseases include the
`group consisting of: allergic in?ammation, arthritis (to
`include osteoarthritis and rheumatoid arthritis), ?bromyal
`gia, chronic fatigue syndrome, in?ammatory boWel disease,
`interstitial cystitis, irritable boWel syndrome, migraines,
`atherosclerosis, coronary in?ammation, ischemia, chronic
`prostatitis, ecZema, multiple sclerosis, psoriasis, sun burn,
`periodontal disease of the gums, super?cial vasodilator ?ush
`syndromes,
`hormonally-dependent
`cancers,
`and
`endometriosis. The olive kernel eXtract alone may be used to
`improve the transmembrane transport of dif?cultly-absorb
`able biomolecules in the intestine, skin and pulmonary
`alveoli.
`
`[0025] In a highly preferred embodiment, the sulfated
`proteoglycan is non-bovine chondroitin sulfate, preferably
`from shark cartilage, Which blocks mast cell activation,
`degranulation and consequent secretion of in?ammatory
`biochemicals from the mast cells. Other natural sulfated
`proteoglycans suitable for practicing this invention include
`keratan sulfate, dermatan sulfate and hyaluronic acid sodium
`salt (sodium hyaluronate). The preferred biological source
`of the chondroitin sulfate is shark cartilage Which is more
`highly sulfated than the common commercial chondroitin
`sulfate isolated from coW trachea; the shark cartilage source
`also avoids the potential dangers associated With bovine
`sources.
`
`[0026] A highly preferred ?avonoid is quercetin Which
`inhibits secretion of in?ammatory molecules from mast cells
`by affecting moesin, a unique 78 kDa mast cell protein
`[Theoharides, T C et al. J Pharm Exp Therap 294:810
`
`RIMFROST EXHIBIT 1030 page 0002
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`(2000), Kempuraj et al. Br. J. Pharmacol. 145:934 (2005)].
`In addition to quercetin, other ?avonoids suitable in carrying
`out the invention include: the quercetin glycoside rutin,
`myricetin, genistein, luteolin, apigenin, (—)-epigallocat
`echin-3 gallate, kaempferol and the kaempferol glycoside
`astragaline, hesperitin and its glycoside hesperidin.
`[0027] The olive kernel extract product component of the
`inventive compositions is preferably an unre?ned (?rst
`pressing, ?ltered, oleic acid-related acidity <3%, Water con
`tent <1%) extract product produced, for one source, on the
`island of Crete in Greece. This kernel extract product is
`especially prepared by applicant’s process consisting essen
`tially of: (1) harvesting ?rst collection ripe olives, preferably
`in December; (2) compressing the oil from the ?esh of the
`ripe olives; (3) Washing the kernels remaining after step (2)
`With Water to remove debris; (4) drying the Washed kernels
`With a stream of hot air; (5) crushing the dried kernels to
`produce an extract; (6) extracting the extract from step (5)
`With an organic solvent (e.g., hexane, heptane, octane) plus
`steam; (7) removing particulate matter from the organic
`extract by centrifugation or micro?ltering through 1-2
`micron pore siZe ?lters; (8) evaporating the organic solvent
`and Water from the clari?ed extract of step (7) by maintain
`ing the extract at 86-100 degrees C. While percolating
`helium (to avoid oxidation) through the ?uid, Which process
`reduces the Water content to <1%, the acidity (as oleic acid)
`to <3%; and, the organic solvent to <1%; and (8) storing the
`?nal kernel extract product in the absence of air.
`[0028] The inventive olive kernel extract surprisingly has
`the unique property of increasing absorption of the other
`components of the anti-in?ammatory compositions through
`the intestinal mucosa or skin, and also adds its oWn content
`of important anti-oxidants, such as omega fatty acids (e.g.,
`eicosapentanoic acid) and alpha tocopherol. The polyphe
`nols found in such olive kernel extracts also have anti
`in?ammatory effects in, for example, arthritis [MartineZ
`DomingueZ et al., In?amm. Res. 50:102 (2001)]. E.B.E.K.,
`Inc., Commercial, Industrial Enterprises of Crete, 118 Eth
`nikis Antistasecos, Heraklion, Crete, 71306, Greece, or
`MINERVA S.A. Edible Oil Enterprises, 31 Valaoriton St.,
`Metamorphosis, AttiZes, Greece Will prepare the extract
`product according to applicant’s above-described procedure
`for commercial users.
`[0029] In addition to its usefulness in increasing the
`absorption of the inventive macromolecular compositions
`across the intestinal Wall and the skin, the inventive olive
`kernel extract product is useful in aiding the dissolution of
`other drugs prior to administration to a patient, and is useful
`in promoting the absorption of other dif?cultly-absorbable
`drugs, e.g., the HDL-increasing drug torcetrapib across
`intestinal mucosa, oral mucosa, nasal mucosa, and skin of
`patients.
`[0030] Supplementation of the compositions described
`above With the methylation reagent S-adenosylmethionine
`(“SAM”) adds antioxidant, anti-in?ammatory and cytopro
`tective properties, particularly in in?ammatory joint and
`cardiovascular diseases. Addition of SAM also accelerates
`metabolism of homocysteine, Which amino acid has been
`implicated in coronary disease, to cysteine, Which is harm
`less. Folic acid may be added to certain of the present
`formulations for similar reasons.
`[0031] Another supplement to the basic compositions of
`the invention is a histamine-I receptor antagonist, such as
`
`hydroxyZine, merelastine, aZelastine, aZatadine, rupatadine,
`and cyproheptadine. Other histamine-1 receptor antagonists
`are described in Table 25-1 in Goodman and Gilman’s The
`Pharmaceutical Basis of Therapeutics, 9th ed., NeW York,
`1996. Histamine-3 receptor agonists are described in the
`Theoharides patents listed above.
`
`[0032] Inhibitors of mast cell activation and secretion of
`in?ammatory biochemicals may be used in the treatment of
`in?ammatory processes such as super?cial vasodilator syn
`drome, such as occurs in menopausal-associated ?ush, car
`cinoid ?ush, MSG-associated ?ush, and niacin-associated
`?ush.
`[0033] Hormone-dependent cancers, including the estro
`gen/progestin linked ovarian, uterine, breast, and endome
`trial cancers, and the androgen-linked prostate and testicular
`cancers, are associated With tissue in?ammation. These
`conditions can be treated With chondroitin sulfate, quercetin,
`genistein, rutin, phenoxodiol iso?avone, (—)-epigallocat
`echin-3-gallate, olive kernel extract, and, optionally, che
`motherapeutic agents such as tomoxifen or raloxifen.
`
`[0034] Pelvic in?ammatory conditions, such as present in
`endometriosis, can also be treated With the inventive com
`positions. Particularly useful in this regard are compositions
`delivering 50-300 mg/day of rutin, quercetin, kaempferol,
`myricetin, or hesperitin.
`
`[0035] The inventive compositions may also be used as
`coatings on implanted medical devices, Which devices may
`lead to or be associated With in?ammation of surrounding
`tissues, in order to provide protection against such in?am
`mations. Not only can the coating of such medical devices
`inhibit or protect against in?ammation caused by the device
`itself, but the coated devices can also be used to deliver the
`inventive compositions to innately in?amed tissues due to
`other causes. Such medical devices include arti?cial skins
`(scaffolding such as naturally occurring polymers, e.g.,
`collagen; man-made polymers, e.g., PTFE, Dacron, PET or
`polyethylene; self-degrading man-made polymers, e.g., PLA
`or PGA; biopolymer matrices from animal tissues including
`fetal and neonatal tissues to be used as tissue engineering
`scaffolds (cf. Bell et al., US. patent application Pub. No.
`20020146393)), arti?cial joints, band-aids, stents for blood
`vessels, arti?cial blood vessels, pacemakers, stents for
`abdominal support in hernia repair, tissue transplants, pros
`theses, breast implants, etc. Particularly useful in this regard
`are compositions containing heavily sulfated, non-bovine
`proteoglycans (e.g., chondroitin sulfate) and a ?avonoid.
`
`[0036] Oral ?avonoids, such as those listed above, are
`reported to in?uence the course of experimental autoim
`mune encephalomyelitis in mice, a model for multiple
`sclerosis (Verbeck, R. et al., Biochem. Pharm. 70(2):220
`(Jul. 15, 2005); Hendriks, J J et alJExp Med. 200(12):1667
`(Dec. 20, 2004). In preferred embodiments of the inventive
`compositions, ?avonoids or ?avonoid glycosides plus one or
`more of a proteoglycan, olive kernel extract, Krill oil,
`hydroxyZine, (—)epigallocatechin-3-gallate, and a long chain
`fatty acid plus injections of interferon and/or glutiramer
`acetate (Copolymer I) (Copaxone, TEVA Pharmaceuticals,
`Israel; Avonex, Biogen., USA) are used in treatment of the
`chronic in?ammation of the central nervous system in
`multiple sclerosis. The glutiramer acetate is of particular
`value in preventing relapsing/remitting forms of multiple
`sclerosis [MeZZapesa, D M et al., Exper. Rev. Neurother.
`
`RIMFROST EXHIBIT 1030 page 0003
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`J. Neurol. Sci.
`5:451 (2005); Schwartz, M. et al.
`233:163(2005); Amon, R., et al., Proc. Nat. Acad. Sci. USA
`102 Suppl. 2114593 (2004)].
`[0037] Sources of CRH antagonists include, in addition to
`the Theoharides patents listed in the Background section
`above: Neurocrine Biochem. Inc.’s D-Phe 12 NIe Ala32,21,
`38hCRH(12-41)NH2, cat no. 1P-36-41; P?zer non-peptide
`CP-154,526-1; Sigma Chem., St. Louis anti-CRH poly
`clonal antiserum; and P?zer, NY patents and applications:
`US. Pat. No. 6,211,195, US. Pat. No. 5,795,905, PCT/
`IB95/00573, PCT/IB95/00439, U.S. Ser. No. 08/448,539,
`US. Ser. No. 08/481,413, US. Ser. No. 09/735,841, and in
`Owens et al. Pharm. Rev. 43:425 (1991).
`[0038] The preferred concentration range of the proteogly
`can, hexosamine sulfate, ?avonoid, polyunsaturated fatty
`acid, phospholipid components of the oral formulations are
`10-3,000 mg per tablet or capsule. The preferred concentra
`tion range for SAM is 3-1,000 mg per capsule or tablet.
`Generally, where present, the amounts of the unre?ned olive
`kernel extract are at least twice those of the other active
`ingredients, preferably 300-1200 mg. The number of cap
`sules or tablets to be taken per day is determined by the
`nature and severity of the medical condition, and is readily
`determinable by the patient’s health provider. Other repre
`sentative formulations are described in the examples below.
`
`[0039] The compositions of the invention may be formu
`lated in any standard means of introducing pharmaceuticals
`into a patient, e.g., by means of tablets or capsules. The
`compositions of the invention include ointments and creams
`for skin conditions, mouth washes and toothpaste for peri
`odontal diseases, and solutions for nasal aerosols. Standard
`excipients and carriers for the active ingredients of the
`inventive compositions are described in Remington’s Phar
`maceutical Sciences, Mack Publishing Co., Easton, Pa.
`[0040] Although not bound by any particular mechanism
`of action of the components of the claimed compositions, the
`inventor contemplates that they inhibit the activation and
`degranulation of the relevant mast cells, and inhibit the
`secretion of in?ammatory biomolecules from these mast
`cells. “Activation” and “degranulation” of mast cells are
`de?ned herein as is standard and well known in this art, that
`is, to mean synthesis and secretion from the activated mast
`cell of any type of molecule(s) that alone or in combination
`triggers in?ammation.
`
`[0041]
`
`EXAMPLES
`
`Example 1
`
`TABLE 1
`
`TABLE 1-continued
`
`Table 1 compares chondroitin sulfate-containing commercial products to
`the present compositions.
`Comparison of Chondroitin Sulfate-Containing Products to Present
`Invention
`
`Product
`
`Most Available
`Compositions
`
`Cow trachea
`Source
`Amount per capsule 100-300
`or tablet
`Degree of sulfation Low, if any
`Absorption from g.i. <5%
`tract
`Target
`
`Unknown
`
`Other ingredients
`
`Vitamins, ?sh oils
`(some preparations)
`
`Present Invention
`
`Shark cartilage
`10-3000 mg
`
`High
`>15%
`
`Mast cells, in?ammatory
`cells
`Flavones, unre?ned olive
`kernel extract, SAM,
`histamine-1 receptor
`antagonists, histamine-3
`receptor agonists, CRH
`antagonists, polyamines,
`caffeine, folic acid
`Anti-allergic, anti
`in?ammatory, anti
`oxidant, cytoprotective
`Risk of mad cow disease, None known
`spongiform
`encephalopathy,
`stomach upset, allergy to
`?sh products
`Relevant conditions Osteoarthritis
`
`Advantages
`
`None known
`
`Adverse effects
`
`Allergic in?ammation
`angina, asthma coronary
`artery disease, arthritis
`(osteoarthritis or
`rheumatoid arthritis),
`chronic prostatitis,
`eczema, ?bromyalgia,
`interstitial cystitis,
`irritable bowel syndrome,
`in?ammatory bowel
`disease, migraines,
`multiple sclerosis,
`psoriasis, periodontal
`disease, ?ush syndrome,
`cancer (including
`hormonally-dependent
`forms).
`Theoharides et al. Br J
`Pharm 131: 1039 (2000)
`Middleton et al. Pharm
`Rev 52; 673 (2000)
`
`Scienti?c
`publications
`
`None found
`
`[0042] In all examples, chondroitin sulfate is to assumed
`to be of a non-bovine variety.
`
`Example 2
`
`[0043]
`
`Table 1 compares chondroitin sulfate-containing commercial products to
`the present compositions.
`Comparison of Chondroitin Sulfate-Containing Products to Present
`Invention
`
`Product
`
`Most Available
`Compositions
`
`Main ingredient
`
`Mixture of chondroitins
`
`Present Invention
`
`Non-bovine chondroitin
`sulfate, preferably the C
`type
`
`Composition For Protecting Against In?ammatory Diseases
`Two capsules to be taken orally 2-3 times daily, at least one
`hour before meals
`
`Ingredients, per capsule,
`
`*Chondroitin sulfate
`*D-Glucosamine sulfate
`*Quercetin
`*Olive kernel extract
`
`mg:
`
`150-300
`150-300
`150-300
`350-1200
`
`RIMFROST EXHIBIT 1030 page 0004
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`Example 3
`
`Example 7
`
`[0044]
`
`[0048]
`
`Composition For Protecting Against Arthritis
`
`Composition For Protecting Against Periodontal In?ammatory Disease
`Toothpaste Composition
`
`Ingredients per capsule,
`
`*D-Glucosamine sulfate
`*Chondroitin sulfate
`*Sodium hyaluronate
`*Quercetin
`*Olive kernel extract
`
`mg:
`
`150-300
`150-300
`100-200
`150-300
`350-1200
`
`Example 4
`
`[0045]
`
`Toothpaste,
`
`*Chondroitin sulfate
`*Quercetin
`*D-glucosamine sulfate
`*Olive kernel extract
`
`mg %:
`
`5
`3
`5
`1
`
`*In a standard toothpaste vehicle
`
`Example 8
`
`[0049]
`
`Topical Composition For Protecting Against Arthritis
`Skin ointment or cream. Apply three times per day to affected areas.
`
`Ingredients
`
`% by Weight
`
`Composition For Protecting Against the In?ammation of Sunburn
`
`Ingredients
`
`% by Weight
`
`*D-glucosamine sulfate
`*Condroitin sulfate
`*Sodium hyaluronate
`*Bitter WilloW bark
`extract
`*Quercetin
`*Aloe Vera
`*Olive kernel extract
`
`5
`5
`0.5
`5
`
`3
`10
`5
`
`*Chondroitin sulfate
`*D-glucosamine sulfate
`*Quercetin
`*Aloe Vera
`*Olive kernel extract
`*Sun screen (e.g., TiO2)
`
`5
`5
`3
`10
`5
`5
`
`Example 9
`
`Example 5
`
`[0050]
`
`[0046]
`
`Composition For Protecting Against Cardiovascular In?ammatorv Disease
`
`mg/capsule:
`
`50
`100
`50
`0.01
`350-1200
`5% by Weight
`100-600
`
`*Chondroitin sulfate
`*Kaempferol
`*S-adenosylmethionine
`*Niacin
`*Olive kernel extract
`*Bitter WilloW bark extract
`*Polyunsaturated fatty acids(DHA,
`DPA)
`
`Example 6
`
`[0047]
`
`Composition For Protecting Against Periodontal In?ammatorv Disease
`
`MouthWash:
`
`*Chondroitin sulfate
`*Quercetin
`
`0.4 M
`0.4 M
`
`*In a standard mouthWash vehicle
`
`Oral Composition For Protecting Against Migraine Headaches
`
`Ingredients,
`
`*Chondroitin sulfate
`*Quercetin
`*Azatadine
`*Optionally, a CRH
`receptor antagonist
`
`mg:
`
`50
`100
`4
`5—300
`
`Example 10A
`
`[0051]
`
`Oral Composition For Protecting Against In?ammation
`in Relapsing Multiple Sclerosis
`
`Ingredients,
`
`*Quercetin
`*Chondroitin sulfate
`*Rutin
`*Hydroxyzine
`*Olive kernel extract
`*Optionally, interferon-beta
`
`*Optionally, glatiramer acetate
`
`mg/day
`
`50-300
`50-300
`50-300
`50-300
`350-1200
`8 million IU Betaferon (Schering), s.c.,
`on alternate days or 30 ,ug Avonex
`Copaxone NPR by parenteral injection
`
`RIMFROST EXHIBIT 1030 page 0005
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`Example 10B
`
`Example 13
`
`[0052]
`
`[0056]
`
`General Composition for Protecting Against the
`Brain In?ammation of Multiple Sclerosis
`
`Components
`
`Mg/tablet or capsule
`
`Quercetin
`Rutin
`(—)Epigallocatechin-gallate
`Docosohexanoic acid (DHA)
`Krill oil
`Olive kernel extract
`
`100-1000
`100-1000
`100-1000
`100-1000
`100-1000
`100-1000
`
`Cream Composition For Protecting Against In?ammatory Skin Allergy
`
`Ingredients:
`
`% by Weight
`
`*Aloe Vera
`*Non-bovine chondroitin sulfate
`*Myricetin
`*Alpha-tocopherol
`*Olive kernel extract
`*Aloe Vera
`*Optionally, aZelastine or hydroxyzine
`
`5
`5
`5
`5
`5
`10
`5
`
`Example 10C
`
`Example 14
`
`[0053]
`
`[0057]
`
`Speci?c Composition for Protecting Against Multiple Sclerosis
`
`Components
`
`Amounts
`
`Quercetin, rutin,
`(—)epigallocatechin3—gallate,
`Docosohexanoic acid
`Krill oil
`Olive kernel extract
`
`Each 150 mg/tab or cap.
`
`50 mg
`450 mg
`
`Composition For Protecting Against In?ammatory
`Allergies and Allergic Asthma
`
`Ingredients,
`
`mg/tablet
`
`*Myricetin
`*Chondroitin sulfate
`*Optionally, aZelastine
`*Rutin
`*Optionally, hydroxyzine
`
`500
`200
`4
`500
`25
`
`Example 11
`
`[0054]
`
`Example 15
`
`[0058]
`
`Composition For Protecting Against the
`In?ammation of Cystitis And Prostatitis
`
`Ingredients,
`
`mg/capsule or tablet:
`
`*D-glucosamine sulfate
`*Chondroitin sulfate
`*Sodium hyaluronate
`*Quercetin
`*Olive kernel extract
`
`50
`100-300
`200
`100-400
`350-1200
`
`Example 12
`
`[0055]
`
`Composition For Protecting Against Brain Metasteses
`from Breast Cancers
`
`Ingredients,
`
`Chondroitin sulfate
`Quercetin
`Genestein
`Phenoxodiol iso?avone
`Olive kernel extract
`Optionally, tomoxifen or raloxifen
`
`mg/day
`
`50-300
`25-250
`50-300
`500-1000
`350-1200
`About 10
`
`Example 16
`
`[0059]
`
`Composition For Protecting Against In?ammatory “Flush”
`
`Ingredients,
`
`*Chondroitin sulfate
`*Qllefcetin
`*Olive kernel extract
`*Bitter WilloW bark extract
`*Optionally, cyproheptadine or
`azatadine
`
`per capsule:
`
`50 mg
`150-350 mg
`100-750 mg
`5% by Weight
`4 mg
`
`Composition For Protecting Against the
`In?ammation of Allergic Conjunctivitis
`
`Ingredients:
`
`*Quercetin
`*Chondroitin sulfate
`*Optionally, aZelastine
`
`Weight %
`
`0.05%
`2.0%
`0.05%
`
`RIMFROST EXHIBIT 1030 page 0006
`
`

`

`US 2006/0013905 A1
`
`Jan. 19, 2006
`
`Example 17
`
`Effect of Olive Kernel Extract on Absorption of a
`Proteoglycan Sulfate In Vivo
`
`[0060] Chondroitin sulfate Was tritiated by NeW England
`Nuclear Corp. to a speci?c activity of 4.3 mCi/ml.
`
`[0061] Unlabeled chondroitin sulfate Was dissolved in
`olive kernel extract at a ratio of about 55 W/v chondroitin
`sulfate poWder to about 450 W/v of olive kernel extract