EP1109548A1 - Utilisation de procedes et de compositions a base de tocotrienols pour traiter et prevenir les maladies osseuses - Google Patents

Utilisation de procedes et de compositions a base de tocotrienols pour traiter et prevenir les maladies osseuses

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Publication number
EP1109548A1
EP1109548A1 EP99930883A EP99930883A EP1109548A1 EP 1109548 A1 EP1109548 A1 EP 1109548A1 EP 99930883 A EP99930883 A EP 99930883A EP 99930883 A EP99930883 A EP 99930883A EP 1109548 A1 EP1109548 A1 EP 1109548A1
Authority
EP
European Patent Office
Prior art keywords
bone
tocotrienol
tocotrienols
composition
vitamin
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.)
Withdrawn
Application number
EP99930883A
Other languages
German (de)
English (en)
Other versions
EP1109548A4 (fr
Inventor
Ronald H. Lane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lipogenics Inc
Original Assignee
Lipogenics Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Lipogenics Inc filed Critical Lipogenics Inc
Publication of EP1109548A1 publication Critical patent/EP1109548A1/fr
Publication of EP1109548A4 publication Critical patent/EP1109548A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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 
    • 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
    • A61K31/33—Heterocyclic compounds
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • IL-6 also appears to promote differentiation of committed osteoblastic cells towards a more mature phenotype (T. Bellido et al. Endocrinology. 138(9), pp. 3666-76 (1997)).
  • a number of well-recognized bone-enhancing substances influence IL-6 production.
  • estrogen is known to be important in regulating the expression of IL-6 in bone marrow ceils (H.K. ⁇ ' aananen and P.L. Harkonen. Matu ⁇ tas. 23 Suppi. pp. S65-9 (1996)).
  • osteoporosis Primary preventive therapy against osteoporosis often involves behavioral and dietary modifications. Secondary prevention in women undergoing menopause often involves estrogen replacement therapy (J.Y. Reginstar et al., Rev. Rhum. Ed. Fr., 61(10), pp. 1555S-64S (1994)). In addition to estrogen, there are a number of other agents being used to prevent and treat osteoporosis and other degenerative bone disorders. These prophylactic and therapeutic options for osteoporosis can generally be divided into twosub sets: those that inhibit bone resorption and those that stimulate bone formation. Included in the first category are calcium (including calcium salts), anti-estrogens (such as tamoxifen), environmental estrogens (such as coumestrol.
  • calcium including calcium salts
  • anti-estrogens such as tamoxifen
  • environmental estrogens such as coumestrol.
  • Some of the agents in this first category also fall into the second, but the most widely used agent to stimulate bone formation is fluoride (usually in the form of sodium fluoride).
  • fluoride usually in the form of sodium fluoride.
  • Synthetic parathyroid hormone, vitamin K (including Kland K2) and cyclic bisphosphonates are also being used as bone-enhancing agents (C. Genera, et al.. Drug Serf . 11 (3), pp. 179-95 (1994) and P. Weber, Int. J. Vita. Nut. Res.. 67(5), pp. 350-56 (1997)).
  • osteoporosis and other bone diseases remain a serious health threat. Accordingly, there is still a well recognized and unmet need for new agents to prevent and treat osteoporosis and other bone diseases.
  • the present invention satisfies the need for new prophylactic and therapeutic agents effective in the prevention and treatment of osteoporosis and other bone diseases.
  • One embodiment of this invention provides a method for preventing osteoporosis and other bone diseases in a patient comprising the step of administering to the patient a prophylactically effective amount of a composition comprising a tocotrienol, a mixture of tocotrienols or a combination of one or more tocotrienols with one or more additional bone-enhancing substances.
  • Another embodiment of this invention provides a method for treating osteoporosis and other bone diseases in a patient comprising the step of administering to the patient a therapeutically effective amount of a composition comprising a tocotrienol, a mixture of tocotrienols or a combination of one or more tocotrienols with one or more additional bone-enhancing substances.
  • compositions comprising a combination of one or more tocotrienols with one or more additional bone-enhancing substances that are especially well suited for treating and preventing osteoporosis and other bone diseases.
  • Bone-enhancing substances refers to agents that have a beneficial effect on bone condition.
  • these bone-enhancing substances inhibit bone resorption and/or stimulate new bone formation and more preferably, these bone-enhancing substances are selected from the individual bone-enhancing agents referred to herein.
  • the markers and tests for measuring these activities are well established in the art (see. for example. M. Gambacciani et al., Calcif. Tissue Int.. 6 1 S 1, pp. S 15-18 (1997)).
  • composition 1 refers to a preparation for administration via any acceptable route known to those of ordinary skill in the art. Such routes include, but are not limited to oral, nasal, inhalation, parenteral, and topical administration. “Composition” encompasses pharmaceutical compositions as well as dietary supplements, foodstuffs, food additives and the like.
  • Patient refers to a warm-blooded mammal and preferably, a human. Patients in need of prophylactic therapy to prevent osteoporosis and other bone diseases (including
  • Paget's disease and Gaucher's disease are those patients possessing one or more risk factors for the development of osteoporosis (including post-menopausal women, older men (i.e., greater than about 50 years old) and patients with inadequate calcium intake) or risk factors associated with other bone diseases.
  • Patients in need of treatment for osteoporosis or other bone diseases are those patients possessing one or more symptoms of osteoporosis, including a decrease in bone mass and an increased susceptibility to bone fractures or symptoms of other bone diseases (e.g., Paget's disease, i.e., pain and deformities due to enlargement of skeletal segments).
  • Paget's disease i.e., pain and deformities due to enlargement of skeletal segments.
  • P 25 tocotrienol and P :5 are trademarks of Bionutrics. Inc. (Phoenix, Arizona).
  • Specific isoprenoid-like units include truncated isoprenoids and truncated or full-length isoprenoids that may be or may not be partially saturated and are optionally substituted with OH, NH2 and C, -C 6 branched or unbranched alkyl or alkoxy.
  • Preferred tocotrienols for use in the methods of this invention are those which are naturally occurring (including tocotrienol, ⁇ -, ⁇ -, ⁇ -, ⁇ -tocotrienol, P 25 , and P 18 ) and may be used individually or in combination. These naturally occurring tocotrienols may be conveniently isolated from biological materials or synthesized from commercially available starting material.
  • the tocotrienols for use in the methods of this invention are obtained from biological materials that have been stabilized and extracted, such as by the processes described in PCT publication WO 91/17985 (the entire disclosure of which is incorporated by reference herein).
  • biological materials that have been stabilized and extracted, such as by the processes described in PCT publication WO 91/17985 (the entire disclosure of which is incorporated by reference herein).
  • preferred biological materials, tocotrienols and methods for obtaining tocotrienols synthetically and from biological materials are referred to in co-owned US patent 5.591,772 and PCT publication WO 91/17985 (the entire disclosures of which are incorporated by reference herein).
  • Preferred biological materials from which the some of the preferred tocotrienols useful in the compositions and methods of this invention may be obtained include those from conifers, legumes, asteraceae.
  • R is selected from the group consisting of H and C,-C 6 branched or unbranched alkyl
  • R 7 is selected from the group consisting of isoprenoid and isoprenoid-like side chains. and more preferably from the group consisting of side chains of formulas (a)-(c).
  • R 7 is a side chain of formula (a), wherein R, 0 and R n are each independently selected from the group consisting of H and C,-C 3 branched or unbranched alkyl and more preferably, H and methyl); each R 8 and R ⁇ , is independently selected from the group consisting of H and C,-C 6 branched or unbranched alkyl (preferably, H and C,-C 3 branched or unbranched alkyl and more preferably, H and methyl);
  • the tocotrienols for use in the compositions and methods of this invention may be in their isomerically pure form or be present as mixtures of isomers.
  • the tocotrienols of this invention may exist as the d- or 1-isomer or the d,l-racemic mixture.
  • the naturally occurring isomer (usually the d-isomer) and the d.l-racemic mixture are preferred.
  • TRF 25 comprises at least about 5% P 25 , more preferably, at least about 10% P 25 , and even more preferably, at least about 15% P 25 w/w. .
  • TRF 25 is a preferred component of the compositions and methods described herein.
  • TRF 25 is a trademark of Bionutrics, Inc. (Phoenix. Arizona).
  • TRF and TRF 23 may be used in any of the methods and compositions described herein for individual tocotrienols or mixtures thereof.
  • tocotrienols may be useful in preventing and treating osteoporosis and other bone disorders due to their unique combination of antioxidant and antiinflammatory properties. As opposed to conventional therapeutics that target a single mechanism, tocotrienols target multiple mechanisms leading to and propagating osteoporosis and other bone disorders. Tocotrienols inhibit the production of a variety of cytokines (including IL-6) which have been linked to the genesis and histology of osteoporosis and other bone disorders. Furthermore, tocotrienols mediate the levels of superoxide and, perhaps, nitric oxide production. These factors have been linked to the process of osteoclastic bone resorption (P.M.
  • compositions of this invention are prepared by combining one or more tocotrienols with an acceptable carrier.
  • the carrier must be pharmaceutically acceptable (i.e.. a carrier which is non-toxic to the patient at the administered level and which does not destroy the activity of the active component(s) of the composition).
  • Acceptable carriers, including pharmaceutically acceptable carriers, are well known to those of ordinary skill in the art.
  • Tocotrienols and mixtures thereof may be used in combination with bone-enhancing agents in the methods described herein. These additional therapeutic and prophylactic agents may be administered separately from the tocotrienols or mixtures thereof, or they may be formulated together in a single dosage form. Such combination therapy advantageously utilizes lower dosages of the other bone-enhancing agents which may reduce or avoid possible toxicity incurred when those agents are used as monotherapies or which may create an additive or synergistic effect.
  • the tocotrienols used in the methods of this invention may be also used in conjunction with any conventional anti-inflammatory or anti-oxidative agent. These conventional agents preferably possess independent boneenhancing properties.
  • one or more tocotrienols may be used in conjunction with one or more of the following bone-enhancing substances: calcium (including calcium salts), estrogen, anti-estrogens (such as tamoxifen), environmental estrogens (such as coumestrol, methoxychlor, bisphenol A and zeranol), vitamin D (including its analogs and metabolites, such as calciferol and 1 -alpha hydroxycholecalciferol), gonadal and anabolic steroids, calcitonin. flavanoids (such as pentahydroxyflavone, naringenin, hesperetin, tangeretin. nobiletin. quercetin. apigenin.
  • calcium including calcium salts
  • estrogen such as tamoxifen
  • environmental estrogens such as coumestrol, methoxychlor, bisphenol A and zeranol
  • vitamin D including its analogs and metabolites, such as calciferol and 1 -alpha hydroxycholecalc
  • IL- 11 inhibitors TNF inhibitors, INF-gamma inhibitors, tocopherols (such as ⁇ tocopherol (Vitamin E)) and selenium.
  • Preferred combinations include one or more tocotrienols with one or more agents selected from calcium (including calcium salts), flavanoids (more preferably, ipriflavone), vitamin D, vitamin K, lipoic acid and tocopherols.
  • Protocol II Dry Heat followeded By Wet Heat Stabilization Dry Heat Stage: Protocol I Wet Heat Stage: Extruder: Anderson 4 inch
  • Discharge Moisture 15% Discharge Rate: 450 lbs/hr
  • Protocol III Drying/Cooling Procedure
  • the wet heat stabilized product of protocol II ( 15% moisture) was discharged onto aluminum trays and placed in a tray oven at 101.1 °C until the moisture content was 8-10% (approximately 1. 5 hrs). The trays were then placed on tray racks and allowed to cool at ambient temperature (approximately 20°C). Oil to Hexane Ratio: 1 :4
  • the hexane was removed from the extract by mild heating (40°C) under a mild vacuum.
  • Example 1 The effects of tocotrienols (in the form of the TRF mixture and individual tocotrienols) on plasma levels of thromboxane B 2 and platelet factor 4 in chickens were determined. These levels are known to correlate with the levels of inflammatory cytokines, such as IL-6. The following feeding conditions were used:
  • Each group of six chickens (6- week old female white leghorn chickens) was administered a chick mash control diet or a control diet containing one or more additives.
  • the amount of feed consumed by all groups was comparable to the control group.
  • the feeding period was 4 weeks.
  • the birds were fasted for a period of 14 hours prior to sacrifice.
  • the chicken mash control diet contained the following ingredients:
  • Results are reported as mean ⁇ standard deviation. Percentages of control are reported in parentheses. The following results were obtained:
  • tocotrienols in the form of the TRF mixture and individual tocotrienols
  • plasma levels of thromboxane B 2 and platelet factor 4 in swine were determined. These levels are known to correlate with the levels of inflammatory cytokines (including IL-6).
  • the following feeding conditions were used:
  • Each group of three swine (5 -month old swine carrying Lpd 5 and Lpu 1 mutant alleles) were administered a control diet or a control diet supplemented with one or more additives. After a 12 hour fast, plasma samples were taken at 42 days from the start of the feeding period.
  • the swine control diet contained the following ingredients:
  • the mineral mixture contained per kg feed zinc sulfate «H20, 110 mg; manganese sulfate •5H 2 0, 70 mg; ferric citrate » H 2 0, 500 mg; copper sulfate»5H 2 0, 16 mg; sodium selenite, 0.2 mg; DL-methionine, 2.5 g; choline chloride (50%), 1.5 g; ethoxyquin (l,2-dihydro-6-ethoxy-2,2,4-trimethyquinoline), 125 mg; and thiamine HCl, 1.8 mg.
  • the vitamin mixture contained per kg feed vitamin A, 1,500 units; vitamin D 3 , 400 units; vitamin E, 10 units: riboflavin. 3.6 mg; calcium panthothenate, 10 mg; niacin, 25 mg; pyridoxine
  • Results are reported as mean ⁇ standard deviation. Percentages of control are reported in parentheses. The following results were obtained:
  • Example 3 The effects of ⁇ -tocotrienol on the release of superoxide in human peripheral blood neutrophils were determined. Superoxide amplifies the inflammatory response thereby increasing bone resorption.
  • the neutrophils tested were isolated by density centrifugation on Ficoll-Hypaque gradients using conventional methods (see E. Serbinova et al., Free Rad. Bio, and Med., 10, pp. 263-75 (1991)). The neutrophils were then placed in a 96-well plate. ⁇ -Tocotrienol and phorbol myristate acetate were added to the wells at the same time. The secretion of superoxide was measured as the superoxide dismutase-inhibitable reduction of ferricytochrome C. The results of this study are displayed in Figure 1.
  • the amount of released superoxide was reduced from 19.7 nmole (5xl0 5 cells/hour) in the control to 8.0 and 0.0 nmole at ⁇ -tocotrienol concentrations of 10 "6 and 10 "5 , respectively.
  • Example 4 The following models can be used to evaluate the efficacy of tocotrienols for the prevention and treatment of osteoporosis and other bone diseases: R. Civitelli et al.. Calcif. Tissue Int., 56, pp. 215-19 (1995) describe a rat model to measure bone biomechanics, impact strength and mineral bone density.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention se rapporte au traitement et à la prévention des maladies osseuses par l'utilisation des tocotriénols. Plus spécifiquement, cette invention se rapporte d'une part à des compositions à base de tocotriénols seuls, de mélanges de tocotriénols et de mélanges contenant un ou plusieurs tocotriénols en plus d'autres substances activant la réparation osseuse, et d'autre part à ces compositions même. Les compositions et procédés de cette invention conviennent tout particulièrement au traitement et à la prévention de l'ostéoporose et d'autres maladies osseuses dégénératives, telles que la maladie de Paget et la maladie de Gaucher.
EP99930883A 1998-07-08 1999-07-08 Utilisation de procedes et de compositions a base de tocotrienols pour traiter et prevenir les maladies osseuses Withdrawn EP1109548A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US9210198P 1998-07-08 1998-07-08
US92101P 1998-07-08
PCT/US1999/015452 WO2000002553A1 (fr) 1998-07-08 1999-07-08 Utilisation de procedes et de compositions a base de tocotrienols pour traiter et prevenir les maladies osseuses

Publications (2)

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EP1109548A1 true EP1109548A1 (fr) 2001-06-27
EP1109548A4 EP1109548A4 (fr) 2001-12-12

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EP (1) EP1109548A4 (fr)
JP (1) JP2002520280A (fr)
CN (1) CN1316903A (fr)
AU (1) AU4732499A (fr)
ID (1) ID28460A (fr)
WO (1) WO2000002553A1 (fr)

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CN104304671A (zh) 2004-12-29 2015-01-28 希尔氏宠物营养品公司 抑制动物学习和/或记忆减退的方法
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AU4732499A (en) 2000-02-01
CN1316903A (zh) 2001-10-10
ID28460A (id) 2001-05-24
EP1109548A4 (fr) 2001-12-12
JP2002520280A (ja) 2002-07-09
WO2000002553A1 (fr) 2000-01-20

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