CN1137088C - 包含l-肉碱或烷酰基-l-肉碱富马酸镁的适合于口服的固相组合物 - Google Patents
包含l-肉碱或烷酰基-l-肉碱富马酸镁的适合于口服的固相组合物 Download PDFInfo
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- CN1137088C CN1137088C CNB988046199A CN98804619A CN1137088C CN 1137088 C CN1137088 C CN 1137088C CN B988046199 A CNB988046199 A CN B988046199A CN 98804619 A CN98804619 A CN 98804619A CN 1137088 C CN1137088 C CN 1137088C
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- Prior art keywords
- carnitine
- salt
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- alkyloyl
- magnesium fumarate
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 26
- QUIOHQITLKCGNW-TYYBGVCCSA-L magnesium;(e)-but-2-enedioate Chemical compound [Mg+2].[O-]C(=O)\C=C\C([O-])=O QUIOHQITLKCGNW-TYYBGVCCSA-L 0.000 title abstract description 3
- 239000008247 solid mixture Substances 0.000 title abstract description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims description 20
- 239000000654 additive Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- -1 butyryl radicals Chemical group 0.000 claims description 4
- XLDYJEBFKCKOEC-KLQYNRQASA-L C(C=CC(=O)[O-])(=O)[O-].[Mg+2].C(C)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O Chemical group C(C=CC(=O)[O-])(=O)[O-].[Mg+2].C(C)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O XLDYJEBFKCKOEC-KLQYNRQASA-L 0.000 claims description 3
- VSSQQROXKQQXDN-UNKACTGFSA-L magnesium;(e)-but-2-enedioate;(3r)-3-hydroxy-4-(trimethylazaniumyl)butanoate Chemical group [Mg+2].[O-]C(=O)\C=C\C([O-])=O.C[N+](C)(C)C[C@H](O)CC([O-])=O VSSQQROXKQQXDN-UNKACTGFSA-L 0.000 claims description 3
- 235000020939 nutritional additive Nutrition 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- GIFXLCSXCSKMIR-RPNZMVPVSA-L C(\C=C\C(=O)[O-])(=O)[O-].[Mg+2].C(CC)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O Chemical group C(\C=C\C(=O)[O-])(=O)[O-].[Mg+2].C(CC)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O GIFXLCSXCSKMIR-RPNZMVPVSA-L 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000007910 chewable tablet Substances 0.000 claims description 2
- 229940068682 chewable tablet Drugs 0.000 claims description 2
- 235000013373 food additive Nutrition 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 244000144977 poultry Species 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 3
- 239000002552 dosage form Substances 0.000 claims 2
- 239000008187 granular material Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 235000015872 dietary supplement Nutrition 0.000 abstract 2
- 230000000378 dietary effect Effects 0.000 abstract 1
- 239000013589 supplement Substances 0.000 abstract 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
- 235000013305 food Nutrition 0.000 description 8
- 239000011777 magnesium Substances 0.000 description 7
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229910001425 magnesium ion Inorganic materials 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 235000016709 nutrition Nutrition 0.000 description 5
- 230000035764 nutrition Effects 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007790 solid phase Substances 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 208000007101 Muscle Cramp Diseases 0.000 description 3
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 3
- 208000005392 Spasm Diseases 0.000 description 3
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GJTJQSPLLQWKMB-SECBINFHSA-N (3R)-3-hydroxy-4-oxo-3-[(trimethylazaniumyl)methyl]pentanoate Chemical compound C(C)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O GJTJQSPLLQWKMB-SECBINFHSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 206010021027 Hypomagnesaemia Diseases 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000005257 alkyl acyl group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000000050 nutritive effect Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RZALONVQKUWRRY-FYZOBXCZSA-N 2,3-dihydroxybutanedioic acid;(3r)-3-hydroxy-4-(trimethylazaniumyl)butanoate Chemical compound OC(=O)C(O)C(O)C(O)=O.C[N+](C)(C)C[C@H](O)CC([O-])=O RZALONVQKUWRRY-FYZOBXCZSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HNSUOMBUJRUZHJ-UEMBJLSASA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;(e)-4-hydroxy-4-oxobut-2-enoate Chemical compound OC(=O)\C=C\C(O)=O.C[N+](C)(C)C[C@H](O)CC([O-])=O HNSUOMBUJRUZHJ-UEMBJLSASA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000386 athletic effect Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/105—Aliphatic or alicyclic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Polymers & Plastics (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Food Science & Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Animal Husbandry (AREA)
- Mycology (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
公开了由L-肉碱或烷酰基-L-肉碱富马酸镁组成的稳定的不吸潮的盐，其适用于制备人用的食品/营养添加剂或畜用饲料添加剂的固相组合物。
Description
本发明涉及稳定的不吸潮的L-肉碱和低级烷酰基-L-肉碱的药学可接受的盐，这有助于将其制备成固相可口服的组合物，该组合物不但可作药用而且可于“健康食品”和“营养药物(nutraceutical)”市场。本发明也涉及该组合物。
各种治疗用的L-肉碱和其烷酰基衍生物已为大家所了解，如L-肉碱在心血管领域可用于治疗急性和慢性心肌缺血、心绞痛、心力衰竭和心率失常。
在肾病领域，L-肉碱可施用于经受定期血液透析处理的慢性尿毒症患者以对抗肌无力和肌肉痉挛发作。
其它的治疗用途涉及HDL∶LDL+VLDL比例的正常化和完全肠道外营养。
烷酰基-L-肉碱、乙酰-L-肉碱已用于治疗病理性中枢神经系统失调、尤其是阿尔茨海默症和糖尿病性神经病；丙酰-L-肉碱已用于治疗外周血管疾病和充血性心力衰竭。
还已知L-肉碱和其烷酰基衍生物的盐和它们的内盐具有同样的治疗或营养作用，假如这些盐是“药学可接受的”，即没有不希望的毒性或副作用，就可用于它们的内盐所用的领域。
实际上，在“内盐”和真正的L(-)-肉碱或烷酰基-L(-)-肉碱的选择中，更主要是从利用度、经济和药剂学的角度考虑，而不是从治疗或营养来考虑。
本发明的目的是提供稳定的不吸潮的L-肉碱和低级烷酰基-L-肉碱的盐，其相对于它们对应的内盐具有增强的治疗和/或营养功效。
因此，必须明确本发明的盐之实用性不光局限于相对于相应的内盐它们没有吸湿性和且稳定性较高，而且在于它们具有增强的治疗和/或营养效价。该效价不仅只归于盐的肉碱或烷酰基-L-肉碱部分。没有吸湿性使这些盐容易混合，特别适用于制备固相、可口服的组合物，这些盐自然可用作“健康食品”或“营养药物”。
如药剂学专家所熟知的，吸湿性产品的贮存和加工需要使用控制湿度容器。
而且最终产品必须包裹于密封的药泡中以防止潮湿引起的不良后果。
这些都涉及用于原料贮存、加工与包装的额外的成本。
在工业化国家的人群中，运动员(业余或专业的)和健康的人使用营养或食品添加剂、“健康食品”或“天然药物”很普遍，并且不断增加。
前者使用L-肉碱或含有L-肉碱的营养/食品添加剂是因为它能促进脂肪酸的氧化，为骨骼肌提供大量的能量，增强肌肉功能，减少运动员肌肉中乳酸的积聚。
健康的人们使用这些营养添加剂作为健康食品，其有利于降低血清中脂肪的水平，调整各种胆固醇成分的比例以防止与脂肪代谢紊乱相关的疾病。
据估计，用于非道德目的的L-肉碱和其衍生物的销售量是用于道德目的的两倍。
美国市场的食品添加剂或天然药物的销售额约为2500亿美元，而在欧洲市场估计为约5000亿美元(Food Labeling News，1994，3月号卷2，n°25；King Communications Group Inc.，1993，全球市场中的食品、饮料，日常食品与饮料，4月号卷3，n°503)。
一些不吸潮的L-肉碱的盐已被大家了解。
如在1990年12月21日递交的EP0434088(LONZA)公开了不吸潮的L(-)肉碱L(+)酒石酸盐(2∶1)(D.Müller和E.Strack于HoppeSeyler’s Z.Physiol.Chem 353，618-622，4月，1972中描述了其制备和物理化学性质)用于制备固相适合口服的制剂。
然而该盐存在一些缺点，如长期贮存后释放微量的三甲胺，使该产品有令人不快的腥臭味。而且L(-)-肉碱L(+)-酒石酸盐(2∶1)在相对湿度稍超过60％时会潮解。此外L(+)-酒石酸不能与烷酰基-L-肉碱如乙酰基-L-肉碱形成非吸湿盐。而且应注意到酒石酸阴离子自身并不能增强L-肉碱的治疗/营养效价。
美国专利4602039(SIGMA-TAU)公开了L-肉碱、乙酰-L-肉碱和丙酰-L-肉碱的酸性富马酸盐。L-肉碱的酸性富马酸盐很不易吸潮，比L-肉碱酒石酸盐能经受更高的相对湿度，该特性似乎随连接于L-肉碱骨架上的烷酰基分子量的增大而下降。
本发明上述的目的，即提供新的药学可接受的L-肉碱和低级烷酰基-L-肉碱的盐具有如下结构式，其不但稳定、不吸潮，而且具有比相应的内盐具有更强的治疗和/或营养功效，见结构式(I)：
其中R是氢或含2-5个碳原子的直链或支链低级烷酰基。
优选的盐结构式中的R选自于乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。优选的，其是L-肉碱富马酸镁，乙酰基L-肉碱富马酸镁，丙酰基L-肉碱富马酸镁。
因镁和L-肉碱在长时间高强度体力活动中随汗和尿大量排除，所以本发明的化合物能用作运动员的食品添加剂。
镁离子是参与肌肉收缩的细胞膜酶的重要辅助因子。
镁离子代谢的紊乱通常与总血浆浓度减少有关。反常的低血镁与因细胞收缩性和兴奋性异常而引起的心血管、神经和骨骼肌系统紊乱相关。
在生理条件下，Mg2++和ATP之间反应的平衡常数有利于形成MgATP2+复合物，其是许多细胞ATP酶的底物。
镁离子也影响多种离子通道的特性，其中很多位于多种可兴奋的细胞中，执行关于其它离子如钠、钙和钾的流入的功能。
镁离子有保护心脏功能的作用。镁离子对心血管功能的影响最近受到广泛关注，其可用作治疗剂减轻电生理性能的紊乱，也是如心肌代偿功能失调和高血压等疾病的致病因素。流行病学研究显示，心脏局部缺血发病率与食物和饮用水中钙离子与镁离子的比例成明显的相关性。低镁血症引起肌肉痉挛和自律系统活性增强。
下面的非限制性实施例说明了关于本发明的一种不吸潮的盐的制备。实施例1
L-肉碱富马酸镁的制备(ST1310)
将L-肉碱富马酸(5.4g；0.02摩尔)溶于水中，加入氢氧化镁(1.1g；0.02摩尔)至所得溶液中。搅拌混合物2小时至完全溶解。
所得溶液于40℃减压浓缩，浓缩物与无水乙醇混合，所得混合物搅拌24小时。
过滤所得溶液，得到不吸潮的固态产品(6g)。热分析：
DSC，该化合物在170℃分解而不熔化。
元素分析C11H17NO7Mg
C％ H％ N％
计算值(含8.8％的水)： 40.3 6.2 4.2
测定值： 40.5 6.6 4.1
[α]D 25＝-12.09(c＝1％，H2O)
NMR D2Oδ6.5(2H，s，CH＝CH)；4.5(1H，m，CHOH)；3.4(2H，d，+NCH2)；3.2(9H，s，(CH3)3 +N)；2.4(2H，d，CH2COOH)
HPLC：
柱： Inertsil-ODS3(5μm)250×4.6mm温度： 30℃洗脱液： NaClO4 0.15M+NaH2PO4 0.05MpH： 2.0 H3PO4肉碱： Rt＝5.0分钟富马酸： Rt＝11.1分钟镁的测定柱： DionexCG12A+CS12A8μm 4.0×250mm温度： 室温洗脱液： HCl25mN流速： 1毫升/分钟Mg： Rt＝6.11分钟实施例2 乙酰基L-肉碱富马酸镁的制备(ST1311) 
乙酰基L-肉碱内盐(4.1g；0.02摩尔)、富马酸(2.3g；0.02摩尔)和氢氧化镁(1.1g；0.02摩尔)悬浮于100mL水中，目标混合物搅拌约2小时直到溶解，然后于40℃减压浓缩。
浓缩物在40℃与无水乙醇混合，目标混合物搅拌约2小时。然后过滤所得溶液，得到6.3g固态、不吸潮的产品。热分析：
DSC，该化合物在160℃分解而不熔化。
元素分析C13H19NO8Mg
C％ H％ N％
计算值(含11.7％的水)： 40.3 6.2 3.1
测定值： 38.8 5.9 2.9
[α]D 25＝-11.9(c＝1％，H2O)
NMR D2Oδ6.5(2H，s，CH＝CH)；5.5(1H，m，CHOH)；3.9-3.5(2H，m，+NCH2)；3.1(9H，s，(CH3)3 +N)；2.6-2.3(2H，m，CH2COOH)；2.1(3H，s，COCH3).
HPLC： 与ST1310所用的相同
乙酰基L-肉碱： Rt＝19.8分钟
富马酸： Rt＝11.1分钟
Mg： Rt＝6.11分钟
本发明也涉及这些组合物，其包含作为活性成分的至少一种前述的不吸潮的药学可接受的盐，和任选的一种或多种药学可接受的赋形剂和药剂学与食品工业领域专家所熟知的活性成分。
优选固相、可口服的组合物，如片剂、咀嚼片和胶囊，其包含一种如分子式(I)的L-肉碱或烷酰基-L-肉碱的盐，含量相当于50-2000mg，优选100-1000mgL-肉碱或烷酰基-L-肉碱的内盐。
比如，一种用于制备片剂的组合物如下：
分子式(I)的不吸潮的L-肉碱的盐： 500mg
淀粉： 20mg
滑石粉： 10mg
硬脂酸钙： 1mg
531mg
一种适合制备胶囊的组合物如下：
分子式(I)的不吸潮的L-肉碱的盐： 500mg
淀粉： 20mg
乳糖 50mg
滑石粉： 5mg
硬脂酸钙： 2mg
577mg
本发明的组合物可用作人用食品/营养添加剂或用作畜用饲料添加剂。
通过本发明的盐的各组分产生的协同作用，可达到如下效果：
- 提高能量代谢相关酶的活性；
- 以高效率和较短的恢复期提高对紧张训练程序的耐受和适应；
- 加强心血管系统的功能；和
- 减少出现肌肉痉挛的倾向。
Claims (11)
1.一种式(I)的L-肉碱或烷酰基-L-肉碱盐
其中R是氢或含2-5个碳原子的直链或支链低级烷酰基。
2.权利要求1的盐，其中R选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
3.权利要求1的盐，其是L-肉碱富马酸镁。
4.权利要求1的盐，其是乙酰基L-肉碱富马酸镁。
5.权利要求1的盐，其是丙酰基L-肉碱富马酸镁。
6.一种适于口服施用的组合物，其包含以权利要求1的盐为活性组分以及一种或多种选自药学可接受的赋形剂。
7.权利要求6的组合物，其为片剂、咀嚼片、胶囊、颗粒剂或粉末。
8.权利要求6的组合物，其以单位剂量形式包含作为活性组分的式(I)的L-肉碱或烷酰基-L-肉碱的盐，其含量相当于50-2000mg烷酰基-L-肉碱内盐。
9.权利要求6的组合物，其以单位剂量形式包含作为活性组分的式(I)的L-肉碱或烷酰基-L-肉碱的盐，其含量相当于100-1000mg烷酰基-L-肉碱内盐。
10.权利要求6的组合物用作人用食品/营养添加剂。
11.权利要求6的组合物用作畜用饲料添加剂。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT97RM000254A IT1290600B1 (it) | 1997-04-30 | 1997-04-30 | Composizioni solide atte alla somministrazione orale comprendenti l-carnitina e alcanoil l-carnitine magnesio fumarato |
| ITRM97A000254 | 1997-04-30 |
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| WO2000030637A1 (en) * | 1998-11-26 | 2000-06-02 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of fumarate salt of l-carnitine or its alkanoyl derivatives in ischaemia |
| IT1305308B1 (it) * | 1999-03-26 | 2001-05-04 | Biosint S P A | Granulato ad alto contenuto di l-carnitina o alcanoil-l-carnitina,particolarmente adatto alla produzione di compresse per compressione |
| US6429230B1 (en) | 2000-01-19 | 2002-08-06 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Treating chronic uremic patients undergoing periodical dialysis |
| US6914076B2 (en) * | 2000-01-19 | 2005-07-05 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Treating chronic uremic patients undergoing periodical dialysis |
| US6335369B1 (en) * | 2000-01-19 | 2002-01-01 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Treating chronic uremic patients undergoing periodical dialysis |
| KR20010084849A (ko) * | 2000-02-29 | 2001-09-06 | 손 경 식 | Ｌ-카르니틴을 이용한 기능성 우유 및 그 제조 방법 |
| ATE295690T1 (de) * | 2000-08-29 | 2005-06-15 | Lonza Ag | Verfahren zur herstellung einer granulierbaren mischung und carnitin-magnesium-hydroxycitrat |
| DE10133200A1 (de) * | 2001-07-07 | 2003-01-23 | Beiersdorf Ag | Carnitin enthaltende kosmetische und dermatologische Zubereitungen zur Behandlung und aktiven Prävention trockener Haut und anderer negativer Veränderungen der physiologischen Homöostase der gesunden Haut |
| ITRM20010695A1 (it) * | 2001-11-26 | 2003-05-26 | Sigma Tau Ind Farmaceuti | Uso della propionil l-carnitina o di un suo sale farmacologicamente accettabile per la preparazione di un medicamento per il trattamento del |
| US20030235646A1 (en) * | 2002-03-15 | 2003-12-25 | Lonza Inc. | Method for improving quality of meat by supplementing pig diets and concentrates used therefor |
| JP4539096B2 (ja) * | 2004-01-16 | 2010-09-08 | 日油株式会社 | 油性成分被覆ｌ−カルニチン塩粉末およびその用途 |
| US20050232911A1 (en) * | 2004-04-19 | 2005-10-20 | Schreiber Brian D | Prevention and treatment of metabolic abnormalities associated with excess intramyocellular lipid |
| JP2006111550A (ja) * | 2004-10-13 | 2006-04-27 | Nisshin Pharma Inc | カルニチン含有製品 |
| CN100518537C (zh) * | 2006-01-13 | 2009-07-29 | 天津天隆农业科技有限公司 | 一种含有二十八烷醇和l-肉碱的水产饲料及其生产方法 |
| CN101209975B (zh) | 2006-12-29 | 2010-12-01 | 沈阳科硕营养科技有限公司 | 左旋肉碱富马酸钙及其制备方法与用途 |
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| GB1153640A (en) * | 1967-04-10 | 1969-05-29 | Soc D Etudes Prod Chimique | A Carnitin Salt |
| FR2529545B1 (fr) * | 1982-07-02 | 1985-05-31 | Sanofi Sa | Nouveaux sels de carnitine ainsi que leur procede de preparation |
| EP0150688B1 (en) * | 1983-12-28 | 1987-04-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Salts of l-carnitine and alkanoyl l-carnitines and process for preparing same |
| CA2018137C (en) * | 1989-06-14 | 2000-01-11 | Thomas Scholl | L-carnitine magnesium citrate |
| US5073376A (en) * | 1989-12-22 | 1991-12-17 | Lonza Ltd. | Preparations containing l-carnitine |
| IT1261688B (it) * | 1993-05-28 | 1996-05-29 | Avantgarde Spa | Uso di esteri sull'ossidrile della l-carnitina per produrre composizioni farmaceutiche per il trattamento di affezioni cutanee. |
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| IL132275A0 (en) | 2001-03-19 |
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| SK146299A3 (en) | 2000-09-12 |
| ITRM970254A0 (it) | 1997-04-30 |
| HUP0002198A2 (hu) | 2000-11-28 |
| IT1290600B1 (it) | 1998-12-10 |
| ES2179485T3 (es) | 2003-01-16 |
| CZ381399A3 (cs) | 2000-02-16 |
| WO1998049134A1 (en) | 1998-11-05 |
| HUP0002198A3 (en) | 2001-10-29 |
| KR100556238B1 (ko) | 2006-03-03 |
| CA2288287A1 (en) | 1998-11-05 |
| PT979224E (pt) | 2002-12-31 |
| DE69806590T2 (de) | 2003-01-30 |
| CA2288287C (en) | 2008-06-10 |
| EP0979224B1 (en) | 2002-07-17 |
| SK283818B6 (sk) | 2004-02-03 |
| AU7077698A (en) | 1998-11-24 |
| DK0979224T3 (da) | 2002-09-02 |
| US6051608A (en) | 2000-04-18 |
| CZ290159B6 (cs) | 2002-06-12 |
| PL189602B1 (pl) | 2005-08-31 |
| HK1025559A1 (en) | 2000-11-17 |
| BR9809368A (pt) | 2000-07-04 |
| KR20010020320A (ko) | 2001-03-15 |
| PL336530A1 (en) | 2000-07-03 |
| IL132275A (en) | 2006-08-01 |
| AU733008B2 (en) | 2001-05-03 |
| EP0979224A1 (en) | 2000-02-16 |
| NZ500536A (en) | 2001-04-27 |
| ITRM970254A1 (it) | 1998-10-30 |
| ATE220659T1 (de) | 2002-08-15 |
| DE69806590D1 (de) | 2002-08-22 |
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