CN1251573A - 适于口服的、包含l－肉碱或链烷酰基－l－肉碱与2－氨基乙磺酸的非吸湿性盐的固体组合物 - Google Patents
适于口服的、包含l－肉碱或链烷酰基－l－肉碱与2－氨基乙磺酸的非吸湿性盐的固体组合物 Download PDFInfo
- Publication number
- CN1251573A CN1251573A CN98803847A CN98803847A CN1251573A CN 1251573 A CN1251573 A CN 1251573A CN 98803847 A CN98803847 A CN 98803847A CN 98803847 A CN98803847 A CN 98803847A CN 1251573 A CN1251573 A CN 1251573A
- Authority
- CN
- China
- Prior art keywords
- carnitine
- salt
- alkanoyl
- composition
- activeconstituents
- 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.)
- Granted
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 35
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 title claims abstract description 31
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 27
- 229960003080 taurine Drugs 0.000 title abstract description 11
- 239000008247 solid mixture Substances 0.000 title abstract 2
- 235000015872 dietary supplement Nutrition 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 230000037213 diet Effects 0.000 claims description 2
- 235000005911 diet 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
- -1 isovaleryl Chemical group 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
- 238000009472 formulation Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 230000000378 dietary effect Effects 0.000 abstract 1
- 239000013589 supplement Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 235000016709 nutrition Nutrition 0.000 description 6
- 235000013305 food Nutrition 0.000 description 5
- 230000035764 nutrition Effects 0.000 description 5
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000050 nutritive effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 210000000941 bile Anatomy 0.000 description 3
- 229960004203 carnitine Drugs 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 2
- 208000017170 Lipid metabolism disease Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000004458 analytical method Methods 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
- 125000001589 carboacyl group Chemical group 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
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007485 conventional hemodialysis Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 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 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 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
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- OHMUZBMXLJEFLT-SBSPUUFOSA-N NCCS(=O)(=O)O.C(C)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O Chemical compound NCCS(=O)(=O)O.C(C)(=O)[C@](O)(C[N+](C)(C)C)CC([O-])=O OHMUZBMXLJEFLT-SBSPUUFOSA-N 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019728 animal nutrition Nutrition 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000386 athletic effect Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000020774 essential nutrients Nutrition 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 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
- 238000003756 stirring Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Polymers & Plastics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Food Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Zoology (AREA)
- Animal Husbandry (AREA)
- Urology & Nephrology (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Nutrition Science (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Fodder In General (AREA)
Abstract
本发明公开了L－肉碱或低级链烷酰基－L－肉碱与2－氨基乙磺酸的稳定且非吸湿性的盐,它们适于制备用作人用的饮食/营养增补剂和用作兽用的饲料增补剂的固体组合物。
Description
本发明涉及L-肉碱和低级链烷酰基-L-肉碱的稳定的、非吸湿性的、药理学上可接受的盐，它们适合制备固体的、可口服给药的组合物。本发明还涉及这样的组合物。
L-肉碱及其链烷酰基衍生物的各种治疗用途是已知的。例如，在心血管领域，L-肉碱可用于治疗急性和慢性心肌缺血、心绞痛、心力衰竭和心律失常。
在肾病学领域，给那些采用常规血液透析法进行治疗的慢性尿毒症患者服用L-肉碱，以对抗肌无力和肌痉挛的发作。
其他治疗用途涉及HDL∶LDL+VLDL比率和全胃肠外营养的正常化。
还已知，L(-)-肉碱及其链烷酰基衍生物的盐存在与那些所谓的内盐相同的治疗或营养活性，因此可用于它们所用的地方，所提供的这些盐是“药理学上可接受的”，即，它们没有不需要的毒性或副作用。
实际上，选择内盐还是真正的L(-)-肉碱或链烷酰基-L(-)-肉碱盐，本质上将取决于有效性、经济和药剂学原因，而不是治疗或营养原因。
本发明的目的是提供L-肉碱和低级链烷酰基-L-肉碱的稳定而非吸湿性的盐，与它们的内盐相应物相比，它们具有增强的治疗和/或营养功效。
因此，应当清楚地理解，本发明的盐的功用并不局限于它们与相应的内盐相比的更低的吸湿性和更高的稳定性，而且在于由它们的阴离子部分提供的盐整体上的综合治疗和/或营养价值。因此，这一价值不再仅仅归功于该盐的“肉碱”部分。
由于它们缺乏吸湿性，这些盐可以容易地化合，特别是制备成固体的、可口服的组合物。
正如药学专家所熟知的那样，加工吸湿产品时，在储存和其加工过程中都必需使用湿度控制室。
另外，完成后的产品必须包装在密封的泡罩(blister)中，以避免因湿度产生的不良后果。
无论是原材料的储存，还是它们的加工和包装，所有这些都牵涉到额外成本。
在工业化国家的人口中，有越来越多的运动员(专业或业余的)和健康的人使用食品增补剂或“营养剂”(nutraceuticals)。
从前使用L-肉碱或含有L-肉碱的食品增补剂，是因为它能促进脂肪酸的氧化，使骨胳肌可获得大量能量，由此使运动员的肌肉增强并使其中乳酸的积聚减少。
健康的人使用这些食品增补剂作为健康食物，即，目的是有助于血清脂肪水平的降低和各种胆固醇成分间的比率的正常化，以预防发生脂质代谢性疾病。
据估计，非凭处方出售的L-肉碱及其衍生物的量是凭处方出售的量的两倍。
美国销售的食品增补剂或营养剂相当于大约2500亿美元，而估计的欧洲市场的销售金额大约为5000亿美元(食品标记新闻(FoodLabeling News)，1994年，“营养剂”市场据说很大，3月，第2卷，第25号；国王通讯集团公司，1993年，全球市场中的“营养剂”食品、饮料。食品与饮料日报(Food and Drink Daily)，4月，第3卷，第503号)。
有一些L-肉碱的非吸湿性的盐是已知的。
例如，1990年12月21日申请的专利EP 0 434 088(LONZA)公开了非吸湿性L(-)肉碱L(+)酒石酸盐(2∶1)(不过，D.Müller和E.Strack在1972年4月的Hoppe Seyler’s Z.Physiol.Chem.353，第618-622页中描述了该盐的制备和物理化学特性)可用于制备适于口服的固体剂型。
但是，该盐存在一些缺点，诸如，经长期储存后，会有微量三甲胺释放出来，使该产品产生一种令人不愉快的腥臭味。另外，L(-)-肉碱L(+)-酒石酸盐(2∶1)在相对温度稍超过60％时就会潮解。而且，L-(+)-酒石酸不能与链烷酰基-L-肉碱类，如乙酰L-肉碱，生成非吸湿性盐。
本发明的上述目的，即，提供一种L-肉碱和低级链烷酰基-L-肉碱的新的、稳定的、非吸湿性的药理学上可接受的盐，其中阴离子部分有助于该盐的治疗和/或营养价值，是通过式(I)的盐实现的，其中该盐的阴离子是2-氨基乙磺酸(或牛磺酸)的阴离子：
其中R是氢或具有2-5个碳原子的直链或支链低级链烷酰基。
优选的盐是其中R选自乙酰、丙酰、丁酰、戊酰和异戊酰基的那些。
牛磺酸或2-氨基乙磺酸是人体中最丰富的氨基酸之一，已在中枢神经系统和骨胳肌中发现了它们，并发现它们集中在脑和心脏中。
长期以来，已知它是哺乳动物生长和发育过程中的必需营养素，事实上，它存在于母乳中，对于小脑和视网膜的发育尤其重要。
牛磺酸还完成非常重要的代谢功能：在胆汁中，胆汁酸与牛磺酸结合，分别形成甘氨胆酸和牛磺胆酸。
胆汁酸的盐具有重要的降低溶液表面张力的性能。由于此原因，它们是极佳的乳化剂，并在肠中在脂质的摄取和消化中起到重要作用。
这些重要的代谢和营养特性使得牛磺酸，当其与L-肉碱结合时，对L-肉碱的功能起到补充作用。
事实上，牛磺酸通过帮助脂肪酸的乳化和消化，产生了与后来的L-肉碱产生的代谢活性互补的活性，即，用于生成能量的脂肪酸的氧化作用。
该盐的两部分(即L-肉碱和牛磺酸)的代谢作用的这种互补性，特别适用于人或动物的营养，无论是在生理学状况，即在健康状态下，还是在儿童及成人的吸收障碍综合征中均适用。
由于牛磺酸促进了更多的能量输出，这种新的盐证明特别可用作运动员(专业或业余的)的食品增补剂。对于健康的人，它们可以作为健康食品，因为它们促进了脂肪的消化，预防了脂质代谢性疾病的发生。
式(I)的盐是非吸湿性的，在长期储存时有高度稳定性。
以下非限制性的实施例显示了按照本发明的一些非吸湿性盐的制备。实施例1L-肉碱2-氨基乙磺酸盐(ST 1290)的制备
P6，15行结构式
将L-肉碱内盐(3.2g；0.02mol)和牛磺酸(2.5g；0.02mol)溶于水(终体积100mL)。所得溶液真空浓缩。
将残余物溶于异丁醇，所得混合物真空浓缩以除去水。将该粗反应产物悬浮于丙酮中。所得混合物在室温下搅拌过夜，然后过滤。
得到5.6g固态的、非吸湿性固体。M.P.＝170℃(分解)[α]D 25＝-15.9(c＝1％，H2O)HPLC：固定相：SGE-SAX(5μm)250×4.0mm，t＝25℃洗脱剂：CH3CN/KH2PO4 50mM 72/28 pH5.6流速：0.75mL/分Rt L-肉碱：11.9分钟 51.3％Rt牛磺酸：9.7分钟 44.3％H2O(K.F.法)：5.7％对C9H21N2O6S的元素分析
C％ H％ N％计算值(有5.7％水)： 35.72 7.63 9.25实测值： 35.32 8.31 9.10NMR D2O δ 4.4(m，1H，CHOH)；3.3(4H，m，N+CH2；NH2CH2)；3.1-3.0(13H，d+s，(CH3)3N+；CH2SO3)；2.2(2H，d，CH2COO)实施例2乙酰L-肉碱2-氨基乙磺酸盐(ST 1294)的制备
如实施例1中所述，制备乙酰L-肉碱2-氨基乙磺酸盐。
得到固体的、非吸湿性化合物。M.P.＝140℃(分解)[α]D 25＝-15.06(c＝1％，H2O)HPLC：固定相：Spherisorb SCX(5μm)250×4mm，t＝25℃洗脱剂：CH3CN/NH4H2PO4 50mM 60/40 pH 4流速： 0.75mL/分Rt乙酰L-肉碱：12.08分钟 54％Rt牛磺酸： 4.711分钟 41％H2O：6.4％对C11H24N2O7S的元素分析
C％ H％ N％计算值(有6.4％水)： 37.65 7.61 7.98实测值： 36.86 7.45 7.9NMR D2O δ 5.6(1H，m，CHOCO)；3.9-3.4(2H，m，N+CH2)；3.4(2H，t，NH2CH2)；3.3-3.1(2H，t，CH2SO3；9H，s，(CH3)3N+)；2.4-2.5(2H，m，CH2COO)；2.1(3H，s，COCH3)
前述实施例的这些化合物都是非吸湿和高度稳定的。
本发明还涉及组合物，该组合物包含作为活性物质的、至少一种上述非吸湿性的药理学上可接受的盐，和可选的，一种或多种药理学上可接受的赋形剂以及药学和食品工艺学专家熟知的活性成分。
特别优选的是固体、可口服的组合物，诸如片剂、咀嚼片和胶囊，该组合物包含式(I)的L-肉碱或链烷酰基-L-肉碱的盐，其量相当于50-2000mg、优选100-1000mg L-肉碱或链烷酰基-L-肉碱内盐。
例如，以下是制备片剂的一种组合物：式(I)的非吸湿性L-肉碱盐： 500mg淀粉 ： 20mg滑石 ： 10mg硬脂酸钙 ： 1mg
531mg
以下是适于制备胶囊的一种组合物：式(I)的非吸湿性L-肉碱盐： 500mg淀粉 ： 20mg乳糖 ： 50mg滑石 ： 5mg硬脂酸钙 ： 2mg
577mg
本发明的组合物可以用作人的饮食/营养增补剂，或用作兽用的饲料增补剂。
Claims (8)
1、式(I)的、L-肉碱或链烷酰基-L-肉碱与2-氨基乙磺酸的盐：
其中R是氢，或具有2-5个碳原子的直链或支链低级链烷酰基。
2、权利要求1所述的盐，其中R选自乙酰、丙酰、丁酰、戊酰和异戊酰基。
3、一种组合物，它包含作为活性成分的、如权利要求1或2定义的通式(I)的盐。
4、权利要求3所述的组合物，它进一步包含一种或多种选自药理学上可接受的赋形剂和活性成分的物质。
5、权利要求3或4所述的组合物，它是片剂、咀嚼片、胶囊、颗粒或粉末形式的。
6、权利要求3-4任一项所述的组合物，每单位剂型中包含作为活性成分的、式(I)的L-肉碱或链烷酰基-L-肉碱的盐，其量相当于50-2000mg、优选100-1000mg L-肉碱或链烷酰基-L-肉碱内盐。
7、权利要求3-6任一项所述的组合物，它作为人用的饮食/营养增补剂。
8、权利要求3-4任一项所述的组合物，它作为兽用的饲料增补剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM97A000184 | 1997-04-01 | ||
| IT97RM000184A IT1291126B1 (it) | 1997-04-01 | 1997-04-01 | Composizioni solide atte alla somministrazione orale comprendenti sali non igroscopici della l-carnitina e delle alcanoil l-carnitine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1251573A true CN1251573A (zh) | 2000-04-26 |
| CN1187318C CN1187318C (zh) | 2005-02-02 |
Family
ID=11404924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988038471A Expired - Lifetime CN1187318C (zh) | 1997-04-01 | 1998-03-19 | 适于口服的、包含l－肉碱或链烷酰基－l－肉碱与2－氨基乙磺酸的非吸湿性盐的固体组合物 |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US6124360A (zh) |
| EP (1) | EP0971880B1 (zh) |
| JP (1) | JP4047935B2 (zh) |
| KR (1) | KR100562055B1 (zh) |
| CN (1) | CN1187318C (zh) |
| AT (1) | ATE210111T1 (zh) |
| AU (1) | AU733272B2 (zh) |
| BR (1) | BR9808461A (zh) |
| CA (1) | CA2285380C (zh) |
| CZ (1) | CZ296465B6 (zh) |
| DE (1) | DE69802789T2 (zh) |
| DK (1) | DK0971880T3 (zh) |
| ES (1) | ES2167878T3 (zh) |
| HK (1) | HK1025560A1 (zh) |
| HU (1) | HU226109B1 (zh) |
| IL (2) | IL131956A0 (zh) |
| IT (1) | IT1291126B1 (zh) |
| NZ (1) | NZ500537A (zh) |
| PL (1) | PL189488B1 (zh) |
| PT (1) | PT971880E (zh) |
| SI (1) | SI0971880T1 (zh) |
| SK (1) | SK283392B6 (zh) |
| WO (1) | WO1998043945A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104276986A (zh) * | 2013-07-12 | 2015-01-14 | 辽宁科硕营养科技有限公司 | 左旋肉碱牛磺酸盐的制备方法 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6090849A (en) * | 1999-03-23 | 2000-07-18 | The Board Of Regents For Oklahoma State University | Carnitine supplemented diet to prevent sudden death syndrome in breeder type poultry |
| 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 |
| IT1317924B1 (it) * | 2000-10-31 | 2003-07-15 | Sigma Tau Ind Farmaceuti | Composizioni solide atte alla somministrazione orale comprendenti salinon igroscopici della l-carnitina e delle alcanoil l-carnitine con |
| DE20321010U1 (de) * | 2003-03-28 | 2005-12-29 | Schymura, Martin | Fruchtgummizusammensetzung |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| IT1188176B (it) * | 1985-07-05 | 1988-01-07 | Bicresearch Spa | Sali della carnitina particolarmente idonei per uso orale |
| SE8701662L (sv) * | 1987-04-22 | 1988-10-23 | Gelder Nico M Van | Saett och medel foer att behandla neurologiska sjukdomar, exempelvis migraen genom paaverkan av nervcellerna |
| 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 |
| US5571783A (en) * | 1993-03-09 | 1996-11-05 | Clintec Nutrition Company | Composition and method for treating patients with hepatic disease |
| 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. |
| US5589468A (en) * | 1995-01-13 | 1996-12-31 | Clintec Nutrition Co. | Method for providing nutrition to elderly patients |
-
1997
- 1997-04-01 IT IT97RM000184A patent/IT1291126B1/it active IP Right Grant
-
1998
- 1998-03-19 PT PT98912695T patent/PT971880E/pt unknown
- 1998-03-19 AT AT98912695T patent/ATE210111T1/de active
- 1998-03-19 EP EP98912695A patent/EP0971880B1/en not_active Expired - Lifetime
- 1998-03-19 CZ CZ0347899A patent/CZ296465B6/cs not_active IP Right Cessation
- 1998-03-19 PL PL98335937A patent/PL189488B1/pl unknown
- 1998-03-19 DE DE69802789T patent/DE69802789T2/de not_active Expired - Lifetime
- 1998-03-19 US US09/381,806 patent/US6124360A/en not_active Expired - Lifetime
- 1998-03-19 CN CNB988038471A patent/CN1187318C/zh not_active Expired - Lifetime
- 1998-03-19 KR KR1019997008943A patent/KR100562055B1/ko not_active IP Right Cessation
- 1998-03-19 JP JP54137798A patent/JP4047935B2/ja not_active Expired - Lifetime
- 1998-03-19 SK SK1350-99A patent/SK283392B6/sk not_active IP Right Cessation
- 1998-03-19 BR BR9808461-5A patent/BR9808461A/pt not_active Application Discontinuation
- 1998-03-19 CA CA002285380A patent/CA2285380C/en not_active Expired - Lifetime
- 1998-03-19 IL IL13195698A patent/IL131956A0/xx active IP Right Grant
- 1998-03-19 SI SI9830060T patent/SI0971880T1/xx unknown
- 1998-03-19 WO PCT/IT1998/000060 patent/WO1998043945A1/en active IP Right Grant
- 1998-03-19 AU AU67455/98A patent/AU733272B2/en not_active Expired
- 1998-03-19 DK DK98912695T patent/DK0971880T3/da active
- 1998-03-19 ES ES98912695T patent/ES2167878T3/es not_active Expired - Lifetime
- 1998-03-19 NZ NZ500537A patent/NZ500537A/xx not_active IP Right Cessation
- 1998-03-19 HU HU0001866A patent/HU226109B1/hu unknown
-
1999
- 1999-09-16 IL IL131956A patent/IL131956A/en not_active IP Right Cessation
-
2000
- 2000-04-20 HK HK00102414A patent/HK1025560A1/xx not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104276986A (zh) * | 2013-07-12 | 2015-01-14 | 辽宁科硕营养科技有限公司 | 左旋肉碱牛磺酸盐的制备方法 |
| CN104276986B (zh) * | 2013-07-12 | 2016-07-06 | 辽宁科硕营养科技有限公司 | 左旋肉碱牛磺酸盐的制备方法 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1137088C (zh) | 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 | |
| CN1187318C (zh) | 适于口服的、包含l－肉碱或链烷酰基－l－肉碱与2－氨基乙磺酸的非吸湿性盐的固体组合物 | |
| CN1177808C (zh) | 适于口服的、包含l-肉碱或链烷酰基-l-肉碱酒石酸镁的固体组合物 | |
| RU2270191C2 (ru) | Твердые композиции для перорального применения, содержащие негигроскопичные соли l-карнитина и алканоил l-карнитинов с тауринхлоридом | |
| MXPA04000754A (es) | Alfa-cetoglutaratos como ingredientes activos y composiciones que los contienen. | |
| EP0975581B1 (en) | Solid compositions suitable for oral administration comprising l-carnitine or alkanoyl-l-carnitine choline tartrate | |
| AU2001295893A1 (en) | Solid compositions suitable for oral administration containing non-hygroscopic salts of L-carnitine and the alkanoyl L-carnitines with taurine chloride and glycine chloride | |
| MXPA99008994A (en) | Solid compositions suitable for oral administration comprising non hygroscopic salts of l-carnitine and alkanoyl-l-carnitine with 2-aminoethanesulfonic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term | ||
| CX01 | Expiry of patent term |
Granted publication date: 20050202 |