WO2017086425A1 - ビオチン含有液剤 - Google Patents

ビオチン含有液剤 Download PDF

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Publication number
WO2017086425A1
WO2017086425A1 PCT/JP2016/084216 JP2016084216W WO2017086425A1 WO 2017086425 A1 WO2017086425 A1 WO 2017086425A1 JP 2016084216 W JP2016084216 W JP 2016084216W WO 2017086425 A1 WO2017086425 A1 WO 2017086425A1
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WO
WIPO (PCT)
Prior art keywords
biotin
vitamin
weight
liquid
present
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2016/084216
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English (en)
French (fr)
Japanese (ja)
Inventor
祐子 井上
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Publication of WO2017086425A1 publication Critical patent/WO2017086425A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention can take the form of solutions comprising biotin and vitamin B 2, a liquid and more particularly comprising biotin and vitamin B 2, biotin stabilization method of the biotin in stabilized solutions and liquid agents.
  • Biotin is a member of the vitamin B group and is also called vitamin H or coenzyme R. Since biotin is involved in fatty acid synthesis and sugar metabolism as a coenzyme for carboxylating enzymes, it is used as a raw material for pharmaceuticals, cosmetics, feed additives, and the like. Biotin itself is stable to light. However, when vitamin B 2 coexists in a liquid preparation containing biotin, it is known that vitamin B 2 generates active oxygen by photoexcitation and decomposes biotin (non-biotin). Patent Document 1).
  • Patent Document 1 the biotin is unstable due to coexistence of vitamin B 2 and biotin, and it is described that can be solved by Toshishi acid that problem.
  • the toshishi extract was used at the concentration described in the example of Patent Document 1, the liquid agent was turbid and the taste and sourness were strong, so it was not suitable for drinking.
  • the residual ratio of biotin may be significantly reduced.
  • Patent Document 2 describes that biotin is unstable in the presence of a reducing sugar (for example, sugar), and Patent Document 3 describes that biotin is unstable in a low pH region.
  • a reducing sugar for example, sugar
  • Patent Document 4 describes that a solution containing vitamin B 1 , ascorbic acid and / or biotin is stabilized in the presence of sucralose. However, in the examples, only the stability of the liquid preparation containing these components alone is examined, and no problems are described in the case where these components coexist.
  • An object of the present invention is a liquid comprising biotin and vitamin B 2, is to provide solutions to biotin in the liquid agent is stabilized, and in the liquid agent stabilizing method of biotin.
  • the present inventors have conducted extensive studies result in solution comprising biotin and vitamin B 2, by including vitamin C, we found that it is possible to obtain a liquid formulation the stability of the biotin is improved, and accomplished the present invention. That is, the present invention includes the following aspects.
  • the present invention it is possible to provide a liquid preparation containing biotin and vitamin B 2 with improved biotin stability. Further, tasty, it is possible to provide a clear, liquid comprising biotin and vitamin B 2. Furthermore, according to the present invention, in addition to the stability, flavor and clarity of biotin, it is possible to provide a liquid agent that is excellent in terms of the stability of other components, low calories, efficacy effects, and the like.
  • FIG. 1 shows the residual ratio (%) of biotin after irradiation with 100 kl ⁇ 12 h of light for each of the solutions of Examples 2-1 to 2-5 and Comparative Examples 2-1 to 2-3.
  • the “liquid agent” refers to a liquid dosage form usually used for pharmaceuticals or foods, and includes, for example, oral liquids (so-called drinks, nutritional supplements, nourishing tonics, etc.), lotions, Drinking water etc. can be mentioned.
  • the liquid preparation of the present invention is preferably an internal use liquid preparation.
  • “clear” means that the transmittance of light having a wavelength of 660 nm is 60% T or more.
  • vitamin B 2 refers to riboflavin and various derivatives of riboflavin such as its phosphate ester and butyrate ester. Specifically, riboflavin, flavin adenine dinucleotide sodium, riboflavin sodium phosphate And riboflavin butyrate.
  • vitamin C refers to ascorbic acid and salts thereof, esters and derivatives thereof, and specifically includes ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, magnesium ascorbate, Examples include ammonium ascorbate.
  • the liquid preparation of the present invention is characterized in that the biotin concentration is 3 ⁇ g / mL or more.
  • the biotin concentration is preferably 3 ⁇ g / mL to 50 ⁇ g / mL, more preferably 4 ⁇ g / mL to 30 ⁇ g / mL.
  • Liquid of the present invention, vitamin B 2, as the concentration of riboflavin usually comprise 0.01 mg / mL or more, preferably 0.01 ⁇ 2.0 mg / mL, more preferably 0.02mg / mL ⁇ 1.2mg / Contains mL.
  • the liquid preparation of the present invention contains vitamin C as free ascorbic acid, usually 0.1 mg / mL or more, preferably 0.5 mg / mL or more, more preferably 2 mg / mL or more, and even more preferably 4 mg / mL or more.
  • the upper limit is not particularly limited, but can be, for example, 150 mg / mL, preferably 100 mg / mL. Therefore, the concentration range of vitamin C (as free ascorbic acid) can be, for example, 0.5 to 150 mg / mL, preferably 2 mg / mL to 100 mg / mL.
  • the pH of the liquid preparation of the present invention is low, vitamin C is easily decomposed.
  • vitamin C (as free ascorbic acid) can be 0.5 mg / mL to 150 mg / mL, and when pH is 3.0, it can be 2 mg / mL to 150 mg / mL. .
  • the liquid preparation of the present invention contains vitamin B 2 (as riboflavin), preferably 2 to 1500 parts by weight, more preferably 4 to 1200 parts by weight, and still more preferably 40 to 1000 parts per 1 part by weight of biotin. Including parts by weight.
  • vitamin B 2 as riboflavin
  • the liquid preparation of the present invention usually contains 10 parts by weight or more of vitamin C (as free ascorbic acid) with respect to 1 part by weight of biotin, preferably 50 parts by weight or more, more preferably 100 parts by weight or more, and still more preferably. Contains 200 parts by weight or more.
  • the upper limit is not specifically limited, For example, it can be 60000 weight part, Preferably it can be 50000 weight part.
  • the range of the amount of vitamin C (as free ascorbic acid) relative to 1 part by weight of biotin can be, for example, 10 to 60000 parts by weight, preferably 50 to 60000 parts by weight, more preferably 200 to 50000 parts by weight. In the case of a solution containing biotin and vitamin C at this blending ratio, it is particularly excellent in terms of biotin stability.
  • the liquid preparation of the present invention usually contains 0.3 part by weight or more of vitamin C (as free ascorbic acid), preferably 1 to 500 parts by weight, more preferably 1 part by weight of vitamin B 2 (as riboflavin). Contains 4 to 250 parts by weight. If a solution containing a vitamin B 2 and vitamin C in the compounding ratio, and particularly excellent in terms of stability of the biotin.
  • the pH of the liquid preparation of the present invention is usually 3.0 to 5.7, preferably 4.5 to 5.5 from the viewpoint of vitamin C stability, more preferably 4.6 to 5.3, and even more.
  • the preferred range is 4.7 to 5.2.
  • the liquid preparation of the present invention may further contain other medicinal ingredients.
  • amino acids such as taurine, L-arginine and L-aspartic acid, vitamin B 1 and its derivatives, pantothenic acid and its salts, vitamin B 6 and its derivatives, vitamins such as nicotinamide, inositol, carnitine or its chloride vitamin-like substance, sodium chondroitin sulfate, such as objects, Muirapuama, six-rowed, carrot, crude drugs such as rehmannia, such as caffeine, vitamin B 12 and its derivatives, folic acid, choline, ursodeoxycholic acid, orotic acid, gamma oryzanol, guru Components such as chronolactone, thioctic acid, rutin, and the like, preferably assisting fat metabolism, particularly nicotinamide, inositol, carnitine chloride, sodium pantothenate and the like can be blended.
  • the compounding amount of these medicinal ingredients in the liquid preparation of the present invention is not particularly limited as long as it does not adversely affect the stability of biotin.
  • 0.000001 to 100 mg / mL per one medicinal ingredient is preferable. Is 0.00001 to 50 mg / mL.
  • the liquid preparation of the present invention includes, in addition to the above components, polyhydric alcohols such as ethanol, glycerin and propylene glycol, saccharides such as sucrose and glucose, high sweetness sweeteners such as sucralose and acesulfame potassium, sorbitol, erythritol and the like.
  • Sugar alcohol e.g, honey, amino acids, salt), flavors (eg, apple flavor, muscat flavor), coloring agents (eg, caramel, ⁇ -carotene), preservatives (eg, sodium benzoate, paraoxybenzoic acid)
  • Additives such as ethyl can also be blended.
  • the blending amount of these additives in the liquid preparation of the present invention is not particularly limited as long as it does not affect the stability of biotin.
  • the liquid preparation of the present invention can contain a pH adjuster as necessary.
  • the pH adjuster is not particularly limited, and is a pH adjuster known in the art, for example, acetic acid, sodium acetate, sodium dihydrogen phosphate, phosphoric acid, potassium dihydrogen phosphate, disodium hydrogen phosphate, water. Examples thereof include sodium oxide, magnesium hydroxide, sodium hydrogen carbonate, DL-malic acid, hydrochloric acid, dilute hydrochloric acid, glycine, tartaric acid, lactic acid, calcium lactate, and anhydrous citric acid. By using an appropriate amount of one or more of these, the pH of the liquid preparation of the present invention can be adjusted to a desired value.
  • the method for producing the liquid preparation of the present invention is not particularly limited, and examples thereof include a method of adjusting by mixing and dissolving a predetermined amount of biotin, vitamin B 2 and vitamin C, and other components as appropriate. . When adjusting such a liquid agent, filtration, sterilization, etc. may be performed as necessary.
  • the present invention provides a liquid comprising biotin and vitamin B 2, characterized in that the inclusion of vitamin C, to provide a method for stabilizing biotin in liquid.
  • the liquid agent in the above method can be adjusted to the pH described for the liquid agent of the present invention, and various components can be blended.
  • Biotin residual rate and transmittance were measured as follows.
  • Biotin residual rate The true residual amount of biotin was measured by HPLC (high performance liquid chromatography) under the following conditions.
  • HPLC conditions For the measurement of biotin, two types of columns, an Intact Corporation, Scherzo SS-C18 column (column 1) and a Shiseido Co., Ltd., CAPCELL PAK C18 MG2 column (columns 2 and 3) were used.
  • mobile phase A As mobile phase, mobile phase A (0.02 mol / L potassium dihydrogen phosphate solution (pH 2.5) / acetonitrile / methanol mixture (45: 3: 2)) and mobile phase B (acetonitrile / 0.02 mol / L phosphorus) Two kinds of potassium dihydrogen acid solution mixed solution (pH 2.5) (3: 2)) were used. These two types of mobile phases and columns 1 to 3 are appropriately switched to separate biotin, and the biotin concentration is measured at a measurement wavelength of 210 nm using an ultraviolet absorptiometer (product name: Lachrom L-7405, manufactured by Hitachi High-Tech Science Co., Ltd.). Asked.
  • the transmittance of the liquid agent was determined as the transmittance (% T) of light having a wavelength of 660 nm using an ultraviolet-visible spectrophotometer (product name: U-3010, manufactured by Hitachi High-Technology Corporation). .
  • Example 1 The range in which the effect of suppressing biotin degradation vitamin C (VC) is exerted, were examined for the concentration of vitamin B 2 and VC.
  • Each component described in Table 1 below was dissolved in purified water, the pH was adjusted using a pH adjuster, and the total amount was 50 mL. Each was filled in a brown bottle, irradiated with light, and the amount of remaining biotin was measured. The results are shown in Table 1 below.
  • each liquid agent of the Example was clear before and after light irradiation.
  • the amount of vitamin B 2 is the minimum amount (2.54 mg), it was found to degrade biotin. On the other hand, it was found that the biotin degradation can be suppressed (stabilized) by adding vitamin C even when the amount of vitamin B 2 is 15.25 mg.
  • Example 2 The range in which the effect of suppressing biotin decomposition VC is exerted, were examined for the concentration of vitamin B 2 and VC in more detail in Example 1. Moreover, the effect was compared with the effect of the toshishi extract used by patent document 1.
  • FIG. Each component described in Table 2 below was dissolved in purified water, the pH was adjusted using a pH adjuster, and the total amount was 50 mL. Each was filled in a brown bottle, irradiated with light, and the amount of remaining biotin was measured. The results are shown in Table 2 below and FIG. In addition, each liquid agent of the Example was clear before and after light irradiation. On the other hand, the solution of Comparative Example 2-3 to which Toshishi extract was added was cloudy.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
PCT/JP2016/084216 2015-11-19 2016-11-18 ビオチン含有液剤 Ceased WO2017086425A1 (ja)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015-226542 2015-11-19
JP2015226542A JP6633896B2 (ja) 2015-11-19 2015-11-19 ビオチン含有液剤

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Publication number Priority date Publication date Assignee Title
CN111511220A (zh) * 2017-12-25 2020-08-07 好侍健康食品株式会社 维生素b族化合物的稳定性优异的含有维生素b族化合物的酸性组合物

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10121044A (ja) * 1996-08-29 1998-05-12 Kikkoman Corp 抗酸化剤、活性酸素消去剤およびそれらの応用
JPH115975A (ja) * 1997-04-23 1999-01-12 Sansho Seiyaku Co Ltd 活性酸素消去剤およびその用途
JPH11158061A (ja) * 1997-09-25 1999-06-15 Otsuka Pharmaceut Factory Inc 中心静脈投与用輸液
JP2006089430A (ja) * 2004-09-27 2006-04-06 Taisho Pharmaceut Co Ltd ビオチン及びビタミンｂ２含有水性液剤組成物
JP2008132319A (ja) * 2006-10-27 2008-06-12 Otsuka Pharmaceut Factory Inc 溶存酸素量が低減された薬液収容体
JP2013515513A (ja) * 2009-12-24 2013-05-09 ビーエム ゴル プロプライエタリー リミテッド 使い捨ての容器およびその用途
JP2013237661A (ja) * 2012-04-19 2013-11-28 Kikkoman Corp ヒアルロン酸の分解制御方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH111436A (ja) * 1997-06-13 1999-01-06 Taisho Pharmaceut Co Ltd 鉄分含有液剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10121044A (ja) * 1996-08-29 1998-05-12 Kikkoman Corp 抗酸化剤、活性酸素消去剤およびそれらの応用
JPH115975A (ja) * 1997-04-23 1999-01-12 Sansho Seiyaku Co Ltd 活性酸素消去剤およびその用途
JPH11158061A (ja) * 1997-09-25 1999-06-15 Otsuka Pharmaceut Factory Inc 中心静脈投与用輸液
JP2006089430A (ja) * 2004-09-27 2006-04-06 Taisho Pharmaceut Co Ltd ビオチン及びビタミンｂ２含有水性液剤組成物
JP2008132319A (ja) * 2006-10-27 2008-06-12 Otsuka Pharmaceut Factory Inc 溶存酸素量が低減された薬液収容体
JP2013515513A (ja) * 2009-12-24 2013-05-09 ビーエム ゴル プロプライエタリー リミテッド 使い捨ての容器およびその用途
JP2013237661A (ja) * 2012-04-19 2013-11-28 Kikkoman Corp ヒアルロン酸の分解制御方法

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JP2017095372A (ja) 2017-06-01
JP6633896B2 (ja) 2020-01-22
TW201726126A (zh) 2017-08-01

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