US20030176514A1 - Method for preparing a mixture that can be granulated and carnitine-magnesium hydroxycitrate - Google Patents
Method for preparing a mixture that can be granulated and carnitine-magnesium hydroxycitrate Download PDFInfo
- Publication number
- US20030176514A1 US20030176514A1 US10/362,730 US36273003A US2003176514A1 US 20030176514 A1 US20030176514 A1 US 20030176514A1 US 36273003 A US36273003 A US 36273003A US 2003176514 A1 US2003176514 A1 US 2003176514A1
- Authority
- US
- United States
- Prior art keywords
- carnitine
- mixture
- acid
- weight
- magnesium
- 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.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 79
- 238000000034 method Methods 0.000 title claims abstract description 40
- ZMJBYMUCKBYSCP-UHFFFAOYSA-N Hydroxycitric acid Chemical compound OC(=O)C(O)C(O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000011777 magnesium Substances 0.000 title claims abstract description 24
- 229910052749 magnesium Inorganic materials 0.000 title claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 43
- 229940091250 magnesium supplement Drugs 0.000 claims abstract description 17
- 239000004337 magnesium citrate Substances 0.000 claims abstract description 4
- 229960005336 magnesium citrate Drugs 0.000 claims abstract description 4
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical group C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 claims description 59
- 229960004203 carnitine Drugs 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 31
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 25
- -1 alkaline earth metal cation Chemical class 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- 150000007524 organic acids Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 12
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 11
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 9
- 150000004692 metal hydroxides Chemical class 0.000 claims description 9
- ZMJBYMUCKBYSCP-AWFVSMACSA-N (1s,2r)-1,2-dihydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)[C@@H](O)[C@@](O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-AWFVSMACSA-N 0.000 claims description 7
- AXFYFNCPONWUHW-UHFFFAOYSA-N 3-hydroxyisovaleric acid Chemical class CC(C)(O)CC(O)=O AXFYFNCPONWUHW-UHFFFAOYSA-N 0.000 claims description 7
- 235000015872 dietary supplement Nutrition 0.000 claims description 7
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical group [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 7
- 239000000347 magnesium hydroxide Substances 0.000 claims description 7
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 7
- 235000011837 pasties Nutrition 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 235000001968 nicotinic acid Nutrition 0.000 claims description 5
- 239000011664 nicotinic acid Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 claims description 4
- 235000019136 lipoic acid Nutrition 0.000 claims description 4
- 229960003512 nicotinic acid Drugs 0.000 claims description 4
- 229960002663 thioctic acid Drugs 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 3
- 229930003268 Vitamin C Natural products 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical class [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011363 dried mixture Substances 0.000 claims description 3
- 235000019154 vitamin C Nutrition 0.000 claims description 3
- 239000011718 vitamin C Substances 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- 229940110767 coenzyme Q10 Drugs 0.000 claims 1
- 229940089491 hydroxycitric acid Drugs 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 150000004665 fatty acids Chemical class 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 239000003925 fat Substances 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 230000002195 synergetic effect Effects 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 6
- 230000037149 energy metabolism Effects 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 5
- 235000013399 edible fruits Nutrition 0.000 description 5
- 238000004898 kneading Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- ZMJBYMUCKBYSCP-CVYQJGLWSA-N Garcinia acid Chemical compound OC(=O)[C@@H](O)[C@](O)(C(O)=O)CC(O)=O ZMJBYMUCKBYSCP-CVYQJGLWSA-N 0.000 description 4
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 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 4
- 229960004106 citric acid Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000002666 Carnitine O-palmitoyltransferase Human genes 0.000 description 3
- 108010018424 Carnitine O-palmitoyltransferase Proteins 0.000 description 3
- 241000593508 Garcinia Species 0.000 description 3
- 235000000885 Garcinia xanthochymus Nutrition 0.000 description 3
- LTYOQGRJFJAKNA-KKIMTKSISA-N Malonyl CoA Natural products S(C(=O)CC(=O)O)CCNC(=O)CCNC(=O)[C@@H](O)C(CO[P@](=O)(O[P@](=O)(OC[C@H]1[C@@H](OP(=O)(O)O)[C@@H](O)[C@@H](n2c3ncnc(N)c3nc2)O1)O)O)(C)C LTYOQGRJFJAKNA-KKIMTKSISA-N 0.000 description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 230000015572 biosynthetic process Effects 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
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007938 effervescent tablet Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000000892 gravimetry Methods 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 229960000816 magnesium hydroxide Drugs 0.000 description 3
- LTYOQGRJFJAKNA-DVVLENMVSA-N malonyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LTYOQGRJFJAKNA-DVVLENMVSA-N 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 3
- 238000007711 solidification Methods 0.000 description 3
- 230000008023 solidification Effects 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VIOYPGDQEDDCJB-UUCJDPIKSA-H trimagnesium;2-hydroxypropane-1,2,3-tricarboxylate;(3r)-3-hydroxy-4-(trimethylazaniumyl)butanoate Chemical compound [Mg+2].[Mg+2].[Mg+2].C[N+](C)(C)C[C@H](O)CC([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O VIOYPGDQEDDCJB-UUCJDPIKSA-H 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 208000016261 weight loss Diseases 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000000035 biogenic effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229960003624 creatine Drugs 0.000 description 2
- 239000006046 creatine Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 230000009969 flowable effect Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000001261 hydroxy acids Chemical class 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 210000001700 mitochondrial membrane Anatomy 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000000711 polarimetry Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229940035936 ubiquinone Drugs 0.000 description 2
- 150000003669 ubiquinones Chemical class 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- VWVRASTUFJRTHW-UHFFFAOYSA-N 2-[3-(azetidin-3-yloxy)-4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound O=C(CN1C=C(C(OC2CNC2)=N1)C1=CN=C(NC2CC3=C(C2)C=CC=C3)N=C1)N1CCC2=C(C1)N=NN2 VWVRASTUFJRTHW-UHFFFAOYSA-N 0.000 description 1
- HHDDCCUIIUWNGJ-UHFFFAOYSA-N 3-hydroxypyruvic acid Chemical compound OCC(=O)C(O)=O HHDDCCUIIUWNGJ-UHFFFAOYSA-N 0.000 description 1
- 102000004146 ATP citrate synthases Human genes 0.000 description 1
- 108090000662 ATP citrate synthases Proteins 0.000 description 1
- 108010036824 Citrate (pro-3S)-lyase Proteins 0.000 description 1
- ODBLHEXUDAPZAU-ZAFYKAAXSA-N D-threo-isocitric acid Chemical compound OC(=O)[C@H](O)[C@@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-ZAFYKAAXSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010025076 Holoenzymes Proteins 0.000 description 1
- ODBLHEXUDAPZAU-FONMRSAGSA-N Isocitric acid Natural products OC(=O)[C@@H](O)[C@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-FONMRSAGSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 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
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229960001009 acetylcarnitine Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229940125528 allosteric inhibitor Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229960000678 carnitine chloride Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000003212 lipotrophic effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 239000008023 pharmaceutical filler Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N threo-D-isocitric acid Natural products OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
- ZNSCFJFCYOTUTP-UUCJDPIKSA-H trimagnesium 1,2-dihydroxypropane-1,2,3-tricarboxylate (3R)-3-hydroxy-4-(trimethylazaniumyl)butanoate Chemical compound [Mg+2].[Mg+2].[Mg+2].C[N+](C)(C)C[C@H](O)CC([O-])=O.[O-]C(=O)C(O)C(O)(C([O-])=O)CC([O-])=O.[O-]C(=O)C(O)C(O)(C([O-])=O)CC([O-])=O ZNSCFJFCYOTUTP-UUCJDPIKSA-H 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 239000010887 waste solvent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- 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
- A23L33/16—Inorganic salts, minerals or trace elements
- A23L33/165—Complexes or chelates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present application relates to a novel method for preparing a mixture which can be granulated and which is suitable for pharmaceutical dosage forms or for dietary supplementation, comprising at least one hygroscopic substance, preferably L-carnitine.
- the application further relates to such novel mixtures that can be granulated, comprising salts of carnitine, at least one alkali metal or alkaline earth metal cation, and an organic, physiologically acceptable acid.
- the present invention further relates to a carnitine-magnesium hydroxycitrate.
- L-( ⁇ )-Carnitine plays an important part in energy metabolism, in the breakdown of fatty acids, in the eukaryotic organism. It is a vitamin-like substance which has been admixed to food products or administered as dietary supplement or pharmaceutical dosage form for some time to prevent and treat manifestations of deficiency. Such manifestations of deficiency may occur in particular in children and elderly people or when the diet is unbalanced. Magnesium and citrate are likewise physiological substances; manifestations of deficiency due to inadequate intake of magnesium in particular are not rare. They can be prevented by taking Mg products. Citrate is utilized without difficulty in energy metabolism. The muscle tissue of a healthy adult contains approximately 20 g of magnesium and 20 g of L-carnitine. A healthy adult can take about 2 g of L-carnitine additionally each day for optimal energy supply. Since carnitine and magnesium are required for metabolic processes which are closely associated, a combination product has a beneficial synergistic effect.
- L-carnitine is very hygroscopic. This is the cause of a lack of storability of the solid substance and of simple powder mixtures prepared therefrom, and causes problems such as inadequate flowability during the further processing of pure solid carnitine or powdered mixtures containing carnitine in the human food, animal feed or drugs industry.
- EP 402 755 describes the stoichiometric complex salt L-carnitine-magnesium citrate which is distinctly less hygroscopic than free carnitine and is thus stable on storage. At a relative humidity of 56%, the water uptake by the complex salt after storage for 1 week is 21% by weight.
- the complex salt is prepared by mixing the components in aqueous solution at 60° C. The solid is then obtained by spray drying or crystallization. The residual hygroscopicity of the carnitine-magnesium citrate prepared in this way still proves to be a certain problem during storage and further processing. A further reduction is desirable.
- Salts which, besides carnitine, comprise exclusively hydroxy acids such as, for example, tartaric acid, without involvement of metal ions, and which are in a similar way less hygroscopic than pure carnitine are also known. All known methods of preparation without exception require the use of relatively large amounts of water or aqueous solvents and, for the crystallization, also organic solvents. The drying methods, e.g. spray drying, require a considerable energy input or the use of organic solvents. The latter is associated with additional costs and the problem of disposal of the waste solvents.
- the mixture comprises at least one hygroscopic substance, preferably L-carnitine
- the solid hygroscopic substance in a first stage the solid hygroscopic substance is mixed with at least one organic acid and at least one metal hydroxide without addition of water or with addition of not more than 15% by weight of water, and in a second, subsequent stage the water content of the resulting mixture is reduced by drying to below 5% by weight, with the resulting composition preferably remaining viscous and, where appropriate, being solidified in a further step of the method.
- Addition of water means in this connection for the purposes of the present invention the water added in liquid form to the mixture in its entirety, excluding the water of reaction from the neutralization reaction between acid and hydroxide. It can be added as separate liquid, but it can also serve as solvent or suspending agent for example for the acid or the hydroxide; such a solution or suspension can then be added to the mixing process.
- the organic acid and the metal hydroxide are starting substances which are solid per se and which add to the mixture no additional water apart from water of crystallization which is possibly present.
- Solid starting substances mean for the purposes of the present invention preferably free-flowing substances which are in the form of coarse granules or fine powder.
- a hygroscopic substance means for the purposes of the present invention a substance which on storage under standard conditions is prone to conglutination or deliquescence through uptake of water.
- substances which on storage at a relative humidity of 56% under standard conditions show a weight gain of more than 20% after 1 week are regarded as hygroscopic substances within the meaning of the present application. Examples of such hygroscopic substances are carnitine and creatine, which bind moisture strongly.
- carnitine chloride or an alkanoylcarnitine in particular acetylcarnitine.
- alkanoylcarnitine is preferably in the physiological L-( ⁇ ) form, However, it is also possible to use racemic DL-carnitine.
- An organic acid or an acid residue means in the sense of the present application in particular physiologically acceptable monobasic or polybasic organic acids, in particular biogenic hydroxy acids or fruit acids and their derivatives such as, for example, ascorbic acid (vitamin C), tartaric acid, malic acid, pyruvic acid, hydroxypyruvic acid, fumaric acid, glutaric acid, citric acid, ( ⁇ )-hydroxycitric acid or isocitric acid, aspartic acid, glutamic acid, succinic acid, as are customary and approved for example in effervescent tablets and for use in food products or medicaments.
- vitamin C ascorbic acid
- malic acid pyruvic acid
- hydroxypyruvic acid fumaric acid
- glutaric acid citric acid
- ( ⁇ )-hydroxycitric acid or isocitric acid aspartic acid
- glutamic acid glutamic acid
- succinic acid as are customary and approved for example in effervescent tablets and for use in food products or medicaments.
- a metal hydroxide means for the purposes of the present invention preferably those hydroxides which are in solid form, for example alkali metal hydroxides or, in a particularly preferred embodiment, alkaline earth metal hydroxides.
- the alkaline earth elements are expediently physiologically acceptable, such as calcium or magnesium, which occur in the mammalian organism in considerable quantity.
- a composition which can be granulated and has been prepared by the method of the invention is surprisingly distinguished by a particularly low hygroscopicity compared with the starting substance, for example pure carnitine.
- a further advantage of the method of the invention is the avoidance of the addition of large amounts of water, so that eventually costly removal of the residual moisture from the final product is necessary, and the simple manner of preparation which requires no additional processing steps.
- the use of a metal hydroxide together for example with citric acid or another organic acid leads in a neutralization reaction advantageously and directly to an optimal distribution of the water of reaction from the neutralization between the solids particles, and thus permits minimization of the addition of water and suitable flow properties of the powdered or pasty composition.
- the content of added water in the mixture is not more than 3%, and in a particularly preferred embodiment is not more than 1% by weight, and in the most preferred embodiment no additional water is admixed.
- mixing apparatuses known per se to the skilled worker, such as, for example, kneading machines like those normally used for solid or pasty substances. It is also possible for example to use suitable extruders such as, for example, a twin screw extruder. Kneading machines are preferably used as mixing apparatus. The drying can then be carried out directly in the equipment and be carried out to a desired degree of predrying or else to complete drying.
- Such apparatuses expediently have suitable control devices to control the product temperature, because the initial neutralization reaction between acid and metal hydroxide may lead to evolution of much heat.
- the product temperature during the mixing process in the first stage should essentially be, apart from a short initial period, 50° C.-120° C. In a preferred embodiment of the method, the product temperature in the first stage should essentially be 70° C.-120° C. It is preferred first to mix the acid component with the hydroxide component and, after the neutralization reaction, to admix the hygroscopic substance or the carnitine.
- the product temperature on addition of the hygroscopic substance or the carnitine should be at least 50° C., preferably at least 70° C., during the first stage of the method.
- the reaction preferably lasts no more than one hour. It is expedient to mix the organic acid and the metal hydroxide in stoichiometric amounts. The combination of heat, finely dispersed solids and a small content of water as solvent leads to a free-flowing, mixable composition.
- L-carnitine, magnesium hydroxide and citric acid are mixed in stoichiometric amounts, i.e. in a molar ratio of approximately 1:1:1.
- the types of these substances are preferably sufficiently pure, i.e. approved for the manufacture of food products or the preparation of pharmaceuticals, as are described, for example, in the European Pharmacopoeia. Anhydrous types are expediently used.
- the pure L-carnitine is preferably added to the mixture as neutral inert salt. Compared with previous methods of preparation, the hygroscopicity of the complex salt L-carnitine-magnesium citrate prepared in this way is reduced further.
- the moisture uptake determined by gravimetry in the way familiar to the skilled worker, of solid carnitine-Mg citrate prepared by the method of the invention and previously dried to constant weight under oil-pump vacuum or over phosphorus pentoxide is not more than 7% by weight after 48 h at 56% relative humidity (rH). This figure is not exceeded even after storage for 330 h.
- carnitine content Based on the amount of carnitine or carnitine derivative present in the mixture, referred to within the scope of the invention as carnitine content based on free base, this corresponds to a moisture uptake of not more than 40% by weight. It is preferred for at least 80% of the carnitine-Mg citrate, based on the carnitine content in the mixture, to be in the form of complex salt in the mixture of the invention.
- a complex salt from carnitine, magnesium hydroxide and hydroxycitric acid (HCA).
- HCA hydroxycitric acid
- HCA has a special function as agent promoting breakdown of fats.
- Such a combination is particularly advantageous because the advantageous material properties of the complex salt is associated with the synergistic cooperation of the latter's components.
- the method of the invention also permits mixtures of salts which crystallize only poorly using known methods, such as, for example, L-carnitine and ascorbic acid, to be prepared.
- the reduction of the water content of the pasty mixture preferably takes place by drying in vacuo at a minimum of 85° C., in a most preferred embodiment at a minimum of 90° C., and a maximum of 120° C., and takes place under a pressure extending to 25 mbar, preferably not more than 50 mbar.
- the drying may, depending on the amount of product, take up to about 3 h.
- the composition produced in this way is still, despite its increase in solidification as the water content decreases, flowable or pasty to a very limited extent.
- pasty is thus regarded as a composition which is flowable only under elevated pressure (>1 bar) and at a minimum of 85° C., in the sense of flow characteristics referred to as extrusion viscosity.
- the pasty composition is movable in the hot state by suitable apparatuses with an adequate torque.
- Definitive solidification takes place only through cooling. It is possible to expedite the cooling by methods known per se, for example extrusion as thin strand and/or solidification on a cooling belt. It is also possible to add an additional after-drying step during or after the cooling process, for example a further vacuum drying.
- the product can be coarsely comminuted for further processing and sent for a final granulation or fine granulation. It may in a preferred embodiment of the present method be comminuted to a particle size not exceeding 1 mm using apparatuses known per se to the skilled worker.
- the comminution is carried out with screening granulators (from FREWITT) and, on use of an extruder with suitable die plates, preferably directly on the coarse granules produced by the extruder without an additional interpolated comminution step.
- coenzymes such as niacin or niacinamide or other substances which promote growth or the breakdown of fats and which may cooperate synergistically with L-carnitine, such as ⁇ -hydroxy- ⁇ -methylbutyrates, ( ⁇ )-hydroxycitrate, lipoic acid or lipotrophic substances such as lecithin or choline.
- L-carnitine such as ⁇ -hydroxy- ⁇ -methylbutyrates, ( ⁇ )-hydroxycitrate, lipoic acid or lipotrophic substances such as lecithin or choline.
- Ca 2+ like Mg 2+ are required for muscle activity, so that this results in a suitable synergistic effect with the effect of carnitine or else creatine which promotes muscle activity and energy metabolism.
- the present application further relates to a mixture that can be granulated, preferably for dietary supplementation or for pharmaceutical dosage, comprising salts of carnitine, preferably L-carnitine, at least one alkali metal or alkaline earth metal and one physiologically acceptable organic acid, characterized in that the water uptake of the previously dried mixture at a relative humidity of 56° C. under atmospheric pressure and at 25° C. is not more than 15% by weight, preferably not more than 10% by weight, and in a most preferred embodiment not more than 7% by weight, after 24 h, and preferably also after 14 days. Based on the carnitine content of the mixture, the water uptake by the previously dried mixture does not exceed 40% by weight.
- Drying means in this connection drying over phosphorus pentoxide to constant weight at 25° C.
- Salts mean in this connection all possible salt compounds between in each case at least two of the substances present in the mixture of the invention.
- Such a mixture can be prepared by the method of the invention and identifies itself by a particularly low hygroscopicity. Especially with carnitine-magnesium citrate or hydroxycitrate, the latter is further reduced by comparison with the type produced using the previous method of preparation.
- the organic acid or the acid residue present in the mixture is preferably a citrate, a ( ⁇ )-hydroxycitrate or an ascorbate and, preferably, the alkaline earth metal is calcium, magnesium or a mixture of the two.
- the acid residue and the alkaline earth metal cation are, in a preferred embodiment, present in stoichiometrically equivalent amounts.
- the mixture additionally contains at least one other substance from the group consisting of ribose, niacin, niacinamide, ⁇ -hydroxy- ⁇ -methylbutyrate, lipoic acid, coenzyme Q 10 and chromium(III) salts, for example chromium picolinates or chromium nicotinates.
- the present invention further relates to a mixture for dietary supplementation comprising L-carnitine or an alkanoyl carnitine, coenzyme Q and ⁇ -hydroxy- ⁇ -methylbutyrate and, optionally, ( ⁇ )-hydroxycitrate. It may also comprise a combination of various carnitine salts including the inner salts or of the carnitine derivatives and the salts thereof.
- a mixture is novel and can likewise be prepared in a solids-mixing method of the invention, for example using an extruder, as mixture that can be granulated. Such a mixture can, however, also be prepared in another known method.
- the organic acids present in this mixture may be present in the mixture in the protonated form or as salt with a counterion.
- the carnitine or carnitine derivative can be present in the mixture as complex salt or as inner salt or as salt with a counterion.
- the mixture of the invention comprises both substances which promote burning up of fats or mobilization of the body fat and substances which inhibit the neosynthesis of fat and fatty acids.
- Such a mixture can be used in particular as dietary supplement assisting the breakdown of body fat or, as part of a diet, as constituent of food substitute preparations or weight-loss agents.
- Carnitine i.e. in its physiologically active form the L-( ⁇ ) enantiomer, promotes the transport of fat and of the basic metabolic building block acetyl-CoA through cell membranes to the site of utilization in energy metabolism, the mitochondrial matrix. Carnitine thus increases the substance flux during the beta oxidation of fatty acids.
- Ubiquinone or coenzyme Q preferably coenzyme Q 10
- the combination of carnitine and ubiquinone thus represents an advantageous cumulative cooperation of two principles of action.
- ( ⁇ )-Hydroxycitrate inhibits ATP-citrate lyase.
- ⁇ -Hydroxy- ⁇ -methylbutyrate reduces, through substrate inhibition, the availability of acetyl-CoA, the central cofactor in fatty acid and cholesterol biosynthesis.
- coenzyme Q has the function, in the mixture stored in the dry, of an antioxidant promoting storage stability.
- Q10 means the differentiation customary in biochemistry of the biogenic ubiquinones through the length of the isoprenyl side chains, the species with 10 carbon atoms in the side chain being the species which is most frequently represented in most mammals, including humans.
- the mixture of the invention with other ubiquinones physiologically active in humans, as can be obtained for example from microorganisms.
- the predominant coenzyme Q species in yeast S. cerevisiae
- Q6 (6 carbon atoms).
- Such a mixture may comprise at least one or, in any combination, a plurality of substances from the group consisting of vitamin C, lipoic acid, vitamin E, ribose, niacin, niacinamide, creatin and Cr(III) salts, preferably Cr picolinate or Cr nicotinate.
- the substances are well known from sports and health diets and play either a part in energy metabolism or fat utilization, the mobilization of the body's reserves or, as cellular antioxidants, have a protective function in relation to an increased energy metabolism.
- ( ⁇ )-hydroxycitric acid which can be obtained as predominant fruit acid from fruits of the genus Garcinia, is another component of the mixture in the most preferred embodiment.
- Preferred practical embodiments of the mixture of the invention, and of other salts or mixtures of the present invention are dosage forms known per se, such as capsules, coated tablets, tablets, injection solutions, effervescent tablets which contain, for example, 10-1 000 mg of carnitine (or a derivative), 10-1 000 mg of coenzyme Q and 10-1 000 mg of ⁇ -hydroxy- ⁇ -methylbutyrate.
- a conventional hard gelatin two-piece capsule may contain 300 mg of each of the three substances of the invention, mixed with colors and microcrystalline cellulose as carrier. It is, however, also possible to add these substances in comparable amounts to a suitable portion of a food product, for example cornflakes, energy bars, jam etc.
- the present invention further relates to carnitine-magnesium hydroxycitrate.
- This is a salt of low hygroscopicity and can be prepared by the present method through mixing magnesium hydroxide, hydroxycitric acid and carnitine or alkanoyl carnitine in the molar ratio 1:1:1. It is a neutral salt in the stoichiometric composition, in relation to the charge distribution and the ionizable functional groups.
- Hydroxycitrate means for the purposes of the present application preferably the ( ⁇ ) enantiomer as described (Lewis, Y. et al., Water extract of ( ⁇ )Hydroxy-Citric acid from fruit of Garcinia Cambogia, Phytochemistry (1965), 4, p.
- the salt can preferably be used within the meaning of the above statements as weight-loss agent, to promote breakdown of body fat.
- weight-loss agent to promote breakdown of body fat.
- hydroxycitrate as such as weight-loss agent and suitable dosages are described for example in U.S. Pat. No. 5,783,603.
- the novel mixed salt of the invention assists, at least on oral administration, in a surprising, more than just additive, way the occurrence of the desired breakdown of fats and weight loss. This involves a synergistic effect of the mixture in the form of a complex salt.
- HCA is prone to spontaneous lactonization in aqueous solution and in the gastrointestinal tract.
- the complexation with Mg before preparation of a solution might have a stabilizing effect in relation to the unwanted rearrangement of the lactone and thus bring about much greater activity in cooperation with carnitine.
- the salt of the invention at least shows an improved storage stability, in relation to the rearrangement of HCA to the lactone, compared with known HCA salts under standard test conditions customary in the pharmaceutical sector.
- HCA Hydroxycitric acid
- CPT carnitine palmitoyltransferase I
- Malonyl CoA is an important allosteric inhibitor of this enzyme.
- CPT is important for the transport function of carnitine for fatty acids through the mitochondrial membrane and may, if the activity is inadequate, be limiting for carnitine-mediated transport and thus for fatty acid oxidation in the mitochondria.
- malonyl CoA is a direct precursor for the biosynthesis of fatty acids and cholesterol.
- the site of action of HCA is the enzyme citrate lyase which is competitively inhibited by HCA.
- the affinity of the enzyme for HCA is more than 100 times higher than for the natural metabolic substrate citric acid.
- the lactone derivative to which HCA spontaneously cyclizes has a clear lower affinity by comparison.
- Preferred practical implements of the mixture of the invention are dosage forms known per se, such as capsules, coated tablets, tablets, injection solutions, effervescent tablets which contain for example 10-2 000 mg of carnitine-magnesium hydroxycitrate.
- a conventional hard gelatin two-piece capsule may contain 1 000 mg of carnitine-magnesium hydroxycitrate mixed with colors and microcrystalline cellulose as carrier.
- the substance of the invention in comparable amounts to a suitable portion of a food product, for example cornflakes, energy bars, jam etc. It is also possible to use carnitine-magnesium hydroxycitrate mixed with ⁇ -hydroxy- ⁇ -methylbutyrate or other aforementioned substances.
- Preparation takes place in the method described in example 2, mixing 83 g of carnitine (free base), 137 g of ( ⁇ )-hydroxycitric acid HCA-650 77.7%, 30 g of Mg hydroxide and 55 g of water.
- the weight gain of the mixture of the invention which had previously been dried was, after 24 h under standard conditions, 0.82% by weight. At a relative humidity of 56%, the water uptake of the mixture determined by gravimetry was ⁇ 10% by weight after 30 h, corresponding to about 30% by weight based on the carnitine content of the mixture.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nutrition Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Child & Adolescent Psychology (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)
Abstract
The invention relates to a method for preparing, from at least one hygroscopic substance, mixtures that can be granulated and that have little hygroscopicity. The invention further relates to the corresponding mixtures, especially carnitine-magnesium citrate and carnitine-magnesium hydroxycitrate.
Description
- The present application relates to a novel method for preparing a mixture which can be granulated and which is suitable for pharmaceutical dosage forms or for dietary supplementation, comprising at least one hygroscopic substance, preferably L-carnitine. The application further relates to such novel mixtures that can be granulated, comprising salts of carnitine, at least one alkali metal or alkaline earth metal cation, and an organic, physiologically acceptable acid. The present invention further relates to a carnitine-magnesium hydroxycitrate.
- L-(−)-Carnitine plays an important part in energy metabolism, in the breakdown of fatty acids, in the eukaryotic organism. It is a vitamin-like substance which has been admixed to food products or administered as dietary supplement or pharmaceutical dosage form for some time to prevent and treat manifestations of deficiency. Such manifestations of deficiency may occur in particular in children and elderly people or when the diet is unbalanced. Magnesium and citrate are likewise physiological substances; manifestations of deficiency due to inadequate intake of magnesium in particular are not rare. They can be prevented by taking Mg products. Citrate is utilized without difficulty in energy metabolism. The muscle tissue of a healthy adult contains approximately 20 g of magnesium and 20 g of L-carnitine. A healthy adult can take about 2 g of L-carnitine additionally each day for optimal energy supply. Since carnitine and magnesium are required for metabolic processes which are closely associated, a combination product has a beneficial synergistic effect.
- It is well known that L-carnitine is very hygroscopic. This is the cause of a lack of storability of the solid substance and of simple powder mixtures prepared therefrom, and causes problems such as inadequate flowability during the further processing of pure solid carnitine or powdered mixtures containing carnitine in the human food, animal feed or drugs industry.
- EP 402 755 describes the stoichiometric complex salt L-carnitine-magnesium citrate which is distinctly less hygroscopic than free carnitine and is thus stable on storage. At a relative humidity of 56%, the water uptake by the complex salt after storage for 1 week is 21% by weight. The complex salt is prepared by mixing the components in aqueous solution at 60° C. The solid is then obtained by spray drying or crystallization. The residual hygroscopicity of the carnitine-magnesium citrate prepared in this way still proves to be a certain problem during storage and further processing. A further reduction is desirable.
- Salts which, besides carnitine, comprise exclusively hydroxy acids such as, for example, tartaric acid, without involvement of metal ions, and which are in a similar way less hygroscopic than pure carnitine are also known. All known methods of preparation without exception require the use of relatively large amounts of water or aqueous solvents and, for the crystallization, also organic solvents. The drying methods, e.g. spray drying, require a considerable energy input or the use of organic solvents. The latter is associated with additional costs and the problem of disposal of the waste solvents.
- It is the object of the present invention to avoid this and other disadvantages of the prior art.
- This object is achieved by the method of preparation as claimed in claim 1, and by mixtures and salts as claimed in claims 9 and 12.
- In one method of the invention for preparing a mixture that can be granulated for dietary supplementation or pharmaceutical use, where the mixture comprises at least one hygroscopic substance, preferably L-carnitine, in a first stage the solid hygroscopic substance is mixed with at least one organic acid and at least one metal hydroxide without addition of water or with addition of not more than 15% by weight of water, and in a second, subsequent stage the water content of the resulting mixture is reduced by drying to below 5% by weight, with the resulting composition preferably remaining viscous and, where appropriate, being solidified in a further step of the method.
- Addition of water means in this connection for the purposes of the present invention the water added in liquid form to the mixture in its entirety, excluding the water of reaction from the neutralization reaction between acid and hydroxide. It can be added as separate liquid, but it can also serve as solvent or suspending agent for example for the acid or the hydroxide; such a solution or suspension can then be added to the mixing process. In this sense, the organic acid and the metal hydroxide are starting substances which are solid per se and which add to the mixture no additional water apart from water of crystallization which is possibly present.
- Solid starting substances mean for the purposes of the present invention preferably free-flowing substances which are in the form of coarse granules or fine powder. A hygroscopic substance means for the purposes of the present invention a substance which on storage under standard conditions is prone to conglutination or deliquescence through uptake of water. In particular, substances which on storage at a relative humidity of 56% under standard conditions show a weight gain of more than 20% after 1 week are regarded as hygroscopic substances within the meaning of the present application. Examples of such hygroscopic substances are carnitine and creatine, which bind moisture strongly. However, a further possibility is the salt or derivative of such a hygroscopic compound, for example carnitine chloride or an alkanoylcarnitine, in particular acetylcarnitine. For the purposes of the present invention, carnitine or alkanoylcarnitine is preferably in the physiological L-(−) form, However, it is also possible to use racemic DL-carnitine. An organic acid or an acid residue means in the sense of the present application in particular physiologically acceptable monobasic or polybasic organic acids, in particular biogenic hydroxy acids or fruit acids and their derivatives such as, for example, ascorbic acid (vitamin C), tartaric acid, malic acid, pyruvic acid, hydroxypyruvic acid, fumaric acid, glutaric acid, citric acid, (−)-hydroxycitric acid or isocitric acid, aspartic acid, glutamic acid, succinic acid, as are customary and approved for example in effervescent tablets and for use in food products or medicaments. A metal hydroxide means for the purposes of the present invention preferably those hydroxides which are in solid form, for example alkali metal hydroxides or, in a particularly preferred embodiment, alkaline earth metal hydroxides. The alkaline earth elements are expediently physiologically acceptable, such as calcium or magnesium, which occur in the mammalian organism in considerable quantity.
- A composition which can be granulated and has been prepared by the method of the invention is surprisingly distinguished by a particularly low hygroscopicity compared with the starting substance, for example pure carnitine. A further advantage of the method of the invention is the avoidance of the addition of large amounts of water, so that eventually costly removal of the residual moisture from the final product is necessary, and the simple manner of preparation which requires no additional processing steps.
- The use of a metal hydroxide together for example with citric acid or another organic acid leads in a neutralization reaction advantageously and directly to an optimal distribution of the water of reaction from the neutralization between the solids particles, and thus permits minimization of the addition of water and suitable flow properties of the powdered or pasty composition. In a preferred embodiment, the content of added water in the mixture is not more than 3%, and in a particularly preferred embodiment is not more than 1% by weight, and in the most preferred embodiment no additional water is admixed. There is merely in situ formation of a small amount of water, depending on the mixing ratios, through the neutralization reaction. The effect of this according to the invention is faster drying and lower hygroscopicity of the solid product.
- It is also possible to admix other substances such as stabilizers, other active ingredients, pharmaceutical carriers or fillers, waxes, desiccants, colors and the like to the mixture. The method of the invention is also suitable in particular for preparing mixtures of solids which are of low compatibility in relation to their solubility characteristics, e.g. hydrophobic and hydrophilic substances such as, for example, carnitine on the one hand and lipid-soluble vitamins or vitamin-like substances such as vitamin E or coenzyme Q on the other hand.
- It is possible to use for mixing the solid starting substances the mixing apparatuses known per se to the skilled worker, such as, for example, kneading machines like those normally used for solid or pasty substances. It is also possible for example to use suitable extruders such as, for example, a twin screw extruder. Kneading machines are preferably used as mixing apparatus. The drying can then be carried out directly in the equipment and be carried out to a desired degree of predrying or else to complete drying.
- Such apparatuses expediently have suitable control devices to control the product temperature, because the initial neutralization reaction between acid and metal hydroxide may lead to evolution of much heat. The product temperature during the mixing process in the first stage should essentially be, apart from a short initial period, 50° C.-120° C. In a preferred embodiment of the method, the product temperature in the first stage should essentially be 70° C.-120° C. It is preferred first to mix the acid component with the hydroxide component and, after the neutralization reaction, to admix the hygroscopic substance or the carnitine. The product temperature on addition of the hygroscopic substance or the carnitine should be at least 50° C., preferably at least 70° C., during the first stage of the method. The reaction preferably lasts no more than one hour. It is expedient to mix the organic acid and the metal hydroxide in stoichiometric amounts. The combination of heat, finely dispersed solids and a small content of water as solvent leads to a free-flowing, mixable composition.
- In a preferred embodiment, L-carnitine, magnesium hydroxide and citric acid are mixed in stoichiometric amounts, i.e. in a molar ratio of approximately 1:1:1. The types of these substances are preferably sufficiently pure, i.e. approved for the manufacture of food products or the preparation of pharmaceuticals, as are described, for example, in the European Pharmacopoeia. Anhydrous types are expediently used. To avoid an unwanted salt loading, the pure L-carnitine is preferably added to the mixture as neutral inert salt. Compared with previous methods of preparation, the hygroscopicity of the complex salt L-carnitine-magnesium citrate prepared in this way is reduced further. For example, the moisture uptake, determined by gravimetry in the way familiar to the skilled worker, of solid carnitine-Mg citrate prepared by the method of the invention and previously dried to constant weight under oil-pump vacuum or over phosphorus pentoxide is not more than 7% by weight after 48 h at 56% relative humidity (rH). This figure is not exceeded even after storage for 330 h. Based on the amount of carnitine or carnitine derivative present in the mixture, referred to within the scope of the invention as carnitine content based on free base, this corresponds to a moisture uptake of not more than 40% by weight. It is preferred for at least 80% of the carnitine-Mg citrate, based on the carnitine content in the mixture, to be in the form of complex salt in the mixture of the invention.
- It is also possible, in a further preferred embodiment, to prepare a complex salt from carnitine, magnesium hydroxide and hydroxycitric acid (HCA). Hydroxycitric acid is described in detail hereinafter in this description. HCA has a special function as agent promoting breakdown of fats. Such a combination is particularly advantageous because the advantageous material properties of the complex salt is associated with the synergistic cooperation of the latter's components.
- The method of the invention also permits mixtures of salts which crystallize only poorly using known methods, such as, for example, L-carnitine and ascorbic acid, to be prepared.
- The reduction of the water content of the pasty mixture preferably takes place by drying in vacuo at a minimum of 85° C., in a most preferred embodiment at a minimum of 90° C., and a maximum of 120° C., and takes place under a pressure extending to 25 mbar, preferably not more than 50 mbar. The drying may, depending on the amount of product, take up to about 3 h. Surprisingly, the composition produced in this way is still, despite its increase in solidification as the water content decreases, flowable or pasty to a very limited extent. For the purposes of the present invention, pasty is thus regarded as a composition which is flowable only under elevated pressure (>1 bar) and at a minimum of 85° C., in the sense of flow characteristics referred to as extrusion viscosity. The pasty composition is movable in the hot state by suitable apparatuses with an adequate torque. Definitive solidification takes place only through cooling. It is possible to expedite the cooling by methods known per se, for example extrusion as thin strand and/or solidification on a cooling belt. It is also possible to add an additional after-drying step during or after the cooling process, for example a further vacuum drying. On use for example of kneading machines with low torque or with a design which is unfavorable for discharge, it may be expedient to discharge the composition while still hot and while still in a viscous state from the mixing apparatus before the first vacuum drying step and only then to undertake the further processing steps according to the method of the invention.
- Once the product has solidified it can be coarsely comminuted for further processing and sent for a final granulation or fine granulation. It may in a preferred embodiment of the present method be comminuted to a particle size not exceeding 1 mm using apparatuses known per se to the skilled worker. In a further preferred embodiment, the comminution is carried out with screening granulators (from FREWITT) and, on use of an extruder with suitable die plates, preferably directly on the coarse granules produced by the extruder without an additional interpolated comminution step.
- It is also possible to add further active substances to the mixture of the invention during the mixing process in the method of the invention, for example coenzymes such as niacin or niacinamide or other substances which promote growth or the breakdown of fats and which may cooperate synergistically with L-carnitine, such as β-hydroxy-β-methylbutyrates, (−)-hydroxycitrate, lipoic acid or lipotrophic substances such as lecithin or choline. Ca2+ like Mg2+ are required for muscle activity, so that this results in a suitable synergistic effect with the effect of carnitine or else creatine which promotes muscle activity and energy metabolism.
- The present application further relates to a mixture that can be granulated, preferably for dietary supplementation or for pharmaceutical dosage, comprising salts of carnitine, preferably L-carnitine, at least one alkali metal or alkaline earth metal and one physiologically acceptable organic acid, characterized in that the water uptake of the previously dried mixture at a relative humidity of 56° C. under atmospheric pressure and at 25° C. is not more than 15% by weight, preferably not more than 10% by weight, and in a most preferred embodiment not more than 7% by weight, after 24 h, and preferably also after 14 days. Based on the carnitine content of the mixture, the water uptake by the previously dried mixture does not exceed 40% by weight. Drying means in this connection drying over phosphorus pentoxide to constant weight at 25° C. Salts mean in this connection all possible salt compounds between in each case at least two of the substances present in the mixture of the invention. Such a mixture can be prepared by the method of the invention and identifies itself by a particularly low hygroscopicity. Especially with carnitine-magnesium citrate or hydroxycitrate, the latter is further reduced by comparison with the type produced using the previous method of preparation.
- Correspondingly, in a preferred embodiment the organic acid or the acid residue present in the mixture is preferably a citrate, a (−)-hydroxycitrate or an ascorbate and, preferably, the alkaline earth metal is calcium, magnesium or a mixture of the two. In addition, the acid residue and the alkaline earth metal cation are, in a preferred embodiment, present in stoichiometrically equivalent amounts. In a further preferred embodiment, the mixture additionally contains at least one other substance from the group consisting of ribose, niacin, niacinamide, β-hydroxy-β-methylbutyrate, lipoic acid, coenzyme Q 10 and chromium(III) salts, for example chromium picolinates or chromium nicotinates.
- The present invention further relates to a mixture for dietary supplementation comprising L-carnitine or an alkanoyl carnitine, coenzyme Q and β-hydroxy-β-methylbutyrate and, optionally, (−)-hydroxycitrate. It may also comprise a combination of various carnitine salts including the inner salts or of the carnitine derivatives and the salts thereof. Such a mixture is novel and can likewise be prepared in a solids-mixing method of the invention, for example using an extruder, as mixture that can be granulated. Such a mixture can, however, also be prepared in another known method.
- The organic acids present in this mixture may be present in the mixture in the protonated form or as salt with a counterion. In particular, the carnitine or carnitine derivative can be present in the mixture as complex salt or as inner salt or as salt with a counterion. The advantage of such a mixture is the synergistic cooperation of the advantageous properties and physiological functions of the components.
- The mixture of the invention comprises both substances which promote burning up of fats or mobilization of the body fat and substances which inhibit the neosynthesis of fat and fatty acids. Such a mixture can be used in particular as dietary supplement assisting the breakdown of body fat or, as part of a diet, as constituent of food substitute preparations or weight-loss agents.
- Carnitine, i.e. in its physiologically active form the L-(−) enantiomer, promotes the transport of fat and of the basic metabolic building block acetyl-CoA through cell membranes to the site of utilization in energy metabolism, the mitochondrial matrix. Carnitine thus increases the substance flux during the beta oxidation of fatty acids. Ubiquinone or coenzyme Q, preferably coenzyme Q 10, is another molecule able to cross membranes which is, during the redox processes of oxidative phosphorylation, an important intermediary as electron donor in the mitochondrial membrane and thus in the utilization of the metabolic energy generated by burning of fatty acids. The combination of carnitine and ubiquinone thus represents an advantageous cumulative cooperation of two principles of action. At the same time, the neosynthesis of fatty acids and the utilization of alternative energy sources during the citrate cycle is impeded. (−)-Hydroxycitrate inhibits ATP-citrate lyase. β-Hydroxy-β-methylbutyrate reduces, through substrate inhibition, the availability of acetyl-CoA, the central cofactor in fatty acid and cholesterol biosynthesis. In addition, coenzyme Q has the function, in the mixture stored in the dry, of an antioxidant promoting storage stability. For the purposes of the present invention, “Q10” means the differentiation customary in biochemistry of the biogenic ubiquinones through the length of the isoprenyl side chains, the species with 10 carbon atoms in the side chain being the species which is most frequently represented in most mammals, including humans. However, it is also possible to prepare the mixture of the invention with other ubiquinones physiologically active in humans, as can be obtained for example from microorganisms. For example, the predominant coenzyme Q species in yeast (S. cerevisiae) is Q6 (6 carbon atoms).
- It is possible to supplement the mixture of the invention with further ingredients which advantageously support the synergistic effect. Such a mixture may comprise at least one or, in any combination, a plurality of substances from the group consisting of vitamin C, lipoic acid, vitamin E, ribose, niacin, niacinamide, creatin and Cr(III) salts, preferably Cr picolinate or Cr nicotinate. The substances are well known from sports and health diets and play either a part in energy metabolism or fat utilization, the mobilization of the body's reserves or, as cellular antioxidants, have a protective function in relation to an increased energy metabolism. In particular, (−)-hydroxycitric acid, which can be obtained as predominant fruit acid from fruits of the genus Garcinia, is another component of the mixture in the most preferred embodiment.
- Preferred practical embodiments of the mixture of the invention, and of other salts or mixtures of the present invention, are dosage forms known per se, such as capsules, coated tablets, tablets, injection solutions, effervescent tablets which contain, for example, 10-1 000 mg of carnitine (or a derivative), 10-1 000 mg of coenzyme Q and 10-1 000 mg of β-hydroxy-β-methylbutyrate. For example, a conventional hard gelatin two-piece capsule may contain 300 mg of each of the three substances of the invention, mixed with colors and microcrystalline cellulose as carrier. It is, however, also possible to add these substances in comparable amounts to a suitable portion of a food product, for example cornflakes, energy bars, jam etc.
- The present invention further relates to carnitine-magnesium hydroxycitrate. This is a salt of low hygroscopicity and can be prepared by the present method through mixing magnesium hydroxide, hydroxycitric acid and carnitine or alkanoyl carnitine in the molar ratio 1:1:1. It is a neutral salt in the stoichiometric composition, in relation to the charge distribution and the ionizable functional groups. Hydroxycitrate means for the purposes of the present application preferably the (−) enantiomer as described (Lewis, Y. et al., Water extract of (−)Hydroxy-Citric acid from fruit ofGarcinia Cambogia, Phytochemistry (1965), 4, p. 619-625; Lewis, Y. et al., Acetone extract of (−)Hydroxy-Citric acid from the fruit of Garcinia Cambogia. The salt can preferably be used within the meaning of the above statements as weight-loss agent, to promote breakdown of body fat. The use of hydroxycitrate as such as weight-loss agent and suitable dosages are described for example in U.S. Pat. No. 5,783,603. Surprisingly, the novel mixed salt of the invention assists, at least on oral administration, in a surprising, more than just additive, way the occurrence of the desired breakdown of fats and weight loss. This involves a synergistic effect of the mixture in the form of a complex salt. Without wishing to be bound to the theory, it is possible that this effect is brought about by a better bioavailability of the complex salt. HCA is prone to spontaneous lactonization in aqueous solution and in the gastrointestinal tract. The complexation with Mg before preparation of a solution might have a stabilizing effect in relation to the unwanted rearrangement of the lactone and thus bring about much greater activity in cooperation with carnitine. The salt of the invention at least shows an improved storage stability, in relation to the rearrangement of HCA to the lactone, compared with known HCA salts under standard test conditions customary in the pharmaceutical sector. It is also possible that a previously unrecognized stimulating effect in particular of magnesium, in the sense of that stated above concerning the mechanism of action of carnitine and hydroxycitrate, is involved. Allosterically regulated enzymes are often regulated by various factors such as, for example, also Mg cations. Magnesium is moreover an important cofactor for various enzymes or constituent of the holo enzyme. It is possible that the enzyme systems which are important for carnitine and hydroxycitrate, or are influenced thereby, are subject to a simultaneous synergistic control by magnesium ions.
- Hydroxycitric acid (HCA) activates indirectly carnitine palmitoyltransferase I (CPT) through suppression of the synthesis of malonyl CoA. Malonyl CoA is an important allosteric inhibitor of this enzyme. CPT is important for the transport function of carnitine for fatty acids through the mitochondrial membrane and may, if the activity is inadequate, be limiting for carnitine-mediated transport and thus for fatty acid oxidation in the mitochondria. In addition, malonyl CoA is a direct precursor for the biosynthesis of fatty acids and cholesterol.
- The site of action of HCA is the enzyme citrate lyase which is competitively inhibited by HCA. The affinity of the enzyme for HCA is more than 100 times higher than for the natural metabolic substrate citric acid. The lactone derivative to which HCA spontaneously cyclizes has a clear lower affinity by comparison.
- Preferred practical implements of the mixture of the invention are dosage forms known per se, such as capsules, coated tablets, tablets, injection solutions, effervescent tablets which contain for example 10-2 000 mg of carnitine-magnesium hydroxycitrate. For example, a conventional hard gelatin two-piece capsule may contain 1 000 mg of carnitine-magnesium hydroxycitrate mixed with colors and microcrystalline cellulose as carrier. It is, however, also possible to add the substance of the invention in comparable amounts to a suitable portion of a food product, for example cornflakes, energy bars, jam etc. It is also possible to use carnitine-magnesium hydroxycitrate mixed with β-hydroxy-β-methylbutyrate or other aforementioned substances.
- Preparation of L-carnitine-magnesium Citrate
- 128 g of anhydrous citric acid and 39 g of Mg(OH)2 pharm. are mixed in a kneader for small batches (HKD-T 0.6 IKA) with 36 g of deionized water (water content based on complete mixture: 11.6%) while heating to 73° C. for 40 min. 107.5 g of L-carnitine are then added thereto and kneading is continued at 49-50 rpm for 35 min until a gummy white consistency results. After drying in vacuo at 90° C. for 4 h, the composition is dry and hard. The product is checked by IR and polarimetry and is very pure. The product dissolves in water without residue. The water content of the dried substance is 10.1% by weight.
- Preparation of L-carnitine-magnesium Citrate
- 134 g of anhydrous citric acid and 38.5 g of Mg(OH)2 pharm. are initially mixed in a centrifugal force mill for 7 min and then mixed together with 36 g of deionized water (water content based on complete mixture: 11.4%) in a kneader for small batches (HKD-T 0.6 IKA) while heating to 79° C. for 30 min. 107.5 g of L-carnitine are then added thereto, and kneading is continued at 40-50 rpm for 45 min until homogeneous. After drying in vacuo at 90° C. for 4 h, the composition is dry and hard. The product is checked for purity by IR and polarimetry and gives a clear solution in water. The water content of the dried substance is 8.8% by weight.
- Hygroscopicity Test
- The product mixtures from example 1 and 2 granulated to a particle size of <0.8 mm using a FREEWIT screening granulator are stored at a relative humidity of 56% at 25° C. under constant test conditions for the stated times. The sample was previously dried to constant weight over phosphorus pentoxide. The moisture uptake from the air is determined by gravimetry. The weight gain is stated in percent based on the total weight of the sample. Conventional L-carnitine-magnesium citrate from the production method of EP 402 755, which has been press-granulated to the same particle size, serves as reference sample and is comparable in terms of the particle properties (flow, low dust).
+% by weight +% by weight +% by weight Storage time/h reference example 1 example 2 4 5.1 2.0 2.7 8 9.1 2.2 3.0 24 18.1 4.6 5.4 36 17.6 4.4 5.5 48 20.4 5.2 6.4 336 15.6 5.1 6.5 - Preparation of L-carnitine-magnesium (−)-hydroxycitrate
- Preparation takes place in the method described in example 2, mixing 83 g of carnitine (free base), 137 g of (−)-hydroxycitric acid HCA-650 77.7%, 30 g of Mg hydroxide and 55 g of water.
- The weight gain of the mixture of the invention which had previously been dried was, after 24 h under standard conditions, 0.82% by weight. At a relative humidity of 56%, the water uptake of the mixture determined by gravimetry was ≦10% by weight after 30 h, corresponding to about 30% by weight based on the carnitine content of the mixture.
Claims (14)
1. A method for preparing a mixture that can be granulated for dietary supplementation, where the mixture comprises at least one hygroscopic substance, characterized in that
a) in a first stage the solid hygroscopic substance is mixed with at least one organic acid and at least one metal hydroxide without addition of water or with addition of not more than 15% by weight of water based on the weight of the complete mixture, and in that
b) in a second stage the water content of a resulting mixture is reduced by drying to below 5% by weight, with the resulting composition preferably remaining pasty.
2. The method as claimed in claim 1 , characterized in that the hygroscopic substance is carnitine, preferably L-carnitine, or a carnitine derivative or salt thereof, in that the organic acid is citric acid, (−)-hydroxycitric acid, vitamin C or another physiologically acceptable organic acid, and in that the metal hydroxide is magnesium hydroxide or calcium hydroxide.
3. The method as claimed in claim 1 , characterized in that the drying is a vacuum drying, and in that the vacuum drying takes place at 85-120° C. under a pressure of not more than 25 mbar, preferably a pressure of not more than 50 mbar.
4. The method as claimed in claim 1 , characterized in that the mixing which takes place in the first stage takes place at a temperature of 50° C.-120° C., preferably at a temperature of 70° C.-120° C.
5. The method as claimed in claim 4 , characterized in that the content of added water in the mixture is not more than 3% by weight, preferably not more than 1% by weight, based on the total weight of the mixture, and in that the drying is a vacuum drying.
6. The method as claimed in any of the preceding claims, characterized in that the resulting composition is a solid or is solidified and is granulated to particles having a size not exceeding 1 mm.
7. The method as claimed in claim 1 , characterized in that the organic acid and the metal hydroxide are mixed in stoichiometric amounts.
8. The method as claimed in claim 2 , characterized in that carnitine, citric acid and magnesium hydroxide are mixed in the first stage in stoichiometric amounts and form a metal-containing complex salt, namely carnitine-magnesium citrate.
9. A mixture that can be granulated, comprising salts of carnitine, preferably L-carnitine, at least one alkali metal or alkaline earth metal cation and one organic, physiologically acceptable acid, characterized in that the water uptake of the previously dried mixture after 24 h at a relative humidity of 56% under atmospheric pressure and at 25° C. is not more than 16% by weight, preferably not more than 10% by weight, based on the total weight of the mixture.
10. The mixture as claimed in claim 9 , characterized in that the metal cation is magnesium or calcium, and in that the acid is citric acid, (−)-hydroxycitric acid or ascorbic acid.
11. The mixture as claimed in claims 9 or 10, characterized in that the mixture also comprises at least one other substance from the group comprising ribose, niacin or nicainamide, beta-hydroxy-beta-methylbutyrates, lipoic acid, coenzyme Q10 and a chromium(III) salt.
12. A salt compound, characterized in that the salt is carnitine-magnesium hydroxycitrate, and in that the magnesium, the carnitine and the hydroxycitrate are present in a molar ratio 1:1:1.
13. The salt compound as claimed in claim 14 , characterized in that the carnitine is L-carnitine.
14. The salt compound as claimed in claim 14 , characterized in that the salt compound can be prepared in a method as claimed in claim 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/785,013 US7230131B2 (en) | 2000-08-29 | 2004-02-25 | Carnitine-magnesium hydroxycitrate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00118656.8 | 2000-08-29 | ||
EP00118656 | 2000-08-29 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2001/009962 A-371-Of-International WO2002017735A2 (en) | 2000-08-29 | 2001-08-29 | Method for preparing a mixture that can be granulated and carnitine-magnesium hydroxycitrate |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/785,013 Division US7230131B2 (en) | 2000-08-29 | 2004-02-25 | Carnitine-magnesium hydroxycitrate |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030176514A1 true US20030176514A1 (en) | 2003-09-18 |
Family
ID=8169680
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/362,730 Abandoned US20030176514A1 (en) | 2000-08-29 | 2001-08-29 | Method for preparing a mixture that can be granulated and carnitine-magnesium hydroxycitrate |
US10/785,013 Expired - Fee Related US7230131B2 (en) | 2000-08-29 | 2004-02-25 | Carnitine-magnesium hydroxycitrate |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/785,013 Expired - Fee Related US7230131B2 (en) | 2000-08-29 | 2004-02-25 | Carnitine-magnesium hydroxycitrate |
Country Status (10)
Country | Link |
---|---|
US (2) | US20030176514A1 (en) |
EP (1) | EP1326502B1 (en) |
JP (1) | JP4668513B2 (en) |
AT (1) | ATE295690T1 (en) |
AU (1) | AU2001289849A1 (en) |
DE (1) | DE50106272D1 (en) |
DK (1) | DK1326502T3 (en) |
ES (1) | ES2242770T3 (en) |
PT (1) | PT1326502E (en) |
WO (1) | WO2002017735A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005025544A1 (en) * | 2003-09-11 | 2005-03-24 | Glykon Technologies Group, Llc | Enteric delivery of (-)-hydroxycitric acid |
US20070142469A1 (en) * | 2005-12-19 | 2007-06-21 | Thomas Debra L | Method of using beta-hydroxy-beta-methylbutyrate |
US8609725B2 (en) | 2004-03-26 | 2013-12-17 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate for reducing tumor growth rate |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20030831A1 (en) * | 2003-04-22 | 2004-10-23 | Laboratorio Chimico Int Spa | BASIC SALT OF TIOTIC ACID WITH L-CARNITINE. |
EP1734974A1 (en) * | 2004-03-18 | 2006-12-27 | Tanabe Seiyaku Co., Ltd. | D-ribose for improving depression-like symptoms |
AU2006265280B2 (en) | 2005-07-05 | 2011-07-14 | Lonza Ag | Spray-drying process for producing a dry carnitine powder or granulate |
US20070072910A1 (en) * | 2005-09-29 | 2007-03-29 | Smith Michael L | Compositions and methods for lowering plasma concentrations of low density lipoproteins in humans |
CN101209975B (en) * | 2006-12-29 | 2010-12-01 | 沈阳科硕营养科技有限公司 | Levulorotation carnitine calcium fumarate and its preparing method and use |
EP2206440A1 (en) * | 2008-12-24 | 2010-07-14 | Taminco | Process for preparing a free-flowing powder containing a deliquescent quaternary ammonium compound |
US9693577B2 (en) | 2010-01-29 | 2017-07-04 | Abbott Laboratories | Method of preparing a nutritional powder comprising spray dried HMB |
MX2012008784A (en) | 2010-01-29 | 2012-08-17 | Abbott Lab | Aseptically packaged nutritional liquids comprising hmb. |
CN102711524B (en) | 2010-01-29 | 2014-09-10 | 雅培制药有限公司 | Nutritional emulsions comprising calcium HMB |
TWI526161B (en) | 2010-06-10 | 2016-03-21 | 亞培公司 | Substantially clear nutritional liquids comprising calcium hmb and soluble protein |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4602039A (en) * | 1983-12-28 | 1986-07-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Salts of-carnitine and alkanoyl L-carnitines and process for preparing same |
US5071874A (en) * | 1989-06-14 | 1991-12-10 | Lonza Ltd. | L-carnitine magnesium citrate |
US5780451A (en) * | 1994-04-01 | 1998-07-14 | Abbott Laboratories | Nutritional product for a person having ulcerative colitis |
US6051608A (en) * | 1997-04-30 | 2000-04-18 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Solid compositions suitable for oral administration comprising L-carnitine or alkanoyl-L-carnitine magnesium fumarate |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1153640A (en) * | 1967-04-10 | 1969-05-29 | Soc D Etudes Prod Chimique | A Carnitin Salt |
IT1172394B (en) * | 1983-12-28 | 1987-06-18 | Sigma Tau Ind Farmaceuti | SALTS OF L-CARNITINE AND CERTAIN ALCANOIL DERIVATIVES OF L-CARNITINE AND PROCEDURE FOR THEIR PREPARATION |
AU5736096A (en) | 1995-05-15 | 1996-11-29 | Sabinsa Corporation | A new process for the production of potassium hydroxy citric acid, and compositions containing the potassium hydroxy cit ric acid |
IT1276253B1 (en) * | 1995-12-15 | 1997-10-27 | Sigma Tau Ind Farmaceuti | PHARMACEUTICAL COMPOSITION CONTAINING L-CARNITINE OR ALCANOIL L-CARNITINE FOR THE PREVENTION AND TREATMENT OF SOFT STATES |
US5817329A (en) * | 1997-02-28 | 1998-10-06 | Gardiner; Paul T. | Nutritional supplement for increased muscle size and strength for body builders |
IT1291134B1 (en) * | 1997-04-08 | 1998-12-29 | Sigma Tau Ind Farmaceuti | SOLID COMPOSITIONS SUITABLE FOR ORAL ADMINISTRATION INCLUDING AN ALCANOYL L-CARNITINE MAGNESIUM CITRATE |
-
2001
- 2001-08-29 AU AU2001289849A patent/AU2001289849A1/en not_active Abandoned
- 2001-08-29 PT PT01969667T patent/PT1326502E/en unknown
- 2001-08-29 US US10/362,730 patent/US20030176514A1/en not_active Abandoned
- 2001-08-29 DK DK01969667T patent/DK1326502T3/en active
- 2001-08-29 WO PCT/EP2001/009962 patent/WO2002017735A2/en active IP Right Grant
- 2001-08-29 ES ES01969667T patent/ES2242770T3/en not_active Expired - Lifetime
- 2001-08-29 AT AT01969667T patent/ATE295690T1/en active
- 2001-08-29 EP EP01969667A patent/EP1326502B1/en not_active Expired - Lifetime
- 2001-08-29 DE DE50106272T patent/DE50106272D1/en not_active Expired - Lifetime
- 2001-08-29 JP JP2002522720A patent/JP4668513B2/en not_active Expired - Fee Related
-
2004
- 2004-02-25 US US10/785,013 patent/US7230131B2/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4602039A (en) * | 1983-12-28 | 1986-07-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Salts of-carnitine and alkanoyl L-carnitines and process for preparing same |
US5071874A (en) * | 1989-06-14 | 1991-12-10 | Lonza Ltd. | L-carnitine magnesium citrate |
US5780451A (en) * | 1994-04-01 | 1998-07-14 | Abbott Laboratories | Nutritional product for a person having ulcerative colitis |
US6051608A (en) * | 1997-04-30 | 2000-04-18 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Solid compositions suitable for oral administration comprising L-carnitine or alkanoyl-L-carnitine magnesium fumarate |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005025544A1 (en) * | 2003-09-11 | 2005-03-24 | Glykon Technologies Group, Llc | Enteric delivery of (-)-hydroxycitric acid |
US20060292216A1 (en) * | 2003-09-11 | 2006-12-28 | Clouatre Dallas L | Enteric delivery of (-)-hydroxycitric acid |
US8609725B2 (en) | 2004-03-26 | 2013-12-17 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate for reducing tumor growth rate |
US8778994B2 (en) | 2004-03-26 | 2014-07-15 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate and fatty acids for treating disease-associated wasting |
US8778993B2 (en) | 2004-03-26 | 2014-07-15 | Abbott Laboratories | Method of using β-hydroxy-β-methylbutyrate for the treatment of disease conditions |
US8785495B2 (en) | 2004-03-26 | 2014-07-22 | Abbott Laboratories | Compositions including beta-hydroxy-beta-methylbutyrate |
US8785496B2 (en) | 2004-03-26 | 2014-07-22 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate for treating disease-associated wasting |
US20070142469A1 (en) * | 2005-12-19 | 2007-06-21 | Thomas Debra L | Method of using beta-hydroxy-beta-methylbutyrate |
US8778992B2 (en) | 2005-12-19 | 2014-07-15 | Abbott Laboratories | Method of using beta-hydroxy-beta-methylbutyrate to treat allergies and asthma |
US8796333B2 (en) | 2005-12-19 | 2014-08-05 | Abbott Laboratories | Method of using β-hydroxy-β-methylbutyrate to treat a condition |
Also Published As
Publication number | Publication date |
---|---|
DE50106272D1 (en) | 2005-06-23 |
JP4668513B2 (en) | 2011-04-13 |
AU2001289849A1 (en) | 2002-03-13 |
US7230131B2 (en) | 2007-06-12 |
US20040167219A1 (en) | 2004-08-26 |
EP1326502A2 (en) | 2003-07-16 |
ATE295690T1 (en) | 2005-06-15 |
PT1326502E (en) | 2005-09-30 |
DK1326502T3 (en) | 2005-08-22 |
ES2242770T3 (en) | 2005-11-16 |
EP1326502B1 (en) | 2005-05-18 |
WO2002017735A3 (en) | 2002-09-12 |
WO2002017735A2 (en) | 2002-03-07 |
JP2004507479A (en) | 2004-03-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5554069B2 (en) | Improved stability in vitamin and mineral supplements | |
DE69614681T2 (en) | PHARMACEUTICAL AND / OR DIETIC COMPOSITIONS WITH ANTIOXYDING EFFECT, WHICH CONTAIN CARNOSINE AND BRANCHED AMINO ACID | |
US7230131B2 (en) | Carnitine-magnesium hydroxycitrate | |
DE69331528T2 (en) | MEDICAL FOOD FOR THE NUTRITIONAL SUPPLEMENT IN METABOLIC DISEASES OF INFANTS / KIDS | |
US8153685B2 (en) | Salts, addition compounds and complex compounds of guinadinoacetic acid | |
EP1909601B1 (en) | Liquid formulation based on a guanidinoacetic acid component | |
JP2010518822A5 (en) | ||
KR20080059564A (en) | Mixture of iron and copper salts masking mettalic taste | |
EP0914315B1 (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 | |
KR100517680B1 (en) | Solid compositions suitable for oral administration comprising an alkanoyl-L-carnitine magnesium citrate | |
AU6822998A (en) | Process for the preparation of stable, non-hygroscopic salts of L(-)carnitine | |
WO2008052712A1 (en) | Solid or aqueous alkaline preparation comprising a creatine component, process for the production thereof and the use thereof | |
PL207586B1 (en) | Alpha-ketoglutarates of active ingredients and compositions containing same | |
KR20010005866A (en) | Solid compositions suitable for oral administration comprising L-carnitine and alkanoyl-L-carnitine magnesium tartrate | |
EP1103259A1 (en) | Use of y-butyrobetaine salts for the preparation of compositions suitable for human or animal nutrition | |
EP0426098B1 (en) | Phosphate binding agent for oral administration | |
EP1219615A2 (en) | Method for extracting flavon mixtures and use of mixtures so obtained in dermocosmetic, food and pharmacy | |
WO1998000148A1 (en) | Drug preparations, containing creatine with at least one salt of calcium, magnesium, manganese or zinc | |
KR100506163B1 (en) | Stable, non-hygroscopic salt compounds of L (-) carnitine and alkanoyl L (-) carnitine, preparation methods thereof, and solid oral administration compositions containing the salt compounds | |
JP2015086171A (en) | Coated powder comprising pyrroloquinoline quinones, and production method thereof, as well as composition thereof | |
US20040024053A1 (en) | Vitamin c compositions | |
JPH03223228A (en) | Preparation of composition of potassium magnesium citrate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: LONZA AG, SWITZERLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:FUHRMANN, MARTIN;PIANZOLA, DANIEL;REEL/FRAME:014068/0177 Effective date: 20030422 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |