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US20080261914A1 - Stabilization of vitamin b12 - Google Patents

Stabilization of vitamin b12 Download PDF

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Publication number
US20080261914A1
US20080261914A1 US12/045,831 US4583108A US2008261914A1 US 20080261914 A1 US20080261914 A1 US 20080261914A1 US 4583108 A US4583108 A US 4583108A US 2008261914 A1 US2008261914 A1 US 2008261914A1
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United States
Prior art keywords
vitamin
acid
butanol
water
injections
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Abandoned
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US12/045,831
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English (en)
Inventor
Iris Heep
Hans-Rolf Taterra
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Bayer Animal Health GmbH
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Bayer Healthcare AG
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Assigned to BAYER HEALTHCARE AG reassignment BAYER HEALTHCARE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TATERRA, HANS-ROLF, HEEP, IRIS
Publication of US20080261914A1 publication Critical patent/US20080261914A1/en
Assigned to BAYER ANIMAL HEALTH GMBH reassignment BAYER ANIMAL HEALTH GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAYER HEALTHCARE AG
Priority to US12/951,581 priority Critical patent/US9089582B2/en
Priority to US14/808,425 priority patent/US9610297B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention relates to preparations comprising vitamin B 12 and a butanol, and to the use of butanol for stabilizing vitamins.
  • Vitamin B 12 is stabilized not only in liquid formulations, but also in tablets or granules, as described for example in EP416773. Most of the studies on the stabilization of vitamin B 12 relate however to liquid formulations.
  • Such solutions can also be used to fill capsules (FR1472901), or the solutions are freeze dried for further stabilization (JP63313736).
  • vitamin B 12 solutions ready for use there are some stabilized by the addition of iron salts (FR1285213, GB902377).
  • the solutions may likewise comprise EDTA (ethylenediaminetetraacetic acid, U.S. Pat. No. 2,939,821 or GB822127).
  • Alkali metal salts or alkaline earth metal salts are also said to have a stabilizing effect on vitamin B 12 (U.S. Pat. No. 2,566,123).
  • Vitamins can also take place by use of amino acids (U.S. Pat. No.
  • vitamin B 12 is said to be stable.
  • vitamin B 12 is stabilized through the use of polyvalent alcohols (JP2311417, JP63313736, JP05124967, FR1263794, JP04-235925, JP2000-319186 or HU150885).
  • the use of alcohols for stabilizing vitamin B 12 is proposed generally in JP2005247800, WO2005/094842, WO02/02145, BE576619 or JP02145521.
  • US2005074443 describes long-chain alcohols for stabilizing vitamin B 12 .
  • vitamin B 12 itself is also used in turn to stabilize other substances (JP2001-048780, JP2005-015368).
  • JP46-15320 propylene glycol is employed for isotonicity and benzyl alcohol as analgesic.
  • the actual stabilization is achieved by dextran and gelatin (hydrophilic macromolecules).
  • JP45-011919 the alcohols propylene glycol, benzyl alcohol, mannitol or glycerol are described for stabilizing 5,6-dimethylbenzimidazolyl cobamide coenzyme.
  • the invention relates to:
  • Vitamin B 12 in the narrower sense frequently means cyanocobalamin, but there are also other compounds which are likewise covered by the generic term vitamin B 12 ; these are also referred to as cobalamins. It is intended herein that the term vitamin B 12 generally means all compounds which act as coenzyme in the human and/or animal body or can be converted into the corresponding coenzyme forms. These vitamin B 12 compounds have in common the Corrin structure with a trivalent cobalt as central atom and with a 5,5-dimethylbenzimidazole residue which is alpha-glycosidically linked via D-ribofuranose 3-phosphate. Most cobalamins differ from one another merely in one axial substituent.
  • Adenosylcobalamin and methylcobalamin are the real active forms (coenzyme forms), and aquocobalamin and hydroxocobalamin are storage forms which likewise occur in the body.
  • the preparations according to the invention additionally comprise a pharmacologically acceptable phosphonic acid derivative.
  • Pharmacologically acceptable phosphonic acid derivatives which can be employed according to the invention are normally organic compounds which are suitable as metabolic stimulants and tonics in particular for productive and domestic animals. Preferred examples which may be mentioned are the compounds butaphosphan and toldimfos which have been known for a long time and are used inter alia for mineral supplementation (phosphorus).
  • Butaphosphan has the chemical name (1-butylamino-1-methyl)ethylphosphonic acid and has the structural formula
  • Butaphosphan is normally employed as free acid.
  • Toldimfos has the chemical name (4-dimethylamino-o-tolyl)phosphonic acid and has the following structural formula
  • Toldimfos is normally employed as sodium salt.
  • the present invention encompasses both the use of the free active ingredients and of their pharmaceutically acceptable salts, and the use of the corresponding hydrates and solvates of the compounds or their salts.
  • Vitamin B 12 is typically employed in the medicaments according to the invention in a proportion of from 0.00001 to 0.1%, preferably 0.0001 to 0.05% and particularly preferably from 0.001 to 0.01%.
  • the percentage data mean percent (M/V). This means: mass of the relevant substance in grams per 100 ml of finished solution.
  • Butanol refers to isomeric aliphatic alcohols which have an alkyl chain with four carbon atoms; they may be linear or branched, specifically as n-butanol, sec-butanol, tert-butanol and isobutanol. Isobutanol and n-butanol are preferred, and especially n-butanol.
  • Butanol is normally employed in concentrations of from 0.1 to 10%, preferably from 0.5 to 7% and particularly preferably from 1 to 5%.
  • the percentage data mean % (M/V).
  • the pharmacologically active phosphonic acids such as, for example, toldimfos or, in particular, butaphosphan, are employed in the medicaments according to the invention in a proportion of from 0.1 to 40%, preferably 1 to 30% and particularly preferably 5 to 20%.
  • the preparations according to the invention are preferably liquid and normally comprise water or a water-miscible substance as solvent.
  • solvent examples which may be mentioned are glycerol, propylene glycol, polyethylene glycols, tolerated alcohols such as ethanol or benzyl alcohol, N-methyl-pyrrolidone, propylene carbonate, glycofurol, dimethylacetamide, 2-pyrrolidone, isopropylidene-glycerol, or glycerolformal.
  • the solvents can also be employed in mixtures or combinations. Water-based formulations are preferred and may, of course, comprise further solvents and cosolvents.
  • the liquid formulation may comprise as solvent apart from water or water-miscible substances also oils in the form of an emulsion. Mention may be made in this connection of vegetable, animal and synthetic oils such as cottonseed oil, sesame oil, soya oil, medium chain triglycerides of a chain length of C 12 -C 18 , propylene glycol octanoate decanoate or else paraffin.
  • the solvent (or solvent mixture) is normally present in concentrations of up to 98%, preferably up to 90%, particularly preferably up to 87%.
  • concentrations of the solvent are ordinarily over 65%, preferably over 75%, particularly preferably over 85%.
  • the percentage data mean % (M/V).
  • the formulations according to the invention may also comprise cosolvents, specifically and preferably when the formulations comprise water; the cosolvents may improve the solubility of certain ingredients of the formulation.
  • the cosolvents are normally employed in proportions of from 0.1 to 30%, preferably from 1 to 10% (percentage data in each case M/V). Examples of cosolvents which may be mentioned are: pharmaceutically acceptable alcohols, dimethyl sulphoxide, ethyl lactate, ethyl acetate, triacetin. Mixtures of the aforementioned solvents can also be employed as cosolvent. In some circumstances, individual cosolvents can also be employed as solvents. Normally, the cosolvents employed in the preparations according to the invention are only those which have not been already used as solvent or in the solvent mixture.
  • Preservatives may be present in the liquid formulation.
  • preservatives which can be used are: aliphatic alcohols such as benzyl alcohol, ethanol, n-butanol, phenol, cresols, chlorobutanol, para-hydroxybenzoic esters (especially the methyl and propyl esters), salts or the free acids of carboxylic acids such as sorbic acid, benzoic acid, lactic acid or propionic acid.
  • the quaternary ammonium compounds such as, for example, benzalkonium chloride, benzethonium chloride or cetylpyridinium chloride.
  • Preservatives are normally employed in proportions of from 0.001 to 5%, preferably from 0.01 to 4%. Where the preparations according to the invention already comprise in sufficient quantity a component which may serve as preservative (e.g. n-butanol), normally no additional proportion is added for preservation purposes. It is, however, where appropriate possible to add other preservatives also.
  • the medicaments according to the invention may comprise further customary, pharmaceutically acceptable additives and excipients. Examples which may be mentioned are
  • the pH of the liquid preparations is 2-11, preferably 3-8 and particularly preferably 4-7.
  • the pH is adjusted where appropriate by adding pharmaceutically acceptable acids or bases. If the preparations comprise a pharmacologically active phosphonic acid, a base is preferably added to adjust the pH values indicated above.
  • bases which can be used are: alkali metal or alkaline earth metal hydroxides (e.g. NaOH, KOH; where appropriate in the form of their aqueous solutions: sodium hydroxide solution, potassium hydroxide solution), or basic phosphates, e.g. sodium phosphate, sodium hydrogenphosphate, basic amino acids such as, for example, lysine, arginine, histidine, ornithine, citrulline, hydroxylysine, choline, meglumine, ethanolamines such as triethanolamine or else buffers (tris(hydroxymethyl)aminomethane, cyclohexylamino-1-propanesulphonic acid).
  • the base preferably employed is: NaOH, KOH or arginine; NaOH is particularly preferred, where appropriate as aqueous sodium hydroxide solution.
  • acids which can be used are: inorganic acids such as, for example, hydrochloric acid, sulphuric acid, phosphoric acid or organic acids such as, for example, methanesulphonic acid, formic acid, acetic acid, propionic acid, lactic acid, malonic acid, adipic acid, tartaric acid, oxalic acid, fumaric acid, malic acid, citric acid, succinic acid, aspartic acid, glutamic acid, gluconic acid, glucuronic acid, galacturonic acid, glutaric acid, lactobionic acid, mandelic acid, salicylic acid, ascorbic acid, benzoic acid, maleic acid, citric acid, octanoic acid, linoleic acid, linolenic acid.
  • inorganic acids such as, for example, hydrochloric acid, sulphuric acid, phosphoric acid or organic acids such as, for example, methanesulphonic acid, formic acid, acetic
  • the required amount of acid or base is governed by the desired pH. Normally the acid or base is used in a proportion of from 0.0001 to 20%, preferably 0.001 to 10%.
  • the acids can be used with a proportion of from 0.0001 to 20%, preferably 0.01 to 10%.
  • the medicaments of the invention can be manufactured by dispersing the vitamin in the solvent.
  • the vitamin can be dispersed directly or, for quantitative conversion, by using a stock solution in the solvent. Apart from the actual solvent it is possible also to use other solvents as stock solution. Where appropriate, the pharmacologically acceptable phosphonic acid derivative is likewise dispersed in the solvent.
  • the butanol or mixtures of butanol and solvent are added. Cosolvents and further ingredients such as, for example, antioxidants may have been added to the solvent or can be admixed later.
  • the pH is adjusted, e.g. with a base.
  • parts of the manufacture and filling of the solutions can take place under a protective gas atmosphere, e.g. introducing nitrogen gas.
  • butanol and, where appropriate, also the pharmacologically acceptable phosphonic acid derivative can initially be dissolved in the solvent and then the vitamin B 12 can be added.
  • the pharmaceutical preparations according to the invention are generally suitable for use in humans and animals. They are preferably employed in animal management and animal breeding among productive and breeding livestock, zoo, laboratory and experimental animals, and pets.
  • the productive and breeding livestock include mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffaloes, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as, for example, mink, chinchilla, raccoon, and birds such as, for example, quail, chicken, geese, turkeys, ducks, pigeons and bird species for keeping at home and in zoos.
  • mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffaloes, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as, for example, mink, chinchilla, raccoon, and birds such as, for example, quail, chicken, geese, turkeys, ducks, pigeons and bird species for keeping at home and in zoos.
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, rabbits, monkeys, dogs and cats.
  • Pets include rabbits, hamsters, rats, guinea pigs, mice, horses, reptiles, appropriate bird species, dogs and cats.
  • the preparations according to the invention are preferably employed for horses, rabbits, cats and dogs. They are particularly suitable for use in cats and dogs.
  • the preparations according to the invention are preferably employed for cattle, sheep, pigs, goats, turkeys and chickens. Particularly preferred productive livestock are cattle and pigs.
  • Liquid formulations according to the invention are preferably emulsions or, in particular, solutions.
  • the formulations described herein can be supplied to the target organism (human or animal) in various ways. They can be administered for example parenterally, in particular by injection (e.g. subcutaneous, intramuscular, intravenous, intramammary, intraperitoneal), dermally, orally, rectally, vaginally or nasally, with preference for oral and parenteral administration—especially by injection. Parenteral administration by injection is particularly preferred.
  • the formulations of the following examples are produced by mixing or dissolving the stated ingredients in water for injections or distilled water or demineralized water. To introduce the cyanocobalamin quantitatively into the main mixture it is advisable to use a stock solution. This is not, however, obligatory.
  • the pH of the solutions can be adjusted by adding acids or bases.
  • the solutions are produced and filled under nitrogen protection.
  • the solutions for injection are sterilized by filtration and transferred into suitable containers. Percentage data in percent by weight are based on the total volume of the finished product (M/V).
  • vitamin B 12 0.0005 g of vitamin B 12 is dissolved in a partial quantity of water for injections by heating.
  • 1.0 g of butaphosphan and 0.3 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin.
  • the pH is adjusted with sodium hydroxide to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 10 ml with water for injections.
  • vitamin B 12 0.0010 g is dissolved in a partial quantity of water for injections by heating. 0.6 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin. The pH is adjusted with sodium hydroxide to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 20 ml with water for injections.
  • vitamin B 12 0.0025 g is dissolved in a partial quantity of water for injections by heating.
  • 5.0 g of butaphosphan and 1.0 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin.
  • the pH is adjusted with sodium hydroxide to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 50 ml with water for injections.
  • vitamin B 12 0.0010 g of vitamin B 12 is dissolved in a partial quantity of water for injections by heating. 2.0 g of butaphosphan and 0.3 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin. The pH is adjusted to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 10 ml with water for injections.
  • vitamin B 12 0.005 g is dissolved in a partial quantity of water for injections by heating. 10.0 g of butaphosphan and 4.0 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin. The pH is adjusted with sodium hydroxide to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 100 ml with water for injections.
  • vitamin B 12 0.00075 g of vitamin B 12 is dissolved in a partial quantity of water for injections by heating.
  • 1.5 g of butaphosphan and 0.3 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin.
  • the pH is adjusted with meglumine to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 10 ml with water for injections.
  • vitamin B 12 0.0015 g of vitamin B 12 is dissolved in a partial quantity of water for injections by heating. 3.0 g of butaphosphan and 0.3 g of n-butanol are dissolved in water for injections and added to the stock solution with cyanocobalamin. The pH is adjusted with arginine to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 10 ml with water for injections.
  • vitamin B 12 0.0010 g of vitamin B 12 is dissolved in a partial quantity of water for injections by heating. 0.3 g of n-butanol is mixed with water for injections and added to the stock solution with cyanocobalamin. The pH is adjusted with arginine to 5.6 (+/ ⁇ 0.2), and the final weight is adjusted to 10 ml with water for injections.
  • FIG. 1 Comparison of the photostabilities of a formulation without n-butanol [A] with a formulation with n-butanol [B, according to Example 1]).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Diabetes (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US12/045,831 2007-03-16 2008-03-11 Stabilization of vitamin b12 Abandoned US20080261914A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/951,581 US9089582B2 (en) 2007-03-16 2010-11-22 Stabilization of vitamin B12
US14/808,425 US9610297B2 (en) 2007-03-16 2015-07-24 Stabilization of vitamin B12

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DE102007012644.3 2007-03-16
DE102007012644A DE102007012644A1 (de) 2007-03-16 2007-03-16 Stabilisierung von Vitamin B12

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US14/808,425 Active US9610297B2 (en) 2007-03-16 2015-07-24 Stabilization of vitamin B12

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EP (1) EP2121024B1 (es)
JP (1) JP5558838B2 (es)
KR (1) KR101508602B1 (es)
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US20110046072A1 (en) * 2008-05-07 2011-02-24 Bayer Animal Health Gmbh Solid pharmaceutical formulation with delayed release
US20140171357A1 (en) * 2011-03-24 2014-06-19 Seachaid Pharmaceuticals, Inc. Vancomycin derivatives
WO2023198854A1 (en) * 2022-04-14 2023-10-19 Dsm Ip Assets B.V. Novel use of psicose

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UA111342C2 (uk) * 2010-10-29 2016-04-25 Троікаа Фармасьютікалс Лімітед Назальні композиції вітаміну b12
PL3566708T3 (pl) * 2012-05-14 2021-11-22 Warburton Technology Limited Roztwór pierwiastków śladowych
KR101400791B1 (ko) * 2012-10-04 2014-05-29 주식회사대성미생물연구소 동물용 복합 기능성 항생제 조성물
CN102908354A (zh) * 2012-11-02 2013-02-06 青岛康地恩药业股份有限公司 一种布他磷注射液的制备方法
RU2529814C1 (ru) * 2013-05-20 2014-09-27 Федеральное государственное бюджетное учреждение "Научный центр экспертизы средств медицинского применения" Министерства здравоохранения Российской Федерации Способ определения подлинности и количественного содержания бензэтония хлорида в лекарственных препаратах
WO2016199165A2 (en) * 2015-06-08 2016-12-15 Zim Laboratories Limited Improved mucosal delivery of vitamin b12
DE102018005078A1 (de) 2018-06-26 2020-01-02 Ilma biochem GmbH Verfahren zur Herstellung und Zusammensetzung von stabilisierten Cob(II)alamin- und Cob(II)inamide-Lösungen als Ausgangszubereitungen zur Herstellung von Arzneimitteln, Medizinprodukten, Nahrungsergänzungsmitteln und Kosmetika
KR102058133B1 (ko) * 2019-02-22 2019-12-20 우진 비앤지 주식회사 혼합제제 내 항생제 용해도를 향상시킬 수 있는 면역 증강용 조성물 및 이의 용도
JP2020196672A (ja) * 2019-05-31 2020-12-10 小林製薬株式会社 ビタミンｂ１２類含有組成物
JP7270465B2 (ja) * 2019-05-31 2023-05-10 小林製薬株式会社 ビタミンｂ１２類の光安定化方法
JP7368108B2 (ja) * 2019-05-31 2023-10-24 小林製薬株式会社 水性組成物
MX2022000455A (es) * 2019-07-12 2022-03-17 Chemvet Australia Pty Ltd Suplemento nutricional inyectable.

Citations (14)

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