WO2009073943A1 - Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) - Google Patents
Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) Download PDFInfo
- Publication number
- 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
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.
Abstract
Description
Claims
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) |
PCT/CA2007/002244 WO2009073943A1 (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) |
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) |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009073943A1 true WO2009073943A1 (en) | 2009-06-18 |
Family
ID=40755195
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2007/002244 WO2009073943A1 (en) | 2007-12-12 | 2007-12-12 | Preparations containing pyridoxine and alpha-hydroxyisocaproic acid (hica) |
Country Status (3)
Country | Link |
---|---|
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 EP EP07855526A patent/EP2231604A1/en not_active Withdrawn
- 2007-12-12 WO PCT/CA2007/002244 patent/WO2009073943A1/en active Application Filing
- 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 |
Also Published As
Publication number | Publication date |
---|---|
AU2007362353A1 (en) | 2009-06-18 |
EP2231604A1 (en) | 2010-09-29 |
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