US20230048403A1 - Prophylactic and therapeutic treatment of alzheimer's disease using phytic acid and phytate to reduce amyloid beta plaque and tau protein - Google Patents

Prophylactic and therapeutic treatment of alzheimer's disease using phytic acid and phytate to reduce amyloid beta plaque and tau protein Download PDF

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US20230048403A1
US20230048403A1 US17/974,055 US202217974055A US2023048403A1 US 20230048403 A1 US20230048403 A1 US 20230048403A1 US 202217974055 A US202217974055 A US 202217974055A US 2023048403 A1 US2023048403 A1 US 2023048403A1
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phytic acid
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • This invention relates to the prophylactic and therapeutic treatment of Alzheimer's Disease, herein-below identified as “AD”.
  • Phytic acid generally accepted as having the structure myo-inositol-hexakis (dihydrogen phosphate), is a major component of plant seeds, constituting 1-3% by weight of many cereals and oil seeds. Most wheat brans contain between 4 and 5% phytic acid. Phytic acid may be prepared in pure form from various plant sources, such as wheat, corn, soybeans, sesame seeds, peanuts, lima beans, barley, oats, wild rice and sunflower seeds. It can be extracted with dilute hydrochloric acid at room temperature, precipitated with various reagents including ferric chloride, bicarbonates, potassium hydroxide, sodium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide or alcohol. It is then further purified by conventional chemical techniques.
  • the compound When one or more of the acidic protons of the phosphate groups in phytic acid are replaced by a counterion, the compound is usually referred to as a phytate salt.
  • the special name phytin is used for the calcium-magnesium salt of phytate derived from plant seeds (a product of Ciba-Geigy).
  • the present invention includes the use not only of phytic acid and phytate salts, but also various isomeric forms of phytic acid and phytate salts. While the Anderson structure for myo-inositol hexakis dihydrogen phosphate is the accepted structure for phytic acid, the present invention covers other isomers which have been previously described in the literature. These isomers include the cis, epi, allo, muco, neo, D-chiro, L-chiro, and scyllo configurations.
  • the present invention includes the use of hydrolysates of phytic acid and phytate salts wherein one or more of the phosphate groups have been removed.
  • phytic acid The main uses of phytic acid include use as a food additive for preservation of foods. Studies on the use of phytic acid as a food additive show that ingestion of large doses of phytic acid elicits no physiological discomfort or symptoms of any toxicological action in humans. See Starkenstein, Biochem. Z. 30: 56 (1911). Phytic acid and its metabolites are thus not believed to be toxic or highly reactive.
  • Phytic Acid is the 6 phosphates ester of inositol.
  • Inositol chemically hexahydroxycylohexane, is any of nine stereoisomeric alcohols that closely resemble glucose in structure. It is a constituent of many cell phosphoglycerides.
  • Meso- or myo-inositol named for its presence in muscle tissue, is biologically the important isomer.
  • Myo-inositol is the precursor in the phosphatidylinositol cycle, a source of two second messengers (diacylglycerol and inositol triphosphate).
  • Inositols and their phosphates lack a hydrolytically labile glycosidic linkage and are stable to degradative enzymes in vivo. They have been used in the stable insulin mediators, inhibitors, and modulators.
  • the phytic acid may be in a salt form, such as, for example, calcium magnesium phytate salt.
  • Scyllo inositol has been shown to prevent and reverse Alzheimer's Disease in a transgenic mouse model of Alzheimer's Disease (See Nature Medicine article) (See “A Sweet Solution to Alzheimer's Disease”) (See “ALD103 May Prevent and Reverse Alzheimer's Disease”) (See “Scyllo-Inositol Appears Promising for Alzheimer's Disease”).
  • Scyllo inositol also inhibits and blocks the aggregation of amyloid-B peptide (AB) in these same transgenic Alzheimer Disease mouse studies.
  • the '082 patent discloses scyllo inositol as an isomeric form of phytic acid. Since the '082 and '430 patents disclose a minimum oral dose of about a half a gram per kilogram/body weight per day, a 75 kilogram AD patient, would take 37.5 grams of scyllo inositol orally per day. This dose is burdensome. Additionally, phytate in food has been successfully consumed at this dose and higher.
  • Scyllo inositol is also disclosed in U.S. patent application Ser. No. 10/787,621 of McLaurin. This application discloses a litany of compounds for the treatment of disorders of protein aggregation, the most preferred compound of which is scyllo inositol.
  • Phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof is administered as a treatment for prevention and treatment of Alzheimer's disease and for treatment of amyloidosis, aggregation of beta amyloid proteins and tau protein in the brain.
  • An effective yet surprisingly low dose of the compounds phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, except for scyllo inositol, are used for. as a prophylactic and therapeutic treatment for Alzheimer's Disease.
  • a dose of about 0.5 gram to about 18.75 gms of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or mixture of any combination thereof, except for scyllo inositol are administered orally per day.
  • This dose is 1/75th to one half (1 ⁇ 2) of the previously disclosed doses in the Sabin patents cited above Phytate salt may also be administered as a capsule, and the calcium magnesium phytate salt, as packaged by many suppliers such as Jarrow Formulations; is desirable.
  • phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof is much more effective than scyllo inositol and myo inositol.
  • compositions for the treatment of Alzheimer's disease and related amyloid plaque development by providing a person in need thereof with an effective amount of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof.
  • a method for the treatment of Alzheimer's disease and the amyloid plaque protein aggregation by the oral administration of 0.5 to 18.75 grams of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof per day.
  • the compounds of the invention may be administered topically as a cream, ointment, gel and the like, transdermally or intradermally.
  • FIG. 1 is a chart of cell viability.
  • FIG. 3 is a chart of cell viability of scyllo inositol and myo inositol.
  • FIG. 4 is a chart of soluble amyloid beta 1-42/ ⁇ g protein, phytic acid and a vehicle carrier.
  • FIG. 5 is a chart of soluble amyloid beta—40/ ⁇ g protein, phytic acid and a vehicle carrier.
  • FIG. 6 is a chart of insoluble amyloid beta 1-42/ ⁇ g protein, phytic acid and vehicle carrier.
  • the method according to the present invention comprises treating a subject, afflicted with Alzheimer's Disease, with a composition in which the active ingredient is phytic acid, a phytate salt, or an isomer or hydrolysate of phytic acid or phytate salt.
  • isomer as used herein, it is intended to include the various conformations of phytic acid, as described hereinabove, and the corresponding conformations of phytate salts.
  • salts is broadly intended to cover any of the various salts formed by the replacement of any or all of the available acidic protons of the phosphate groups with a counterion.
  • the counterion may be any pharmaceutically acceptable counterion such as sodium, magnesium, potassium, zinc, ferric, ferrous, and the like, including organic counterions such as quaternary ammonium ions and ions of organic bases.
  • the present invention also includes the hydrolysates of phytic acid and phytate salts wherein one or more of the phosphate groups have been removed.
  • the phytic acid or phytate salt may be hydrolyzed by digestive, blood or cellular enzymes, thereby removing one or more of the phosphate groups on the cyclohexane ring.
  • these hydrolysates of phytic acid and phytate salts may also be administered directly to the subject and therefore are within the scope of the present invention.
  • the hydrolysates of phytic acid and phytate salts may be prepared by partial acid or basic hydrolysis or by hydrolysis using enzymes prior to preparation of dosage fauns for administration.
  • the hydrolysates will be made in vivo by coadministering with phytic acid or phytate salt an enzyme which hydrolyzes phosphate groups, such as 3-phytase, 6-phytase or acid phosphatase.
  • the phytic acid or phytate salt may be absorbed into or adsorbed onto a solid carrier to facilitate pharmaceutical administration.
  • phytic acid may be formulated into a starch powder by spray drying or vacuum drying an aqueous mixture of phytic acid and dextrin.
  • compositions for administration are the mono-, di-potassium phytate salts and mixtures thereof which may be prepared from commercially and readily available sodium phytate by initially removing the sodium using ion exchange chromatography on a suitable resin, such as Dowex beads. The free phytic acid may then be treated with potassium hydroxide to convert to the mono- and di-potassium phytate salt.
  • compositions according to the present invention are through oral administration in liquid or tablet form.
  • compositions may be administered as pharmaceutically acceptable salts such as salts with alkali metal cations (sodium, potassium, lithium), ammonium salts and salts with organic bases such as piperidine, triethanolamine, diethylaminoethylamine salts, and the like.
  • the composition may also contain an effective proportion, usually from 0.001 to 0.1% weight by volume, of a pharmaceutically acceptable preservative or sterilizing agent such as cetyl pyridinium chloride, tetradecyltrimethyl ammonium bromide (commercially known as Centramide), benzyl dimethyl [2-(2-)p-(1,1,3,3-tetramethyl butyl)) phenoxy) ethoxy] ammonium chloride (known commercially as Benzethonium Chloride) and myristyl-gamma-picolinium chloride.
  • a pharmaceutically acceptable preservative or sterilizing agent such as cetyl pyridinium chloride, tetradecyltrimethyl ammonium bromide (commercially known as Centramide), benzyl dimethyl [2-(2-)p-(1,1,3,3-tetramethyl butyl)) phenoxy) ethoxy] ammonium chloride (known commercially as Benzethonium Chloride) and myr
  • the pharmaceutical composition may also contain conventional excipients, e.g., sodium chloride, dextrose, mannitol, and buffers such as sodium dihydrogen ortho phosphate, disodium hydrogen phosphate, sodium citrate/citric acid, and boric acid/sodium borate.
  • excipients e.g., sodium chloride, dextrose, mannitol, and buffers such as sodium dihydrogen ortho phosphate, disodium hydrogen phosphate, sodium citrate/citric acid, and boric acid/sodium borate.
  • the proportion and concentration of excipients and buffers may be varied within fairly wide ranges, providing the resulting solution is stable and nonirritating when administered.
  • the preferred method of administration is by oral administration as a solid compound.
  • the composition may be prepared in the conventional manner as tablets, pills or powders, using conventional carriers.
  • the phytic acid may be combined with other inactive substances as are known in the pharmaceutical arts such as, for example, lactates, silicates, and magnesium stearate, as well as with other active substances, such as pharmaceutical drugs and vitamins, etc.
  • the active ingredient of the composition will also contain an enzyme such as 3-phytase (EC 3.1.38), 6-phytase (EC 3.1.3.26) or acid phosphatase which, when exposed to the digestive tract, will assist in hydrolyzing one or more of the phosphate groups from the active ingredient.
  • an enzyme such as 3-phytase (EC 3.1.38), 6-phytase (EC 3.1.3.26) or acid phosphatase which, when exposed to the digestive tract, will assist in hydrolyzing one or more of the phosphate groups from the active ingredient.
  • 3-phytase EC 3.1.38
  • 6-phytase EC 3.1.3.26
  • acid phosphatase which, when exposed to the digestive tract, will assist in hydrolyzing one or more of the phosphate groups from the active ingredient.
  • the active ingredient be administered with one or more of the aforementioned enzymes, with the preferred enzyme being 3-phytase (EC 3.1.38).
  • the phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof can be administered in any manner as known in the art.
  • the phytic acid is administered orally in encapsulated form.
  • the oral administration can be in the form of a capsule, quick dissolve tablet, table, or other form as known in the art.
  • the dosage of phytic acid is an amount that is effective for the disease state of the Alzheimer's patient and an amount effective as a prophylactic treatment for prevention of Alzheimer's disease.
  • the dosage is from orally about 0.5 g to about 18.75 g of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof per day.
  • APP is a precursor/source to beta amyloid plaque and is considered by many to be a “bad actor”, “cause”, of Alzheimer's Disease. See DDN BENCH PRESS. Neither scyllo inositol nor myo inositol previously used by Barak et al, “inositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trial”, Prog. Neuro-Psychopharmacol. & Biol. Psychiatry., 20 (4): 729-735, 1996 attenuated APP CTF-induced neurotoxicity.
  • Phytic acid is shown to be active, while scyllo inositol and myo inositol are shown to be inactive.
  • Phytic acid protected the cells from APP CTF-induced death in a concentration dependent manner with an EC 50 concentration of approximately 100 ⁇ M and concentrations of 200 ⁇ M and higher providing near complete protection from cytotoxicity. Treatment with 100 ⁇ M phytic acid suppressed oxidative stress associated with APP CTF expression, as measured by concentrations of hydrogen peroxide in the cell media
  • Stereoisomers of cyclohexanehexol-(the parent compound of phytic acid) protect primary cultured neurons from Ab oligomer-induced cytotoxicity and prevent/reverse Alzheimer phenotype in a mouse model ⁇ McLaurin, 2006 #103 ⁇ , ⁇ McLaurin, 2000 #104 ⁇ .
  • Mc65 cells were treated with the cyclohexanehexol isomers scyllo and myo-inositol at doses of 10 ⁇ M (a dose that rescues NGF-differentiated PC12 cells from Ab-induced neurotoxicity) ⁇ McLaurin, 2000 #104 ⁇ and 100 mM (the EC 50 of phytic acid). Neither isomer rescued MC65 cells from APP CTF-induced cytotoxicity.
  • Applicant also submits Table 1 and FIGS. 4 - 6 showing data from in vivo testing of the subject matter compounds in Alzheimer's transgenic mice.
  • These Alzheimer's transgenic mice are genetically altered to produce Abeta plaque, and were treated for about six months with compounds of the Applicant's invention. Namely, the drinking water was infused with phytic acid so that the final concentration of phytic acid in the drinking water was 2%.
  • FIGS. 4 - 6 are graphs comparing the tested compound in vivo with the control vehicle. In all three cases, there was a reduction in Abeta plaque after treatment with 2% phytic acid, compared to the control vehicle without phytic acid.
  • ALS amyotrophic lateral sclerosis

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Abstract

A composition and method for the treatment of Alzheimer's disease and related amyloid plaque development and reduction of amyloid plaque, amyloidosis and amyotrophic lateral sclerosis, includes an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, being administered to a person in an amount from about 0.5 grams to about 18.75 grams per day.

Description

    RELATED APPLICATIONS
  • This application is a continuation of application Ser. No. 17/064,536 filed Oct. 6, 2020, which '536 application is a continuation of application Ser. No. 12/661,964 filed Mar. 26, 2010, which '964 application claims priority from provisional application No. 61/211,230 filed Mar. 27, 2009 and provisional application No. 61/273,126, filed Jul. 29, 2009 and claims benefit and priority under 35 U.S.C. § 119(e). These applications are incorporated by reference herein. The applicant claims priority under 35 USC § 120 from the '536 and '964 applications herein.
  • All Patents, Scientific Articles, and other Documents mentioned herein are incorporated by reference as if reproduced in full below.
    • FIELD OF THE INVENTION
  • This invention relates to the prophylactic and therapeutic treatment of Alzheimer's Disease, herein-below identified as “AD”.
    • BACKGROUND OF THE INVENTION
  • Phytic acid, generally accepted as having the structure myo-inositol-hexakis (dihydrogen phosphate), is a major component of plant seeds, constituting 1-3% by weight of many cereals and oil seeds. Most wheat brans contain between 4 and 5% phytic acid. Phytic acid may be prepared in pure form from various plant sources, such as wheat, corn, soybeans, sesame seeds, peanuts, lima beans, barley, oats, wild rice and sunflower seeds. It can be extracted with dilute hydrochloric acid at room temperature, precipitated with various reagents including ferric chloride, bicarbonates, potassium hydroxide, sodium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide or alcohol. It is then further purified by conventional chemical techniques.
  • When one or more of the acidic protons of the phosphate groups in phytic acid are replaced by a counterion, the compound is usually referred to as a phytate salt. The special name phytin is used for the calcium-magnesium salt of phytate derived from plant seeds (a product of Ciba-Geigy). The present invention includes the use not only of phytic acid and phytate salts, but also various isomeric forms of phytic acid and phytate salts. While the Anderson structure for myo-inositol hexakis dihydrogen phosphate is the accepted structure for phytic acid, the present invention covers other isomers which have been previously described in the literature. These isomers include the cis, epi, allo, muco, neo, D-chiro, L-chiro, and scyllo configurations.
  • Also, while phytic acid contains six phosphate groups, when introduced into the digestive tract of an animal, one or more of the phosphate groups may be hydrolyzed by the action of the digestive acids and enzymes. Therefore, the present invention includes the use of hydrolysates of phytic acid and phytate salts wherein one or more of the phosphate groups have been removed.
  • The main uses of phytic acid include use as a food additive for preservation of foods. Studies on the use of phytic acid as a food additive show that ingestion of large doses of phytic acid elicits no physiological discomfort or symptoms of any toxicological action in humans. See Starkenstein, Biochem. Z. 30: 56 (1911). Phytic acid and its metabolites are thus not believed to be toxic or highly reactive.
  • Phytic Acid is the 6 phosphates ester of inositol. Inositol, chemically hexahydroxycylohexane, is any of nine stereoisomeric alcohols that closely resemble glucose in structure. It is a constituent of many cell phosphoglycerides. Meso- or myo-inositol, named for its presence in muscle tissue, is biologically the important isomer. Myo-inositol is the precursor in the phosphatidylinositol cycle, a source of two second messengers (diacylglycerol and inositol triphosphate). Inositols and their phosphates lack a hydrolytically labile glycosidic linkage and are stable to degradative enzymes in vivo. They have been used in the stable insulin mediators, inhibitors, and modulators. The phytic acid may be in a salt form, such as, for example, calcium magnesium phytate salt.
  • Two reports from Science Magazine of 3 Nov. 2006 support the importance of reducing Abeta plaque production as a therapeutic goal. See Goedert and Spillantini “A Century of Alzheimer's Disease”, SCIENCE, Vol. 314, 3 Nov. 2006, pp 779-781. See also Roberson and Mucke, “100 Years and Counting: Proposals for Defeating Alzheimer's Disease,” SCIENCE, Vol. 314, 3 Nov. 2006, pp. 781-784.
  • U.S. Pat. No. 4,847,082 (referred to herein as the '082 patent) and U.S. Pat. No. 4,758,430 (referred to herein as the '430 patent) both to Sabin, each of which is expressly incorporated herein by reference, disclose one embodiment for administration of phytic acid or equivalent phytate salt, isomer or hydrolysate as about one-half to three grams per kilogram of body weight orally per day.
  • Scyllo inositol, has been shown to prevent and reverse Alzheimer's Disease in a transgenic mouse model of Alzheimer's Disease (See Nature Medicine article) (See “A Sweet Solution to Alzheimer's Disease”) (See “ALD103 May Prevent and Reverse Alzheimer's Disease”) (See “Scyllo-Inositol Appears Promising for Alzheimer's Disease”).
  • Scyllo inositol also inhibits and blocks the aggregation of amyloid-B peptide (AB) in these same transgenic Alzheimer Disease mouse studies. The '082 patent discloses scyllo inositol as an isomeric form of phytic acid. Since the '082 and '430 patents disclose a minimum oral dose of about a half a gram per kilogram/body weight per day, a 75 kilogram AD patient, would take 37.5 grams of scyllo inositol orally per day. This dose is burdensome. Additionally, phytate in food has been successfully consumed at this dose and higher.
  • Scyllo inositol is also disclosed in U.S. patent application Ser. No. 10/787,621 of McLaurin. This application discloses a litany of compounds for the treatment of disorders of protein aggregation, the most preferred compound of which is scyllo inositol.
    • SUMMARY OF THE INVENTION
  • Phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof is administered as a treatment for prevention and treatment of Alzheimer's disease and for treatment of amyloidosis, aggregation of beta amyloid proteins and tau protein in the brain.
  • An effective yet surprisingly low dose of the compounds phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, except for scyllo inositol, are used for. as a prophylactic and therapeutic treatment for Alzheimer's Disease. In a preferred embodiment, a dose of about 0.5 gram to about 18.75 gms of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or mixture of any combination thereof, except for scyllo inositol, are administered orally per day. This dose is 1/75th to one half (½) of the previously disclosed doses in the Sabin patents cited above Phytate salt may also be administered as a capsule, and the calcium magnesium phytate salt, as packaged by many suppliers such as Jarrow Formulations; is desirable.
  • Surprisingly, it has been discovered that very low doses of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof are effective in the treatment and prevention of aggregation of beta amyloid proteins as are commonly seen in the brains of Alzheimer's patients. Treatment with such a low dose of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof prevents the occurrence of potential side effects observed with high dose treatments and allows for ease of administration to Alzheimer's patients who may find it difficult to take high doses of the substance. Furthermore, it has been discovered that phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof is much more effective than scyllo inositol and myo inositol.
  • In one embodiment there is disclosed a composition for the treatment of Alzheimer's disease and related amyloid plaque development by providing a person in need thereof with an effective amount of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof.
  • In another embodiment, there is disclosed a method for the treatment of Alzheimer's disease and the amyloid plaque protein aggregation by the oral administration of 0.5 to 18.75 grams of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof per day. Alternatively, the compounds of the invention may be administered topically as a cream, ointment, gel and the like, transdermally or intradermally.
  • For a better understanding of the present invention, together with other and further objects, reference is made to the following description, taken in conjunction with the examples, and its scope will be pointed out in the appended claims.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • The features and advantages of the present invention will become apparent from the following detailed description of a preferred embodiment thereof, taken in conjunction with the accompanying drawings, in which:
  • FIG. 1 is a chart of cell viability.
  • FIG. 2 is a chart of a bar graph of the percentage of H 202, where V=control and PA=phytic acid.
  • FIG. 3 is a chart of cell viability of scyllo inositol and myo inositol.
  • FIG. 4 is a chart of soluble amyloid beta 1-42/μg protein, phytic acid and a vehicle carrier.
  • FIG. 5 is a chart of soluble amyloid beta—40/μg protein, phytic acid and a vehicle carrier.
  • FIG. 6 is a chart of insoluble amyloid beta 1-42/μg protein, phytic acid and vehicle carrier.
    •  DETAILED DESCRIPTION
  • The method according to the present invention comprises treating a subject, afflicted with Alzheimer's Disease, with a composition in which the active ingredient is phytic acid, a phytate salt, or an isomer or hydrolysate of phytic acid or phytate salt. By the term isomer as used herein, it is intended to include the various conformations of phytic acid, as described hereinabove, and the corresponding conformations of phytate salts. The term salts is broadly intended to cover any of the various salts formed by the replacement of any or all of the available acidic protons of the phosphate groups with a counterion. The counterion may be any pharmaceutically acceptable counterion such as sodium, magnesium, potassium, zinc, ferric, ferrous, and the like, including organic counterions such as quaternary ammonium ions and ions of organic bases.
  • The present invention also includes the hydrolysates of phytic acid and phytate salts wherein one or more of the phosphate groups have been removed. Once administered into the digestive tract, bloodstream, the phytic acid or phytate salt may be hydrolyzed by digestive, blood or cellular enzymes, thereby removing one or more of the phosphate groups on the cyclohexane ring. However, it is contemplated to be within the scope of the invention that these hydrolysates of phytic acid and phytate salts may also be administered directly to the subject and therefore are within the scope of the present invention.
  • The hydrolysates of phytic acid and phytate salts may be prepared by partial acid or basic hydrolysis or by hydrolysis using enzymes prior to preparation of dosage fauns for administration. Preferably, the hydrolysates will be made in vivo by coadministering with phytic acid or phytate salt an enzyme which hydrolyzes phosphate groups, such as 3-phytase, 6-phytase or acid phosphatase.
  • The phytic acid or phytate salt may be absorbed into or adsorbed onto a solid carrier to facilitate pharmaceutical administration. For example, phytic acid may be formulated into a starch powder by spray drying or vacuum drying an aqueous mixture of phytic acid and dextrin.
  • The preferred compositions for administration, particularly in oral dosage form, are the mono-, di-potassium phytate salts and mixtures thereof which may be prepared from commercially and readily available sodium phytate by initially removing the sodium using ion exchange chromatography on a suitable resin, such as Dowex beads. The free phytic acid may then be treated with potassium hydroxide to convert to the mono- and di-potassium phytate salt.
  • The preferred method of administration of the compositions according to the present invention is through oral administration in liquid or tablet form. As described hereinabove, the compositions may be administered as pharmaceutically acceptable salts such as salts with alkali metal cations (sodium, potassium, lithium), ammonium salts and salts with organic bases such as piperidine, triethanolamine, diethylaminoethylamine salts, and the like.
  • In addition to the active ingredients, the composition may also contain an effective proportion, usually from 0.001 to 0.1% weight by volume, of a pharmaceutically acceptable preservative or sterilizing agent such as cetyl pyridinium chloride, tetradecyltrimethyl ammonium bromide (commercially known as Centramide), benzyl dimethyl [2-(2-)p-(1,1,3,3-tetramethyl butyl)) phenoxy) ethoxy] ammonium chloride (known commercially as Benzethonium Chloride) and myristyl-gamma-picolinium chloride.
  • The pharmaceutical composition may also contain conventional excipients, e.g., sodium chloride, dextrose, mannitol, and buffers such as sodium dihydrogen ortho phosphate, disodium hydrogen phosphate, sodium citrate/citric acid, and boric acid/sodium borate. The proportion and concentration of excipients and buffers may be varied within fairly wide ranges, providing the resulting solution is stable and nonirritating when administered. The preferred method of administration is by oral administration as a solid compound. The composition may be prepared in the conventional manner as tablets, pills or powders, using conventional carriers.
  • The phytic acid may be combined with other inactive substances as are known in the pharmaceutical arts such as, for example, lactates, silicates, and magnesium stearate, as well as with other active substances, such as pharmaceutical drugs and vitamins, etc.
  • For oral administration, in a preferred embodiment, the active ingredient of the composition will also contain an enzyme such as 3-phytase (EC 3.1.38), 6-phytase (EC 3.1.3.26) or acid phosphatase which, when exposed to the digestive tract, will assist in hydrolyzing one or more of the phosphate groups from the active ingredient. Since phytic acid or phytate salts are not naturally present in animals, the digestive enzymes in animals are believed to be insufficient to completely hydrolyze the phosphate groups. Therefore, to enhance the hydrolysis of the phosphate groups in an animal or man, it is preferred that the active ingredient be administered with one or more of the aforementioned enzymes, with the preferred enzyme being 3-phytase (EC 3.1.38).
  • The phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof can be administered in any manner as known in the art. In one embodiment the phytic acid is administered orally in encapsulated form. The oral administration can be in the form of a capsule, quick dissolve tablet, table, or other form as known in the art. The dosage of phytic acid is an amount that is effective for the disease state of the Alzheimer's patient and an amount effective as a prophylactic treatment for prevention of Alzheimer's disease. In one embodiment the dosage is from orally about 0.5 g to about 18.75 g of phytic acid, phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof per day.
  • The present invention can be better understood by reference to the following examples. The following examples illustrate the present invention and are not intended to limit the invention or its scope in any manner.
    • EXAMPLES
  • The Applicant tested compounds disclosed in the above referenced patents of Sabin using well established standard routine testing, as known in the art, at Oregon Science and Health University in an in-vitro challenge test.
  • The Applicant submits two pages of the data of these in vitro tests. In the first test, phytic acid attenuates APP CTF-induced neurotoxicity. APP is a precursor/source to beta amyloid plaque and is considered by many to be a “bad actor”, “cause”, of Alzheimer's Disease. See DDN BENCH PRESS. Neither scyllo inositol nor myo inositol previously used by Barak et al, “inositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trial”, Prog. Neuro-Psychopharmacol. & Biol. Psychiatry., 20 (4): 729-735, 1996 attenuated APP CTF-induced neurotoxicity. Phytic acid is shown to be active, while scyllo inositol and myo inositol are shown to be inactive. These surprising and unexpected results with phytic acid attenuating APP CTF-induced neurotoxicity, while scyllo inositol and myo inositol fails in these same tests, suggests that phytic acid would be effective as a treatment for Alzheimer's Disease at a surprising, unexpected, non-obvious, severely reduced dose, as against the previously cited claimed dosages in the Alzheimer's Treatment Patents, especially since phytic acid proved scyllo inositol inactive in this in vitro challenge test. These results from this in vitro test demonstrate superiority over scyllo inositol and myo-inositol; and demonstrate novelty and reduction to practice for the prophylactic and therapeutic treatment of Alzheimer's disease.
  • In vitro studies were conducted in MC65 cells, an established human neuroblastoma line that conditionally expresses the first 17 amino-terminal residues and the 99 carboxy-terminal residues of amyloid precursor protein (APP CTF). Detectable APP CTF expression occurs within 3-4 h of tetracycline withdrawal, appearance of aggregates and initial losses of culture viability occurs at about 2 days and near complete death occurs by approximately 3 days.
    • Phytic Acid Attenuates APP CTF-induced Neurotoxicity
  • Phytic acid protected the cells from APP CTF-induced death in a concentration dependent manner with an EC50 concentration of approximately 100 μM and concentrations of 200 μM and higher providing near complete protection from cytotoxicity. Treatment with 100 μM phytic acid suppressed oxidative stress associated with APP CTF expression, as measured by concentrations of hydrogen peroxide in the cell media
    • Scyllo- and Myo-inositol do not Rescue Cells from Ab-induced Neurotoxicity
  • Stereoisomers of cyclohexanehexol-(the parent compound of phytic acid) protect primary cultured neurons from Ab oligomer-induced cytotoxicity and prevent/reverse Alzheimer phenotype in a mouse model {McLaurin, 2006 #103}, {McLaurin, 2000 #104}. To test the specific of phytic acid's effects on Mc65 cells, cells were treated with the cyclohexanehexol isomers scyllo and myo-inositol at doses of 10 μM (a dose that rescues NGF-differentiated PC12 cells from Ab-induced neurotoxicity) {McLaurin, 2000 #104} and 100 mM (the EC50 of phytic acid). Neither isomer rescued MC65 cells from APP CTF-induced cytotoxicity.
    • In Vivo Test Results
  • Applicant also submits Table 1 and FIGS. 4-6 showing data from in vivo testing of the subject matter compounds in Alzheimer's transgenic mice. These Alzheimer's transgenic mice are genetically altered to produce Abeta plaque, and were treated for about six months with compounds of the Applicant's invention. Namely, the drinking water was infused with phytic acid so that the final concentration of phytic acid in the drinking water was 2%.
  • After six months, the animals were put down for autopsy and necropsy so that Abeta plaque in the brains was assayed, separated and weighed.
  • There was no toxicity from the phytic acid in the treated group, nor any significant weight loss.
    • RESULTS
  • The production of two different fractions of Abeta plaque insoluble species was lowered or reduced. One species of soluble Abeta plaque was lowered or reduced. All species tested were lowered or reduced, resulting in a complete in vivo success, without toxicity.
  • Table 1 is a tabulation of all results. FIGS. 4-6 are graphs comparing the tested compound in vivo with the control vehicle. In all three cases, there was a reduction in Abeta plaque after treatment with 2% phytic acid, compared to the control vehicle without phytic acid.
    • Key for Table 1 and FIGS. 4-6
    • Phy=IP6 at 2% phytic acid in mixed liquid drinking water with food
    • Veh=Negative control vehicle with laboratory food alone.
    • ID numbers=which animal was treated
  • TABLE 1
    AS 1-40 Results AB1-40 AB 1-42 Results AB1-42
    ID# Animal # Tx Genotype Dilution A Dilution B A B Dilution A Dilution B A B
     1 4562 Phy app 16 200 2320.14 70486.195 2 3200 N/A 880713.806
     2 4563 Phy app 16 200 2851.523 61486.942 2 3200 N/A 696145.624
     3 4575 Phy app 16 200 N/A 30256.773 2 3200 N/A 480035.385
     4 4586 Phy app 16 200 8.402 38495.306 2 3200 N/A 705489.347
     5 4570 Phy app 16 200 1219.51 64667.238 2 3200 N/A 207020.619
     6 4631 Phy app 16 200 1425.681 36921.948 2 3200 N/A 703352.803
     7 4567 Phy app 16 200 356.289 33040.457 2 3200 N/A 650661.541
     8 4582 Phy app 16 200 571.272 50066.569 2 3200 N/A 528179.357
     9 4564 Veh app 16 200 13828.275 92831.01 2 3200 N/A 1349168.224
    10 4559 Veh app 16 200 2819.85 55137.189 2 3200 N/A 800295.049
    12 4579 Veh app 16 200 19.911 34501.466 2 3200 N/A 772672.856
    13 4581 Veh app 16 200 148.018 44625.892 2 3200 N/A 983346.715
    14 4617 Vab app 16 200 1309.039 56358.841 2 3200 N/A 759029.966
    15 4675 Veh app 16 200 560.149 63099.902 2 3200 N/A 947059.623
    16 4622 Veh app 16 200 4527.412 62445.043 2 3200 N/A 659260.411
    17 4811 C Veh Wt 4 3200 NA N/A 2 800 N/A 53327.115
    13 4809 C Veh App 4 3200 144.004 1306162.415 2 800 N/A 186553.084
    19 4824 C Ven Wt 4 3200 N/A N/A 2 800 N/A 90689.325
    20 4811 H Veh Wt 4 800 NIA N/A 2 800 N/A 28596.199
    21 4809 H Veh App 4 800 91.304 69277.345 2 800 N/A 52953.772
    22 4824 H Veh Wt 4 800 N/A N/A 2 800 N/A 27824.951
    23 4812 C Veh Apo 4 3200 82.825 975775 2 800 N/A 193869
    24 4812 H Veh App 4 800 48.555 16341 2 800 N/A 78863
    11 4561 Veh ' wt 16 200 N/A N/A 2 3200 N/A N/A
    BCA Results [pg]AB1-42/μg Protein [pg]AB1-42/μg Protein
    ID# Fraction A Fraction B A B A B
     1 5889.725 519.558 0.39413036 135,665691 N/A 1695.12125
     2 4147.397 577.817 0.68754522 106.412484 N/A 1208.24694
     3 2933.003 227.379 N/A 133.067579 N/A 2111.17282
     4 4586.985 465.21 0.0018317 84.5660377 N/A 1549.81074
     5 5218.961 491.604 0.2337587 131.570115 N/A 421.198238
     6 5967.692 687.425 0.23900747 53.710511 N/A 1023.17024
     7 6690.816 699.027 0.05354937 47.2683674 N/A 930.810313
     8 8193.309 604.247 0.06972421 82.8577866 N/A 874.111675
     9 6840.047 670.862 2.01989192 138.375717 N/A 2011.09651
    10 6917.157 485.928 0.40766028 118.338432 N/A 1717.63674
    12 4740.048 413.594 0.00420059 83.4186811 N/A 1868.19165
    13 3521.983 395.894 0.04202689 112.721819 N/A 2483.8665
    14 6026.783 545.157 0.21720361 103.380936 N/A 1392.31445
    15 6633.192 542.265 0.10123433 97.9224217 N/A 1746.48857
    16 7442.838 723.057 0.60829108 86.3625464 N/A 911.768244
    17 7002.482 567.048 N/A N/A N/A 94.0433879
    13 7063.165 524.516 0.02038797 2490.22416 N/A 317.536708
    19 5218.073 394.671 N/A N/A N/A 299.531242
    20 5424.769 488.096 N/A N/A N/A 62.4240312
    21 5473.284 354.333 0.01668176 195.514798 N/A 149.446346
    22 6269.239 525.337 N/A N/A N/A 52.9659076
    23 6814.989 515.843 0.01215336 1891.61237 N/A 375.829467
    24 6097.491 510.085 0.00790492 32.0370933 N/A 154.613628
    11 4062.036 332.112 N/A N/A N/A N/A
    [pg]AB1-40/μg Protein
    a b a b
    Phy 0.23994 Phy 96.88957 Phy N/A Phy 1226.706
    Veh 0.48579 Veh 105.7887 Veh N/A Veh 1733.051
    SE a SE b SE a SE b
    Phy 0.09056 Phy 12.52249 Phy N/A Phy 169.3871
    Vah 0.2683 Veh 7.258733 Veh N/A Veh 185.8251
  • Because of the unexpected finding that phytic acid lowers both soluble and insoluble Amyloid production in Alzheimer's transgenic mice, therefore it is reasonable that phtyic acid will be useful in Amyloidosis an example of a protein aggregating Disease.
  • Furthermore, because the phytic acid and its related compounds disclose in vitro neuroprotective activity suggesting usefulness in treatment of Alzheimer's Disease, then it follows that the same compounds will be useful for treatment of motor neuron disease, or amyotrophic lateral sclerosis (ALS), in which the motor neurons unexplainably die off.
  • In the foregoing description, certain terms and visual depictions are used to illustrate the preferred embodiment. However, no unnecessary limitations are to be construed by the terms used or illustrations depicted, beyond what is shown in the prior art, since the terms and illustrations are exemplary only, and are not meant to limit the scope of the present invention.
  • It is further known that other modifications may be made to the present invention, without departing the scope of the invention.

Claims (19)

1. (canceled)
2. (canceled)
3. A method for the treatment of Alzheimer's disease and related amyloid plaque development, attenuating amyloid toxicity or plaque formation and reduction of amyloid plaque, protein aggregation and amyloidosis consisting essentially of the steps of orally administering to a patient afflicted with Alzheimer's disease an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, being administered in an amount from about 0.5 grams to about 18.75 grams per day to effectively attenuate APP CTF-induced neurotoxicity to treat Alzheimer's disease and related amyloid plaque development and reduce amyloid plaque, amyloid plaque protein aggregation and amyloidosis.
4. The method for the treatment of Alzheimer's disease and related amyloid plaque development, attenuating amyloid toxicity or plaque formation and reduction of amyloid plaque, protein aggregation and amyloidosis as in claim 3 wherein the steps of administering an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, is administered in an amount from about 5 grams to about 9 grams per day in a single dose.
5. The method for the treatment of Alzheimer's disease and related amyloid plaque development, attenuating amyloid toxicity or plaque formation and reduction of amyloid plaque, protein aggregation and amyloidosis as in claim 3 wherein the steps of administering an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, is administered in an amount from about 2 grams to about 18.75 grams per day.
6. A method for the treatment of Alzheimer's disease and related amyloid plaque development, attenuating amyloid toxicity or plaque formation and reduction of amyloid plaque, protein aggregation and amyloidosis comprising the steps of orally administering to a patient afflicted with Alzheimer's disease an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, being administered in an amount from about 0.5 grams to about 18.75 grams per day to effectively attenuate APP CTF-induced neurotoxicity to treat Alzheimer's disease and related amyloid plaque development and reduce amyloid plaque, protein aggregation and amyloidosis, wherein said step of administering an effective amount of said compound is the only step performed for treating Alzheimer's disease and related amyloid plaque development and reduction of amyloid plaque, protein aggregation and amyloidosis.
7. The method for the treatment of Alzheimer's disease and related amyloid plaque development attenuating amyloid toxicity or plaque formation and reduction of amyloid plaque, protein aggregation and amyloidosis as in claim 6 wherein the steps of administering an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, is administered in an amount from about 5 grams to about 9 grams per day in a single dose.
8. The method for the treatment of Alzheimer's disease and related amyloid plaque development attenuating amyloid toxicity or plaque formation, and reduction of amyloid plaque, protein aggregation and amyloidosis as in claim 6 wherein the steps of administering an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, is administered in an amount from about 2 grams to about 18.75 grams per day.
9. The method of claim 3, wherein said compound is administered to a patient on an empty stomach.
10. A method for the treatment of protein aggregating diseases consisting essentially of the steps of orally administering to a patient afflicted with one or more protein aggregating diseases an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof being administered in an amount from about 0.5 grams to about 18.75 grams per day to effectively treat protein aggregating diseases.
11. A method for the prevention of aggregation of beta amyloid proteins consisting essentially of the steps of orally administering to a patient an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate or phytic acid or a phytate salt, or a mixture of any combination thereof being administered in an amount from about 0.5 grams to about 18.75 grams per day to effectively prevent Alzheimer's Disease.
12. The method of claim 11 wherein the steps of administering an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, is administered in an amount from about 5 grams to about 9 grams per day in a single dose.
13. The method of claim 11 wherein the steps of administering an effective amount of a compound selected from the group consisting of phytic acid, a phytate salt, an isomer or hydrolysate of phytic acid or a phytate salt, or a mixture of any combination thereof, is administered in an amount from about 2 grams to about 18.75 grams per day.
14. The method of claim 11 wherein said step of administering an effective amount of said compound is the only step performed for preventing Alzheimer's disease.
15. The method of claim 11, wherein said compound is administered to a patient on an empty stomach.
16. The method of claim 11, wherein said compound is the only active substance administered.
17. The method of claim 3, wherein said compound is administered in liquid form.
18. The method of claim 11, wherein said compound is infused into water.
19. The method of claim 11, wherein said final concentration of said compound in water is 2%.
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