WO2009073943A1 - Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) - Google Patents
Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) Download PDFInfo
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- WO2009073943A1 WO2009073943A1 PCT/CA2007/002244 CA2007002244W WO2009073943A1 WO 2009073943 A1 WO2009073943 A1 WO 2009073943A1 CA 2007002244 W CA2007002244 W CA 2007002244W WO 2009073943 A1 WO2009073943 A1 WO 2009073943A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- salt
- pyridoxine
- hydroxyisocaproic acid
- composition
- hydroxyisocaproate
- Prior art date
Links
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 title claims abstract description 86
- LVRFTAZAXQPQHI-UHFFFAOYSA-N alpha-hydroxyisocaproic acid Natural products CC(C)CC(O)C(O)=O LVRFTAZAXQPQHI-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 229940011671 vitamin b6 Drugs 0.000 title claims abstract description 39
- 235000008160 pyridoxine Nutrition 0.000 title claims abstract description 38
- 239000011677 pyridoxine Substances 0.000 title claims abstract description 38
- LVRFTAZAXQPQHI-RXMQYKEDSA-N (R)-2-hydroxy-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](O)C(O)=O LVRFTAZAXQPQHI-RXMQYKEDSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 239000007910 chewable tablet Substances 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007766 cera flava Substances 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- 238000001816 cooling Methods 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 2
- 239000011369 resultant mixture Substances 0.000 claims 2
- 239000000706 filtrate Substances 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 238000003828 vacuum filtration Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 2
- 235000016709 nutrition Nutrition 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 239000008247 solid mixture Substances 0.000 abstract 1
- 229940024606 amino acid Drugs 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 238000005891 transamination reaction Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- -1 esters Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000005693 branched-chain amino acids Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229930195712 glutamate Natural products 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 235000019158 vitamin B6 Nutrition 0.000 description 3
- 239000011726 vitamin B6 Substances 0.000 description 3
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical class OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 2
- BKAJNAXTPSGJCU-UHFFFAOYSA-N 4-methyl-2-oxopentanoic acid Chemical compound CC(C)CC(=O)C(O)=O BKAJNAXTPSGJCU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000004716 alpha keto acids Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000005515 coenzyme Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 2
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 2
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 2
- 229960001327 pyridoxal phosphate Drugs 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OCUSNPIJIZCRSZ-ZTZWCFDHSA-N (2s)-2-amino-3-methylbutanoic acid;(2s)-2-amino-4-methylpentanoic acid;(2s,3s)-2-amino-3-methylpentanoic acid Chemical compound CC(C)[C@H](N)C(O)=O.CC[C@H](C)[C@H](N)C(O)=O.CC(C)C[C@H](N)C(O)=O OCUSNPIJIZCRSZ-ZTZWCFDHSA-N 0.000 description 1
- OIXVDFZUALXJNM-UHFFFAOYSA-N 2,4,5-trimethylpyridin-3-ol Chemical compound CC1=CN=C(C)C(O)=C1C OIXVDFZUALXJNM-UHFFFAOYSA-N 0.000 description 1
- QUKRTJQSGPLQKQ-UHFFFAOYSA-N 5-methylsulfonyl-3h-1,3-benzoxazol-2-one Chemical compound CS(=O)(=O)C1=CC=C2OC(=O)NC2=C1 QUKRTJQSGPLQKQ-UHFFFAOYSA-N 0.000 description 1
- 102100030840 AT-rich interactive domain-containing protein 4B Human genes 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 101000792935 Homo sapiens AT-rich interactive domain-containing protein 4B Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000020930 dietary requirements Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000036433 growing body Effects 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003581 pyridoxal Drugs 0.000 description 1
- 235000008164 pyridoxal Nutrition 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 150000003227 pyridoxines Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
- C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
Definitions
- the present invention relates to a structure and method for producing stable salts of pyridoxine and ⁇ -hydroxyisocaproic acid (HICA). More specifically, formed salts of the present invention are particularly well suited for oral administration thereby providing enhanced nutritional and/or therapeutical efficacy in relation to the individual components alone.
- HICA pyridoxine and ⁇ -hydroxyisocaproic acid
- Pyridoxine is often referred to as vitamin B6, however, it is actually only one of three components which constitute vitamin B6; the others being pyridoxal and pyridoxamine.
- the active form of pyridoxine in the body is pyridoxal 5-phosphate, which is a coenzyme for all transamination and some decarboxylation and deamination reactions.
- pyridoxal 5- phosphate is required as a coenzyme for all transamination reactions which occur in the body (Peterson DL, Martinez-Carrion M. The mechanism of transamination. Function of the histidyl residue at the active site of supernatant aspartate transaminase. J Biol Chem.
- HICA ⁇ -hydroxyisocaproic acid
- KICA ketoisocaproic acid
- Transamination is the transfer of the amino group from an amino acid to an ⁇ -keto acid, e.g. ⁇ -ketoisocaproic acid can be converted to Leucine in this manner.
- ⁇ -keto acid e.g. ⁇ -ketoisocaproic acid
- HICA ⁇ -ketoisocaproic acid
- oral administration of analogues of branched-chain amino acids will increase the cellular content of the corresponding branched-chain amino acid, while substantially simultaneously reducing plasma and cellular ammonia.
- UK Patent No. 1,248,324 discloses the formation of pyridoxine and ⁇ -ketoglutarate salts.
- ⁇ -Ketoglutarate is the deaminated form of glutamate, and is an intermediate in the citric acid cycle.
- Transamination of branch chain amino acids occurs primarily with ce-ketoglutarate to form glutamate; however the reverse reaction of Glutamate to branch chain amino acids does not occur.
- the compound is a salt comprising a molecule of pyridoxine and a molecule of ⁇ - hydroxyisocaproic acid (HICA), and having a structure of Formula 1 :
- HICA ⁇ - hydroxyisocaproic acid
- the present invention is directed towards the structure and synthesis of salts of pyridoxine and ⁇ -hydroxyisocaproic acid (HICA).
- HICA ⁇ -hydroxyisocaproic acid
- the present invention provides for the production of a stable salt which may afford a synergistic combination of pyridoxine and HICA, free of physiologically unsafe additives to an individual upon administration to a mammal.
- the present invention is particularly well suited for use in tablets, capsules, powders, granules, powdered beverage mixes and other forms known in the art of dietary supplements.
- the term 'pyridoxine ⁇ -hydroxyisocaproate' is to be understood as the salt of pyridoxine with HICA reacted in an equimolar ratio.
- Pyridoxine ⁇ -hydroxyisocaproate is a non-hygroscopic crystalline powder, which is stable in storage and can be processed without special precautions. Due to the non-hygroscopic nature of the pyridoxine ⁇ -hydroxyisocaproate it would be understood by one of skill in the art, that the salt is easy to process and is particularly suitable for processing with rapidly running machines, since it does not tend to stick together or become lumpy.
- 'pyridoxine' refers to the chemical 2-methyl-3-hydroxy-4,5- dihydroxymethylpyridine, (CAS Registry No. 65-23-6), also known as 3-hydroxy-4,5- bis(hydroxymethyl)-2-methylpyridine, 3-hydroxy-4,5-dimethyl- ⁇ -picoline, 5-hydroxy-6-methyl- 3,4-pyridinedimethanol, or Vitamin B6. Additionally, as used herein, 'pyridoxine' also includes derivatives of pyridoxine such as esters, and amides, and salts, as well as other derivatives, including derivatives having substantially similar pharmacoproperties to pyridoxine upon metabolism to an active form.
- ' ⁇ -hydroxyisocaproic acid' refers to the chemical 2-hydroxy-4- methylvaleric acid, (CAS Registry No. 498-36-2), also known as HICA, or leucic acid. Additionally, as used herein, ' ⁇ -hydroxyisocaproic acid' also includes derivatives of ⁇ - hydroxyisocaproic acid such as esters, and amides, and salts, as well as other derivatives, including derivatives having substantially similar pharmacoproperties to ⁇ -hydroxyisocaproic acid upon metabolism to an active form.
- 'lower alcohol' refers to aliphatic alcohols having about 1 to about 4 carbon atoms as is known in the art, such as, without limitation, methanol, ethanol, propanol, and isopropanol. These lower alcohols may be used singly or in admixture containing two or more alcohols.
- excipients refers to substances added to produce quality tablets, chewable tablets, capsules, granulates or powders, but which do not provide nutritive value.
- excipients includes monoglycerides, magnesium stearate, modified food starch, gelatin, microcrystalline cellulose, glycerin, stearic acid, silica, yellow beeswax, lecithin, hydroxypropylcellulose, croscarmellose sodium, and crosprovidone.
- the compounds disclosed herein comprise an ⁇ - hydroxyisocaproic acid molecule combined with a pyridoxine molecule to form a salt having a structure according to Formula 1.
- the aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1 : Scheme 1
- the py ⁇ doxme (1) is dissolved in an excess of hot lower alcohol
- the lower alcohol is considered to be hot when it is heated to a temperature below the boiling point of the corresponding lower alcohol
- the lower alcohol is selected from the group consisting of methanol, ethanol, propanol, and isopropanol These lower alcohols may be used singly or in admixture containing two or more alcohols
- the ohydroxyisocaproic acid (2) is dissolved into an excess of hot lower alcohol
- the lower alcohol is considered to be hot when it is heated to a temperature below the boiling point of the corresponding lower alcohol
- diethyl ether can be added until the cloud point, as would be known to one of skill in the art, is reached after the mixture is cooled to room temperature This will facilitate greater precipitation of the product thus yielding more of the pyridoxme ⁇ -hydroxyisocaproate (3), which would be desired in industrial settings
- Py ⁇ doxine ⁇ -hydroxyisocaproate is used advantageously alone or with additional active ingredients, such as, trace elements, vitamins, mineral substances, or other ammo acids as well as, optionally, excipients usually used for the preparation of the respective forms of administration.
- the forms of administration include, particularly, all varieties of tablets, both those that are swallowed without being chewed, and tablets to be chewed or dissolved in the mouth of an individual, as well as those that are dissolved in a liquid before being ingested by an individual.
- the tablet forms include uncoated tablets, one-layer or multilayer or encased forms or effervescent tablets.
- Further preferred forms of administration are capsules of hard and soft gelatin, the latter having particularly suitable to include a liquid core.
- pyridoxine ⁇ -hydroxyisocaproate can be used advantageously for the preparation of solutions and suspensions and as a powder, either effervescent or granulated. While not wishing to be bound by theory, it is understood by the inventors that pyridoxine ⁇ -hydroxyisocaproate and its derivatives corresponding to Formula 1 above, are useful compounds, since they combine within a single molecule both the pyridoxine and the ⁇ -hydroxyisocaproate, thus resulting in the increase of the useful activities of these two compounds. Particularly, it is herein understood by the inventors that pyridoxine ⁇ -hydroxyisocaproate will have enhanced pH stability in water within a substantially broad range of concentrations.
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to stable salts of pyridoxine and α-hydroxyisocaproic acid (HICA) endowed with enhanced nutritional and/or therapeutical efficacy in respect to their individual effects and to solid compositions containing such salts, particularly suited to oral administration. A method of preparation is also provided.
Description
Preparations containing Pyridoxine and a- Hydroxyisocaproic acid (HICA)
Related Applications
This application is related to the Applicant's co-pending U. S Patent Application Serial No. , entitled "Method for maintaining physiological pH levels during intensive physical exercise" filed on December 12, 2007, the contents of which is hereby fully incorporated by reference in it's entirety.
Field of the Invention
The present invention relates to a structure and method for producing stable salts of pyridoxine and α-hydroxyisocaproic acid (HICA). More specifically, formed salts of the present invention are particularly well suited for oral administration thereby providing enhanced nutritional and/or therapeutical efficacy in relation to the individual components alone.
Background of the Invention
Pyridoxine is often referred to as vitamin B6, however, it is actually only one of three components which constitute vitamin B6; the others being pyridoxal and pyridoxamine. The active form of pyridoxine in the body is pyridoxal 5-phosphate, which is a coenzyme for all transamination and some decarboxylation and deamination reactions. Furthermore, pyridoxal 5- phosphate is required as a coenzyme for all transamination reactions which occur in the body (Peterson DL, Martinez-Carrion M. The mechanism of transamination. Function of the histidyl residue at the active site of supernatant aspartate transaminase. J Biol Chem. 1970 Feb 25,245(4):806-13) α-hydroxyisocaproic acid (HICA), is an end product of the metabolism of the branched chain amino acids, and is a nitrogen-free pre-cursor from which amino acids can be synthesized. Since branched chain amino acid analogs may be reaminated back to their correspondent amino acid (e.g HICA can be converted to ketoisocaproic acid (KICA), which can subsequently be converted back to Leucine), they can act to provide the dietary requirements for BCAA without increasing level of ingested nitrogen (Boebek KP, Baker DH. Comparative utilization of the α-keto
and D- and L-α-hydroxy analogs of Leucine, Isoleucine and Valine by chicks and rats. J Nutr. 1982 Oct; 112(10): 1929-39). Transamination is the transfer of the amino group from an amino acid to an α-keto acid, e.g. α-ketoisocaproic acid can be converted to Leucine in this manner. As the product of transamination reactions depend on the availability of α-keto acids, providing exogenous HICA would make the formation of Leucine more favorable. Thus oral administration of analogues of branched-chain amino acids will increase the cellular content of the corresponding branched-chain amino acid, while substantially simultaneously reducing plasma and cellular ammonia.
There is now an extensive and ever growing body of literature, particularly patents, disclosing the formation of various salts having physiological functions in mammals. UK Patent No. 1,248,324 ('324') discloses the formation of pyridoxine and α-ketoglutarate salts. α-Ketoglutarate is the deaminated form of glutamate, and is an intermediate in the citric acid cycle. Transamination of branch chain amino acids occurs primarily with ce-ketoglutarate to form glutamate; however the reverse reaction of Glutamate to branch chain amino acids does not occur. It would be desirable for the development of new salts of amino acid metabolites capable of being reaminated and transaminated to branch chain amino acids for use in the body of a mammal using the nitrogen found in the body of said mammal without the requirement of adding additional nitrogen to the system. It would therefore also be desirable to produce a compound having the aforementioned qualities while additionally providing required co-factors for transamination reactions to occur. Summary of the Invention
In the present invention, a compound and methods for its production are disclosed. Specifically, the compound is a salt comprising a molecule of pyridoxine and a molecule of α- hydroxyisocaproic acid (HICA), and having a structure of Formula 1 :
Formula 1
Detailed Description of the Invention
In the following description, for the purposes of explanations, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one of ordinary skill in the art that the present invention may be practiced without these specific details.
The present invention is directed towards the structure and synthesis of salts of pyridoxine and α-hydroxyisocaproic acid (HICA). The present invention provides for the production of a stable salt which may afford a synergistic combination of pyridoxine and HICA, free of physiologically unsafe additives to an individual upon administration to a mammal. Furthermore, the present invention is particularly well suited for use in tablets, capsules, powders, granules, powdered beverage mixes and other forms known in the art of dietary supplements. As used herein, the term 'pyridoxine α-hydroxyisocaproate' is to be understood as the salt of pyridoxine with HICA reacted in an equimolar ratio.
Pyridoxine α-hydroxyisocaproate is a non-hygroscopic crystalline powder, which is stable in storage and can be processed without special precautions. Due to the non-hygroscopic nature of the pyridoxine α-hydroxyisocaproate it would be understood by one of skill in the art, that the salt is easy to process and is particularly suitable for processing with rapidly running machines, since it does not tend to stick together or become lumpy.
As used herein, 'pyridoxine' refers to the chemical 2-methyl-3-hydroxy-4,5- dihydroxymethylpyridine, (CAS Registry No. 65-23-6), also known as 3-hydroxy-4,5-
bis(hydroxymethyl)-2-methylpyridine, 3-hydroxy-4,5-dimethyl-α-picoline, 5-hydroxy-6-methyl- 3,4-pyridinedimethanol, or Vitamin B6. Additionally, as used herein, 'pyridoxine' also includes derivatives of pyridoxine such as esters, and amides, and salts, as well as other derivatives, including derivatives having substantially similar pharmacoproperties to pyridoxine upon metabolism to an active form.
As used herein, 'α-hydroxyisocaproic acid' refers to the chemical 2-hydroxy-4- methylvaleric acid, (CAS Registry No. 498-36-2), also known as HICA, or leucic acid. Additionally, as used herein, 'α-hydroxyisocaproic acid' also includes derivatives of α- hydroxyisocaproic acid such as esters, and amides, and salts, as well as other derivatives, including derivatives having substantially similar pharmacoproperties to α-hydroxyisocaproic acid upon metabolism to an active form.
As used herein, 'lower alcohol' refers to aliphatic alcohols having about 1 to about 4 carbon atoms as is known in the art, such as, without limitation, methanol, ethanol, propanol, and isopropanol. These lower alcohols may be used singly or in admixture containing two or more alcohols.
As used herein, 'pharmaceutically acceptable excipients' refers to substances added to produce quality tablets, chewable tablets, capsules, granulates or powders, but which do not provide nutritive value. A non-exhaustive list of examples of excipients includes monoglycerides, magnesium stearate, modified food starch, gelatin, microcrystalline cellulose, glycerin, stearic acid, silica, yellow beeswax, lecithin, hydroxypropylcellulose, croscarmellose sodium, and crosprovidone.
According to the present invention, the compounds disclosed herein comprise an α- hydroxyisocaproic acid molecule combined with a pyridoxine molecule to form a salt having a structure according to Formula 1. The aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1 :
Scheme 1
With reference to Scheme 1, in the first step of the reaction the pyπdoxme (1) is dissolved in an excess of hot lower alcohol The lower alcohol is considered to be hot when it is heated to a temperature below the boiling point of the corresponding lower alcohol
In various embodiments of the present invention, the lower alcohol is selected from the group consisting of methanol, ethanol, propanol, and isopropanol These lower alcohols may be used singly or in admixture containing two or more alcohols
Concurrently, in the second step of the reaction the ohydroxyisocaproic acid (2) is dissolved into an excess of hot lower alcohol The lower alcohol is considered to be hot when it is heated to a temperature below the boiling point of the corresponding lower alcohol
Both solutions above are then mixed together and heated to about the boiling point of the corresponding lower alcohol If there are solids still present the solution is filtered at this temperature to remove unreacted starting materials The solution is then allowed to cool to room temperature and then covered and placed in a refrigerator until crystallization occurs, preferably for between about 24 to about 48 hours The resultant crystals are filtered under vacuum and washed with ice cold lower alcohol, yielding a crystalline powder, the pyridoxme ohydroxyisocaproate (3)
In larger scale preparations of the present invention diethyl ether can be added until the cloud point, as would be known to one of skill in the art, is reached after the mixture is cooled to room temperature This will facilitate greater precipitation of the product thus yielding more of the pyridoxme α-hydroxyisocaproate (3), which would be desired in industrial settings
Pyπdoxine α-hydroxyisocaproate is used advantageously alone or with additional active ingredients, such as, trace elements, vitamins, mineral substances, or other ammo acids as well as,
optionally, excipients usually used for the preparation of the respective forms of administration. The forms of administration include, particularly, all varieties of tablets, both those that are swallowed without being chewed, and tablets to be chewed or dissolved in the mouth of an individual, as well as those that are dissolved in a liquid before being ingested by an individual. The tablet forms include uncoated tablets, one-layer or multilayer or encased forms or effervescent tablets. Further preferred forms of administration are capsules of hard and soft gelatin, the latter having particularly suitable to include a liquid core. Additionally, pyridoxine α-hydroxyisocaproate can be used advantageously for the preparation of solutions and suspensions and as a powder, either effervescent or granulated. While not wishing to be bound by theory, it is understood by the inventors that pyridoxine α-hydroxyisocaproate and its derivatives corresponding to Formula 1 above, are useful compounds, since they combine within a single molecule both the pyridoxine and the α-hydroxyisocaproate, thus resulting in the increase of the useful activities of these two compounds. Particularly, it is herein understood by the inventors that pyridoxine α-hydroxyisocaproate will have enhanced pH stability in water within a substantially broad range of concentrations.
The examples given below explain the execution of the invention with respect to the production of pyridoxine α-hydroxyisocaproate. Provided below is the a basic method of producing pyridoxine α-hydroxyisocaproate, however those of skill in the art will appreciate certain changes may be made in the process of "scaling-up" the reaction to manufacture larger batches of pyridoxine α-hydroxyisocaproate which may be required for commercial uses and supply requirements. Other methods of synthesis may also be apparent to those of skill in the art. Examples 0C) 4 0C)
Example 1 (Laboratory Scale)
132.16 g (1 mol) of α-hydroxyisocaproic acid (2) is dissolved into 20OmL of hot ethanol, solution 1. Concurrently, 169.18 g (1 mol) of pyridoxine (1) is dissolved in 30OmL of hot ethanol, solution 2. Solution 2 is added to solution 1 with stirring and the resultant solution is heated to the boiling point. If there are solids still present the solution is filtered at this temperature to remove unreacted starting materials. The solution is then allowed to cool to room temperature and then covered and placed in a refrigerator until crystallization occurs; about 24 hours. The resultant crystals are filtered under vacuum and washed with ice cold ethanol, yielding a crystalline powder, the pyridoxine α-hydroxyisocaproate (3). Example 2 (Industrial Scale)
781.179 kg (5910.86 mol) of α-hydroxyisocaproic acid (2) is dissolved into 800 L of hot ethanol, solution 3. Concurrently, 1000 kg (5910.86 mol) of pyridoxine (1) is dissolved in 1000 L of hot ethanol, solution 4. Solution 3 is added to solution 4 with stirring and the resultant solution is heated to the boiling point. If there are solids still present the solution is filtered at this temperature to remove unreacted starting materials. The solution is then allowed to cool to room temperature, diethyl ether is added until the cloud point is reached, and the mixture is then cooled for 48 hours to induce crystallization. The resultant crystals are then vacuum-filtered and washed with ice cold ethanol, yielding a crystalline powder, the pyridoxine α-hydroxyisocaproate (3).
Extensions and Alternatives
In the foregoing specification, the invention has been described with specific embodiments thereof; however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.
Claims
1. A salt of pyridoxine and α-hydroxyisocaproic acid, having the Formula:
2. A composition comprising the compound of claim 1 , further comprising pharmaceutically acceptable excipients.
3. The composition of claim of claim 2 wherein the pharmaceutically acceptable excipients are selected from the group consisting of monoglycerides, magnesium stearate, modified food starch, gelatin, microcrystalline cellulose, glycerin, stearic acid, silica, yellow beeswax, lecithin, hydroxypropylcellulose, croscarmellose sodium, and crosprovidone.
4. The salt of pyridoxine and α-hydroxyisocaproic acid of claim 1 wherein said salt of pyridoxine and α-hydroxyisocaproic acid is provided in a dosage form selected from the group consisting of ingestible tablets, chewable tablets, capsules, granulates or powders.
5. The composition of claim 2 wherein the composition is in a dosage form selected from the group consisting of ingestible tablets, chewable tablets, capsules, granulates or powders.
6. The salt of pyridoxine and α-hydroxyisocaproic acid of claim 1 wherein said salt of pyridoxine and α-hydroxyisocaproic acid is administered to a mammal.
7. The composition of claim 4 wherein the composition is administered to a mammal.
8. The salt of pyridoxine and α-hydroxyisocaproic acid of claim 6 wherein said salt of pyridoxine and α-hydroxyisocaproic acid is orally administered to a said mammal.
9. The composition of claim 7 wherein the composition is orally administered to a said mammal. A method for producing a pyridoxme α-hydroxyisocaproate salt compnsing at least the steps of a) dissolving α-hydroxyisocaproic acid in hot lower alcohol, b) dissolving pyridoxme in hot lower alcohol, c) mixing the resultant solutions of a) and b), d) cooling the resultant mixture, and e) isolating the resulting pyridoxme α-hydroxyisocaproate salt The method of claim 10 wherein the lower alcohol is selected from the group consisting of methanol, ethanol, propanol, butanol, and isopropanol The method of claim 10 wherein the α-hydroxyisocaproic acid and the pyridoxme are present m an eqmmolar ratio The method of claim 10 wherein the resultant mixture is cooled until crystallization occurs The method of claim 13 wherein crystallization occurs between about 24 to about 48 hours following the commencement of the cooling The method of claim 10 wherein the pyπdoxme α-hydroxyisocaproate salt is isolated by vacuum filtration followed by washing of the filtrate with cold lower alcohol The pyridoxme α-hydroxyisocaproate salt of claim 10 having the molecular structure of
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2007362353A AU2007362353A1 (en) | 2007-12-12 | 2007-12-12 | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (HICA) |
| EP07855526A EP2231604A1 (en) | 2007-12-12 | 2007-12-12 | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
| PCT/CA2007/002244 WO2009073943A1 (en) | 2007-12-12 | 2007-12-12 | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CA2007/002244 WO2009073943A1 (en) | 2007-12-12 | 2007-12-12 | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
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| Publication Number | Publication Date |
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| WO2009073943A1 true WO2009073943A1 (en) | 2009-06-18 |
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| PCT/CA2007/002244 WO2009073943A1 (en) | 2007-12-12 | 2007-12-12 | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
Country Status (3)
| Country | Link |
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| EP (1) | EP2231604A1 (en) |
| AU (1) | AU2007362353A1 (en) |
| WO (1) | WO2009073943A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3627774A (en) * | 1969-07-24 | 1971-12-14 | Raymond Francois Jacques Sarba | Pyridoxine pyridoxamine and pyridoxal flufenamate salts |
| US3784553A (en) * | 1972-01-17 | 1974-01-08 | Made Labor Sa | Pyridoxine alpha-ketoglutarate and its derivatives |
| WO1994018965A1 (en) * | 1993-02-23 | 1994-09-01 | Laboratori Baldacci Spa | Therapeutic use of pyridoxine pyrrolidone carboxylate |
| US20040228884A1 (en) * | 2003-05-15 | 2004-11-18 | Gupta Shyam K. | Ion-pair delivery system for cosmetic and pharmaceutical compositions |
-
2007
- 2007-12-12 WO PCT/CA2007/002244 patent/WO2009073943A1/en active Application Filing
- 2007-12-12 EP EP07855526A patent/EP2231604A1/en not_active Withdrawn
- 2007-12-12 AU AU2007362353A patent/AU2007362353A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3627774A (en) * | 1969-07-24 | 1971-12-14 | Raymond Francois Jacques Sarba | Pyridoxine pyridoxamine and pyridoxal flufenamate salts |
| US3784553A (en) * | 1972-01-17 | 1974-01-08 | Made Labor Sa | Pyridoxine alpha-ketoglutarate and its derivatives |
| WO1994018965A1 (en) * | 1993-02-23 | 1994-09-01 | Laboratori Baldacci Spa | Therapeutic use of pyridoxine pyrrolidone carboxylate |
| US20040228884A1 (en) * | 2003-05-15 | 2004-11-18 | Gupta Shyam K. | Ion-pair delivery system for cosmetic and pharmaceutical compositions |
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| EP2231604A1 (en) | 2010-09-29 |
| AU2007362353A1 (en) | 2009-06-18 |
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