CN1244191A - 稳定的、非吸湿性的l(-)肉碱和链烷酰基l(-)肉碱的盐和其制备方法以及含有此盐的固体口服组合物 - Google Patents
稳定的、非吸湿性的l(-)肉碱和链烷酰基l(-)肉碱的盐和其制备方法以及含有此盐的固体口服组合物 Download PDFInfo
- Publication number
- CN1244191A CN1244191A CN97195145A CN97195145A CN1244191A CN 1244191 A CN1244191 A CN 1244191A CN 97195145 A CN97195145 A CN 97195145A CN 97195145 A CN97195145 A CN 97195145A CN 1244191 A CN1244191 A CN 1244191A
- Authority
- CN
- China
- Prior art keywords
- carnitine
- salt
- alkanoyl
- mutate
- composition
- 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
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical class C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 150000003839 salts Chemical class 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title claims abstract description 22
- 125000001589 carboacyl group Chemical class 0.000 title claims abstract description 14
- 239000007787 solid Substances 0.000 title claims abstract description 13
- 230000008569 process Effects 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title description 10
- -1 butyryl radicals Chemical class 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 21
- 239000002002 slurry Substances 0.000 claims description 18
- 239000011541 reaction mixture Substances 0.000 claims description 13
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims description 12
- 239000003826 tablet Substances 0.000 claims description 11
- 235000005911 diet Nutrition 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 235000013305 food Nutrition 0.000 claims description 9
- 230000037213 diet Effects 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000007910 chewable tablet Substances 0.000 claims description 5
- 229940068682 chewable tablet Drugs 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 5
- 238000006297 dehydration reaction Methods 0.000 claims description 5
- 235000015872 dietary supplement Nutrition 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000007937 lozenge Substances 0.000 claims description 3
- 235000008935 nutritious Nutrition 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000013589 supplement Substances 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
- 239000006187 pill Substances 0.000 claims 1
- 229940023488 pill Drugs 0.000 claims 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical group C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 abstract description 7
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 abstract 2
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 abstract 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 238000000227 grinding Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229960004203 carnitine Drugs 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000016709 nutrition Nutrition 0.000 description 4
- 230000035764 nutrition Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004026 adhesive bonding Methods 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000001851 biosynthetic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000005357 flat glass Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229960001518 levocarnitine Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000011837 pasties Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VOTPLFCPIRIALF-UHFFFAOYSA-N 3-(2,4-dioxo-1h-pyrimidine-6-carbonyl)oxy-4-(trimethylazaniumyl)butanoate Chemical compound C[N+](C)(C)CC(CC([O-])=O)OC(=O)C1=CC(=O)NC(=O)N1 VOTPLFCPIRIALF-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000011805 ball Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical group O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019680 high-energy food Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011268 mixed slurry Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical group OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000007967 peppermint flavor Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000010891 toxic waste Substances 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/285—Polyhydroxy dicarboxylic acids having five or more carbon atoms, e.g. saccharic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
Abstract
公开了稳定的、非吸湿性的式(Ⅰ)的L(-)肉碱和链烷酰基L(-)肉碱和半乳糖二酸的盐,其中,肉碱部分和半乳糖二酸的摩尔比为2∶1。还公开了这种盐的制备方法和含有这种盐的固体口服的组合物。
Description
本发明涉及稳定的、非吸湿性的L(-)肉碱和链烷酰基L(-)肉碱的盐,其制备方法和包含有此盐的固体口服组合物。
这些盐适宜于制备适合口服的固体药物组合物,例如:锭剂、药片、咀嚼片、胶囊、颗粒剂、粉末等。其中,L(-)肉碱或链烷酰基L(-)肉碱构成活性成份可任选地和常用药用赋形剂调配。
这些稳定的、非吸温性的盐还方便可包含其它活性成份的固体组合物的生产,其它活性成份例如是具有营养和/或饮食作用的物质。对于广大的使用者来说,这些口服组合物是最优选的服用形式。并且其自身正在所谓的保健食品、药用食品(Medical food)或药物营养品(nutraceutical)市场逐渐发展壮大。从常规的观点来看,这些术语还没有经过严格地定义。它们是指食品或食品成份,如食品补充物(food supplements)、食用产品(dietetic Products)、高能食品(energy foods)等。即为混配物,这些混配物并不致力于主要的或专门的治疗目的,而是致力于增进健康和改善消费者的总体健康状况,或防止由于饮食缺陷或由于年龄增长而造成必要的内生物质的生物合成的不充足从而导致的新陈代谢紊乱。
在本领域当中,对L(-)肉碱和其衍生物日益增加兴趣,这源于日益增长的广泛认识,并得到科学证据的证实:L(-)肉碱和低级链烷酰基L(-)肉碱,除了具有众所周知的治疗各种疾病的医疗价值外,而且还对职业运动员和任何从事运动者(包括业余运动员)的骨骼肌肉系统供能和增强对长期、紧张压力的耐受性具有突出贡献,其可增强这些人的运动能力。
另外,对于素食主义者来说,L(-)肉碱或其低级链烷酰基衍生物是必不可少的营养补充物,因为,其饮食中的肉碱成份以及两种氨基酸,即赖氨酸和蛋氨酸的含量较低。而这两种氨基酸是L(-)肉碱在肾和肺中生物合成的前体。
这些同样的考虑因素不仅对那些必须进行长时间节食和摄入蛋白质较少的人适用,而且,通常还适用于那些虽然并不表现出任何明显的确定的病理特征,但感到虚弱、体验到特定的紧张或生理和/或精神疲痨状态的人。
所有的这些应用表明,固体口服组合物是优选的存在形式,因为其使得使用者特别方便服用这些物质并遵守最佳的剂量规则。
而且,日益感兴趣的还在于L(-)肉碱和其衍生物可用于兽医领域,作为动物饲料补充物用于饲养牲畜、一些种类的鱼和最值得一提的是用于饲养贵重的动物,如赛马和良种马。
很久就知道L(-)肉碱和其链烷酰基衍生物,当其以如下式所示的内盐(或“甜菜碱”)的形式存在时,极容易吸湿并且很不稳定其中,R=H或C1~C5低级链烷酰基。
这导致原材料和最终产物的处理、稳定性和贮藏比较复杂。例如:L(-)肉碱药片必须包在附加的外壳中以使其不接触空气,因为,否则的话即使在通常湿度条件下,这些药片都会发生变化、膨胀并且变得成糊状的或胶粘的。而且由于其不够稳定而释放出痕量的三乙胺而产生令人不适的腥味。
众所周知,L(-)肉碱和其链烷酰基衍生物的盐也表现出与所谓内盐的(或“甜菜碱”)同样的治疗、营养或饮食作用,因此可代替使用。前提是这些盐是“药物学上可接受的”,即不表现出有害的毒性或副作用。实际上,选择“内盐”还是真正的L(-)肉碱或链烷酰基L(-)肉碱的盐主要取决于药物上的考虑因素,而不是治疗、营养或饮食考虑因素。
为方便处理,药物技术人员真正感兴趣的在于L(-)肉碱和其衍生物的盐(不象其内盐)为固体并且稳定,特别是在长时间贮藏条件下是非吸湿性的。因此,可很容易地加以加工以及与常用赋形剂通过传统形式的混和、制片等装置加以调配。而且,当转变成最终产品后,没有裹包的问题。无论是原材料形式的还是调配成最终产品的这些盐,即使在不理想的贮藏条件下也不应释放痕量的三乙胺,从而不会产生令使用者讨厌的效果。
目前,有大量的文献、尤其是专利公开了生产稳定的、非吸湿性的L(-)肉碱的盐和其衍生物的方法。
公开于1962年6月19日的日本专利No.30367(Tanabe Seiyaku)(公开文本No.5199/19),公开了肉碱乳清酸盐的制备方法,并声称“其吸湿性比肉碱和其典型的盐(即氯化肉碱盐)要小得多,因此可很容易加工处理”。
美国专利4,602,039(Sigma-Tau)(授权日1986年7月22日)公开了L(-)肉碱马来酸盐和富马酸盐。
法国专利申请No.82 11626(Sanofi)(公开于1984年1月6日,公开号No.2529545)公开了非吸湿性的L(-)肉碱硫酸盐和草酸盐。
最后,欧州专利EP0434088(LONZA)公开了利用非吸湿性的L(-)肉碱L(+)酒石酸盐(2∶1)(然而,其制备和物理化学特征由D.Müller和E.Strack描述在Hoppe Seyler′sS.Physiol.Chem.第353卷,618-622页,1972年4月)制备适合于口服的固体形式的如药片、胶囊、粉末或颗粒。
所有的这些L(-)肉碱盐,虽然其吸湿性要大大小于内盐,并具有比内盐或多或少的重要的优点,然而还存在某些缺点。
首先,L(-)肉碱的富马酸、马来酸和乳清酸形式的盐,其中L(-)肉碱和酸的摩尔比相等,即1∶1而不是2∶1。这构成的不利之处在于L(-)肉碱部分,它才是具有有益的治疗、营养或饮食作用的部分,与不产生这些作用的部分相比较,其百分含量较低而不能令人满意。而且所采用的成盐的酸分子量越大,其含量就越低。所以,例如在L(-)肉碱乳清酸盐中,L(-)肉碱的含量仅为约51%。
L(-)肉碱草酸盐(也是1∶1的盐)由于草酸的毒性而能不使用。
L(-)肉碱酒石酸盐,它具有是2∶1的盐的优点。(L(-)肉碱的百分含量为68%),但其长时间贮藏不够稳定,释放出痕量的三乙胺而造成上面提到的极令人不适的气味,并且在相对湿度稍为超过60%时即潮解。
另外,上述任何一种酸都不能和L(-)肉碱及低级链烷酰基L(-)肉碱、尤其是乙酰基L(-)肉碱,同时形成稳定的、非吸湿性的盐。例如,L(-)肉碱富马酸盐和L(-)肉碱酒石酸盐很容易结晶并且是非吸湿性化合物(参见US4,602,039,Müller和Strack,loc.cit.和EP0434088),但相应地,乙酰基L(-)肉碱富马酸盐和酒石酸盐均为严重吸湿性化合物,存在和相应内盐一样的缺点。
本发明提供了L(-)肉碱和链烷酰基L(-)肉碱的可药用盐,其既没有相应内盐的易吸湿性、贮藏稳定性差、加工处理困难和裹包问题的缺点,也没有上面提到的已知非吸湿性盐的缺点。
更具体地,本发明提供了固体的、非吸湿性的盐,这种盐稳定,甚至在贮藏条件(就持续时间、温度和相对湿度而言)比已知盐释放三乙胺的那些条件要差得多的情况下,也不释放痕量的三乙胺。另外,在本发明的非吸湿性的L(-)肉碱盐和链烷酰基L(-)肉碱盐中具有同样的阴离子。在所有的这些盐中,L(-)肉碱部分和酸部分的摩尔比均为2∶1。
本发明的盐为L(-)肉碱和链烷酰基L(-)肉碱与半乳糖二酸所形成的具有式(I)的盐:其中,R为氢或含有2-12个碳原子的直链或支链的链烷酰基。
链烷酰基优选为含有2-5个碳原子的低级链烷酰基。
链烷酰基更优选选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
根据本发明的特别优选的盐的实例有:L(-)肉碱半乳糖二酸盐(2∶1)、乙酰基L(-)肉碱半乳糖二酸盐(2∶1)、丙酰基L(-)肉碱半乳糖二酸盐(2∶1)和异戊酰基L(-)肉碱半乳糖二酸盐(2∶1)。
半乳糖二酸(或粘酸)及其盐均是无毒性化合物。
实际上,曾建议用半乳糖二酸的铵盐代替酒石酸氢钾用于油炸馅饼粉(backing powder)中和生产粒状泡腾盐。而且,半乳糖二酸根阴离子是包含在FDA认可的可在市场销售的盐的目录中(参见:药物学杂志(Journalof Pharmaceutical Sciences)第66卷,第1期1977年1月,第3页)。
本发明方法也比现有技术方法具有突出的优点。
已知方法需要使用大量的水或醇-水混和物或有机溶剂(如甲醇、乙醇、异丁醇)来溶解L(-)肉碱内盐和/或合适的酸[如L(+)酒石酸或富马酸],以进行成盐化反应和后续的结晶过程。例如:按照上文引用的专利EP0434088,首先制备L(+)酒石酸于含水的90%乙醇中的沸腾溶液,然后向其中加入L(-)肉碱内盐。这使得必须在较高的温度(50-60℃)和减压(约200Torr)的条件下浓缩大量的包含有这种肉碱盐的溶液,而这造成明显的能量浪费。而且,使用有机溶剂的成本较高,并造成溶剂循环利用、环境污染和有毒废料处理的严重问题。
本发明方法克服了已知方法的这些缺点,从下面的详细描述,可以很清楚地看到这一点。
本发明制备固体的、非吸湿性和稳定的式(I)的盐的方法包括以下步骤:
(a)在室温下将L(-)肉碱内盐或链烷酰基L(-)肉碱内盐(其中链烷酰基如前定义)和得到糊状的淤浆或半液体稠状物所必需的最少量的水混和;
(b)在室温下,向所制备的淤浆中加入摩尔量为L(-)肉碱内盐或如前所述的链烷酰基L(-)肉碱内盐的一半的半乳糖二酸并且充分混和均匀所得的反应混合物;
(c)通过将反应混合物置于相对湿度不高于50%的空气中的方法进行反应混和物的固化/脱水,或通过干燥的手段来加速固化/脱水过程;和
(d)可选择地,研磨固化反应混合物得到颗粒或粉末的产品盐。
在进行步骤(c)的过程中,如果优选用加速固化/脱水步骤(b)中所得到的反应混和物的方法来代替放置反应混和物的方法,可将其加料到连续干燥器中或分批干燥器中,如化工领域技术人员熟知的汽轮盘式干燥器(turbotray drier)、直热旋转式干燥器(direct-heat rotary drier)、转鼓式干燥机、带式干燥机(belt drier)、喷雾干燥器、流化床干燥器和类似的工业干燥器(参见,如Kirk-Othmer化工技术百科全书的“干燥”部分(“Drying”in Kirk-Othmer′s Encyclopedia of Chemical Technology),第8卷,91-112页,1979年。)
或者,可通过用极少量的无毒易挥发的、与水互溶,但L(-)肉碱半乳糖二酸盐和链烷酰基L(-)肉碱半乳糖二酸盐不溶的溶剂(如丙酮)处理来进行反应混和物的脱水过程。
下述非限制性的实施用来说明根据本发明方法制备L(-)肉碱和一些链烷酰基L(-)肉碱的半乳糖二酸盐的方法及其物化特征。实施例1:L(-)肉碱半乳糖二酸盐(2∶1)
(1.a)将161.2g(1.0mol)的L(-)肉碱内盐和30ml的蒸馏水在研缸中混和得到半液体的淤浆。向淤浆中加入105.1g(0.5mol)的半乳糖二酸。所得混和物用杵充分混和均匀。一旦形成均匀的、半透明的、胶粘的和灰白色的“糊状物”,其可以平展在研缸的底部和壁上。为了加速这种半乳糖二酸盐的固化过程,将所形成的产物暴露于风扇的空气流(空气相对湿度约为40~45%,室温约为22℃)。15-20分钟后,固化的L(-)肉碱半乳糖二酸盐可研磨成所需大小的颗粒。
通过重复几次如前所述的制备方法,发现最终产品[L(-)肉碱半乳糖二酸盐(2∶1)]中的含水量是一致的,为1.7-1.9%(重量)。
收率:100%
IR(KBr)cm-1 3500-3000(OH),1726(COOH);1594(COO-);
1244(C-Osp2);1106-1048(C-Osp3)
1H-NMR(200MHz,DMSO-d6,ppm以TMS为参照):2.10-2.35
(m,4H,CH2COO);3,14(s,18H,(CH3)3-N+);3,32(d,4H,CH2-N+);
3.62(s,2H,(CHOH-CHOH-COOH)2);
3.95(s,2H,(CHOH-CHOH-COOH)2);
4.31-4.37(m,2H,CH2-CH-CH2);4.86-5.21(m,8H,OH)
元素分析结果 C20H40N2O14
计算值: C45.10 H7.57 N5.25
实验值: C44.97 H7.54 N5.33(1.b)还可通过简单地将产物放置数小时,即无需将产物暴露于任何气流中,来使L(-)肉碱半乳糖二酸盐固化和去水自然发生,直至得到可研磨的产品。(1.c)或者,不用杵在研缸中混和淤浆,而用刮刀将L(-)肉碱和半乳糖二酸的淤浆在玻璃板上进行均化。
为了加速水份的自然除去,将所得到的半乳糖二酸盐平铺在玻璃板上形成薄薄一层。这个结果类似于(1.b)中所述的方法,但是,水份除去的时间更短。
在所有的上文情况下,L(-)肉碱含量(基于无水产品计算)为60.5%实施例2:L(-)肉碱半乳糖二酸盐(2∶1)
将16.2g(0.1mol)的L(-)肉碱内盐和3ml的蒸馏水在研缸中混和得到半液体淤浆。向所制得的淤浆中加入10.5g(0.05mol)的半乳糖二酸,并将所得混合物用杵充分混和均匀直到形成半透明的、胶粘的和灰白色的“糊状物”。
当“糊状物”开始固化时,继续用杵搅拌混和的同时,向其中加入70ml的丙酮。其后不久在室温下再用30ml的丙酮洗涤、过滤并且在真空条件下干燥,得到精细的粉状半乳糖二酸盐固体。
这样,实际得到的化合物是无水的。
收率:大于99%实施例3:乙酰基L(-)肉碱半乳糖二酸盐(2∶1)
将203.2g(1.0mol)的乙酰基L(-)肉碱内盐和35ml的蒸馏水在研缸中混和得到半液体淤浆。向此液浆中加入105.1g(0.5mol)的半乳糖二酸,然后接着进行与实施例1相同的程序。反应混和物的特性和实施例1的相同。
重复几次上述制备过程,发现最终产品[乙酰基L(-)肉碱半乳糖二酸盐(2∶1)]的含水量为2.7-3.1%(重量)
收率:100%
乙酰基L(-)肉碱的含量(按无水产品计算)为65.9%。
IR(KBr)cm-13500-3000(OH),1740(COCH3,COOH);
1592(COO-),1234(C-O)sp2);1106-1048(C-Osp3)
1H-NMR(200MHz,DMSO-d6,ppm以TMS为参照);
2,05(s,6H,COCH3);2.3-2.6(m,4H,CH2COO);
3.11(s,18H,(CH3)3-N+);3.61(s,2H,(CHOH-CHOH-COOH)2);
3.67-3.73(m,4H,CH2-N+);3.95(s,2H,(CHOH-CHOH-COOH)2);
5.36-5.42(宽峰m,8H,CH2-CH-CH2和OH)
元素分析结果 C24H44N2O16
计算值: C46.74 H7.19 N4.54
实验值: C46.62 H7.14 N4.61实施例4:丙酰基L(-)肉碱半乳糖二酸盐(2∶1)
将217.2g(1.0mol)的丙酰基L(-)肉碱内盐和35ml的蒸馏水在研缸中混和得到半液体淤浆。然后向此淤浆中加入105.1g(0.5mol)的半乳糖二酸,然后接着进行与实施例1相同的程序。反应混和物的特性和实施例1的相同。重复制备几次,得到最终产品[丙酰基L(-)肉碱半乳糖二酸盐(2∶1)]的含水量一致为2.4-2.9%(重量)。
收率:100%
丙酰基L(-)肉碱的含量(按无水产品计算)为67.4%
IR(KBr)cm-1 3500-3000(OH),1738(COCH2CH3,COOH),
1590(COO-),1240(C-Osp2),1104-1040(C-Osp3)
1H-NMR(200MHz,DMSO-d6,ppm以TMS为参照);
1,03(t,6H,CH2CH3);2.2-2.6(m,8H,CH2CH3和CH2COO);
3.11(s,18H,(CH3)3-N+);3.62(s,2H,(CHOH-CHOH-COOH)2);
3.67-3.80(m,4H,CH2-N+);3.96(s,2H,(CHOH-CHOH-COOH)2);
5.30-5.45(宽峰m8H,CH2-CH-CH2和OH)
元素分析结果: C26H48N2O16
计算值: C48.44 H7.50 N4.34
实验质: C48.22 H7.44 N4.25实施例5:异戊酰基L(-)肉碱半乳糖二酸盐(2∶1)
将245.2g(1.0mol)的异戊酰基L(-)肉碱内盐和38ml的蒸馏水在研缸中混和得到半液体的淤浆,然后,向此淤浆中加入105.1g(0.5mol)的半乳糖二酸。接着进行和实施例1相同的程序。反应混和物的特性和实施例1的相同。
重复制备几次,得到最终产品[异戊酰基L(-)肉碱半乳糖二酸盐(2∶1)]的含水量一致为3.3-3.7%(重量)
收率: 100%
异戊酰基L(-)肉碱的含量(按无水产品来计算)为70.0%。
很明显,最终产物中的含湿量取决于多种因素,如起始L(-)肉碱或链烷酰基肉碱的含湿量、进行生产操作的工厂内空气的相对湿度和温度、整个加工操作时间和最终产品的颗粒大小。
而且,显然本发明方法比较现有技术具有几个突出的优点,
a)本方法是在室温和环境压力下进行的;
b)避免使用有机溶剂(或者仅用极少量的有机溶剂),这样就避免了环境污染;
c)收率实际上是定量的;
d)起始的L(-)肉碱或链烷酰基L(-)肉碱内盐不需要是无水的,只要知道其起始含湿量就足够了。
e)通过简单地调整所加的水量(10%-30%,基于整个淤浆的重量),即可使起始混和物的稠度发生变化,从半液体淤浆到不同流动性的浓淤浆。这使得可对脱水方法进行选择:从在相对湿度较低(如:30-40%)的环境中进行水份自然蒸发到用如前所述的工业干燥器来加速水的除去。
本发明的组合物也可以是药物组合物、非处方(OTC)组合物、食品补充物、饮食补充物、保健食品、药用食品、药物营养品、兽医产品和饲料的形式。
本发明的组合物可任选地包括:常用的赋形剂,填料,粘合剂,润滑剂,脱模剂,流动性调节剂,色素和调味剂以及其它的活性成份如维生素、氨基酸、痕量元素、矿物质等。
本发明组合物可以以单位剂量形式出现而作成药片、咀嚼片、丸、粒剂、锭剂和胶囊,它们分别包含有量为相当于50-1000mg、优选100-500mg的L(-)肉碱内盐或链烷酰基L(-)肉碱内盐的式(I)的盐。
对于在兽医领域的应用或作为饲料,优选粉末和颗粒剂。
下面描述的是一些单位剂量形式的组合物实施例。
a)L(-)肉碱半乳糖二酸盐咀嚼片组成
单个咀嚼片包含:
活性成份
L(-)肉碱半乳糖二酸盐 1.650g
(相当于1g的L(-)肉碱内盐)
赋形剂:
薄荷调味粉 0.075g
甘草调味粉 0.075g
蔗糖 1.730g
玉米淀粉 0.090g
硬脂酸镁 0.090g
(b)乙酰基L(-)肉碱药片的组成
单个药片包含:
活性成份: 759mg
乙酰基L(-)肉碱半乳糖二酸盐
(相当于500g的乙酰基L(-)肉内盐)赋形剂微晶纤维素、聚乙烯基吡咯烷酮、硬脂酸镁、纤维素、乙酸酯邻苯二甲酸酯、邻苯二甲酸二乙酯、二甲硅油。(c)丙酰基L(-)肉碱半乳糖二酸盐药片的组成单个药片包含:活性成份丙酰基L(-)肉碱半乳糖二酸盐 635mg(相当于500mg的丙酰基L(-)肉碱内盐)赋形剂微晶纤维素 54.0mg聚乙烯基吡咯烷酮 18.0mgCrospovidone 30.0mg硬脂酸镁 15.0mg沉淀出的二氧化硅 3.0mg羟丙基甲基纤维素 10.0mg聚乙二醇6000 2.5mg二氧化钛 1.8mg甲基丙烯酸酯共聚物 8.3mg纯净的滑石 2.4mg
Claims (10)
2.权利要求1的盐,其中链烷酰基是含有2-5个碳原子的低级链烷酰基。
3.权利要求2的盐,其中低级链烷酰基选自乙酰基、丙酰基、丁酰基、戊酰基和异戊酰基。
4.权利要求1-3的盐,它选自L(-)肉碱半乳糖二酸盐(2∶1)、乙酰基L(-)肉碱半乳糖二酸盐(2∶1)、丙酰基L(-)肉碱半乳糖二酸盐(2∶1)和异戊酰基L(-)肉碱半乳糖二酸盐(2∶1)。
6.权利要求5的方法,其中干燥手段选自连续干燥器、分批干燥器、汽轮盘式干燥器、直热旋转式干燥器、转鼓式干燥机、带式干燥机、喷雾干燥器和流化床干燥器。
8.权利要求7的组合物,它包括药物组合物、OTC组合物、保健食品、药用食品、药物营养品、饮食补充物、营养补充物、兽医产品或饲料。
9.权利要求8的组合物,它为药片、咀嚼片、片剂、丸剂、锭剂、胶囊、粉末或颗粒的形式。
10.权利要求7-9的组合物,它为单位剂量形式,包含式(I)的盐的量相当于50-1000mg、优选100-500mg的L(-)肉碱内盐或链烷酰基L(-)肉碱内盐。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI96A001116 | 1996-05-31 | ||
ITMI961116 IT1283086B1 (it) | 1996-05-31 | 1996-05-31 | Sali stabili e non igroscopici di l-carnitina e di alcanoil l-carnitine |
ITMI97A000409 | 1997-02-25 | ||
IT97MI000409A IT1289974B1 (it) | 1997-02-25 | 1997-02-25 | Procedimento per la produzione di sali stabili e non igroscopici di l(-)carnitina e di alcanoli l(-)-carnitine |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1244191A true CN1244191A (zh) | 2000-02-09 |
CN1177807C CN1177807C (zh) | 2004-12-01 |
Family
ID=26331398
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB971951454A Expired - Lifetime CN1177807C (zh) | 1996-05-31 | 1997-05-26 | 稳定的、非吸湿性的l(-)肉碱和链烷酰基l(-)肉碱的盐和其制备方法以及含有此盐的固体口服组合物 |
Country Status (24)
Country | Link |
---|---|
US (1) | US5952379A (zh) |
EP (1) | EP0914315B1 (zh) |
JP (1) | JP4160634B2 (zh) |
CN (1) | CN1177807C (zh) |
AT (1) | ATE200479T1 (zh) |
AU (1) | AU718308B2 (zh) |
BR (1) | BR9709627A (zh) |
CZ (1) | CZ290902B6 (zh) |
DE (1) | DE69704561T2 (zh) |
DK (1) | DK0914315T3 (zh) |
EE (1) | EE03604B1 (zh) |
ES (1) | ES2156381T3 (zh) |
GR (1) | GR3035969T3 (zh) |
HK (1) | HK1024463A1 (zh) |
HU (1) | HU228008B1 (zh) |
IL (1) | IL127266A (zh) |
IS (1) | IS2085B (zh) |
NO (1) | NO323593B1 (zh) |
NZ (1) | NZ333061A (zh) |
PL (1) | PL188558B1 (zh) |
PT (1) | PT914315E (zh) |
SK (1) | SK283105B6 (zh) |
TR (1) | TR199802492T2 (zh) |
WO (1) | WO1997046512A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106045919A (zh) * | 2016-07-07 | 2016-10-26 | 黄冈华阳药业有限公司 | 一种左旋肉碱乳清酸盐的制备方法 |
CN106748845A (zh) * | 2016-12-23 | 2017-05-31 | 东北制药集团股份有限公司 | 一种左旋肉碱盐微粉的制备方法 |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1289974B1 (it) | 1997-02-25 | 1998-10-19 | Aldo Fassi | Procedimento per la produzione di sali stabili e non igroscopici di l(-)carnitina e di alcanoli l(-)-carnitine |
IT1312018B1 (it) * | 1999-03-19 | 2002-04-04 | Fassi Aldo | Procedimento migliorato per la produzione di sali non igroscopicidella l(-)-carnitina. |
AU770563B2 (en) * | 1999-09-03 | 2004-02-26 | Alfasigma S.p.A | Ultrafine l-carnitine, methods of preparing the same, compositions containing the same, and methods of using the same |
IT1316988B1 (it) * | 2000-02-10 | 2003-05-26 | Sigma Tau Ind Farmaceuti | Procedimento migliorato di preparazione industriale di mucati dellal-carnitina e di alcanoil l-carnitine. |
US8252309B2 (en) * | 2000-04-04 | 2012-08-28 | Sigma-Tau Industrie Farmaceutiche Riunite Spa | Dietary supplement energy-providing to skeletal muscles |
ITRM20010029A1 (it) * | 2001-01-23 | 2002-07-23 | Aldo Fassi | Sali metallici di carnitine utili come integratori dietetici/nutrizionali o come farmaci, composizioni che li contengono e procedimenti per |
ITRM20010030A1 (it) * | 2001-01-23 | 2002-07-23 | Aldo Fassi | Sali di carnitine utili come integratori dietetici/nutrizionali o come farmaci, composizioni che li contengono e procedimenti per la loro pr |
ITRM20010044A1 (it) * | 2001-01-29 | 2002-07-29 | Sigma Tau Healthscience Spa | Integratore alimentare ad effetto dimagrante. |
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 |
ITRM20020055A1 (it) * | 2002-02-04 | 2003-08-04 | Aldo Fassi | Sali metallici di carnitine, integratori dietetici/nutritivi che li contengono e kit dietetici per contrastare disturbi sessuali in soggetti |
JP2006111550A (ja) * | 2004-10-13 | 2006-04-27 | Nisshin Pharma Inc | カルニチン含有製品 |
ES2385046T3 (es) * | 2005-07-05 | 2012-07-17 | Lonza Ag | Procedimiento de secado por pulverización para producir un polvo o granulado de carnitina seco |
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 |
EP2425834A1 (en) * | 2010-09-06 | 2012-03-07 | Lonza Ltd. | Process for the production of l-carnitine tartrate |
CN102911067A (zh) * | 2011-08-04 | 2013-02-06 | 广州市奥海生物科技有限公司 | 左旋肉碱丙酮酸盐及其制备方法与用途 |
CN102911068A (zh) * | 2011-08-04 | 2013-02-06 | 广州市奥海生物科技有限公司 | 左旋肉碱l-苹果酸盐及其制备方法与用途 |
US9637479B2 (en) * | 2013-04-26 | 2017-05-02 | Sanofi | Tartrate salt of 5-chloro-thiophene-2-carboxylic acid [(S)-2-[2-methyl-3-(2-oxo-pyrrolidin-1-yl)-benzenesulfonylamino]-3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]amide |
CN103664667A (zh) * | 2013-12-16 | 2014-03-26 | 天津天成制药有限公司 | 乙酰左旋肉碱硝酸盐的制备方法 |
CN112250588B (zh) * | 2020-11-06 | 2023-03-31 | 哈尔滨工业大学(深圳) | 一种左旋肉碱离子液体及其制备方法、应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR5656M (zh) * | 1965-10-12 | 1967-12-26 | ||
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 |
US5073376A (en) * | 1989-12-22 | 1991-12-17 | Lonza Ltd. | Preparations containing l-carnitine |
IT1258370B (it) * | 1992-03-02 | 1996-02-26 | Sigma Tau Ind Farmaceuti | Esteri della l-carnitina e di acil l-carnitine dotati di attivita' miorilassante selettiva sull'apparato gastro-intestinale e composizioni farmaceutiche che li contengono. |
IT1261808B (it) * | 1993-07-06 | 1996-06-03 | Impiego di l-carnitina o acido l-carnitine e valproato nel trattamentodei disosrdini convulsivi |
-
1997
- 1997-05-26 EP EP97924007A patent/EP0914315B1/en not_active Expired - Lifetime
- 1997-05-26 TR TR1998/02492T patent/TR199802492T2/xx unknown
- 1997-05-26 ES ES97924007T patent/ES2156381T3/es not_active Expired - Lifetime
- 1997-05-26 JP JP50017398A patent/JP4160634B2/ja not_active Expired - Lifetime
- 1997-05-26 US US09/194,608 patent/US5952379A/en not_active Expired - Lifetime
- 1997-05-26 EE EE9800422A patent/EE03604B1/xx unknown
- 1997-05-26 WO PCT/EP1997/002693 patent/WO1997046512A1/en active IP Right Grant
- 1997-05-26 PL PL97330189A patent/PL188558B1/pl unknown
- 1997-05-26 NZ NZ333061A patent/NZ333061A/xx not_active IP Right Cessation
- 1997-05-26 SK SK1649-98A patent/SK283105B6/sk not_active IP Right Cessation
- 1997-05-26 BR BR9709627A patent/BR9709627A/pt not_active IP Right Cessation
- 1997-05-26 AT AT97924007T patent/ATE200479T1/de active
- 1997-05-26 CZ CZ19983915A patent/CZ290902B6/cs not_active IP Right Cessation
- 1997-05-26 DK DK97924007T patent/DK0914315T3/da active
- 1997-05-26 PT PT97924007T patent/PT914315E/pt unknown
- 1997-05-26 IL IL12726697A patent/IL127266A/en not_active IP Right Cessation
- 1997-05-26 DE DE69704561T patent/DE69704561T2/de not_active Expired - Lifetime
- 1997-05-26 AU AU29612/97A patent/AU718308B2/en not_active Expired
- 1997-05-26 HU HU9903455A patent/HU228008B1/hu unknown
- 1997-05-26 CN CNB971951454A patent/CN1177807C/zh not_active Expired - Lifetime
-
1998
- 1998-11-27 NO NO19985562A patent/NO323593B1/no not_active IP Right Cessation
- 1998-11-30 IS IS4914A patent/IS2085B/is unknown
-
2000
- 2000-06-21 HK HK00103735A patent/HK1024463A1/xx not_active IP Right Cessation
-
2001
- 2001-05-31 GR GR20010400820T patent/GR3035969T3/el unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106045919A (zh) * | 2016-07-07 | 2016-10-26 | 黄冈华阳药业有限公司 | 一种左旋肉碱乳清酸盐的制备方法 |
CN106045919B (zh) * | 2016-07-07 | 2022-08-09 | 湖北楚维药业有限公司 | 一种左旋肉碱乳清酸盐的制备方法 |
CN106748845A (zh) * | 2016-12-23 | 2017-05-31 | 东北制药集团股份有限公司 | 一种左旋肉碱盐微粉的制备方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1177807C (zh) | 稳定的、非吸湿性的l(-)肉碱和链烷酰基l(-)肉碱的盐和其制备方法以及含有此盐的固体口服组合物 | |
CN1610541A (zh) | 新型铬(III)-α氨基酸络合物 | |
US6271258B1 (en) | Process for the preparation of stable, non-hygroscopic salts of L(-)carnitine | |
CN1887882A (zh) | 右旋硫辛酸氨基酸盐及其制备方法 | |
CN1714655A (zh) | 银杏饼干、米饼及其制作方法 | |
CN1253544A (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 | |
CN1194967A (zh) | 具有改进水溶性的蜂胶提取物 | |
CN1137267A (zh) | 用作螯合剂的n,n′-二(2-羟基苄基)-乙二胺n,n′-二乙酸衍生物 | |
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 | |
CN1196672C (zh) | 具有治疗和/或营养活性的活性成分的不吸湿的盐以及含有它们的可口服的组合物 | |
CN1219748C (zh) | 含有l-肉碱和烷酰基l-肉碱与牛磺酸氯化物和甘氨酸氯化物形成的非吸湿性盐的适合于口服给药的固体组合物 | |
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 | |
CA2256712C (en) | Stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines, a process for their preparation and solid, orally administrable compositions containing such salts | |
JP6964876B2 (ja) | オロット酸−カルニチン混合体粉体又はフマル酸−カルニチン混合体粉体の製造方法 | |
CN1241494C (zh) | 畜禽骨超微粉及其制备工艺 | |
EP4362697A1 (en) | Carnitine formulation | |
MXPA98010098A (en) | Stable non-hygroscopic salts of l (-) carnitine and alcanoil-l (-) carnitines, a procedure for their preparation, and solid oral organically administrative compositions containing dichas sa | |
MXPA99007888A (en) | Process for the preparation of stable, non-hygroscopic salts of l(-)carnitine and alkanoyl l(-)carnitines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20041201 |