WO2025224342A1

WO2025224342A1 - Compositions comprising vitamin b12 or vitamin b6 and a medium chain fatty acid

Info

Publication number: WO2025224342A1
Application number: PCT/EP2025/061426
Authority: WO
Inventors: Jenni PESSI; Nathalie Richard; Alexandros KANELLOPOULOS
Original assignee: DSM IP Assets BV
Current assignee: DSM IP Assets BV
Priority date: 2024-04-26
Filing date: 2025-04-25
Publication date: 2025-10-30
Anticipated expiration: 2026-10-26

Abstract

The present invention relates to a combination of a vitamin B selected from cobalamin and or vitamin B6, and a medium chain fatty acid or a salt thereof, and compositions comprising the combination.

Description

COMPOSITIONS COMPRISING VITAMIN B12 OR VITAMIN B6 AND A MEDIUM CHAIN FATTY ACID

FIELD OF THE INVENTION

The present invention relates to a combination of a cobalamin and/or vitamin B6, and a medium chain fatty acid or a salt thereof, and compositions comprising the combination.

BACKGROUND OF THE INVENTION

Vitamin B12 is the largest and most complex of all the vitamins and it is essential for numerous physiological functions in the body, including blood cell formation, nerve function, DNA synthesis, and energy metabolism. In humans, vitamin B12 functions primarily as a cofactor in intermediary metabolism.

Deficiencies of vitamin B12 are more common in elderly people, with approximately 20 % of individuals over the age of 60 being affected. There are several reasons for this increased prevalence:

1) reduced stomach acid: as people age, they tend to produce less stomach acid, which is essential for the absorption of vitamin B12 from food. This reduction in stomach acid can impair the breakdown of dietary protein-bound B12, making it more difficult for the body to absorb;

2) decreased intrinsic factor: intrinsic factor is a protein produced by the stomach lining that is necessary for the absorption of vitamin B12 in the small intestine. Aging can lead to decreased production of intrinsic factor, further impairing B12 absorption;

3) poor diet: elderly individuals may have dietary habits that are lacking in foods rich in vitamin B12, such as meat, fish, eggs, and dairy products. Poor appetite or difficulty chewing or swallowing may also contribute to inadequate intake of B12-rich foods;

4) gastrointestinal disorders: certain gastrointestinal conditions, such as atrophic gastritis, celiac disease, Crohn's disease, and pernicious anaemia, can interfere with B12 absorption or increase B12 requirements, further predisposing elderly individuals to deficiency;

5) medications: some medications commonly used by elderly individuals, such as proton pump inhibitors (PPIs), H2-receptor antagonists and metformin, can reduce stomach acid production, potentially impairing B12 absorption.

Vitamin B12 is a coordination complex of cobalt, which occupies the centre of a corrin ligand. A number of related species are known and these behave similarly, in particular all function as vitamins. This collection of compounds is referred to as cobalamins. Cobalamin vitamers include adenosylcobalamin, cyanocobalamin, hydroxocobalamin and methylcobalamin.

Vitamin B12 is synthesized exclusively by microbial organisms and is found in animal-derived foods such as meat, fish, eggs and dairy products. This means that individuals following a strict vegan diet need to supplement vitamin B12 to meet their dietary requirements.

Vitamin B12 from food sources is bound to proteins and only released by an adequate concentration of hydrochloric acid in the stomach. Free vitamin B12 is then immediately bound to glycoproteins originating from the stomach and salivary glands. This glycoprotein complex protects vitamin B12 from chemical denaturation. Gastrointestinal absorption of vitamin B12 occurs in the small intestine by an active process requiring the presence of an intrinsic factor, another glycoprotein, which the gastric parietal cells secrete after being stimulated by food. The vitamin B12 intrinsic factor complex is then absorbed through phagocytosis by specific ileal receptors. Once absorbed, the vitamin is transferred to a plasma-transport protein which delivers the vitamin to target cells. A lack of intrinsic factor prevents vitamin B12 absorption, because only cca. 1 % of vitamin B12 is absorbed by passive diffusion, so this process becomes quantitatively important at pharmacological levels of exposure.

The principal form of vitamin B12 used in supplements is cyanocobalamin. It is available in the form of injections and as a nasal gel for the treatment of pernicious anaemia. Cyanocobalamin is also available in tablet and oral liquid form for vitamin B-complex, multivitamin and vitamin B12 supplements. Vitamin B12 is widely used to enrich cereals and certain beverages. Fortification with vitamin B12 is especially important for products aimed at people with a low dietary vitamin B12 intake, such as vegans. For the supplements, cyanocobalamin is produced commercially from bacterial fermentation.

Vitamin B6 plays a crucial role in a wide range of physiological functions, primarily due to its role as a coenzyme in many enzymatic reactions. Vitamin B6 is involved, inter alia, in amino acid metabolism, glycogen metabolism, hemoglobin synthesis, nervous system functions, lipid metabolism, immune function and gene expression, which underscores its importance in maintaining overall health. A deficiency in vitamin B6 can lead to various health issues such as anemia, dermatitis, depression and confusion, weakened immune function and peripheral neuropathy.

Vitamin B6 refers to a group of chemically similar compounds, vitamers, which can be interconverted in biological systems: pyridoxine, pyridoxal, pyridoxamine and their phosphorylated derivatives, respectively. Pyridoxal 5’-phosphate is the most active coenzyme form. Pyridoxine hydrochloride is the most commonly used form of vitamin B6 due to its stability, bioavailability, and ease of conversion to the active coenzyme form in the body, making it a preferred choice for dietary supplements and food fortification.

It was reported that an oral formulation containing cyanocobalamin (5 mg) and salcaprozate sodium (SNAC, 100 mg), an absorption enhancer, provided significantly improved bioavailability for cyanocobalamin in a small study of normal healthy subjects compared with a commercially available 5-mg cyanocobalamin oral formulation (Castelli et al. Clin. Therap. 33, 934 (2011)).

Nevertheless, there is a need to provide further developed oral formulations of vitamin B6 and/or B12.

SUMMARY OF THE INVENTION

The first aspect of this invention relates to a combination of a) a vitamin B selected from cobalamin and/or vitamin B6, and b) a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof. The combination, in the present context, means that it consists essentially of or consists of a) a cobalamin, a vitamin B6 or both, and b) a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof. Preferably, the cobalamin is cyanocobalamin. Also preferably, the vitamin B6 is pyridoxine or it pharmaceutically or nutritionally acceptable salt like hydrochloride salt. Further preferably, the pharmaceutically or nutritionally acceptable salt of the C8-C12 fatty acid is sodium salt. More preferably, the C8-C12 fatty acid sodium salt is sodium octanoate or decanoate. An especially preferred combination consists essentially or consists of cyanocobalamin and sodium decanoate.

The second aspect of the invention relates to a synthetic composition comprising the combination as disclosed in the first aspect including the preferred, more preferred and especially preferred embodiments and a pharmaceutically or nutritionally acceptable excipient. The synthetic composition is, in one embodiment, a nutritional composition that confers a nutritional (that is non-therapeutical) benefit to the human consuming it. The synthetic composition, in other embodiment, is a pharmaceutical composition, preferably suitable for the treatment of vitamin B6 and/or B12 deficiency in a human.

The third aspect of the invention relates to the combination as disclosed in the first aspect of the invention including the preferred, more preferred and especially preferred embodiments for use in a therapy or as a medicament, preferably for use in the treatment of vitamin B6 and/or B12 deficiency in a human.

The fourth aspect of the invention relates to a pharmaceutical composition comprising the combination as disclosed in the first aspect of the invention including the preferred, more preferred and especially preferred embodiments for use in therapy or as a medicament. The fifth aspect of the invention relates to a method for treating vitamin B6 and/or B12 deficiency in a human, the method comprising orally or enterally administering to or providing for consumption by the human an effective amount of a combination as disclosed in the first aspect of the invention including the preferred, more preferred and especially preferred embodiments, the combination optionally being comprised in a synthetic composition as defined in the second aspect of the invention.

The sixth aspect of the invention relates to a non-therapeutic use of the combination as disclosed in the first aspect of the invention including the preferred, more preferred and especially preferred embodiments for enhancing brain performance, alertness and/or mental energy in a healthy human when the combination comprises cobalamin, or for maintaining and supporting energy metabolism, immune function and/or cognitive function in a heathy human when the combination comprises vitamin B6.

The seventh aspect of the invention relates to a non-therapeutic use of the synthetic composition as disclosed in the second aspect of the invention including the preferred, more preferred and especially preferred embodiments for enhancing brain performance, alertness and/or mental energy in a healthy human when the composition contains the combination comprising cobalamin, or for maintaining and supporting energy metabolism, immune function and/or cognitive function in a heathy human when the composition contains the combination comprising vitamin B6.

BRIEF DESCRIPTION OF THE FIGURES

The invention will be described in further detail hereinafter with reference to the accompanying figures, in which:

Figure 1 shows the change of TEER of Caco-2 monolayer cells in function of time according to Example 1 ;

Figure 2 shows the cyanocobalamin (B12) concentration in the basolateral compartment after 120 mins according to Example 1 ;

Figures 3 to 6 show the concentration of cyanocobalamin (B12) in the basolateral compartment after 2 hours at various concentrations and ratios according to Example 2.

Figure 7 shows the concentration of pyridoxine (B6) in the basolateral compartment after 2 hours according to Example 3.

DETAILED DESCRIPTION OF THE INVENTION

Herein, the following terms have the following meanings:

‘About” or “around” means +/- 5 %. “Cobalamin” is a collective term for vitamers having a corrin-like structure in the form of cobalt coordination complex and preferably includes adenosylcobalamin, cyanocobalamin, hydroxocobalamin and methylcobalamin. Cobalamin and vitamin B12 can be used interchangeably.

The collective term “C8-C12 fatty acid”, for avoidance of doubt, means saturated fatty acids having the given number of carbon in their structure, that is a group of fatty acids consisting of caprylic (octanoic) acid, pelargonic (nonanoic) acid, capric (decanoic) acid, undecylic (undecanoic) acid and lauric (dodecanoic) acid.

"Effective amount" means an amount of the combination as defined in the first aspect of the invention, optionally in a suitable composition, that provides the combination in a sufficient amount to render a desired health outcome in a human. An effective amount can be administered or provided for consumption in one or more doses to achieve the desired health outcome.

“Enhancing brain performance, alertness, mood regulation and mental energy” refers to improving cognitive function, increasing focus and boosting overall mental vitality. “Brain performance” encompasses various cognitive abilities such as memory, learning, problemsolving, and decision-making. “Enhancing brain performance” means improving these cognitive functions, resulting in sharper mental acuity and better cognitive outcomes. “Alertness” refers to a state of heightened awareness and responsiveness to stimuli in the environment. It involves being awake, attentive, and vigilant. “Enhancing alertness” means to increase wakefulness, reduce drowsiness and maintain sustained attention and focus. “Mental energy” refers to the capacity to concentrate, think clearly and maintain cognitive stamina throughout the day. It involves having the mental resilience and vitality to tackle tasks effectively without experiencing mental fatigue or burnout. “Enhancing mental energy” involves optimizing factors such as nutrition, sleep, stress management, and cognitive stimulation to sustain mental vigor and productivity.

“Enteral administration” means any conventional form for delivery of the combination as defined in the first aspect of the invention, optionally in a suitable composition, to a human that causes the deposition of the combination in the gastrointestinal tract (including the stomach). Methods of enteral administration include feeding through a naso-gastric tube or jejunum tube, oral, sublingual and rectal.

“Non-therapeutical use” means - as opposed to the purpose of therapy which is to restore the organism from a pathological to its original condition, or to prevent pathology in the first place - an improvement of performance of the organism in a normal state. Therefore, the purpose of the non-therapeutical use is to enhance performance and perception of well-being in a healthy state of a human or at least in a human who is not likely to develop a pathological state.

"Oral administration" means any conventional form for the delivery of the combination as defined in the first aspect of the invention, optionally in a suitable composition, to a human through the mouth. Accordingly, oral administration is a form of enteral administration.

“Synthetic composition” means a composition which is artificially prepared and preferably means a composition containing at least one compound that is produced ex vivo chemically and/or biologically, e.g. by means of chemical reaction, enzymatic reaction or recombinantly. In some embodiments, the synthetic compositions may comprise one or more nutritionally or pharmaceutically active components which do not affect adversely the efficacy of the active ingredients. Some non-limiting embodiments of a synthetic composition of the invention are also described below.

“Therapy” means treatment given or action taken to reduce or eliminate symptoms of a disease or pathological condition.

“Treat” means to address a medical condition or disease with the objective of improving or stabilising an outcome in the person being treated or addressing an underlying nutritional need. Treat, therefore, includes the dietary or nutritional management of the medical condition or disease by addressing nutritional needs of the person being treated. “Treating” and “treatment” have grammatically corresponding meanings.

“Vitamin B6” refers to all 2-methyl-3-hydroxy-5-hydroxymethylpyridine derivatives exhibiting the biological activity of pyridoxine, preferably pyridoxine, pyridoxal, pyridoxamine, their respective phosphorylated derivatives and their pharmaceutically and nutritionally acceptable salts.

It has been surprisingly found that vitamin B12 co-formulated with sodium decanoate improved the bio-accessibility of vitamin B12 in ex vivo model. More surprisingly, the vitamin B12 permeation was more effective compared to the mixture of vitamin B12 with SNAC. The combination offers a uniquely designed solution to shorten absorption path with a direct access to the bloodstream through gastric lining instead of stomach. Similarly, vitamin B6 co-formulated with sodium decanoate improved the bio-accessibility of vitamin B6 in ex vivo model.

Accordingly, the first aspect of the invention relates to a combination of a) a vitamin B selected from cobalamin and/or vitamin B6, and b) a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof. Preferably, the cobalamin is cyanocobalamin or methylcobalamin, and/or the vitamin B6 is pyridoxine or its pharmaceutically or nutritionally acceptable salt like hydrochloride salt. A preferred embodiment of the first aspect of the invention relates to a combination of a) a cobalamin and b) a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof. Preferably, the cobalamin is cyanocobalamin or methylcobalamin, more preferably cyanocobalamin. Also preferably, the pharmaceutically or nutritionally acceptable salt is sodium salt. More preferably, the C8-C12 fatty acid sodium salt is sodium octanoate and/or decanoate. In an especially preferred embodiment, the combination consists essentially or consists of a) cyanocobalamin or methylcobalamin, and b) sodium decanoate.

Preferably, the weight ratio of the cobalamin and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof in the combination including the combination of cyanocobalamin and sodium decanoate is 1 :100 to 1 :1 , more preferably from 1 :75 to 1 :4 like around 1 :50 to 1 :25 or 1 :4 to 1 :6.5.

Also preferably, the weight ratio of the vitamin B6 and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof in the combination including the combination of pyridoxine hydrochloride and sodium decanoate is 1 :100 to 1 :1 , more preferably from 1 :50 to 1 :4, even more preferably 1 :25 to 1 :5.

The second aspect of the invention relates to a synthetic composition comprising the combination according to the first aspect of the invention, including the preferred and more preferred embodiments as disclosed above.

The synthetic compositions are primarily solid and can be administered orally in the form of e.g. a unit dosage like tablet, capsule or pellet containing a predetermined amount of the ingredients, or as a powder or granules containing a predetermined concentration of ingredients. The orally administered compositions can include further excipients like binder, lubricant, inert diluent, disintegrant, glidant, surface active agent and/or flavouring agent. The combination according to the first aspect of the invention, including the preferred and more preferred embodiments as disclosed above, is comprised in the solid composition in at least 50 wt%, preferably at least 60 wt%, more preferably at least 70 wt%, particularly around 80-90 wt%.

The composition preferably comprises the combination according to the first aspect of the invention, including the preferred and more preferred embodiments as disclosed above, together with sorbitol. More preferably, the weight ratio of sorbitol and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, is around 1 :50 to 1 :1 , more preferably from around 1 :20 to 1 :2, most preferably from around 1 :8 to 1 :4.

In one particular embodiment, the composition comprises the combination according to the first aspect of the invention, including the preferred, more preferred and further preferred embodiments as disclosed above, and does not comprise mono- and/or diglyceride fatty acid esters. With other words, mono- and/or diglyceride fatty acid esters are absent from the composition comprising the combination according to the first aspect of the invention including the preferred, more preferred and further preferred embodiments as disclosed above.

The orally administered composition comprising the combination according to the first aspect of the invention, including the preferred and more preferred embodiments, as disclosed above is preferably a tablet. Tablet formulations typically contain a variety of ingredients, each serving a specific purpose to ensure the tablet's efficacy, stability, and manufacturability. A tablet formulation may contain binders that hold the ingredients together, providing the necessary mechanical strength (e.g., microcrystalline cellulose, polyvinylpyrrolidone), inert fillers (diluents) that add bulk to the tablet, making it a practical size for handling (e.g., lactose, starch, sorbitol, mannitol, calcium phosphate), disintegrants that help the tablet break down into smaller fragments in the digestive tract, ensuring the release of the active ingredient (e.g., croscarmellose sodium, sodium starch glycolate), lubricants that reduce friction during tablet manufacturing, preventing sticking to equipment (e.g., magnesium stearate, stearic acid), glidants that coat the tablet to protect the active ingredient, mask taste, or control the release of the drug (e.g., hydroxypropyl methylcellulose, enteric coatings like cellulose acetate phthalate), colorants and flavorings that improve the appearance and taste of the tablet, antioxidants that prevent oxidation of the active ingredient (e.g., ascorbic acid, butylated hydroxytoluene), preservatives that inhibit microbial growth (e.g., parabens, sodium benzoate), pH adjusters hat maintain the desired pH level to ensure stability and efficacy (e.g., citric acid, sodium hydroxide) and/or solubilizers that enhance the solubility of the active ingredients. The tablet, in a preferred embodiment, comprises granules and the granules comprise a binder; the binder is preferably maltodextrin. The weight of maltodextrin in the tablet in relation to the other ingredients, the ingredients being preferably the combination as disclosed above together with sorbitol, more preferably a mixture comprising, consisting essentially or consisting of cyanocobalamin, sodium decanoate and sorbitol, is around 0.5-1.0 %, such as around 0.7 % (calculated on water-free dry solids). Further excipients like one or more of the above may be incorporated into tablet forms either intragranularly or extragranularly, and tablets may comprise the same or different excipients as intragranular or extragranular components. For example, a tablet formulation may comprise an intragranular lubricant, an extragranular lubricant, or both an intragranular and an extragranular lubricant which may be the same or different. The tablet can then optionally be coated and can be formulated to provide sustained, delayed or controlled release of the mixture therein. A particular aspect of the tablet formulation is mini-tablet that is typically smaller than conventional tablets (usually less than 4 mm in diameter), making them easier to swallow especially for children, the elderly, or individuals with difficulty swallowing larger pills. Another embodiment of orally administered composition comprising the combination according to the first aspect of the invention, including the preferred and more preferred embodiments, as disclosed above, is a hard capsule, wherein the combination is comprised in the fill material as e.g. a powder with suitable excipients and additives or in the form of granules or pellets if the composition is for controlled or sustained release. The suitable excipients and additives can be diluents (e.g., maltodextrin, starch, lactose, microcrystalline cellulose, dicalcium phosphate, mannitol, sorbitol, calcium carbonate), binders (e.g., polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), carrageenan), disintegrants (e.g., croscarmellose sodium, sodium starch glycolate), lubricants (e.g., magnesium stearate, stearic acid), glidants (e.g., talc, colloidal silicon dioxide), antioxidants (like ascorbic acid), preservatives (like parabens), pH buffering agents (like sodium citrate), controlled release agents (e.g., glycerol dibehenate) and/or colorants (e.g., titanium dioxide, indigo carmine (E 132), Ponceau 4R (E 124)).

The amount of cobalamin in a unit dosage like tablet is around 2.5 pg to 10 mg, preferably 0.1- 1.0 mg, more preferably 0.25-0.75 mg, even more preferably around 0.4-0.5 mg. Typically, a unit dosage like tablet contains 1.5-3.5 wt% of cobalamin, 76.5-88.5 wt% of C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, 9.0- 20.0 wt% of sorbitol and 0-1.0 wt% of maltodextrin.

The amount of vitamin B6 in a unit dosage like tablet is around 1-100 mg. Typically, a unit dosage like tablet contains 1-10 wt% of vitamin B6, 70-90 wt% of C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, 8.0-20.0 wt% of sorbitol and 0-1 .0 wt% of maltodextrin.

Another embodiment of orally administered composition comprising the combination of a cobalamin and/or vitamin B6, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof as disclosed above is a liquid formulation, preferably pre-filled in a suitable container (ready-to-drink container, drinking bottle). The liquid formulation may contain sorbitol and/or mannitol, preservative, aroma etc. dissolved/suspended in cleaned water.

The synthetic composition, especially if intended to use as dietary supplement, can be formulated in on-the-go formats (gummies, chewables, sprays, ready-to-mix powder, etc.).

The various kind of formulations disclosed above may contain additional active ingredients besides the combination of a cobalamin and/or vitamin B6 together with a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, for example one or more of vitamins (other than vitamin B6 and/or B12), carotenoids, minerals, botanicals, amino acids (like glutamine) and DL-phosphonoserine. In one embodiment, the formulation is a multivitamin composition containing a balanced mix of essential vitamins and minerals designed to support overall health comprising - besides vitamin B6 and/or B12 - for example one or more of vitamin A, B1 , B2, B3, B5, B7, B9, C, D, E and K. In other embodiment, the formulation is a multivitamin B complex comprising several vitamin Bs but at least vitamin B1 , B6 and B12.

The synthetic compositions can be prepared by any commonly used manufacturing techniques that can provide molecular proximity between the cobalamin and/the vitamin B6, and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof so that they are coreleased and high local concentration for all is achieved. The cobalamin and/or the vitamin B6, and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof can be mixed to produce a physical blend. Alternatively, granules of cobalamin and/or vitamin B6 with the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof are made by wet, dry or melt granulation method (for example high shear mixing, single or twin screw granulation, hot melt extrusion, roller compaction, spray-drying, etc.), most preferably by way of wet granulation in a high shear mixer. The blend or granules can further contain further excipients. A typical process is disclosed in the examples.

Another aspect of the invention relates to the non-therapeutic use of the combination of a cobalamin, preferably cyanocobalamin, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, as disclosed in one embodiment of the first aspect of the invention or the synthetic compositions comprising said combination as disclosed in one embodiment of the second aspect of the invention for enhancing brain performance, alertness and/or mental energy in a healthy human. The highly bioavailable and faster acting vitamin B12 provides brain power boost and/or peak mental performance, prevents mental fatigue and maintains high alertness without the “jitters” and “peak & crash” of caffeine and other stimulants, and thus results in improvement of the quality of life and perception of well-being. Vitamin B12 plays a crucial role in maintaining the health of the nervous system. It supports the formation of myelin, a protective sheath around nerve fibres, which facilitates efficient nerve impulse transmission. By ensuring optimal nervous system function, vitamin B12 can help improve cognitive processes such as memory, focus, and mental clarity. Vitamin B12 is involved in energy metabolism, helping convert food into usable energy. Adequate levels of B12 can reduce fatigue and increase energy levels, promoting mental alertness and productivity throughout the day. Vitamin B12 plays a role in various cognitive processes, including memory, concentration, and problem-solving. Ensuring sufficient intake of B12 can support optimal cognitive function, leading to improved brain performance and mental acuity. A target group of population is, but not limited to, people with need to prevent mental fatigue and maximize cognitive output, like teens and young adults, busy professionals, e- gamers, etc. Also, another aspect of non-therapeutic use of the combination as disclosed in the first aspect of the invention or the synthetic compositions comprising said combination as disclosed in the second aspect of the invention is to support uptake of vitamin B12 and therefore to enhance the absorption of vitamin B12 in elderly individuals, preferably those over the age of 60.

Another aspect of the invention relates to the non-therapeutic use of the combination of a vitamin B6, preferably pyridoxine, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, as disclosed in one embodiment of the first aspect of the invention or the synthetic compositions comprising said combination as disclosed in one embodiment of the second aspect of the invention for maintaining and supporting energy metabolism, immune function and/or cognitive function in a heathy human.

Another aspect of the invention relates to the combination of a cobalamin, preferably cyanocobalamin, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, as disclosed in one embodiment of the first aspect of the invention or the synthetic compositions comprising said combination as disclosed in one embodiment of the second aspect of the invention for use in a therapy or as a medicament, preferably for use in the treatment of vitamin B12 deficiency in a human and/or treating conditions of a human where vitamin B12 deficiency is associated with pathological conditions or clinical situations. Deficiency of vitamin B12 may leads to defective DNA synthesis in cells, which affects the growth and repair of all cells. The tissues most affected are those with the greatest rate of cell turnover, e.g. those of the hematopoietic system. This can lead to megaloblastic anaemia (characterized by large and immature red blood cells) and neuropathy, with numerous symptoms including: glossitis, weakness, loss of appetite, loss of taste and smell, impotence, irritability, memory impairment, mild depression, hallucination, breathlessness (dyspnoea) on exertion, tingling and numbness (paraesthesia). Vitamin B12 has been linked to mood regulation and mental health. Deficiency in B12 can lead to symptoms such as depression, irritability, and cognitive decline. By maintaining adequate B12 levels, you can support overall mental well-being and promote a positive mood. Vitamin B12 deficiency can also lead to hyperhomocysteinemia, a possible risk factor for occlusive vascular disease. Vitamin B12 deficiency may lead to an elevated rate of DNA damage and altered methylation of DNA. These are obvious risk factors for cancer. Low vitamin B12 has been associated with a variety of chronic diseases of aging such as dementia and cognitive impairment, cardiovascular disease (CVD) and osteoporosis. Deficiency is usually caused as a result of vitamin B12 malabsorption. Without intrinsic factor, absorption is not possible and a severe and persistent deficiency develops that cannot be prevented by the usual dietary intakes of vitamin B12. Patient groups having a risk of vitamin B12 deficiency are usually, but not limited to, vegetarians, the elderly, alcoholics and people with pernicious anaemia (autoimmune disease, chiefly affects people post middle age), food-bound vitamin B12 malabsorption (in patients receiving long-term treatment with certain drugs, elderly patients with gastric atrophy, patients with atrophic gastritis), after gastrectomy, after ingestion of corrosive agents with destruction of gastric mucosa, lesions of the small bowel, bacterial overgrowth, small intestinal defects; inborn errors of cobalamin metabolism, pancreatic insufficiency or AIDS.

Another aspect of the invention relates to the combination of a vitamin B6, preferably pyridoxine, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, as disclosed in one embodiment of the first aspect of the invention or the synthetic compositions comprising said combination as disclosed in one embodiment of the second aspect of the invention for use in a therapy or as a medicament, preferably for use in the treatment of vitamin B6 deficiency in a human and/or treating conditions of a human where vitamin B6 deficiency is associated with pathological conditions or clinical situations.

EXAMPLES

Example 1

Caco-2 cells ECACC 86010202 (European Collection of Cell Cultures, Salisbury, UK) were cultured in DMEM medium supplemented with 4.5 g/l D-glucose, 4 mM L-glutamine, 1 mM sodium pyruvate, 1 % MEM non-essential amino acids, 50 pg/ml gentamicin (Life Technologies Europe B.V., Zug, Switzerland) and 10 % heat-inactivated FBS (Sigma-Aldrich, Buchs, Switzerland) at 37 °C in atmosphere of 5 % CO2. Sub-confluent cells were trypsinized using 0.25 % trypsin/EDTA and passaged at a ratio of 1 :5 - 1 :10 twice a week. Cells between passages 57 and 75 were used for the experiments described here. Cells were seeded at a density of 70000 cells/well in 12 mm Transwell®-COL collagen-coated inserts (Costar, 0.4 pm pore size, PTFE membrane insert, cell growth area 1.12 cm², Corning, Glendale, AZ). Media was changed every second to third day. After 21 days in culture, the barrier integrity of the differentiated cell monolayers grown on insert plates was confirmed by measuring transepithelial electrical resistance (TEER) using an EVOM2 Voltohmmeter (World Precision Instruments, Berlin) equipped with STX2-PLUS Electrodes. The TEER values correlate with the tightness of the confluent monolayer.

After 21 days the insert plates were rinsed 2 times with HBSS solution (HBSS pH 7.4 with Ca²⁺ and Mg²⁺, containing 5.5 mM D-glucose, sodium bicarbonate, and supplemented with 4 mM L- glutamine and 20 mM HEPES (Life Technologies Europe B.V., Zug, Switzerland) and incubated for 60 min at 37 °C in the CO2 incubator followed by TEER measurement to obtain baseline resistance readings. Sodium decanoate (C10), SNAC and cyanocobalamin (B12) were prepared in HBSS solution. The HBSS solutions were replaced by the tested solutions on the apical chamber (500 pl) and by 1.5 ml of HBSS solution in the basolateral chamber. The plate was then incubated for 120 min at 37 °C in the CO2 incubator. TEER was measured at 15, 30, 60 and 120 min. After incubation transport across the monolayers was followed by basolateral sampling at 120 min.

Figure 1 shows the change of TEER in function of time. Both sodium decanoate and SNAC significantly enhanced the permeability the Caco-2 cell monolayer at fixed cyanocobalamin concentration, however markedly less sodium decanoate was necessary to achieve the same range of permeability.

Figure 2 shows the cyanocobalamin concentration in the basolateral compartment after 120 mins. While SNAC increased the vitamin B12 flux cca. by 6-fold compared to the negative control, lower amount of sodium decanoate increased it by cca. 7-fold.

Conclusion: sodium decanoate is more effective in enhancing the permeability of Caco-2 cell monolayer and increasing vitamin B12 permeation than SNAC.

Example 2

Caco-2 ECACC 86010202 and HT29-MTX-E12 12040401 cells (European Collection of Cell Cultures, Salisbury, UK) were cultured as described before. Cells were seeded at a density of 70000 cells/well in a 9:1 ratio (Caco-2 :HT29-MTX-E 12) in 12 mm Transwell®-COL collagen- coated inserts. The cell monolayers were cultured for 15 days and treated as described in Example 1. The effect of sodium decanoate (C10) on the transport of cyanocobalamin (B12) (apical to basolateral flux) was examined as disclosed in Example 1.

Figures 3 to 6 show the concentration of cyanocobalamin (B12) in the basolateral compartment after 2 hours at various starting concentrations and ratios.

Conclusion: the results showed that sodium decanoate (C10) effectively increased the vitamin B12 flux.

Example 3

The experiment disclosed in Example 2 were carried out with the difference that pyridoxine hydrochloride (B6) was used instead of cyanocobalamin. Figure 7 shows the concentration of pyridoxine (B6) in the basolateral compartment after 2 hours.

Conclusion: the results showed that sodium decanoate (C10) effectively increased the vitamin B6 flux.

Dry cyanocobalamin, sodium decanoate and sorbitol (Neosorb XTAB 200S, food grade) were mixed volumetrically and blended for 5 minutes in a tubular mixer. The wet granulation process in a high shear mixer (Diosna) consisted of 3 different process phases. A binder (water or 10 % aqueous solution of maltodextrin; applied in 7 wt% in relation to the mix above) was sprayed on the powder blend with an impeller speed of 500 rpm and chopper speed of 800 rpm during a 2 minute time interval. This was followed by first mixing granulation phase of 6 min duration with an impeller speed of 800 rpm and chopper speed of 1000 rpm. This was followed by second mixing granulation phase of 5 min duration with an impeller speed of 1000 rpm and chopper speed of 1500 rpm. The wet granulate was consequently sieved to obtain the desired particle size of 355-500 pm. The sieved product was dried in a fluid bed dryer with temperature of 40 °C for 60 min. The water content was determined post and prior drying. After adding magnesium stearate a Korsch tableting machine was used to compress round tablets with diameter of 6 mm to hardness of 25 N. The target weight of the tablets was 75 mg containing 0.5 mg cyanocobalamin with an envelope density of > 1.12 mg/mm³.

The following ratios were used:

Claims

1. A combination of a cobalamin and/or vitamin B6, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof.

2. The combination according to claim 1 comprising, consisting of or consisting essentially of a cobalamin and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof.

3. The combination according to claim 1 or 2, wherein the cobalamin is cyanocobalamin or methylcobalamin, preferably cyanocobalamin.

4. The combination according to any of the claims 1 to 3, wherein the pharmaceutically or nutritionally acceptable salt is sodium salt.

5. The combination according to any of the precedent claims wherein the salt of the C8-C12 fatty acid is sodium decanoate.

6. The combination according to any of the claims 2 to 5, wherein the weight ratio of the cobalamin and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably of cyanocobalamin and sodium decanoate, is around 1 :50 to 1 :25.

7. The combination according to claim 1 comprising, consisting of or consisting essentially of a vitamin B6, preferably pyridoxine hydrochloride, and a C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate.

8. A synthetic composition comprising the combination according to any of the precedent claims.

9. The synthetic composition according to claim 8 comprising the combination as defined in any of the claims 2 to 6.

10. The synthetic composition according to claim 9, further comprising sorbitol.

11 . The synthetic composition according to claim 10, wherein the weight ratio of sorbitol and the C8-C12 fatty acid or a pharmaceutically or nutritionally acceptable salt thereof, preferably sodium decanoate, is around 1 :8 to 1 :4.

12. The synthetic composition according to claim 8 comprising the combination as defined in claim 7.

13. Non-therapeutic use of the combination according to any of claims 2 to 6 or the synthetic composition according to any of the claims 9 to 11 for enhancing brain performance, alertness and/or mental energy in a healthy human.

14. A combination as defined in any of claims 2 to 6 or a synthetic composition as defined in any of the claims 9 to 11 for use in the therapy or as a medicament, preferably for use in the treatment of vitamin B12 deficiency in a human.

15. Non-therapeutic use of the combination according to claim 7 or the synthetic composition according to claim 12 for maintaining and supporting energy metabolism, immune function and/or cognitive function in a heathy human.

16. A combination as defined in claim 7 or a synthetic composition as defined in claim 12 for use in the therapy or as a medicament, preferably for use in the treatment of vitamin B6 deficiency in a human.