DE202015105351U1 - Dietetic composition - Google Patents

Abstract

A pharmaceutical or dietetic composition comprising as active ingredients: (a) at least one uridine derivative selected from the group consisting of deoxyuridine, deoxyuridine esters, uridine, uridine esters, and phosphates, salts, solvates and solvates of the salts thereof; and (b) pyridoxal-5-phosphate and at least one pharmaceutically or dietally suitable excipient.

Description

Field of the invention

The invention relates to a pharmaceutical or dietetic composition comprising uridine derivatives and other bioactive vitamin metabolites, such as pyridoxal-5-phosphate. The invention also relates to the use of this composition for the treatment or prevention of diseases and in particular for the treatment of peripheral nerve damage.

Background of the invention

The use of uridine derivatives is known in the art. Uridine is a pyrimidine nucleotide and, as such, essential for the synthesis of ribonucleic acids and tissue glycogen with UDP-glucose and UTP-glucose as intermediates. Uridine was first used to treat genetic disorders in pyrimidine synthesis, such as orotic acid aziduria ( Becroft DM et al., 1969, J. Pedriatr 75: 885-891 ). Another less common application of uridine monotherapy concerns the treatment of seizures and epilepsy ( Roberts et al., 1974, Epilepsy 15: 497-500 ). Uridine is used in particular in combination with cytidine for the treatment of some neurological diseases ( Monticone et al., 1966, Minerva Med. 57: 4348-4352 ).

The WO 2007/089703 A2 relates to the methods and compositions for the treatment of neurological disorders and in particular of dementia. It teaches to use a combination of choline and a uridine source such as UMP. This combination of active ingredients primarily supports the new synthesis of membrane phospholipids, thereby pharmacologically addressing only a cellular relevant aspect.

In view of the complex pathophysiology of neurological diseases, there is a great medical need for improved, therapeutically or dietary active substances or combinations of active substances.

Summary of the invention

It is an object of the present invention to provide an improved pharmaceutical or dietetic composition.

According to the invention the object is achieved by a pharmaceutical or dietetic composition according to claim 1. Specific embodiments of the invention are the subject of the additional dependent or independent claims.

In a first aspect, the invention provides a pharmaceutical or dietetic composition comprising as active ingredients at least one uridine derivative selected from the group consisting of deoxyuridine, deoxyuridine esters, uridine, uridine esters, and phosphates or salts thereof; and pyridoxal-5-phosphate and moreover comprises at least one pharmaceutically or dietally suitable excipient.

The composition according to the invention has numerous advantages over the compositions known from the prior art.

As the inventors have found, the composition according to the invention represents an advantageous combination of active substances which is both regenerative and also serves to alleviate spinal syndromes, neuralgias and polyneuropathies and also chronic pain.

As a result, the composition according to the invention allows an accelerated recovery of the corresponding inflammatory or neurological diseases.

Targeted use of bioactive vitamin metabolites can help block the cellular inflammatory cascade. The active compounds present, and in particular the uridine derivative, which is preferably present as uridine monophosphate, are important for the repair processes of the nerves.

The individual active ingredients of the composition of the invention begin at different points in the repair process of cells and their metabolism. As a result, this composition makes it possible at the same time to effectively interrupt the inflammatory cascade at the cellular level at various sites.

A particular advantage of the composition according to the invention is the use of the bioactive metabolites of the corresponding active ingredients.

The active ingredient combinations currently available on the market contain the body's important substances only in bound form, or only as a prodrug. The body must first metabolise these substances in order to be able to use the physiologically active (ie bioactive) constituents. Some patients are physically unable to do so (eg due to liver damage, interactions with active substances or food or a genetic constitution as a "poor metabolizer") and therefore have to, for example, in inflammatory diseases alternative therapies with non-steroidal anti-inflammatory drugs (eg, ibuprofen, celecoxib, etc.) or in the field of neuropathic pain effective analgesics (eg, pregabalin or amitryptiline) with the known side effects claim.

The composition of the invention, however, contains the active ingredients in their activated form. For the body eliminates the splitting and converting the substances. The absorption in the body is thereby facilitated and made possible in certain groups of patients just by this. The intake levels are increased and waste products of the splitting, which negatively influence the radical balance of the body, do not arise at all. Non-steroidal anti-inflammatory drugs commonly used for pain therapy can be in significantly lower doses. Consequently, it does not come to the known side effects.

Of particular advantage here is that the active ingredients used are all approved as dietary supplements. The composition according to the invention can therefore also be used as a dietetic composition for the prevention or treatment of corresponding, in particular inflammatory or (neuro) degenerative diseases.

The invention in detail

In a first aspect of the invention, the composition contains as active ingredients a uridine derivative and the pyridoxal-5-phosphate.

The uridine derivative, and in particular its form as uridine monophosphate, is an essential building block in the body and important for the cell metabolism and repair processes of the nerves. After nerve lesions, the need for neurotrophic pyrimidine nucleotides is increased. However, nerve cells are not able to produce them themselves because of their enzyme content, and thus rely on the external supply. On the damaged neuron, the uridine derivatives then intervene in the synthesis processes of the nucleic acids as well as in energy-supplying metabolic processes.

The uridine or deoxyuridine as Uridinderivat can be used according to the invention also in esterified form. The person skilled in the uridine esters from the prior art are well known. So reveal Morris & Gotor (J. Organic Chemistry, 1993; 58: 653-660) Uridine esters with a 5 'bound fatty acid group. Furthermore, in the WO 1989/03837 A1 and the EP 1 390 378 A1 Acyl-substituted uridine esters are disclosed which are also suitable, inter alia, for the treatment of neurological diseases.

Pyridoxal-5-phosphate is the activated form of vitamin B6, so here again there are no conversion steps for the body. It belongs to the so-called neurotropic B vitamins, thus plays an important role in the proper functioning of the nerves by participating in the synthesis of important neurotransmitters.

Compounds of the invention are the above-listed uridine derivatives and especially the uridine monophosphate and its esters, salts, solvates and solvates of the salts, as far as the following uridine derivatives are not already salts, solvates and solvates of the salts.

Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, trifluorosulfonic, toluenesulfonic, benzenesulfonic, 1-naphthalenedisulfonic, 2-naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, malic, lactic, tartaric, malic, citric, fumaric, maleic, Malonic acid, oxalic acid, succinic acid, salicylic acid, benzoic acid, phenylacetic acid and α-hydroxyphenylacetic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

The physiologically tolerable salts or acid or base addition salts can be prepared by the customary methods known to the person skilled in the art, for example by reacting the 5-methyltetrahydrofolic acid with the corresponding base, or by reacting a basic active substance with the appropriate acid in aqueous solution.

Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

• (a) einen bioaktiven Folsäure-Metaboliten, der ausgewählt ist aus der Gruppe enthaltend Folinsäure, Tetrahydrofolsäure, 5-Formyl-Tetrahydrofolsäure und 5-Methyl-Tetrahydrofolsäure (5-MTHF) und Salze hiervon, wobei hier 5-MTHF bevorzugt ist; und/oder
• (b) einen bioaktiven Vitamin B12-Metaboliten, der ausgewählt ist aus der Gruppe umfassend Methylcobalamin, Adenosylcobalamin und Hydroxylcobalamin, und der bevorzugt Methylcobalamin ist.

In a preferred embodiment, the pharmaceutical or dietetic composition additionally comprises:

• (A) a bioactive folic acid metabolite selected from the group consisting of folinic acid, tetrahydrofolic acid, 5-formyl-tetrahydrofolic acid and 5-methyl-tetrahydrofolic acid (5-MTHF) and salts thereof, wherein 5-MTHF is preferred here; and or
• (b) a bioactive vitamin B12 metabolite selected from the group comprising methylcobalamin, adenosylcobalamin and hydroxylcobalamin, and which is preferably methylcobalamin.

The composition of the invention preferably contains a bioactive folic acid metabolite. Folic acid is the precursor of the coenzyme tetrahydrofolic acid (THF), which is present under physiological conditions as a tetrahydrofolate anion. This has a central position in C1 metabolism. In particular, THF acts as a source of methyl, methylene, and formyl groups, and is involved in the synthesis of purine bases and deoxythymidine monophosphate (dTMP), which are necessary for DNA replication. In addition, THF is a coenzyme of methylation of homocysteine to methionine. The regeneration of neurons requires a high degree of folate involvement. It is essential for the synthesis of structural and functional proteins.

Folic acid is found in food of plant and animal origin. However, particularly good folic acid suppliers are green leafy vegetables, legumes, broccoli, wheat germ, nuts, whole grains, meat, liver, dairy products and eggs. The folic acid is present in the food (75%) in bound form, as a folate compound, which can be absorbed only poorly by the body, so that in the best case, only 40% of the folic acid of a mixed diet are available to the body.

The folic acid losses in food preparation are 60-95%, as folic acid is very sensitive to heat and oxygen and, due to the water solubility, easily passes into the cooking water. In addition, there may well be problems regarding the utilization of folic acid. Because folic acid must be activated in the body first, so that they can actually develop their full health. Only complicated metabolic processes of the liver bring folic acid into a biologically active form: 5-methyltetrahydrofolate (5-MTHF).

5-MTHF is the main active form with a share of more than 98%. In about half of the population, however, there is an impairment of the Folatstoffwechsels by a so-called "enzyme polymorphism". A key enzyme for the synthesis of the biologically active folate form (5-MTHF) can only diminish its task, so that in these people a deficiency of folic acid can result with significant health consequences.

It should be noted that the folic acid is also subject to a specific transport mechanism. In order to first reach the cell interior, beginning with the intestinal mucosa cells, the folic acid molecule relies on the presence of the transport protein "proton-coupled folate transporter" (also called "heme carrier"), which is also responsible for export into the bloodstream. For THF and 5-derivatives of THF such as 5-MTHF, the so-called "Folate Transporter 1" is responsible for the import, also and especially in the intestine. The existence of this transport system ensures that even the bioactive folic acid metabolites are sufficiently absorbed by the body and can fulfill their efficacy at the destination.

The 5-MTHF is present as an optically active form in two enantiomers, the (6S) -5-MTHF and the (6R) -5-MTHF. According to the invention, the use of the racemate, ie the (6R, 6S) -5-MTHF form, is preferred here, and in particular the use of the (6S) -5-MTHF form as the biologically relevant enantiomer.

The MTHF and in this case preferably the (6S) -5-MTHF is present in a particularly preferred form as calcium salt or as glucosamine salt.

The composition suitably comprises a bioactive vitamin B12 metabolite selected from the group comprising methylcobalamin, adenosylcobalamin and hydroxylcobalamin. The methylcobalamin or the adenosylcobalamin is preferably used here.

The adenosyl and the methylcobolamine represent the actual active forms of the vitamin B12, so have clear advantages for therapeutic and preventive use. It is noteworthy that in the cyanocobalamin commonly used (industrially preferred because it is inexpensive to synthesize and stable on storage) four metabolic steps are needed to generate the bioactive final stages methylcobalamin and adenosylcobalamin. The commonly used Cyanocobalamin is not only very slowly converted by the body (so there are always only small amounts of active form available), but the body must also dispose of a cyano group as a toxic substance. The waste product is reflected negatively in the radical balance. B12 is also very important for the nerve function, it is partly responsible for the formation of the lipid-rich envelope (myelin sheaths), which strip the nerve cells segment by segment and thus enable a fast (so-called saltatory) excitation conduction. In addition, it is essential for the uptake of folic acid into the cell, which is why the two substances should always be substituted together.

The active ingredients used according to the invention, ie the uridine derivative, the pyridoxal-5-phosphate, the bioactive folic acid metabolite and / or the bioactive vitamin B12 metabolite can exist in different stereoisomeric forms, depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers). The present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.

If the active compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

The present invention also encompasses all suitable isotopic variants of the active compounds according to the invention. An isotopic variant of an active ingredient according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁹ I and ¹³¹ I. Certain isotopic variants of a compound of the invention, such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with ³ H or ¹⁴ C isotopes in particular are suitable for this purpose. Moreover, the incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the methods known to the person skilled in the art, for example by the customary methods for preparing the active compounds according to the invention, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.

In a particularly preferred embodiment of the invention, the uridine derivative present in the composition is uridine monophosphate (UMP). Uridine monophosphate is the linchpin of the endogenous synthesis of pyrimidine nucleotides as building blocks of nucleic acids and thus of DNA and RNA. UMP has many functions in cell metabolism and cell regeneration. In the case of nerve damage, the physiologically active uridine and cytidine phosphates arising from the UMP promote intraneuronal protein biosynthesis and ensure sufficient enzyme supply. In the damaged neuron, nucleotides interfere with both the synthesis processes of the nucleic acids and myelin sheaths as well as with energy-supplying metabolic processes.

In one embodiment of the invention, the 5-MTHF is present as the glucosamine salt. Preferably, the glucosamine salt or the calcium salt of (6S) -5-methyltetrahydrofolic acid is used here. Both the glucosamine salt and the calcium salt of the 5-MTHF dissociate immediately in the aqueous environment of the digestive tract to 5-MTHF and glucosamine.

According to the EP 1 044 975 B1 In addition to the amorphous state, the calcium salt of the 5-MTHF may also be present in several polymorphic crystal forms, namely type I, type II, type III or type IV. According to the invention, all these crystal forms can be used, the type I polymorph having 2 theta Values of 6.5, 13.3, 16.8 and 20.1 is preferred.

• (a) Uridinmonophosphat;
• (b) Pyridoxal-5-Phosphat;
• (c) 5-Methyl-Tetrahydrofolsäure (5-MTHF);
• (d) Methylcobalamin;

und mindestens einen pharmazeutisch oder diätetisch geeigneten Hilfsstoff.In a particularly preferred embodiment of the invention, the pharmaceutical or dietetic composition comprises:

• (a) uridine monophosphate;
• (b) pyridoxal-5-phosphate;
• (c) 5-methyltetrahydrofolic acid (5-MTHF);
• (d) methylcobalamin;

and at least one pharmaceutically or dietally suitable excipient.

In a further preferred embodiment, the pharmaceutical or dietetic composition consists of the active substances listed above under (a) to (d) and, in addition, at least one pharmaceutically or dietally suitable excipient.

• (a) Uridinmonophosphat in einer Menge zwischen 25 und 75 mg;
• (b) Pyridoxal-5-Phosphat in einer Menge zwischen 5 bis 15 mg;
• (c) Ein Salz der 5-Methyl-Tetrahydrofolsäure (5-MTHF) in einer Menge zwischen 0,5 und 1,5 mg bezogen auf das 5-MTHF;
• (d) Methylcobalamin in einer Menge zwischen 0,5 und 1,5 mg;

und mindestens einen pharmazeutisch oder diätetisch geeigneten Hilfsstoff.In one embodiment of the invention, the pharmaceutical or dietetic composition comprises:

• (a) uridine monophosphate in an amount between 25 and 75 mg;
• (b) pyridoxal-5-phosphate in an amount of between 5 to 15 mg;
• (c) a salt of 5-methyl-tetrahydrofolic acid (5-MTHF) in an amount between 0.5 and 1.5 mg relative to the 5-MTHF;
• (d) methylcobalamin in an amount between 0.5 and 1.5 mg;

and at least one pharmaceutically or dietally suitable excipient.

In a further preferred embodiment, the pharmaceutical or dietetic composition consists of the active substances listed above under (a) to (d) in the stated amounts and moreover from at least one pharmaceutically or dietally suitable excipient. This combination of active ingredients with the amounts given here has proven to be particularly advantageous therapeutically.

• (a) 50 mg Uridinmonophosphat;
• (b) 10 mg Pyridoxal-5-Phosphat;
• (c) 1 mg 5-MTHF, bevorzugt als Glucosaminsalz;
• (d) 1 mg Methylcobalamin;

und mindestens einen pharmazeutisch oder diätetisch geeigneten Hilfsstoff.In a specific embodiment of the invention, the pharmaceutical or dietetic composition comprises:

• (a) 50 mg uridine monophosphate;
• (b) 10 mg pyridoxal-5-phosphate;
• (c) 1 mg of 5-MTHF, preferably as glucosamine salt;
• (d) 1 mg of methylcobalamin;

and at least one pharmaceutically or dietally suitable excipient.

In a likewise specific embodiment, the pharmaceutical or dietetic composition consists of the active substances listed above under (a) to (d) in the stated amounts and, in addition, of at least one pharmaceutically or dietally suitable excipient. This combination of active ingredients with the amounts given here has proven to be particularly advantageous therapeutically.

The pharmaceutical or dietetic composition may comprise one or more substances selected from the group consisting of vitamins, minerals, omega-3 fatty acids, phospholipids, colorants, flavors, preservatives and antioxidants, or combinations thereof.

The additional use of omega-3 fatty acids is particularly advantageous in applications in which the phospholipid metabolism is to be supported. Particularly suitable omega-3 fatty acids for a composition according to the invention together with preferred amounts (proportions) of the WO 2013/125020 A1 or the WO 2013/066167 A1 discloses, the disclosure of which is fully incorporated herein by reference.

Preferably, additional substances used are those which are selected from the group comprising vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, niacin, pantothenic acid, biotin, choline, chromium, copper, iodine, Molybdenum, calcium, selenium, iron, zinc, magnesium, manganese, potassium, boron, lutein, vanadium, lutein, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), α-linolenic acid (ALA), phytochemicals, or combinations thereof.

In a preferred embodiment, flavones, reserpine, polyphenols, sulfides, phytin, phenolic acids, polysaccharides, saponins, phytosterols, carotenoids or lipoic acid are used as secondary plant substances.

The flavone as phytochemical may be selected from the structural class of flavans, isoflavonoids, neoflavonoids or chalcones.

According to the invention, the flavone is selected from the group comprising amphibulinsin, apigenin, biochanin A, chrysin, daidzein, dihydrokaempferol, 2`, 4-dihydroxychalcone, 3`, 4`-dihydroxyflavone, epicatechin, epifzelechin, epifzelechin gallate, epigallocatechin (EGC), epicatechingallate , Eriodictyol, Fisetin, Galangin, Genistein, Gingketine, Hesperitin, Homoeriodyctiol, Isorhamnetin, Isoxanthohumol, Isoxanthohumol, Kaempferol, Luteolin, Myricetin, Naringenin, Orobol, Pachypodol, Pratensein, Primetin, Prunetin, Quercetagetine, Quercetrin, Rhamnazine, Rutin, Santal, Taxifolol and xanthohumol.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, such as oral, parenteral, pulmonary, nasal, inhalatively, sublingually, lingually, buccally, rectally, dermally, intrathecally, intramuscularly, intravenously, intraarterially, transdermally, subcutaneously, mucocutaneously, otically or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, nasal solutions or nasal sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments , Creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral administration.

The compounds according to the invention can be converted into the stated administration forms, ie the corresponding dietetic or pharmaceutical compositions. This can be done in a conventional manner by mixing with inert, non-toxic, dietary or pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (eg antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides), and taste and / or odoriferous agents.

In another aspect of the invention, the pharmaceutical or dietetic composition is used to treat or prevent a disease. This disease is preferably selected from the group consisting of diabetes mellitus type I and II, inflammation, cancer, necrosis, gastric ulcers, neurodegenerative diseases (Alzheimer's disease, M. Parkinson), neuropathic diseases, neuropathic pain and polyneuropathy, diseases of the peripheral and / or of the central nervous system, degradation of the peripheral and / or central nervous system, heavy metal poisoning, ischemic diseases and ischemic heart disease, liver diseases and liver dysfunction, allergies, cardiovascular diseases, Chlamydia pneumoniae, depression, obesity, stroke, pain and / or retroviral infections ( HIV, AIDS) including opportunistic infections.

In a particularly preferred embodiment, the pharmaceutical or dietetic composition is used for the treatment and prevention of chronic pain, inflammation or neurodegenerative diseases.

embodiments

Example recipe (per capsule):

• Uridine monophosphate sodium salt 57.1 mg;
• • pyridoxal 5-phosphate 10 mg;
• 5-MTHF-glucosamine salt 1.39 mg;
• • Methylcobalamin 1 mg;
• • microcrystalline cellulose quantum satis

Other variants of the invention and their execution will become apparent to those skilled in the art from the foregoing disclosure, the embodiment and the claims.

definitions

In the context of the present invention, a "physiologically acceptable salt" (synonymously "pharmaceutically acceptable salt") means a salt which is suitable for the preparation of a pharmaceutical or dietetic composition in that it is safe and non-toxic and the effectiveness of the active substance is not impaired. It thus includes all salts which are suitable for use on animals or humans.

In the context of the present invention, a "pharmaceutically or dietary adjuvant" (synonymous with the term "physiologically acceptable carrier") means an adjuvant which is either solid, gel, liquid or gaseous and which is suitable for the preparation of a pharmaceutical composition insofar as it is safe and non-toxic and does not affect the efficacy of the active substance formulated therewith. It therefore includes all excipients that are suitable for use on animals or humans.

According to the invention, the term "treatment" is to be understood as any application of the phenol conjugates to the individual which serves to symptomatically or causally alleviate or even suppress the disease or to arrest, delay or postpone the progression of the disease.

In the context of the present invention, "prevention" is understood to mean the prevention of the occurrence of diseases, and in particular of neurological diseases, and thus the reduction of their spread and the reduction of their effects on morbidity and mortality of the population. The central strategy is to push back the triggering factors of diseases or to eliminate them altogether.

Prevention encompasses both primordial prevention, primary prevention, secondary prevention, tertiary prevention and quaternary prevention.

Primary prevention starts before the onset of the disease and aims to prevent a new onset of the disease. Primary prevention targets at-risk groups, healthy people and people without disease symptoms.

Primary prevention can be used to distinguish the primordial prevention that starts even earlier. It's about preventing the onset of risk factors.

Secondary prevention starts with the early stages of a disease. It serves the early detection of diseases and the curbing of their progression (progression) or the chronification of the disease. Often without a disease symptom perceivable for the affected person, the pathogenetic process has already begun here. The target group are people who participate as healthy or symptomless in the prevention measure, but by the diagnostic measure to patients.

Tertiary prevention occurs after an acute treatment or the manifestation of a disease. It is intended to prevent consequential damage and relapses. It is aimed at patients with chronic impairments and rehabilitants. An example here is the prevention of recurrences in tumor diseases.

Furthermore, there is the Quaternary Prevention, which aims to prevent unnecessary medicine or prevent overdose and the principle of "primum non nocere" considered as a cornerstone of all medicine.

Terms used in the claims, such as "comprising," "comprising," "including," "containing," and the like, do not exclude other elements or steps. The use of the indefinite article does not exclude a majority. A single device can perform the functions of several units or devices mentioned in the claims. Reference signs indicated in the claims should not be regarded as limitations on the means and steps employed.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2007/089703 A2 [0003]
• WO 1989/03837 A1 [0019]
• EP 1390378 A1 [0019]
• EP 1044975 B1 [0042]
• WO 2013/125020 Al [0050]
• WO 2013/066167 A1 [0050]

Cited non-patent literature

• Becroft DM et al., 1969, J. Pedriatr 75: 885-891 [0002]
• Roberts et al., 1974, Epilepsy 15: 497-500. [0002]
• Monticone et al., 1966, Minerva Med. 57: 4348-4352 [0002]
• Morris & Gotor (J. Organic Chemistry, 1993; 58: 653-660). [0019]

Claims (13)

A pharmaceutical or dietetic composition comprising as active ingredients: (a) at least one uridine derivative selected from the group consisting of deoxyuridine, deoxyuridine esters, uridine, uridine esters, and phosphates, salts, solvates and solvates of the salts thereof; and (b) pyridoxal-5-phosphate and at least one pharmaceutically or dietally suitable excipient. A pharmaceutical or dietetic composition according to claim 1, wherein the composition additionally comprises: (a) a bioactive folic acid metabolite selected from the group consisting of folinic acid, tetrahydrofolic acid, 5-formyl-tetrahydrofolic acid and 5-methyl-tetrahydrofolic acid (5-MTHF) and salts thereof, which is preferably 5-MTHF; and or (b) a bioactive vitamin B12 metabolite selected from the group comprising methylcobalamin, adenosylcobalamin and hydroxylcobalamin, and which is preferably methylcobalamin. A pharmaceutical or dietetic composition according to claim 1 or 2, wherein the uridine derivative is a uridine monophosphate. A pharmaceutical or dietetic composition according to any one of claims 1 to 3, wherein the 5-MTHF is present as a glucosamine salt and is preferably the glucosamine salt of (6S) -5-methyltetrahydrofolic acid. A pharmaceutical or dietetic composition according to any preceding claim, comprising or consisting of: (a) uridine monophosphate; (b) pyridoxal-5-phosphate; (c) 5-methyltetrahydrofolic acid (5-MTHF), preferably as a salt; (d) methylcobalamin; and at least one pharmaceutically or dietally suitable excipient. A pharmaceutical or dietetic composition according to any one of the preceding claims comprising or containing: (a) uridine monophosphate in an amount between 25 and 75 mg; (b) pyridoxal-5-phosphate in an amount of between 5 to 15 mg; (c) 5-methyl-tetrahydrofolic acid (5-MTHF) in an amount between 0.5 and 1.5 mg; (d) methylcobalamin in an amount between 0.5 and 1.5 mg; and at least one pharmaceutically or dietally suitable excipient. A pharmaceutical or dietetic composition according to any one of the preceding claims comprising: (e) 50 mg uridine monophosphate; (f) 10 mg pyridoxal-5-phosphate; (g) 1 mg of 5-MTHF, preferably as a glucosamine salt; (h) 1 mg of methylcobalamin; and at least one pharmaceutically or dietally suitable excipient. A pharmaceutical or dietetic composition according to any one of the preceding claims, which composition further comprises one or more substances selected from the group consisting of vitamins, minerals, omega-3 fatty acids, phospholipids, dyes, flavorings, preservatives or antioxidants, or combinations thereof , A pharmaceutical or dietetic composition according to claim 8, wherein said substances are selected from the group consisting of vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, niacin, pantothenic acid, biotin, choline, chromium salt, copper, iodine, Molybdenum, calcium, selenium, iron, zinc, magnesium, potassium, manganese, boron, vanadium, lutein, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), α-linolenic acid (ALA), phytochemicals, or combinations thereof. A pharmaceutical or dietetic composition according to any one of the preceding claims, which composition is formulated as a tablet, dragee, capsule, granule, powder, solution, suspension or emulsion, and preferably as a capsule. A pharmaceutical or dietetic composition according to any one of the preceding claims, which composition is for oral, parenteral, pulmonary, nasal, inhalative, sublingual, lingual, buccal, rectal, dermal, intrathecal, intramuscular, intravenous, intraarterial, transdermal, subcutaneous, mucocutaneous or otic Administration is suitable. A pharmaceutical or dietetic composition according to any one of the preceding claims for use in the treatment or prevention of Type I and II diabetes mellitus, inflammation, cancer, necrosis, gastric ulcers, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), neuropathic diseases, neuropathic pain and Polyneuropathy, diseases of the peripheral and / or central nervous system, degradation of the peripheral and / or central nervous system, heavy metal poisoning, ischemic diseases and ischemic heart disease, liver diseases and liver dysfunction, allergies, cardiovascular diseases Diseases, Chlamydia pneumoniae, depression, obesity, stroke, pain and / or retroviral infections (HIV, AIDS) including opportunistic infections. A pharmaceutical or dietetic composition according to claim 12 for use in the treatment and prevention of chronic pain, inflammation or neurodegenerative diseases.