WO2016147040A1 - Pharmaceutical composition comprising folic acid and (6s)-5-methyltetrahydrofolic acid glucosamine salt and the use thereof - Google Patents

Pharmaceutical composition comprising folic acid and (6s)-5-methyltetrahydrofolic acid glucosamine salt and the use thereof Download PDF

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WO2016147040A1
WO2016147040A1 PCT/IB2015/060027 IB2015060027W WO2016147040A1 WO 2016147040 A1 WO2016147040 A1 WO 2016147040A1 IB 2015060027 W IB2015060027 W IB 2015060027W WO 2016147040 A1 WO2016147040 A1 WO 2016147040A1
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folic acid
acid
glucosamine salt
methyltetrahydrofolic
pharmaceutical composition
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PCT/IB2015/060027
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French (fr)
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Jarosław WYPYCH
Aneta PAKIEŁA-RAJTKOWSKA
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Sequoia Sp. Z O.O.
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Priority to PL411635A priority patent/PL411635A1/en
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Publication of WO2016147040A1 publication Critical patent/WO2016147040A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, 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
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15Vitamins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/02Nutrients, e.g. vitamins, minerals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06Antianaemics

Abstract

The object of the invention is a pharmaceutical composition comprising a therapeutically effective amount of folic acid and (6S)-5-methyltetrahydrofolic acid glucosamine salt for the use in prophylaxis of neural tube defects in children as well as in folate and folic acid deficiencies in anaemia and iron deficiencies.

Description

PHARMACEUTICAL COMPOSITION COMPRISING FOLIC ACID AND (6S)-5-METHYLTETRAHYDROFOLIC ACID GLUCOSAMINE SALT AND THE USE THEREOF
The object of the invention is a pharmaceutical composition comprising folic acid together with (6S)-5-methyltetrahydrofolic acid glucosamine salt which occurs naturally in the human body. The object of the invention is also the use of the pharmaceutical composition in the prophylaxis of neural tube defects in children as well as in folates and folic acid deficiencies in anaemia and iron deficiencies.
It is generally accepted that folic acid (also called pteroylglutamic acid) belongs to the B group of vitamins. At molecular structure it consists of a pteridine derivative (2-amino-4-hydroxy-6-methylpteridine), p-aminobenzoic acid (PABA) and glutamic acid. Folic acid was extracted for the first time in 1941. Folic acid is an essential ingredient for normal functioning of the human body, and its deficiency causes numerous diseases of neural or cardiovascular system (source: Gabriela Ktaczkow, Elzbieta L. Anuszewska, Kwas foliowy i jego znaczenie dla prawidtowego rozwoju organizmu czfowieka. Profilaktyka wad wrodzonych uktadu nerwowego, Przewodnik Lekarski 2000, nr 5, p. 86-90). The attention is drawn by recommendations of the World Health Organisation (WHO) on the necessity of folic acid supplementation among pregnant women in order to prevent the development of anaemia and to improve the birth weight of a foetus (World Health Organization 2012, Guideline: Intermittent iron and folic acid supplementation in non-anaemic pregnant women).
A range of vitamin preparations for pregnant women comprises a traditional source of folates, namely folic acid. Moreover, many studies showed that during pregnancy women have an increased demand for this substance which is responsible for the normal development of the neural system in the foetus. However, a proper level of folates should be provided also before the pregnancy, because folate deficiency in the first weeks of pregnancy may result in neural system defects in the foetus. The folate content in food is insufficient to provide the proper level thereof in the organism, thus, a woman who is planning the pregnancy should additionally supplement them. The studies on Polish population of women clearly show that around 50% of women may have a decreased activity of methylenetetrahydrofolate enzyme what leads to the higher risk of defects in the foetus and thrombotic complications during the pregnancy. Methylenetetrahydrofolate reductase is a key enzyme in the folate metabolism. A mutation of methylenetetrahydrofolate gene (a gene coding methylenetetrahydrofolate reductase) in a form of 677C->T leads to the increased concentration of homocysteine in plasma, abnormalities in DNA methylation and abnormalities in nucleotide synthesis. This type of mutation can be also a risk factor for many complications of the pregnancy, such as numerous abortions, foetal hypotrophy, neural tube defects and Down syndrome (source: Agnieszka Seremak- Mrozikiewicz, Magdalena Barlik, Paulina Borowczak, Grazyna Kurzawiriska, Witold Krasnik, Grzegorz Nowocieri, Krzysztof Drews, The frequency of 677C>T polymorphism of MTHFR gene in the Polish population, Archives of Perinatal Medicine 19(1), 12-18, 2013).
As studies show, the folate content in the everyday diet among Polish population in single whole-day food rations ranges between 162-680 μg. In the everyday diet, the main source of folates are cereal products, out of which the best source is whole-grain bread providing almost 40% of this vitamin in relation to its total daily intake. Also, around 25% of folates is from vegetables, 13% from potatoes and 6- 7% from fruits, milk and dairy products as well as eggs (source: Hanna Czeczot, Kwas foliowy w fizjologii i patologii, Katedra i Zaktad Biochemii, Warszawski Uniwersytet Medyczny, 2008, nr 62, 405-419). According to the author, the most important factors which influence the bioavailability of folates from food are: the form of folates comprised in the diet, the type of products containing folic acid (natural, synthetic), the manner of serving (raw, cooked), processing operations to which food products are subjected, proper digestion and absorption, drugs taken for therapeutic purposes. According to this author, the most important neurological disorders and diseases connected with the folic acid deficiency in the human body also include disorders in the neural tube development, changes in central nervous system and the development of certain types of cancers.
It is generally accepted that the main causes of the folic acid deficiency include, in the first place, insufficient supply of this vitamin in everyday food, increased demand for this vitamin (e.g. pregnancy, lactation), impaired intestinal absorption, disorders in folic acid biochemical metabolism resulting from interactions with certain drugs used in therapies of various diseases. Pregnant women, premature infants and infants with the low birth weight are mainly at risk of the folic acid deficiency. Pregnancy is a very important time of the formation of neural tube which later develops into child's brain and spinal cord. Failure of neural tube closure leads to the formation of developmental defects out of which the most severe are anencephaly and cerebrospinal hernias. They result from a defect in the process of central nervous system (CNS) formation - source: Hanna Czeczot, Kwas foliowy w fizjologii i patologii, Katedra i Zaktad Biochemii, Warszawski Uniwersytet Medyczny, 2008, nr 62, 405-419.
Poland belongs to the countries with the highest rate of deaths resulting from inborn neural tube defects in Europe. The occurrence of neural tube defects in Poland is 8.61 per 10,000 live births and it is significantly higher than the average in Europe which is 2.97/10,000 live births. In 2002, the occurrence of neural tube defects in the Greater Poland was 10.83 per 10,000 all born newborns (live and dead) - source: Brzeziriski Z.J., Kwas foliowy w zapobieganiu wadom wrodzonym cewy nerwowej, Medycyna Wieku Rozwojowego, 1998; 2: 453-461; Brzozowska A., Siciriska E., Roszkowski W., Rola folianow w zywieniu osob starszych, Roczn. PZH, 2004; 55: 159- 164 ). In general, the occurrence of neural tube defects in foetus among Polish population is 2-3 per 1000 births (source: Wyka J, Mikotajczak J., Podaz kwasu foliowego w racjach pokarmowych Wroctawianek w wieku 20-25 lat oraz ocena wiedzy o jego znaczeniu dla zdrowia, ROCZN PZH. 2007, nr 58, p. 633-540).
The actions of public authorities responsible for the health care confirm the significance of the prophylaxis in connection with the neural tube defects. The Primary Prevention Program for Neural Tube Defects in Poland was introduced in 1997. The deficiency of folic acid or its gradual release results from the small amount of folates deposited earlier in the woman's body which run out relatively fast when the demand for them is increased during the foetal development. The studies conducted among women having children with CNS defects and among children with spina bifida confirmed that the deficiency of folic acid and its derivatives in the organism with a simultaneous increase in the amount of homocysteine impairs the organogenesis process of foetal CNS - source: Hanna Czeczot, Kwas foliowy w fizjologii i patologii, Katedra i Zaktad Biochemii, Warszawski Uniwersytet Medyczny, 2008, nr 62, 405-419). This article also indicates that at the average insufficient daily intake of folic acid of around 250 μg, it is recommended to supplement the folic acid deficiency even before pregnancy not only with a proper diet, but also with pharmaceutical preparation supplementation. The author, referring to the research, points out that due to a large percentage (over 50%) of unplanned pregnancies women at a reproductive age and families with neural tube defects cases should take 0.4 mg of folic acid a day in a diet. Women at risk of giving birth to a child with a neural tube defect should take 4 mg of folic acid a day. On the other hand, women who are planning pregnancy should take 0.4 and not more than 1 mg of folic acid a day for four weeks before planned fertilisation. Pregnant women should take 0.4 and not more than 1 mg of folic acid a day till the end of 12-13 week of pregnancy (source: Bazzano L.A., He J., Ogden L.G., Loria C, Vupputuri S., Myers L, Whelton P.K.: Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study, 2002; 33: 1183-1188; Brouwer I.A., van Dusseldorp M., West C.E., Meyboom S., Thomas CM., Duran M., van het Hof K.H., Eskes T.K., Hautvast J.G., Steegers-Theunissen R.P., Dietary folate vegetables and citrus friut decreases plasma homocysteine concentrations in humans in a dieatry controlled trial, J. Nutr., 1999; 129: 1135-1139; de Bree A., van Dusseldorp M., Brouwer I.A., van het Hof K.H., Steegers Theunissen R.P., Folate intake in Europe: recommended, actual and desired intake, Eur. J. Clin. Nutr., 1997; 51: 643-660; McLone D.G., The etiology of neural tube defects: the role of folic acid, Childs Nerv. Syst., 2003; 19: 537-539). In USA, since 2000 the recommended daily intake of folic acid during pregnancy is 600 μg, what relates to the necessity of supplementation and/or taking enriched food (source: McLone D.G., The etiology of neural tube defects: the role of folic acid, Childs Nerv. Syst., 2003; 19: 537-539; Molloy A.M., Is impaired folate absorption a factor in neutral tube defects?, Am. J. Clin. Nutr., 2000; 72: 3-4; Oakley G.P., Ericson J.D., Adams M.J. Jr, Urgent need to increase folic acid consumption. JAMA, 1995; 274: 1717-1718; Schwarz R.H., Johnston R.B. Jr, Folic amid supplementation-when and how, Obstet. Gynecol., 1996; 88: 886-887). The same view was presented by the Panel of Experts of the Ministry of Health and Social Welfare regarding the prevention of inborn neural tube defects in offspring through folic acid supplementation (source: Zyw Cztow Metabol 1997; nr 24, p. 91-95).
Defects of neural tube development in foetus are most frequently causes of such disorders as spina bifida, brain and spinal cord hernia and anencephaly. In order to describe in detail the influence of folic acid deficiency on foetal development, the attention should be drawn to the process of slowing down DNA synthesis and lack of proper cell division as well as lower absorption of nutrients from the gastrointestinal tract. Insufficient supply of folic acid and its derivatives with a simultaneous increase of homocysteine level impairs the organogenesis process of foetal central nervous system (CNS) - source: Refsum H. Folate, vitamin B12 and homocysteine in relations to birth defects and pregnancy outcome, Br J Nutr 2001, nr 85, S109-S113).
The neural tube itself is a tissue fold in a shape of a gutter which is the primordium of the central nervous system (CSN). The neural tube closes between the 16 and 28 day since conception. Its anterior part develops into the brain, and its posterior part develops into the spinal cord. In case of abnormal closure of the neural tube, abortion or impairment in a newborn occurs. Neural tube defects in foetus form before a woman knows she is pregnant (in 3 and 4 week of foetal life). In case of unplanned pregnancy, its confirmation takes place between 4 and 8 week, when it is too late to provide the proper level of folic acid for the organism of the foetus (source: Ryan-Harshman M, Aldoori W., Folic acid and prevention of neural tube defects, Can Fam Physician 2008, nr 54, p. 36-38). As a result of many scientific studies conducted, it has been shown that taking folic acid supplements during the pre-conception period and during the first twelve weeks of the pregnancy lowers the number of cases of neural tube defects in offspring by 70% (source: Ewa Cieslik, Agnieszka Gqbusia, Skutki niedostatecznej podazy kwasu foliowego ze szczegolnym uwzglednieniem znaczenia dla kobiet w wieku rozrodczym, Hygeia Public Health 2011, 46(4), p. 432-436).
The proper folate supply has also a very significant influence on nullifying the risk of developing anaemia. Anaemia is a medical condition in which haemoglobin concentration and the total mass of red blood cells occur in concentration being insufficient to enable proper tissue oxidation. Although even 80% of diagnosed anaemias results from iron deficiency, in as many as 25% cases they are accompanied by megaloblastic anaemia caused by folate or vitamin B12 deficiency (Cieslik E., Skutki niedostatecznej podazy kwasu foliowego zze szczegolnym uwzglednieniem znaczenia dla kobiet w wieku rozrodczym. Hygeia Public Health 2011, 46(4): 431-4360).
The most active form of folic acid is tetrahydrofolate (TH4-folate) which is formed as a result of the reduction of folic acid by dehydrofolate reductase and NADPH. TH4-folate participates in the transfer of monocarbon groups, such as -CH3, =CH2, =CH-, -CH=0, -CH=NH, engaged in the synthesis of purine, pyrimidine compounds, nucleic acid methylation and conversion of homocysteine to methionine. Folic acid is essential for normal development and functioning of the cells of haematopoietic and nervous system as well as tissues built of intensively dividing cells (gastrointestinal tract epithelium, foetal tissues). Folates deficiency resulting from the insufficient intake, absorption or increased demand of the human body might induce some disease entities, especially among certain groups of population.
In 1930, it was observed that megaloblastic anaemia, which is characterised by the presence of large, immature red blood cells in the blood smear, can be effectively treated with extracts from yeasts and liver. As it was shown later, folic acid present in these extracts was responsible for that. During the process of erythropoesis (formation of red blood cells) taking place in bone marrow, folic acid is being built in erythroblasts. In case of folic acid deficiency, the synthesis of nucleic acids is impaired and the ability of haematopoietic system cells to biosynthesise precursors necessary for DNA synthesis is decreased. The consequences are megaloblastic erythropoesis, macrocytic anaemia, leucopenia and thrombocytopenias (Kapka-Skrzypczak L, Kwas foliowy - skutki niedoboru i zasadnosc suplementacji, Medycyna Ogolna i Nauka o Zdrowiu, 2012, Tom 18, Nr 1, 65-69). Megaloblastic erythropoesis leads to the formation of large or giant cells of haematopoietic system called megaloblasts, and in the peripheral blood there are macrocytes (MCV >100 fl) with a trait of hyperchromism (MCHC >34 g/dl). To diagnose megaloblastic anaemias, the bone marrow test is recommended. Apart from the mentioned megaloblastosis, bone marrow is hypercellular with the prevalence of immature precursors of erythrocytic system, the presence of giant metamyelocytes and band cells. In the peripheral blood smear, hipersegmentation of granulocyte nuclei and large platelets may occur. Reticulocytosis is decreased. In more advanced cases, pancytopenia occurs, that is a decrease in the number of all blood morphotic elements below normal values. Due to the haemolysis of microcytes, an increased bilirubin level and an increase in LDH activity can be observed. The above changes are common for vitamin B12 and folic acid deficiency, hence in further testing it should be determined which deficiency is being dealt with (Hellmann A., Niedokriwstosci niedoborowe - diagnostyka i leczenie, Przewodnik Lekarza).
Megaloblastic anaemia, which requires treatment with folic acid, is seen in the course of malabsorption syndromes or intestinal inflammation (ulcerative intestinal inflammation, Crohn's disease, coeliac disease). The risk of anaemia increases also in case of pregnant women, in cirrhosis, leukaemia, protein malnutrition and in the use of antiepileptic drugs, thus in all cases in which the demand for folates is higher. Even in case of using a diet with proper caloric value and proper balance, folate intake might be at a lower level than optimal which, according to Polish norms is 250 μg. This results form the current ways of food processing, especially in case of cereal products. During the production of flour from wheat grains, the loss of valuable mineral ingredients, vitamins, cellulose and phytocompounds amounts even to 90%. Folic acid belongs to vitamins which are vulnerable to external factors. A large portion of folates is lost while transporting, storing and cooking food products. With such a broad food processing, providing folate intake according to the norms seem to be quite difficult without simultaneous supplementation. Moreover, the above mentioned folate bioavailability is higher in case of synthetic preparations, and lower in case of products being its natural source.
The described above supplementation of the organism with folates concerns folates in a form of folic acid. The composition which is the object of the present invention additionally comprises a new source of folates in a form of (6S)-5- methyltetrahydrofolic acid glucosamine salt (active form of folic acid). Folic acid does not show biological activity - it has to be converted in the organism into dihydrofolate or tetrahydrofolate. However, the ability to convert folic acid might substantially differ between particular individuals (Obeid R., Holzgreve W., Pietrzik K., Is 5- methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects? (J. Perinat. Med. 2013; 41(5): 469-483).
New studies show particularly preferable properties of the source of obtaining folates in the form of (6S)-5-methyltetrahydrofolic acid glucosamine salt. According to the European Commission Implementing Decision as of 19 March 2014, (6S)-5- methyltetrahydrofolic acid glucosamine salt can be a completely safe ingredient of vitamins and minerals in food supplements. Its use does not cause any concerns in terms of safety of human health. Many scientific papers published recently indicate (6S)-5-methyltetrahydrofolic acid glucosamine salt as a new source of folates with very beneficial effect on women's health. A range of studies was conducted whose aim was to compare bioavailability of (6S)-5-methyltetrahydrofolic acid glucosamine salt and other folate sources, including folic acid. The supply of (6S)-5-methyltetrahydrofolic acid glucosamine salt resulted in faster absorption thereof in comparison with folic acid, what was confirmed by testing the maximal concentration of this substance one hour after the preparation was administered. It was also shown that the total absorption in intestines of (6S)-5-methyltetrahydrofolic acid glucosamine salt is higher in comparison to other folates, including folic acid (Executive summary, Pre-clinical study in vivo, Comparative oral bioavailability of Quatrefolic® in rats versus folic acid and (6s)-5-mthf calcium salt, Research Toxicology Center (RTC), N. 71640EXT). The research concerning also other folate sources, such as (6S)-5-methyltetrahydrofolate calcium salt, show higher bioavailability of (6S)-5-methyltetrahydrofolic acid glucosamine salt (Executive summary, Clinical study, Crossover comparative bioavailability study of Quatrefolic® compared, with the reference Metafolin® in healthy volunteers, IPAS report IPAS-5MTHFA-583-09). There is an enormous social need to decrease the risk of nervous system diseases in the foetus, including the prophylaxis of neural tube defects.
Known compositions do not comprise the folic acid salt bioavailable to the organism, especially for women, in the form of (6S)-5-methyltetrahydrofolic acid glucosamine salt.
The object of the invention is the pharmaceutical composition comprising a combination of active ingredients, wherein it comprises folic acid and (6S)-5- methyltetrahydrofolic acid glucosamine salt as active ingredients.
Preferably, the pharmaceutical composition comprises active ingredients together with at least one pharmaceutical carrier.
Preferably, the pharmaceutical composition is in a form of a capsule, or a tablet, or powder, or fluid.
Preferably, the pharmaceutical composition comprises folic acid and (6S)-5- methyltetrahydrofolic acid glucosamine salt at the molar ratio of folic acid/(6S)-5- methyltetrahydrofolic acid glucosamine salt of 1/1.
Preferably, the pharmaceutical composition comprises folic acid in amount of 200- 4000 μg and (6S)-5-methyltetrahydrofolic acid glucosamine salt in amount of 200-4000
Preferably, the pharmaceutical composition has a form of a pharmaceutical agent or a foodstuff or a diet supplement.
Preferably, the pharmaceutical composition is for the use in the prophylaxis of neural tube defects in children as well as in folate and folic acid deficiencies in anaemia and iron deficiencies. The capsule composition might be as follows:
Example 1
Ingredient Capsule content folic acid 200 [\ g]
(6S)-5-methyltetrahydrofolic acid
200 [\ g] glucosamine salt
carbohydrates 100 [mg]
Example 2.
Ingredient Capsule content folic acid 400 [Mg]
(6S)-5-methyltetrahydrofolic acid
400 [μ§] glucosamine salt
carbohydrates 100 [mg]
Example 3.
Ingredient Capsule content folic acid 800 [Mg]
(6S)-5-methyltetrahydrofolic acid
800 [Mg] glucosamine salt
carbohydrates 100 [mg]
Example 4.
Ingredient Capsule content folic acid 1000 [ ig]
(6S)-5-methyltetrahydrofolic acid
1000 [ ig] glucosamine salt
carbohydrates 100 [mg]
Example 5.
Ingredient Capsule content folic acid 2000 [Mg]
(6S)-5-methyltetrahydrofolic acid
2000 [μ§] glucosamine salt
carbohydrates 100 [mg]
Example 6.
Ingredient Capsule content folic acid 4000 [Mg]
(6S)-5-methyltetrahydrofolic acid
4000 [Mg] glucosamine salt
carbohydrates 100 [mg]

Claims

Claims
1. A pharmaceutical composition comprising a combination of active ingredients, characterised in that it comprises folic acid and (6S)-5-methyltetrahydrofolic acid glucosamine salt as active ingredients.
2. The composition according to claim 1, characterised in that it comprises active ingredients together with at least one pharmaceutical carrier.
3. The composition according to claim 1 or 2, characterised in that it is in a form of a capsule, or a tablet, or powder, or fluid.
4. The composition according to claim 1 or 2, characterised in that it comprises folic acid and (6S)-5-methyltetrahydrofolic acid glucosamine salt at the molar ratio of folic acid/(6S)-5-methyltetrahydrofolic acid glucosamine salt of 1/1.
5. The pharmaceutical composition according to claim 1 or 2 or 4, characterised in that it comprises folic acid in amount of 200-4000 μg and (6S)-5- methyltetrahydrofolic acid glucosamine salt in amount of 200-4000 μg.
6. The pharmaceutical composition according to any one of the preceding claims, characterised in that it has a form of a pharmaceutical agent or a foodstuff or a diet supplement.
7. The pharmaceutical composition according to any one of the preceding claims, characterised in that it is a complex source of folates.
8. The composition according to claim 1 for the use in the prophylaxis of neural tube defects in children as well as in folate and folic acid deficiencies in anaemia and iron deficiencies.
PCT/IB2015/060027 2015-03-18 2015-12-29 Pharmaceutical composition comprising folic acid and (6s)-5-methyltetrahydrofolic acid glucosamine salt and the use thereof WO2016147040A1 (en)

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WO2001084962A2 (en) * 2000-05-10 2001-11-15 Basf Aktiengesellschaft Compositions containing folic acid and reduced folate
WO2006099237A1 (en) * 2005-03-10 2006-09-21 Sciele Pharma, Inc. Nutritional preparations
US20090209543A1 (en) * 2008-02-20 2009-08-20 Gnosis S.P.A. Folates, compositions and uses thereof
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"Executive summary, Clinical study, Crossover comparative bioavailability study of Quai-refolic® compared, with the reference Metafolin® in healthy volunteers", IPAS REPORT IPAS-SMTHFA-583-09
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