WO2012014746A1 - Complexe d'acide α-lipoïque - Google Patents

Complexe d'acide α-lipoïque Download PDF

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Publication number
WO2012014746A1
WO2012014746A1 PCT/JP2011/066447 JP2011066447W WO2012014746A1 WO 2012014746 A1 WO2012014746 A1 WO 2012014746A1 JP 2011066447 W JP2011066447 W JP 2011066447W WO 2012014746 A1 WO2012014746 A1 WO 2012014746A1
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Prior art keywords
lipoic acid
dihydro
complex
cyclodextrin
suspension
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PCT/JP2011/066447
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English (en)
Japanese (ja)
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直子 生田
大介 中田
寺尾　啓二
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株式会社シクロケム
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Priority to JP2012526446A priority Critical patent/JPWO2012014746A1/ja
Publication of WO2012014746A1 publication Critical patent/WO2012014746A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 invention relates to an ⁇ lipoic acid complex and a method for producing the ⁇ lipoic acid complex. More specifically, ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S-form, dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form, or an alkali metal salt or alkaline earth metal salt thereof is complexed (encapsulated) with high probability.
  • the present invention relates to a high-purity ⁇ -lipoic acid complex obtained by contact) and a method for producing the ⁇ -lipoic acid complex.
  • ⁇ -Lipoic acid is a substance that functions as a coenzyme for mitochondrial enzymes in the biological energy production system.
  • Alpha lipoic acid has a chiral center at the C3 carbon atom of the 1,2-dithiolane ring and has an optically active carbon.
  • ⁇ -lipoic acid R form exists, and this ⁇ -lipoic acid R form is particularly abundant in the liver, kidney, and heart of animal meat. This ⁇ -lipoic acid R form is also present in low concentrations in vegetables such as spinach, tomato or broccoli.
  • ⁇ -lipoic acid has been used as an active ingredient in pharmaceuticals and health foods, and is listed in the European Pharmacopeia in Europe.
  • Alpha lipoic acid is used as a therapeutic agent for diabetes or a complication associated with diabetic neuropathy.
  • ⁇ -lipoic acid sodium salt is listed in the Japanese Pharmacopoeia as an injection.
  • the ⁇ -lipoic acid used in these is almost always an ⁇ -lipoic acid racemate containing an equal amount of ⁇ -lipoic acid R-form and ⁇ -lipoic acid S-form, which can be easily and inexpensively produced industrially. is there.
  • only ⁇ -lipoic acid R form effectively acts in the human body.
  • a large amount of medication is required to obtain a sufficient effect in a drug using ⁇ -lipoic acid racemate.
  • ⁇ -lipoic acid racemate For example, in Germany, it is necessary to take a large amount of ⁇ -lipoic acid racemate as 600 mg per day. Ingesting large amounts of drugs is a burden on patients. Therefore, in order to reduce the burden on such patients and improve the quality of life (QOL), the same effect can be obtained by using ⁇ -lipoic acid R-form and half the amount when using ⁇ -lipoic acid racemate. Is desired.
  • ⁇ -lipoic acid R in hypoglycemia is by expressing GLUT-4 (type 4 glucose transporter) in cells and increasing the receptor for insulin, whereas ⁇ -lipoic acid S is rather GLUT -4 has been reported to suppress expression and decrease insulin receptors. Also from this report, it is much more effective to use only the ⁇ -lipoic acid R-form than the ⁇ -lipoic acid racemate containing the ⁇ -lipoic acid S-form in the production of drugs and the like.
  • GLUT-4 type 4 glucose transporter
  • ⁇ -lipoic acid R form has been reported to have 10 times stronger anti-inflammatory action than ⁇ -lipoic acid racemate, there is a possibility that a sufficient amount can be obtained in a smaller amount than when ⁇ -lipoic acid racemate is used. There is also.
  • ⁇ -lipoic acid S-form is also 5 to 6 times stronger in analgesic action than ⁇ -lipoic acid racemate (see, for example, Patent Document 1), and thus is likely to be used more effectively than ⁇ -lipoic acid racemate. .
  • ⁇ -lipoic acid R-form and ⁇ -lipoic acid S-form can be industrially isolated.
  • the ⁇ -lipoic acid R form is poor in thermal stability because the melting point (46-49 ° C.) is lower than the melting point (60-62 ° C.) of the ⁇ -lipoic acid racemate.
  • ⁇ -lipoic acid R form tends to form an adhesive polymer and is extremely unstable.
  • these ⁇ -lipoic acid R isomers are clathrated with cyclodextrin or a derivative thereof and used as an inclusion compound in effervescent tablets, granules or the like (for example, see Patent Document 2).
  • Patent Document 2 suggests that an inclusion compound encapsulated with cyclodextrin or a derivative thereof can be produced using ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form, but it was produced specifically. No examples are given.
  • ⁇ -cyclodextrin is dissolved in water at 40 ° C.
  • ⁇ -lipoic acid is dissolved, cooled to 15 ° C., and filtered off after 12 hours, and dried.
  • An inclusion compound has been obtained.
  • ⁇ -lipoic acid R-form and ⁇ -lipoic acid S-form are merely “can be used” instead of the racemic form.
  • ⁇ -lipoic acid and cyclodextrin are dissolved in an alkaline (basic) aqueous solution, and the pH is adjusted with an acid such as hydrochloric acid to obtain a cyclodextrin / ⁇ -lipoic acid complex or lipoic acid-containing cyclodextrin complex.
  • Manufacturing a body Patent Document 3, [Claim 1], Patent Document 4, [Claim 8], etc.).
  • the present inventors confirmed that the obtained product was slightly It was colored yellow and the purity was low.
  • the present inventors have a high probability of ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form, dihydro- ⁇ -lipoic acid R-form or dihydro-alpha lipoic acid S-form, or an alkali metal salt or alkaline earth metal salt thereof.
  • the present inventors have found a method for producing a high-purity ⁇ -lipoic acid complex obtained by complexing.
  • An object of the present invention is to provide an ⁇ lipoic acid complex and a method for producing the ⁇ lipoic acid complex. More specifically, ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form, dihydro-alpha lipoic acid R-form or dihydro-alpha lipoic acid S-form, or an alkali metal salt or alkaline earth metal salt thereof is obtained with high probability. It is an object of the present invention to provide a highly pure ⁇ -lipoic acid complex and a method for producing the ⁇ -lipoic acid complex.
  • ⁇ lipoic acid complex ⁇ lipoic acid, dihydro ⁇ lipoic acid, or the sulfur odor or pungent taste (throat or tongue of these alkali metal salts or alkaline earth metal salts). It is also an object to make it easy to take these ⁇ -lipoic acids, etc., excluding the difficulty of taking due to irritation that becomes hot) and discomfort at the time of burping.
  • an alkali metal salt of ⁇ -lipoic acid R-form is produced by the production methods (A) to (C) having the following steps 1) and 2):
  • a high-purity ⁇ -lipoic acid complex can be produced by using an alkaline earth metal salt or an alkali metal salt of an ⁇ -lipoic acid S-form or an alkaline earth metal salt for complexation, thereby completing the present invention. It came.
  • the production method (A) or the production method (B) is a production method having the following steps 3) and 4) in addition to the steps 1) and 2). 3) Adjusting the solution or suspension of 2) above to pH 4.0 and stirring to obtain a suspension 4) Residue obtained by filtering the suspension of 3) above as it is or by filtering The process of drying things
  • the production method (C) is a production method having the following step 3) in addition to the steps 1) and 2). 3) Step of drying the residue obtained by stirring the suspension of 2) as it is or after filtering.
  • the present inventors use ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form for complexation by the production methods (D) and (E) having the following steps 1) and 2).
  • the inventors have found that a pure ⁇ -lipoic acid complex can be produced, and have completed the present invention.
  • the production method (D) is a production method having the following steps 3) and 4) in addition to the steps 1) and 2). 3) Adjusting the solution or suspension of 2) above to pH 4 or less to obtain a suspension 4) Step of drying the residue obtained by filtering the suspension of 3) above or as it is
  • the production method (E) is a production method having the following step 3) in addition to the steps 1) and 2). 3) A step of drying the residue obtained by filtering or filtering the solution or suspension of 2) above.
  • the present inventors use the following production methods (F) and (G) to use a dihydro ⁇ -lipoic acid R-form or dihydro ⁇ -lipoic acid-S form for complexation, thereby producing a highly pure ⁇ -lipoic acid complex. Has been found to be able to be produced, and the present invention has been completed.
  • the production method (F) is a production method having the following steps 1) to 3). 1) Step of dissolving cyclodextrin in water 2) After cooling the solution or suspension of 1) above to a certain temperature, dihydro ⁇ lipoic acid R-form or dihydro ⁇ lipoic acid S-form is added. Step 3) Obtaining a suspension of a cyclodextrin complex of dihydro ⁇ -lipoic acid R-form or dihydro ⁇ -lipoic acid S-form 3) Drying the residue obtained from the suspension of 2) as it is or by filtering. Process
  • the production method (G) is a production method having the following steps 1) to 4).
  • the ⁇ -lipoic acid complex obtained by these production methods found in the present invention includes ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form, dihydro-alpha lipoic acid R-form or dihydro-alpha lipoic acid S-form, or an alkali metal thereof. It is a composite of a salt or an alkaline earth metal salt, and is not intended for the composite of ⁇ -lipoic acid racemate.
  • the production method of the present invention is characterized in that, using water as a solvent, the obtained aqueous solution is cooled and adjusted to a certain temperature, then cyclotextrin is added, and the reaction is carried out at that temperature. .
  • the production method of the ⁇ -lipoic acid complex of the present invention which can complex ⁇ -lipoic acid with a high probability and produce a highly purified ⁇ -lipoic acid complex, is completed. It is done.
  • ⁇ -lipoic acid complexes obtained according to the present invention are ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form, dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form, or an alkali metal salt or alkaline earth thereof.
  • the reliable complexation of the metal salt is proved in the present invention by physicochemical data such as nuclear magnetic resonance spectrum (NMR) and Fourier infrared absorption spectrum (FT-IR).
  • the ⁇ lipoic acid complex of the present invention comprises ⁇ lipoic acid R form or ⁇ lipoic acid S form, dihydro alpha lipoic acid R form or dihydro alpha lipoic acid S form, or an alkali metal salt or alkaline earth metal salt thereof. It is also confirmed that the compound is highly stable against heat, artificial gastric acid solution (15th revised Japanese Pharmacopoeia, formulation test method, disintegration (solute) test first solution) and the like.
  • the present invention relates to the ⁇ -lipoic acid complex, the method for producing the ⁇ -lipoic acid complex, and the like described in (1) to (17) below.
  • An ⁇ -lipoic acid complex containing 6.7% or more of ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form, or dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form, Body or ⁇ lipoic acid S form, dihydro ⁇ lipoic acid R form or dihydro ⁇ lipoic acid S form, or an ⁇ lipoic acid complex in which an alkali metal salt or alkaline earth metal salt thereof is complexed.
  • a step of drying the residue obtained by filtering or filtering the solution or suspension of 2) as described above (5) A method for producing the ⁇ -lipoic acid complex according to (3) above, Furthermore, the manufacturing method of the alpha lipoic acid complex including the following process. 3) Adjusting the solution or suspension of 2) above to pH 4.0 and stirring to obtain a suspension 4) Residue obtained by filtering the suspension of 3) above as it is or by filtering (6)
  • the method for producing an ⁇ -lipoic acid complex according to (1) or (2) above which comprises the following steps (1) and (2): 1) Step of dissolving ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form in water while dropping alkali metal salt or alkaline earth metal salt 2) After cooling the aqueous solution of 1) above to a constant temperature
  • Step 3) Obtaining a suspension of a cyclodextrin complex of dihydro ⁇ -lipoic acid R form or a suspension of a cyclodextrin complex of dihydro ⁇ lipoic acid S form 3)
  • alpha lipoic acid R form or alpha lipoic acid S form is complexed with high probability.
  • the ⁇ lipoic acid complex, dihydro ⁇ lipoic acid, etc. contained in the ⁇ lipoic acid complex of the present invention are produced without racemization while maintaining optical activity as the R or S form. It is maintained in the body and can be used according to the function of each optically active substance.
  • ⁇ lipoic acid complexes obtained by the present invention ⁇ lipoic acid R form or ⁇ lipoic acid S form, dihydro alpha lipoic acid R form or dihydro alpha lipoic acid S form, or an alkali metal salt or alkaline earth metal thereof
  • the ⁇ -lipoic acid complex in which the salt is complexed is stable to heat or an artificial gastric acid solution, and can particularly exhibit a sufficient effect as a component of a pharmaceutical or health food.
  • the ⁇ lipoic acid complex obtained by the present invention is encapsulated by cyclodextrin, unpleasant sulfur odor and pungent taste are masked, and there is an advantage that it is easy to take.
  • ⁇ lipoic acid complex refers to ⁇ lipoic acid R form or ⁇ lipoic acid S form, dihydro ⁇ lipoic acid R form or dihydro ⁇ lipoic acid S form, or an alkali metal salt or alkaline earth metal thereof. This refers to a complex of salt with cyclodextrin.
  • ⁇ lipoic acid racemic body, dihydro ⁇ lipoic acid racemic body, and a substance obtained by complexing alkali metal salt or alkaline earth metal salt of ⁇ lipoic acid racemic body with cyclodextrin Is not included.
  • the “ ⁇ -lipoic acid complex” of the present invention is an ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form, dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ , as compared with the conventional complexed ⁇ -lipoic acid with cyclodextrin
  • the lipoic acid S form, or an alkali metal salt or alkaline earth metal salt thereof be contained with high purity.
  • it is preferably an ⁇ -lipoic acid complex containing 6.7% or more of ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form, or dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form.
  • An ⁇ -lipoic acid complex containing 5% or more of ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form or dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form is more preferable.
  • an ⁇ -lipoic acid complex containing 10% or more of ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form, or dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form, more preferably 13 % Lipoic acid complex containing ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form, or dihydro-alpha lipoic acid R-form or dihydro-alpha lipoic acid S-form.
  • ⁇ -lipoic acid complex in which ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S-form or dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form is complexed with these alkali metal salts or alkaline earth metal salts
  • ⁇ lipoic acid R-form itself or ⁇ -lipoic acid S-form itself, or dihydro ⁇ -lipoic acid R-form itself or dihydro ⁇ -lipoic acid S-form itself It is preferable to contain 10% or more.
  • alpha lipoic acid R form or alpha lipoic acid S form includes alpha lipoic acid R Body itself, alpha lipoic acid S form itself, alkali metal salt or alkaline earth metal salt of alpha lipoic acid R form, or alkali metal salt or alkaline earth metal salt of alpha lipoic acid S form.
  • alkali metal salts or alkaline earth metal salts include alkali metal salts or alkaline earth metal salts of ⁇ -lipoic acid R form, alkali metal salts or alkaline earth metal salts of ⁇ -lipoic acid S form, dihydro ⁇ -lipoic acid Any alkali metal salt or alkaline earth metal salt of R form, or alkali metal salt or alkaline earth metal salt of dihydro ⁇ -lipoic acid S form is included.
  • ⁇ lipoic acid R form sodium salt
  • alpha lipoic acid S form sodium salt
  • alpha lipoic acid R form potassium salt
  • ⁇ lipoic acid S form potassium salt
  • ⁇ lipoic acid R form calcium salt
  • ⁇ lipoic acid S form calcium salt
  • examples include ⁇ -lipoic acid R-form magnesium salt and ⁇ -lipoic acid S-form magnesium salt.
  • alkali metal salts or alkaline earth metal salts are obtained by adding an alkali metal salt or an alkaline earth metal salt in an aqueous solution to ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form, or dihydro ⁇ -lipoic acid R Body or dihydro-alpha lipoic acid S form may be added to prepare a corresponding salt, or a commercially available product may be used.
  • ⁇ lipoic acid R form” or “ ⁇ lipoic acid S form”, “dihydro alpha lipoic acid R form” or “dihydro alpha lipoic acid S form” used in the production of the ⁇ lipoic acid complex of the present invention are also included. You may use what is marketed.
  • “Cyclodextrin” of the present invention includes ⁇ -cyclodextrin (cyclohexaamylose, which is composed of 6-glucose units in a cyclic form), ⁇ -cyclodextrin produced by a conventionally known method from raw materials such as potato and corn. Dextrin (cycloheptaamylose, composed of 7-glucose units in a ring) or ⁇ -cyclodextrin (cyclooctaamylose, composed of 8-glucose units in a ring) is included.
  • cyclodextrin of the present invention includes hydroxypropyl ⁇ cyclodextrin, sulfobutyl ether ⁇ cyclodextrin, branched chain cyclodextrin and the like.
  • the branched-chain cyclodextrin is a known branched-chain sugar chain derivative of cyclodextrin such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin, and glucose, maltose, cellobiose, lactose, sucrose are added to these cyclodextrins.
  • the branched-chain cyclodextrin in the present invention may be a mixture of branched-chain cyclodextrins such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • the branched sugar chain is preferably a sugar chain consisting of saccharides from monosaccharides to decasaccharides, more preferably a sugar chain consisting of saccharides from monosaccharides to pentasaccharides, and a sugar consisting of saccharides from monosaccharides to trisaccharides.
  • a chain is more preferable, and a sugar chain consisting of a monosaccharide or a disaccharide is most preferable.
  • sugar chains composed of monosaccharides include sugar chains derived from monosaccharides such as glucose, mannose, galactose, or N-acetylglucosamine, and sugar chains composed of disaccharides include maltosyl and the like. .
  • a sugar chain composed of three or more sugars is a sugar chain derived from a sugar produced by dehydration condensation of three or more molecules of a monosaccharide by a glycosidic bond, and examples thereof include maltooligosyl such as maltotriosyl.
  • the number of branched sugar chains is 1 to 6 for ⁇ cyclodextrin, 1 to 7 for ⁇ cyclodextrin, and 1 to 8 for ⁇ cyclodextrin, preferably 1 to 2 in any case. is there.
  • the branched chain cyclodextrin in the present invention is, for example, ⁇ -glucosyl cyclodextrin, ⁇ -glucosyl cyclodextrin or ⁇ -glucosyl cyclodextrin, ⁇ -diglucosyl cyclodextrin, ⁇ -diglucosyl cyclodextrin or ⁇ -diglucosyl cyclodextrin, ⁇ -maltosyl cyclodextrin, ⁇ maltosyl cyclodextrin or ⁇ maltosyl cyclodextrin, ⁇ dimaltosyl cyclodextrin, ⁇ dimaltosyl cyclodextrin or ⁇ dimaltosyl cyclodextrin, ⁇ maltotriosyl cyclodextrin, ⁇ maltotriosyl cyclodextrin or ⁇ maltotrio Silcyclodextrin, ⁇ -
  • cyclodextrins may be used singly or as a mixture of plural kinds.
  • ⁇ -cyclodextrin or ⁇ -cyclodextrin is preferably used for complexation, and ⁇ -cyclodextrin is particularly preferably used.
  • the “method for producing an ⁇ -lipoic acid complex” of the present invention comprises 6.7% or more of ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form or dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form. Any conventionally known method may be used as long as the “ ⁇ -lipoic acid complex” of the invention can be produced.
  • the following manufacturing method is mentioned as "the manufacturing method of (alpha) lipoic acid complex" of such this invention.
  • the manufacturing method of alpha lipoic acid complex which has the process of following 1) and 2).
  • the production method further comprising the following steps 3) and 4) is shown in the Examples as the production method (A) or the production method (B). It was. 3) Adjusting the solution or suspension of 2) above to pH 4.0 or lower and stirring to obtain a suspension 4) After stirring the suspension of 3) above, or after filtering. Drying the obtained residue
  • the step 1) comprises the steps of alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R-form, or alkali metal salt or alkaline earth of ⁇ -lipoic acid S-form.
  • This is a step of dissolving a metal salt in water. Stirring is preferably performed until the water in which the alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R-form or the alkali metal salt or alkaline-earth metal salt of ⁇ -lipoic acid S-form is dissolved becomes transparent.
  • the aqueous solution thus obtained preferably exhibits neutral to weak alkalinity even if the pH is not particularly adjusted with an alkaline substance or the like, and is particularly preferably an aqueous solution having a pH of 14.0 or less.
  • Step 2) is a step in which cyclodextrin is added to the aqueous solution obtained in step 1) to obtain a solution or suspension.
  • the cyclodextrin is preferably added after the aqueous solution obtained in the step 1) is cooled and adjusted to a certain temperature, and the subsequent steps are preferably performed at the adjusted temperature.
  • the temperature should just be 40 degrees C or less under atmospheric pressure.
  • the temperature is preferably 25 ° C. or less, more preferably less than 10 ° C., still more preferably 0 ° C. to 9 ° C., and particularly preferably 0 to 6 ° C.
  • the cyclodextrin added to the aqueous solution is an alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R form (1.0 mol), or an alkali metal salt or alkaline earth metal salt of alpha lipoic acid S form (1 Is preferably added in an amount of 0.5 mol to 1.4 mol, more preferably 0.5 mol to 1.1 mol, and even more preferably 0.6 mol to 0.7 mol. It is particularly preferred to add.
  • the alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R-form, or the alkali metal salt or alkaline-earth metal salt of ⁇ -lipoic acid S-form in a solution or suspension A complex is formed.
  • Alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R-form, or alkali metal salt or alkaline-earth metal salt of ⁇ -lipoic acid S-form, and cyclodextrin are combined in this solution or suspension. It is preferable to add such that it is contained in an amount of ⁇ 50 wt%, preferably 5 to 35 wt%, particularly preferably 10 to 25 wt%. This is because handling is difficult at 50 wt% or more.
  • an equimolar or equimolar or higher acid is gradually added to the alkaline metal salt or alkaline earth metal salt of lipoic acid S to adjust the pH to 4.0 or lower.
  • the alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R form, or the alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid S form is neutralized, and ⁇ -lipoic acid R-form or ⁇ -lipoic acid S is neutralized.
  • the acid is preferably added while stirring the solution or suspension, and any acid that can be used for pH adjustment may be used.
  • any acid that can be used for pH adjustment may be used.
  • inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid can be used.
  • the acid is preferably added until the pH of the solution or suspension becomes 4.0 or less, and particularly preferably added uniformly until the pH becomes 3.5 or 3.5 or less.
  • the pH when producing an ⁇ -lipoic acid complex in which ⁇ -lipoic acid R-form sodium salt is complexed, it is extremely preferable to adjust the pH to about 3.0 to 3.5. After the acid has been added, the resulting suspension may be stirred, and this stirring may be no more than 1 hour, and preferably no more than 18 hours.
  • the step 3) in the production method (C) and the step 4) in the production method (A) or (B) are the same as the step 2) in the production method (C) and the production method (A) or (B).
  • the ⁇ -lipoic acid complex contained in the suspension obtained in the step 3) is dried as it is, or filtered to take out the residue containing the ⁇ -lipoic acid complex and dry it.
  • the ⁇ -lipoic acid complex contained in the suspension is dried as it is without performing filter filtration or the like, and thus the ⁇ -lipoic acid complex containing an alkali salt generated by neutralization.
  • the residue containing the ⁇ -lipoic acid complex is taken out by, for example, a filtration method, a centrifugal separation method or a belt filtration method, washed with water and dried.
  • a filtration method a centrifugal separation method or a belt filtration method
  • an ⁇ -lipoic acid complex from which alkali salts have been removed can also be obtained.
  • a commonly used practical method such as a method using an ion exchange membrane or a reverse osmosis membrane (RO membrane) can also be used as a method for removing an alkali salt.
  • the drying may be performed by any conventionally known method regardless of the presence or absence of an alkali salt. For example, a vacuum drying method, a freeze drying method, a spray drying method, an oven drying method, a belt drying method, a pulse drying method, or the like. Law.
  • the “method for producing an ⁇ -lipoic acid complex” of the present invention may be a method for producing an ⁇ -lipoic acid complex having the following steps 1) and 2). 1) Step of dissolving ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form in water while dropping alkali metal salt or alkaline earth metal salt 2) After cooling the aqueous solution of 1) above to a constant temperature Addition of cyclodextrin, solution or suspension of ⁇ -lipoic acid R-form alkali metal salt or alkaline earth metal salt cyclodextrin complex, or ⁇ -lipoic acid S-form alkali metal salt or alkaline earth metal A step of obtaining a solution or suspension of a salt cyclodextrin complex
  • Step 2) Adjusting the solution or suspension of 2) above to pH 4 and stirring to obtain a suspension 4) Residue obtained by filtering the suspension of 3) above as it is or by filtering. Drying process
  • a method including the following step 3) is shown in the Examples as a production method (E).
  • 3) A step of drying the residue obtained by subjecting the suspension of 2) as it is or by filtering through a filter.
  • the step 1) is a step of dissolving ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form in water while dropping an alkali metal salt or an alkaline earth metal salt. It is. Stirring is preferably performed until water in which ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form is dissolved becomes transparent.
  • the pH of the solution obtained by this step is preferably 9-14.
  • step 2) cyclodextrin is added to the aqueous solution obtained in step 1), and a solution or suspension of a cyclodextrin complex of an alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R form. Or a solution or suspension of a cyclodextrin complex of ⁇ -lipoic acid S-form alkali metal salt or alkaline earth metal salt.
  • the cyclodextrin is preferably added after the aqueous solution obtained in the step 1) is cooled and adjusted to a certain temperature, and the subsequent steps are preferably performed at the adjusted temperature.
  • the temperature should just be 40 degrees C or less under atmospheric pressure.
  • the temperature is preferably 25 ° C.
  • aqueous solution or suspension preferably exhibits neutral to weak alkalinity even if pH is not particularly adjusted with an alkaline substance or the like, and particularly preferably an aqueous solution having a pH of 9 to 14.
  • the cyclodextrin added to the aqueous solution is preferably added in an amount of 0.5 mol to 1.4 mol with respect to ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form (1.0 mol). It is particularly preferable to add 5 mol to 1.1 mol, and more preferably 0.6 mol to 0.7 mol.
  • ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form cyclodextrin complex is formed in the solution or suspension.
  • ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form and cyclodextrin are combined in the solution or suspension in an amount of 5 to 50 wt%, preferably 5 to 35 wt%, more preferably 10 to 25 wt%, 20 to 25 wt%. It is particularly preferable to add it so that it is contained. This is because handling is difficult at 50 wt% or more.
  • step (3) of the production method (E) the solution or suspension of the ⁇ -lipoic acid R-form alkali metal salt or alkaline earth metal salt cyclodextrin complex obtained in step 2), or ⁇ Alkaline metal salt or alkaline earth metal salt of ⁇ -lipoic acid R-form, or ⁇ -lipoic acid S-form in solution or suspension of cyclodextrin complex of lipoic acid S-form alkali metal salt or alkaline earth metal salt
  • an equimolar or equimolar or more acid is gradually added to the alkali metal salt or alkaline earth metal salt to adjust the pH to 4.0 or less.
  • the alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid R form, or the alkali metal salt or alkaline earth metal salt of ⁇ -lipoic acid S form is neutralized, and ⁇ -lipoic acid R-form or ⁇ -lipoic acid S is neutralized. It is possible to convert to ⁇ -lipoic acid complex in which ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form is complexed through this step.
  • the acid is preferably added while stirring the solution or suspension, and any acid that can be used for pH adjustment may be used.
  • inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid can be used.
  • the acid is preferably added until the pH of the solution or suspension becomes 4.0 or less, and particularly preferably added uniformly until the pH becomes 3.5 or 3.5 or less.
  • the pH it is extremely preferable to adjust the pH to 3.0 to 3.5.
  • the resulting suspension may be stirred, and this stirring may be no more than 1 hour, and preferably no more than 18 hours.
  • the step 3) in the production method (E) and the step 4) in the production method (D) were obtained by the step 2) in the production method (E) and the step 3) in the production method (D).
  • the ⁇ -lipoic acid complex contained in the suspension is dried as it is, or filtered to take out a residue containing the ⁇ -lipoic acid complex, followed by drying.
  • the ⁇ -lipoic acid complex contained in the suspension can be dried as it is without filter filtration or the like, and the ⁇ -lipoic acid complex containing an alkali salt produced by neutralization.
  • the alkali salt is obtained by taking out the residue containing the ⁇ -lipoic acid complex by, for example, filtration, centrifugation or belt filtration, washing with water and drying. It is also possible to obtain an ⁇ -lipoic acid complex from which is removed.
  • a commonly used practical method such as a method using an ion exchange membrane or a reverse osmosis membrane (RO membrane) can also be used as a method for removing an alkali salt.
  • the drying may be performed by any conventionally known method regardless of the presence or absence of an alkali salt. For example, a vacuum drying method, a freeze drying method, a spray drying method, an oven drying method, a belt drying method, a pulse drying method, or the like. Law.
  • the “method for producing an ⁇ -lipoic acid complex” of the present invention may include the following steps 1) to 3). This method is shown in the examples as the production method (F). 1) Step of dissolving cyclodextrin in water 2) After cooling the solution or suspension of 1) above to a certain temperature, dihydro ⁇ lipoic acid R-form or dihydro ⁇ lipoic acid S-form is added. Step 3) Obtaining a suspension of a cyclodextrin complex of dihydro ⁇ -lipoic acid R form or a suspension of a cyclodextrin complex of dihydro ⁇ lipoic acid S form 3) The step of drying the residue obtained by filtration
  • the “method for producing an ⁇ -lipoic acid complex” of the present invention may include the following steps 1) to 4). This method is shown in the Examples as the production method (G). 1) Step of dissolving cyclodextrin in water 2) After cooling the solution or suspension of 1) above to a certain temperature, dihydro ⁇ lipoic acid R-form or dihydro ⁇ lipoic acid S-form is added. A step of stirring and dissolving the dihydro ⁇ -lipoic acid R form while adding potassium hydroxide dropwise.
  • step 1) is a step of dissolving cyclodextrin in water.
  • the cyclodextrin to be dissolved in water is 0.5 mol to 1.4 mol with respect to dihydro ⁇ -lipoic acid R form (1.0 mol) or dihydro ⁇ lipoic acid S form (1.0 mol). It is preferably dissolved so that it is 0.5 mol to 1.1 mol, more preferably 0.6 mol to 0.7 mol.
  • the aqueous solution obtained in this step is preferably substituted with nitrogen or degassed in order to prevent oxidation of dihydrolipoic acid. Nitrogen replacement and deaeration treatment can be performed by a conventionally known method or the like.
  • step 2) in the production method (F) dihydro ⁇ -lipoic acid R-form or dihydro ⁇ -lipoic acid S-form is added to the solution or suspension obtained in the step 1), and the dihydro ⁇ -lipoic acid R-form is added.
  • This is a step of obtaining a suspension of a cyclodextrin complex or a suspension of a cyclodextrin complex of dihydro ⁇ -lipoic acid S form.
  • step 2) in the production method (G) dihydro ⁇ lipoic acid R-form or dihydro ⁇ lipoic acid S-form is added to the solution or suspension obtained in the step 1), and these alkali metal salts are added.
  • the solution or suspension obtained in the step 1) is preferably dropped while stirring, and the stirring speed is preferably 300 to 5000 rpm. In order to disperse more uniformly, it can be performed by increasing the stirring speed by a conventionally known method.
  • the dropped dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form is in the form of beads, it is preferable to perform ultrasonic treatment and uniformly disperse.
  • the solution of the above 1) it is preferable to cool the solution of the above 1) to a constant temperature when dropping the dihydro ⁇ -lipoic acid R-form or dihydro ⁇ -lipoic acid-S form, and the subsequent steps are also included. It is preferable to carry out at the adjusted temperature.
  • the temperature may be 40 ° C. or lower under atmospheric pressure and atmospheric pressure.
  • the temperature is preferably 25 ° C. or less, more preferably less than 10 ° C., still more preferably 0 ° C. to 9 ° C., and particularly preferably 0 to 6 ° C.
  • a cyclodextrin complex of dihydro ⁇ -lipoic acid R form or a cyclodextrin complex of dihydro ⁇ lipoic acid S form is formed in a cyclodextrin solution or suspension.
  • Dihydro ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form and cyclodextrin are 5 to 50 wt%, preferably 5 to 35 wt%, more preferably 10 to 25 wt%, 20% in total in this solution or suspension. It is particularly preferable to add such that it is contained in an amount of ⁇ 25 wt%. This is because handling is difficult at 50 wt% or more.
  • Step 3) in the production method (G) is a solution or suspension of an alkali metal salt or alkaline earth metal cyclodextrin complex of dihydro ⁇ lipoic acid R obtained by the step 2), or dihydro ⁇ -lipoic acid S-form alkali metal salt or alkaline earth metal cyclodextrin complex in solution or suspension, dihydro-alpha lipoic acid R-form alkali metal salt or alkaline earth metal salt, or dihydro-alpha lipoic acid
  • This is a step of gradually adding an equimolar or equimolar amount of acid to the S-form alkali metal salt or alkaline earth metal salt to adjust the pH to 4.0 or less.
  • inorganic acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid can be used.
  • the acid is preferably added until the pH of the solution or suspension becomes 4.0 or less, and particularly preferably added uniformly until the pH becomes 3.5 or 3.5 or less.
  • the resulting suspension may be stirred, and this stirring may be no more than 1 hour, and preferably no more than 18 hours.
  • the step 3) in the production method (F) and the step 4) in the production method (G) were obtained by the step 2) in the production method (F) and the step 3) in the production method (G).
  • the drying may be performed by any conventionally known method regardless of the presence or absence of an alkali salt. For example, a vacuum drying method, a freeze drying method, a spray drying method, an oven drying method, a belt drying method, a pulse drying method, or the like. Law.
  • the ⁇ lipoic acid complex obtained by the production method of the present invention can be contained in “pharmaceuticals” and “food”.
  • Such “food” such as “pharmaceuticals” and health foods, for example, anti-fatigue action, treatment, improvement mitigation, prevention of all diseases and symptoms for which alpha lipoic acid such as anti-diabetic drugs or antidote effectively acts Can be used for etc.
  • alpha lipoic acid such as anti-diabetic drugs or antidote effectively acts
  • ⁇ -lipoic acid complex ⁇ Production of ⁇ -lipoic acid complex> 1.
  • Sample ⁇ -lipoic acid and cyclodextrin used were commercially available or donated as shown below.
  • ⁇ -lipoic acid ⁇ -lipoic acid R-form (R-Alpha Lipoic Acid): Changshu Fushirai Co., Ltd.
  • ⁇ -lipoic acid R-form sodium salt (R-(+)-Lipoic Acid Sodium Salt): Changshu Fushirai-type dihydro ⁇ -lipoic acid (R-Dihydro-lipoic Acid): GeroNova Research Inc.
  • ⁇ -lipoic acid S form (S-Alpha Lipoic Acid): Changshu Fushirai 2) cyclodextrin ⁇ -cyclodextrin: CAVAMAX W6 Food (Wacker) ⁇ cyclodextrin: CAVAMAX W7 Food (Wacker) ⁇ cyclodextrin: CAVAMAX W8 Food (Wacker) Maltosyl ⁇ -cyclodextrin (maltosyl ⁇ CD mixture): Fuji Nippon Seiko Co., Ltd. Maltosyl ⁇ cyclodextrin (G2- ⁇ -CD): Shimizu Minato Sugar Co., Ltd. Maltosyl ⁇ cyclodextrin mixture (maltosyl ⁇ CD mixture): Fuji Nippon Seiko Co., Ltd. Isoelite P: Salt water Minato Seika Co., Ltd.
  • An ⁇ -lipoic acid complex was produced by the following steps 1) to 4). 1) While mixing water, ⁇ -lipoic acid R-form sodium salt or ⁇ -lipoic acid S-form sodium salt was added to dissolve ⁇ -lipoic acid R-form sodium salt or ⁇ -lipoic acid S-form sodium salt. 2) The solution of 1) above is cooled and adjusted to a certain temperature, then cyclodextrin is added and stirred, and a solution or suspension of ⁇ -lipoic acid R-form sodium salt cyclodextrin complex, or ⁇ A solution or suspension of cyclodextrin complex of lipoic acid S form sodium salt was obtained.
  • ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form was complexed from ⁇ -lipoic acid R-form sodium salt or alpha-lipoic acid S-form sodium salt for neutralization by dropping hydrochloric acid (1N).
  • An ⁇ -lipoic acid complex could be produced.
  • Method for producing ⁇ -lipoic acid complex (B) Similarly to the production method (A) of the ⁇ -lipoic acid complex, the steps 1) to 3) were performed, and then the step 4) was performed as follows.
  • ⁇ -lipoic acid complex in which ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form is complexed can be produced as in production method (A). Is not washed with water, an ⁇ -lipoic acid complex containing an alkali salt is obtained. 4) The suspension of 3) above was dried as it was to produce an ⁇ -lipoic acid complex.
  • Method for producing ⁇ -lipoic acid complex (C) Similarly to the production method (A) of the ⁇ -lipoic acid complex, after performing steps 1) to 2), in step 3), the suspension was stirred without dropping hydrochloric acid (1N), The process of 4) was performed. In this production method, hydrochloric acid (1N) was not added dropwise, so ⁇ -lipoic acid R-form sodium salt or ⁇ -lipoic acid S-form sodium salt was complexed instead of ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form. An ⁇ -lipoic acid complex could be produced.
  • ⁇ -lipoic acid complex An ⁇ -lipoic acid complex was produced by the following steps 1) to 4). 1) ⁇ -lipoic acid R-form or ⁇ -lipoic acid-S form was added while stirring water, and ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form was dissolved while potassium hydroxide was added dropwise. 2) The solution of 1) above is cooled and adjusted to a certain temperature, then cyclodextrin is added and stirred, and a solution or suspension of ⁇ -lipoic acid R-form potassium salt cyclodextrin complex, or ⁇ A solution or suspension of a cyclodextrin complex of lipoic acid S form potassium salt was obtained.
  • ⁇ -lipoic acid R-form potassium salt or ⁇ -lipoic acid S-form potassium salt can be converted into ⁇ -lipoic acid R-form or ⁇ -lipoic acid S-form.
  • An ⁇ -lipoic acid complex was produced by the following steps 1) to 3). 1) Cyclodextrin was added and dissolved while stirring water. 2) The solution or suspension of 1) above is cooled and adjusted to a certain temperature, and then dihydro ⁇ -lipoic acid R-form or dihydro ⁇ -lipoic acid S-form is added and stirred, and the dihydro ⁇ -lipoic acid R-form is added. A suspension of a cyclodextrin complex or a suspension of a cyclodextrin complex of dihydro ⁇ -lipoic acid S was obtained. 3) The suspension of the above 2) was dried to produce an ⁇ -lipoic acid complex including the target dihydro- ⁇ -lipoic acid R-form or dihydro- ⁇ -lipoic acid S-form.
  • ⁇ -lipoic acid complex An ⁇ -lipoic acid complex was produced by the following steps 1) to 3). 1) Cyclodextrin was added and dissolved while stirring water. 2) After cooling and adjusting the solution or suspension of 1) above to a certain temperature, dihydro ⁇ -lipoic acid R-form or dihydro- ⁇ lipoic acid S-form is added and stirred while potassium hydroxide is added dropwise. Dihydro alpha lipoic acid R-form or dihydro alpha lipoic acid S-form was dissolved. The pH of this solution or suspension was approximately 9-10. 3) Hydrochloric acid (1N) was added dropwise to the solution or suspension of 2) above, the pH was adjusted, and the suspension was obtained by stirring. The pH of this solution or suspension was approximately 3-4. 4) The ⁇ -lipoic acid complex encapsulating the target dihydro- ⁇ -lipoic acid R form was produced by drying the suspension of 3) above.
  • Example 1 While stirring in 240 g of water, 10 g of ⁇ -lipoic acid R-form sodium salt was added and dissolved. Upon cooling, the reaction temperature was adjusted to 5 ° C., 46 g of ⁇ -cyclodextrin was added and stirred, and a suspension of ⁇ -cyclodextrin complex of ⁇ -lipoic acid R-form sodium salt was obtained. After stirring for 10 minutes, 48 ml of 1N hydrochloric acid was added dropwise to adjust the pH of the solution to 3.0. The residue was washed with water and dried under reduced pressure to obtain 51.6 g of the desired product.
  • Examples 2 to 24 In accordance with the above-described production methods (A) to (E) of the ⁇ -lipoic acid complex or the production methods (F) and (G) of dihydro ⁇ -lipoic acid, or ⁇ -lipoic acid S form, dihydro ⁇ lipoic acid R form or dihydro ⁇ Lipoic acid S-forms, or ⁇ -lipoic acid complexes obtained by complexing these alkali metal salts or alkaline earth metal salts were produced.
  • the production conditions and the like in Examples 1 to 24 are shown in Tables 1 to 3.
  • the alpha lipoic acid R form sodium salt used in Examples 1 to 6 has a purity of 79%
  • the alpha lipoic acid R form sodium salt used in Example 7 has a purity of 85%.
  • the ⁇ -lipoic acid R-form sodium salt used in No. 9 had a purity of 80%.
  • the purity of ⁇ -lipoic acid R-form sodium salt used in Examples 10 to 17 and 23 was 90%
  • the purity of ⁇ -lipoic acid R-form used in Examples 18 to 20 was 99%
  • the dihydro ⁇ used in Example 21 The purity of the lipoic acid R form was 99%
  • the purity of the dihydroalpha lipoic acid R form used in Example 22 was 90%
  • the purity of the dihydrolipoic acid used in Example 24 was 92%.
  • the ⁇ -lipoic acid R form used in the Comparative Example also had a purity of 79%.
  • Example 25 The ⁇ -lipoic acid complex was produced according to the ⁇ -lipoic acid complex production method (A) described above. The production conditions and the like in Example 25 are shown in Table 1. The alpha lipoic acid S-form sodium salt used in Example 25 had a purity of 76%.
  • Tables 1 to 3 collectively show the yield of the ⁇ -lipoic acid complex produced in Examples 1 to 25, the ⁇ -lipoic acid complex, and the crystals produced in the comparative example (comparative).
  • Tables 1 to 3 depending on the purity of ⁇ -lipoic acid R-form sodium salt, ⁇ -lipoic acid S-form sodium salt, ⁇ -lipoic acid R-form or dihydro ⁇ -lipoic acid R-form used as a sample, The amount of lipoic acid R form, the amount of alpha lipoic acid S form or the amount of dihydro alpha lipoic acid R form is shown in parentheses as * .
  • the ⁇ lipoic acid complex produced by the production methods (A) to (G) of the present invention was compared with the ⁇ lipoic acid complex produced by the comparative example. It was shown that the lipoic acid R-form is contained in high purity of 6.79% or more, dihydro-alpha lipoic acid R-form is 13.4% or more, and alpha lipoic acid S-form is 12.1% or more.
  • ⁇ -lipoic acid R-form As the yield of ⁇ -lipoic acid complex, ⁇ -lipoic acid R-form, ⁇ -lipoic acid R-form sodium salt, ⁇ -lipoic acid S-form sodium salt used as a sample in the production of the ⁇ -lipoic acid complex of the present invention or Depending on the purity of the dihydro- ⁇ -lipoic acid R-form, how much of the pure ⁇ -lipoic acid R-form, ⁇ -lipoic acid S-form or dihydro- ⁇ -lipoic acid R-form contained in these samples is finally utilized in the reaction It was calculated
  • the ⁇ lipoic acid complex produced by the production methods (A) to (G) of the present invention compared with the ⁇ lipoic acid complex produced by the comparative example was 70 A high yield of more than% was shown. Therefore, based on this result, the production methods (A) to (G) of the present invention efficiently use ⁇ -lipoic acid R-form, ⁇ -lipoic acid R-form sodium salt, ⁇ -lipoic acid S-form sodium salt or dihydro ⁇ -lipoic acid R-form. It was confirmed that this is a method for producing an ⁇ -lipoic acid complex that can be used in a complex manner.
  • the “prescription value” used to determine the yield * 2 of ⁇ -lipoic acid complex is ⁇ -lipoic acid R-form, ⁇ -lipoic acid R-form sodium salt, ⁇ -lipoic acid S-form sodium used as a sample. It means the pure ⁇ lipoic acid R isomer weight, ⁇ lipoic acid S isomer weight or dihydro ⁇ lipoic acid R isomer weight determined according to the purity of the salt or dihydro ⁇ lipoic acid R isomer.
  • the prescription values of ⁇ lipoic acid in each Example or Comparative Example are 7.9 g in Examples 1 to 6, 850 g in Example 7, 4 g in Example 8, 2 g in Example 9, and 3.2 g in Comparative Example. there were.
  • Examples 10 to 12 were 4 g
  • Example 13 was 170 kg
  • Examples 14 to 16 were 1.1 g
  • Example 17 was 2.2 g
  • Examples 18 to 20 were 4.9 g
  • Example 21 was 1.g. 85 g
  • Examples 22 and 24 were 1.61 g
  • Example 23 was 1.1 g
  • Example 25 was 7.6 g.
  • a diluting solvent (5 mM potassium dihydrogen phosphate and acetonitrile mixed at a volume ratio of 1: 1 and adjusted to pH 3.5 with phosphoric acid) was added. Diluted and suspended uniformly.
  • the ⁇ -lipoic acid R-form content contained in this solution portion was measured using HPLC in the same manner as in Test Example 1.
  • the ⁇ -lipoic acid R-form content before the treatment with the artificial gastric acid solution was set to 100%, the content after the treatment was calculated as a percentage with respect to the amount before the treatment, and this was used as the residual rate.
  • the stability of the artificial gastric acid solution was investigated. As a result, as shown in Table 7, the ⁇ lipoic acid complex produced in the present invention remained in a high proportion of ⁇ lipoic acid R-form, indicating that the stability of the artificial gastric acid solution was high.
  • Example 5 A mixed preparation having the following composition was produced.
  • Each ⁇ -lipoic acid complex (250 g) containing ⁇ -lipoic acid R form produced in the same manner as in Examples 1 to 4 was uniformly pulverized together with 750 g of microcrystalline cellulose.
  • 250 g of starch, 732.5 g of lactose, 15 g of magnesium stearate and 2.5 g of silicon oxide were added and mixed well.
  • a tablet having a weight of 400 mg was produced by a tableting machine.
  • mice were fasted from 18 hours before the start of the test.
  • the rats were divided into 3 groups each consisting of 6 animals. Blood was collected from the carotid artery using a heparin-injected syringe under ether anesthesia without administering either ⁇ -lipoic acid complex or ⁇ -lipoic acid R-form itself (comparative) to one of the three rats. (Control group).
  • the obtained blood was centrifuged immediately after blood collection, and the obtained plasma was stored at ⁇ 80 ° C.
  • a solution of ⁇ -lipoic acid complex dissolved in pure water was orally administered to the rats in the remaining 1 group so as to be 30 mg / kg body weight in terms of ⁇ -lipoic acid content.
  • ⁇ lipoic acid R form dissolved in pure water was orally administered to the remaining one group of rats so that the ⁇ lipoic acid content was 30 mg / kg body weight.
  • the concentration of ⁇ -lipoic acid R-form in plasma in each group of rats was separated by HPLC under the conditions shown in Table 10, and using API 3200 (registered trademark) LC / MS / MS System (manufactured by AB SCIEX). It was measured. As a result, the group to which the ⁇ -lipoic acid complex containing the ⁇ -lipoic acid R-form of the present invention was administered had significantly improved oral absorbability compared to the group to which the ⁇ -lipoic acid R-form itself was administered.
  • Test Example 8 Evaluation of taste of ⁇ -lipoic acid complex The taste of ⁇ -lipoic acid complex obtained by the production method of the present invention was evaluated. Twenty panelists were fed with ⁇ -lipoic acid complex produced in Example 13 above as a test substance and ⁇ -lipoic acid R-form or ⁇ -lipoic acid R-form sodium salt as a comparative control and evaluated the taste respectively. It was. Taste evaluation was performed as follows. That is, 20 panelists were divided into two groups of 10 people, and one type of sample was fed to each group once a day during the 2-day test period. After rinsing the mouth with water at 10:00 in the morning, the sample was placed on the tongue and evaluated for taste and irritation for 1 minute, and then rinsed with water.
  • the complexed ⁇ -lipoic acid complex can be widely used in pharmaceuticals, health foods and the like as a component that is stable to heat and artificial gastric acid solution and exhibits a sufficient effect.

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Abstract

L'invention concerne un complexe d'acide α-lipoïque obtenu par la complexation d'acide R-α-lipoïque ou d'acide S-α-lipoïque, d'acide R-dihydro-α-lipoïque ou d'acide S-dihydro-α-lipoïque, ou d'un sel de métal alcalin ou un sel de métal alcalino-terreux de ceux-ci, et un procédé de production du complexe d'acide α-lipoïque. Un complexe d'acide α-lipoïque qui est stable à la chaleur et vis-à-vis d'une solution d'acide gastrique artificiel et a une haute pureté, peut être produit par exemple par addition de cyclodextrine à une solution aqueuse contenant, dissous dans celle-ci, de l'acide R α-lipoïque ou de l'acide S α-lipoïque, de l'acide R-dihydro-α-lipoïque ou de l'acide S-dihydro-α-lipoïque, ou un sel de métal alcalin ou un sel métallique alcalino-terreux de ceux-ci, et ainsi complexification de l'acide R-α-lipoïque ou de l'acide S α-lipoïque, de l'acide R-dihydro-α-lipoïque ou de l'acide S-dihydro-α-lipoïque ou du sel de métal alcalin ou du sel métallique alcalino-terreux de ceux-ci, à une probabilité élevée.
PCT/JP2011/066447 2010-07-30 2011-07-20 Complexe d'acide α-lipoïque WO2012014746A1 (fr)

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US10607773B2 (en) 2015-03-05 2020-03-31 Shin-Etsu Chemical Co., Ltd. Powder molding apparatus and manufacture of rare earth sintered magnet using the apparatus
CN115536631A (zh) * 2021-06-30 2022-12-30 江苏同禾药业有限公司 一种高纯度的右旋硫辛酸镁盐的制备方法

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