EP2903596A1 - Solutions à usage oral comprenant de l'acide folique - Google Patents

Solutions à usage oral comprenant de l'acide folique

Info

Publication number
EP2903596A1
EP2903596A1 EP13821079.4A EP13821079A EP2903596A1 EP 2903596 A1 EP2903596 A1 EP 2903596A1 EP 13821079 A EP13821079 A EP 13821079A EP 2903596 A1 EP2903596 A1 EP 2903596A1
Authority
EP
European Patent Office
Prior art keywords
folic acid
solution
oral
solutions
propylene glycol
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.)
Withdrawn
Application number
EP13821079.4A
Other languages
German (de)
English (en)
Inventor
Angelos Karatzas
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.)
Lamda Laboratories SA
Original Assignee
Lamda Laboratories SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Lamda Laboratories SA filed Critical Lamda Laboratories SA
Publication of EP2903596A1 publication Critical patent/EP2903596A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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 refers to oral solutions comprising folic acid.
  • Folic acid which is also known as vitamin B9, is necessary for synthesis, repair and function of DNA and RNA, the basic building blocks of life.
  • Folic acid undergoes extensive decomposition when admixed with common excipients and presents low stability under conditions of elevated temperature and humidity. According to US4931442 and GB725683, the aqueous solutions of folic acid exhibit reduced stability, especially in the presence of atmospheric oxygen.
  • stable folic acid solutions may be prepared by mixing the active ingredient with a liquid organic carrier which comprises liquid sorbitol, glycerin and propylene glycol and by simultaneous adjustment of the pH of the solution to the range of 5 to 5.5. It is important that according to the study, the presence of water as an excipient in the proposed compositions is excluded due to its strong destabilising action.
  • impurities A, D and E As main impurities of folic acid are considered impurities A, D and E, as described in the relevant European Pharmacopoeia monograph of folic acid.
  • the present invention addresses the problem of the prior art by advantageously providing folic acid oral solutions, which exhibit as low as possible levels of known and unknown impurities during their manufacturing and storage.
  • the present invention provides oral solutions of folic acid that exhibit excellent stability and extended lifetime.
  • the oral solutions comprise folic acid as active ingredient and a liquid carrier comprising 300 mg/ml to 600 mg/ml propylene glycol, 100 mg/ml to 300 mg/ml glycerin and water, wherein the pH of the solution is from 7.5 to 9.5.
  • the concentration of folic acid in the solutions of the present invention is up to 30 mg/ml. More preferably, the concentration of folic acid is from 5 mg/ml to 25 mg/ml.
  • the present invention provides stable oral solutions comprising folic acid in combination with a liquid carrier.
  • the folic acid oral solutions according to the invention may have application both as food supplements and as pharmaceutical products.
  • the folic acid oral solutions are pharmaceutical products and in this case the liquid carrier is a pharmaceutically acceptable carrier.
  • impurity refers to reaction products or decomposition products of folic acid which may be present in the active ingredient or formed during the preparation and storage of the oral solution.
  • total impurities refers to the sum of all folic acid impurities being present in the oral solution.
  • the commercially available pharmaceutical aqueous Lexpec® 2.5mg/5ml Oral Solution which is marketed in the United Kingdom by Rosemont Laboratories Inc., contains 0.5 mg/ml folic acid.
  • this product also comprises as excipients mannitol, glycerin, disodium edetate, methyl-p- hydroxybenzoic acid, propyl-p-hydroxybenzoic acid, ethyl-p-hydroxybenzoic acid, dihydrogen phosphate sodium, disodium phosphate, strawberry flavour (containing propylene glycol) and water.
  • the quantitative composition of the product was approached by a set of laboratory studies, including inter alia a study of the rheological behavior of the solution for assessing the concentration of mannitol and glycerol, a pH measurement for assessing the concentration of phosphates and organoleptic tests for the assessment of the concentration of the flavouring agent.
  • This approach resulted in the following concentration values for the excipients of the product Lexpec ® 2.5mg/5ml Oral Solution: approximately 100 mg/ml for mannitol, about 200 mg/ml for glycerin, about 2.5 mg/ml for sodium dihydrogen phosphate, about 2.5 mg/ml for disodium phosphate and about 5 mg/ml for the strawberry flavour (which contains propylene glycol).
  • the pH value of the commercial solution was measured and found to be 6.3.
  • the commercially available aqueous solution "Folic acid liquid nutritional supplement” which is marketed in the United States by Pure Encapsulations contains 3.2 mg/ml folic acid.
  • This product as stated in the PIL also comprises as excipients 300 mg/ml glycerin and about 700 mg/ml purified water.
  • compositions were studied in relation to their stability at accelerated conditions of temperature (40°C) and relative humidity (75%) for six months.
  • the quantification of the major impurities and total impurities in the solutions before and after the storage period was carried out by HPLC. All compositions were analyzed in triplicate and the results are reported in Table 1.
  • the oral solutions comprise folic acid as active ingredient and a liquid carrier comprising from 300 mg/ml to 600 mg/ml propylene glycol, 100 mg/ml to 300 mg/ml glycerin and water, wherein the pH of the solution is from 7.5 to 9.5.
  • the concentration of folic acid in the solutions of the present invention is up to 30 mg/ml.
  • the concentration of folic acid is from 5 mg/ml to 25 mg/ml.
  • Propylene glycol and glycerin are known to exhibit antimicrobial activity. Propylene glycol has been defined as a true preservative with fungistatic and fungicidal effect, while glycerin displays general antimicrobial action especially in combination with other antimicrobial agents.
  • compositions of the present invention exhibit excellent stability even when they do not comprise additional antioxidants and/or antimicrobial agents.
  • the folic acid oral solutions of the present invention do not comprise, in addition to propylene glycol and glycerin, further antimicrobial agents and/or antioxidants.
  • the presence of such further antimicrobial agents and/or antioxidants may raise additional safety and toxicity issues.
  • the absence of antimicrobial agents and antioxidants is very important, especially in the case of preparations intended for children.
  • the oral solutions of folic acid according to the invention may also optionally comprise additional excipients commonly used in the preparation of oral liquid compositions, such as viscosity adjusting agents, natural sweetening agents, non- sugar based artificial sweetening agents and flavouring agents.
  • Viscosity adjusting agents may be, for example, starch, sodium carboxy methylcellulose, methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, maltitol or mixtures thereof.
  • Natural sweetening agents that can be used in the present invention comprise mannitol, maltitol, sorbitol and mixtures thereof.
  • non-sugar based artificial sweetening agents which may be used in the present invention comprise saccharin sodium, sucralose, saccharin, aspartame and acesulfame potassium and mixtures thereof.
  • the solutions of the present invention exhibit excellent stability and extended lifetime. According to a preferred example, the solutions of the present invention remain physicochemically stable when stored for at least six months at a temperature of 40°C and relative humidity of 75%, with impurity A being less than 1 .0%, impurity D being less than 0.4%, impurity E being less than 0.3% and total impurities being less than 2.0% of the initial amount of folic acid. Additionally, the solutions of the present invention remain physicochemically stable when stored for at least twenty four months at room temperature (15-30°C).
  • the present invention also provides stable folic acid solutions at concentrations much higher than those of the corresponding prior art solutions.
  • compositions of the present invention may be prepared using methods well known in the art. For example, they can be prepared using the following process: 1 . An amount of water is added to a main mixing vessel.
  • the pH of the solution is adjusted to the range of 7.5 to 9.5.
  • the volume is adjusted to the desired batch volume by adding water.
  • the pH of the solution is adjusted, if needed, to the range of 7.5 to 9.5 by adding sodium hydroxide solution.
  • compositions were studied in relation to their stability at storage conditions of 40°C temperature and 75% relative humidity for six months.
  • Table 4 Compositions with increasing concentration of folic acid
  • Table 5 shows preferred oral solution compositions according to the present invention.
  • Table 6 shows preferred oral solution compositions according to the present invention. Room storage conditions were applied to both compositions for a period of twenty four months.
  • composition 15 Composition 16

Landscapes

  • 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)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Non-Alcoholic Beverages (AREA)

Abstract

L'invention porte sur des solutions à usage oral comprenant de l'acide folique en tant que principe actif et un véhicule liquide comprenant du propylèneglycol, du glycérol et de l'eau. Le pH de la solution est réglé dans la plage de 7,5 à 9,5. Les solutions de la présente invention présentent une excellente stabilité même sans la présence d'autres agents antimicrobiens et/ou antioxydants, en plus du propylèneglycol et du glycérol.
EP13821079.4A 2012-12-12 2013-12-11 Solutions à usage oral comprenant de l'acide folique Withdrawn EP2903596A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20120100628A GR1008101B (el) 2012-12-12 2012-12-12 Ποσιμα διαλυματα φυλλικου οξεος
PCT/EP2013/076255 WO2014090889A1 (fr) 2012-12-12 2013-12-11 Solutions à usage oral comprenant de l'acide folique

Publications (1)

Publication Number Publication Date
EP2903596A1 true EP2903596A1 (fr) 2015-08-12

Family

ID=49956130

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13821079.4A Withdrawn EP2903596A1 (fr) 2012-12-12 2013-12-11 Solutions à usage oral comprenant de l'acide folique

Country Status (3)

Country Link
EP (1) EP2903596A1 (fr)
GR (1) GR1008101B (fr)
WO (1) WO2014090889A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114096162A (zh) * 2019-05-01 2022-02-25 联合利华知识产权控股有限公司 强化剂组合物
CN115959944B (zh) * 2023-01-13 2024-02-13 天津市汉邦植物保护剂有限责任公司 植酸钙悬浮肥及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090232943A1 (en) * 2008-03-12 2009-09-17 Aly Gamay Stabilized vitamin solutions; use thereof; process for their production; and formulations comprising the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2014090889A1 *

Also Published As

Publication number Publication date
GR1008101B (el) 2014-02-04
WO2014090889A1 (fr) 2014-06-19

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