Mannuronate, guluronic acid, and glumannuronate tablets, capsules, or ampoules, and methods for producing the same

Abstract

The present invention relates to oral and / or injectable tablets, capsules, and ampoules containing caffeic acid or a salt thereof (e.g., in powder form) that contains β-D-mannuronic acid or α-L-guluronic acid or a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts, wherein the total amount of β-D-mannuronic acid or α-L-guluronic acid, or the mixture thereof, its oligomers, or its pharmaceutically acceptable salts is 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule, or 20% by weight to 60% by weight based on the total weight of the ampoule; and the content of caffeic acid or a salt thereof (e.g., in powder form) is preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule. The present invention also relates to the use of oral and / or injectable tablets, capsules and ampoules (preferably as supplements or medicines) in methods for treating neurodegenerative diseases, inflammatory responses, pain, cancer, ageing, diabetes and / or heart disease, and to methods for producing such formulations.

Description

[Technical Field]

[0001] The present invention relates to oral and / or injectable tablets, capsules, and ampoules containing β-D-mannuronic acid or α-L-guluronic acid, or a mixture of β-D-mannuronic acid and α-L-guluronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof, wherein the total amount of β-D-mannuronic acid or α-L-guluronic acid, or the mixture, oligomer, or pharmaceutically acceptable salt thereof is 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule, or 20% by weight to 60% by weight based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof, the content of which is preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule. The present invention also relates to the use of oral and / or injectable tablets, capsules and ampoules, preferably as supplements or pharmaceuticals, in methods for treating neurodegenerative diseases, inflammatory responses, pain, cancer, ageing, diabetes and / or heart disease, and to methods for producing such formulations. [Background technology]

[0002] Mannuronic acid and guluronic acid are naturally occurring uronic acids isolated and purified from various forms of alginate, a polymer used as a thickener, binder, gelling agent, or lubricant. Alginate may originate from brown algae (e.g., brown algae and kelp) and / or bacteria belonging to the genera Pseudomonas and Azotobacter. The properties of alginate vary depending on its species of origin. Alginate exists primarily in the form of sodium, calcium, and ammonium salts. The chemical and physical properties of alginate polymers and oligomers are determined by the structure of their monomers (mannuronic acid and guluronic acid) and the distribution, proportion, and length of their monomer blocks.

[0003] Mannuronic acid and guluronic acid are epimers of each other. Therefore, many of the physicochemical and biological properties of these two molecules, such as the molecular formula (CH), are different. 10 O7), molecular weight (194.14 g / mol), boiling point (553.4 ± 50.0 °C at 760 mmHg) and density (1.7 ± 0.1 g / cm 3 ) are identical or very similar.

[0004] The therapeutic properties of mannuronic acid in various animal models were first reported in 2004. The results of these studies demonstrated the therapeutic efficacy and tolerability of mannuronic acid in in vitro and in vivo experiments. The potent therapeutic effect of mannuronic acid was reported by Mirshafiey et al. in 2005 (Mirshafiey A, Cuzzocrea S, Rehm BHA, and H. Matsuo H., "M2000: a revolution in pharmacology", Med Sci Monit. 2005.11(8):153-163). Since then, research has been ongoing to clarify the safety profile, potential cellular, molecular, and immunological mechanisms, and therapeutic efficacy in human clinical trials. The results of various studies and clinical trials have confirmed that mannuronic acid is very safe and has a wide range of therapeutic effects on various diseases, such as rheumatoid arthritis, ankylosing spondylitis, breast cancer, multiple sclerosis, and myelodysplastic syndromes (Fattahi MJ, Jamshidi AR, Mahmoudi M, et al., "Evaluation of the efficacy and safety of β-D-mannuronic acid in patients with ankylosing spondylitis," "A 12-week randomized, placebo-controlled, phase I / II clinical trial," International Immunopharmacology 2018, 54: 112-117; Ahmadi H, Jamshidi AR, Gharibdoost F, et al., "A phase I / II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients," Inflammopharmacology 2018;26(3): 737-745;Rezaieyazdi Z、Farooqi A、Soleymani-Salehabadi Hら, 「International multicenter randomized, placebo-controlled phase III clinical trial of β-D-mannuronic acid in rheumatoid arthritis patients」, Inflammopharmacology 2019;27(5):911-921;Kashefi S、Omranipour R、Mahmoodzadeh H、Ahmadi H、Mirshafiey A, 「Clinical improvement of diabetes mellitus type 1 by β-D-mannuronic acid (M2000)in a breast cancer patient-as a case report」,Clin Diabetol. 2019, 8(4): 227-229;Najafi S、Moghadam NB、Saadat Pら,「A controlled, randomized phase II clinical trial for efficacy andsafety evaluation of mannuronic acid insecondary progressive form of multiplesclerosis」,Int J Neurosci. 2022; 132(4): 403-412;Ghaderi A、Nodehi SRS、Bakhtiari Tら,「Mannuronic Acid in Low-Risk and Intermediate-1-Risk Myelodysplastic Syndromes」, J Clin Pharmacol. 2020, 60(7):879–888;

[0005] Mirshafiey et al. began systematic pharmacological and medical research on guluronic acid in 2013, and the results were published in 2015 (Afraei S, Azizi G, Zargar SJ, Sedaghat R, and Mirshafiey A., "New therapeutic approach by G2013 in an experimental model of multiple sclerosis," Acta Neurol Belg., September 2015, 115(3): 259-66). Furthermore, research has been conducted on the safety and pharmacotoxicological properties of guluronic acid, as well as its clinical therapeutic effects on inflammatory diseases.

[0006] These studies have revealed that these two types of uronic acids not only share many physicochemical properties, but also have identical or similar biological and medicinal properties. Summary of the Invention [Problem to be solved by the invention]

[0007] Surprisingly, we have found that β-D-mannuronic acid or α-L-guluronic acid, their oligomers, and their pharmaceutically acceptable salts, or a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts, preferably mannuronate or guluronate or gulumannuronate, in the form of tablets, capsules, or ampoules, can be effectively administered orally and / or by injection, for example, as an antioxidant. [Means for solving the problem]

[0008] Therefore, in a first aspect, the present invention provides a method for producing a cellular membrane comprising: (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof with α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate. 1. An oral and / or injectable tablet, capsule or ampoule comprising: the total amount of β-D-mannuronic acid or α-L-guluronic acid or a mixture thereof, an oligomer thereof, or a pharmaceutically acceptable salt thereof is 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule, and / or 20% by weight to 60% by weight based on the total weight of the ampoule; The tablet, capsule, or ampoule for oral and / or injection further comprises caffeic acid or a salt thereof (e.g., powdered) in an amount of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule.

[0009] In various embodiments, the tablet, capsule or ampoule is an oral and / or injectable, preferably an oral, tablet or capsule, and the formulation comprises: (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof with α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate; the total amount of β-D-mannuronic acid or α-L-guluronic acid, or a mixture thereof, an oligomer thereof, or a pharmaceutically acceptable salt thereof is 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule; The tablet or capsule further contains caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, in an amount of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight, based on the total weight of the tablet or capsule.

[0010] In various embodiments, the tablet, capsule or ampoule is for oral and / or injectable use, preferably an injectable ampoule, and the formulation comprises: (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof with α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate; the total amount of β-D-mannuronic acid or α-L-guluronic acid, or a mixture thereof, an oligomer thereof, or a pharmaceutically acceptable salt thereof is 20% by weight to 60% by weight based on the total weight of the ampoule; The ampoule further contains caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, in an amount of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight, relative to the total weight of the ampoule.

[0011] Preferably, (i) the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a β-D-mannuronate, more preferably selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, or ammonium β-D-mannuronate, and combinations thereof, more preferably sodium β-D-mannuronate; and / or (ii) The α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is an α-L-guluronic acid salt, more preferably selected from the group consisting of sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, or ammonium α-L-guluronic acid, and combinations thereof, more preferably sodium α-L-guluronic acid.

[0012] In embodiments using a mixture of β-D-mannuronic acid and α-L-guluronic acid, their respective oligomers, or their respective pharmaceutically acceptable salts, the active (drug) agent may be glumannuronate; Preferably, β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof are mixed, preferably selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate or ammonium β-D-mannuronate with sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid or ammonium α-L-guluronic acid and combinations thereof, most preferably sodium β-D-mannuronate and / or sodium α-L-guluronic acid; or A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts (preferably glumannuronate) is an alginate hydrolysate (powder).

[0013] In various embodiments, the total amount of the following ingredients in the tablet or capsule is 30% by weight to 100% by weight, preferably 50% by weight to 99.999% by weight, based on the total weight of the tablet or capsule, and / or the total amount of the following ingredients in the ampoule is 30% by weight to 60% by weight, preferably 40% by weight to 60% by weight, more preferably 50% by weight to 60% by weight, based on the total weight of the ampoule, (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof.

[0014] In various embodiments, the tablet, capsule, or ampoule may further comprise at least one additional supplement and / or medication and / or at least one additional ingredient described herein. Preferably, the tablet, capsule, or ampoule is a supplement and / or a pharmaceutical product. In various embodiments, the tablet, capsule, or ampoule is for oral and / or injectable use as an antioxidant as described herein.

[0015] In a second aspect, the tablet, capsule or ampoule is for oral and / or injection use in a method for treating (or preventing) the diseases described below. (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or (ii) an inflammatory response, preferably an inflammatory response in rheumatic diseases; and / or (iii) pain, preferably joint and / or muscle pain; and / or (iv) cancer, preferably breast cancer and prostate cancer; and / or (v) aging; and / or (vi) diabetes; and / or (vii) Heart disease, preferably arrhythmia.

[0016] In a third aspect, the present invention relates to a method for producing a tablet, capsule or ampoule according to the invention, preferably said tablet, capsule or ampoule being an antioxidant tablet, capsule or ampoule.

[0017] In various embodiments, the method is a method for making an antioxidant tablet, capsule, or ampoule, comprising: (a) β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 10% by weight to 100% by weight based on the total weight of the tablet or capsule, and / or 20% by weight to 60% by weight based on the total weight of the ampoule; and further containing caffeic acid or a salt thereof (e.g., in powder form) in a content of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule; or (b) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salts, in a total amount of 10% to 100% by weight, based on the total weight of the tablet or capsule, and / or 20% to 60% by weight, based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in a content of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule; or (c) A composition comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronic acid, glumannuronate, or their oligomers, in a total amount of 10% by weight to 100% by weight based on the total weight of the tablet or capsule, and / or 20% by weight to 60% by weight based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in a content of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule. The method includes the step of providing:

[0018] These and other aspects, embodiments, features, and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and claims. Each feature of one aspect of the present invention is applicable to any other aspect of the present invention. Furthermore, the examples included herein are intended to explain and illustrate the present invention, but are not intended to limit the present invention. In particular, the present invention is not limited to these examples. DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, "at least one" means one or more such species, i.e., 1, 2, 3, 4, 5, 6, 7, 8, or 9 or more such species. Similarly, as used herein, "one or more" refers to at least one, including 1, 2, 3, 4, 5, 6, 7, 8, or 9 or more. For a given species, the term refers to the type of species, not the total number of molecules. For example, "at least one preservative" means that there can be one type of preservative or two or more different types of preservatives. For a dose, the term refers to the total amount of such species. For example, in the case of a preservative, this means that the given dose is the total amount of all preservatives in the composition / formulation.

[0020] As used herein, the singular forms "a," "an," and "the" include the plural reference unless otherwise specified. For example, "the oligomer" includes multiple oligomeric molecules or oligomeric species, such as mixtures or combinations of various oligomeric species. Also, unless otherwise specified, the use of plural forms such as "the oligomers" or "pharmaceutically acceptable salts thereof" includes the singular reference to one type of oligomer or one type of salt.

[0021] In this specification, unless otherwise defined, a numerical value without a specified decimal point refers to the full numerical value to one decimal point, for example, 99% means 99.0%.

[0022] The term "about" in reference to a numerical value refers to a variation of ±10%, preferably ±5%, from the stated numerical value.

[0023] In the context of the present invention, the term "substantially free" is understood to mean that the respective compound is contained in the formulation in an amount of less than 5%, 4%, 3%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.25%, 0.1%, 0.01%, or 0.001% by weight, based on the total weight of the formulation, with the respective descending amounts being more preferred, e.g., 4% by weight is more preferred than 5% by weight, and 3% by weight is more preferred than 4% by weight.

[0024] In this specification, all percentages for formulations are by weight (wt%) based on the total weight of the respective formulation unless otherwise specified. Numerical ranges specified in the format "x to y" are inclusive. When multiple preferred numerical ranges are specified in this format, it is understood that all ranges created by combining the different endpoints are also included.

[0025] In the following, the term "tablet, capsule or ampoule" is used to describe oral and / or injectable tablets, capsules or ampoules, preferably as supplements and / or medicines, in particular as antioxidants.

[0026] The terms "tablet" and "tablets" and "capsules" and "capsules" are intended to encompass all solid dosage forms commonly used in the art, including lozenges, pills, film-coated tablets, compressed tablets, and pellets, which are commonly used for oral administration.

[0027] In various embodiments, tablets are compacted powders, granules, or bases, e.g., compressed under pressure, preferably compressed powders. They can have any suitable shape and size, e.g., a biconvex shape.

[0028] In various embodiments, capsules, such as hard and soft capsules, microcapsules, or enteric-coated capsules, can contain a solid fill such as a powder, particles, tablets, or smaller capsules, or a liquid or paste fill such as a solution, suspension, or emulsion. Preferably, hard capsules contain a solid fill. The capsule coating may include or consist of, but is not limited to, gelatin, cellulose, carrageenan, starch, glue, or derivatives thereof, or combinations thereof.

[0029] Preferably, the tablets and / or capsules are administered orally to a subject (in need thereof). In various embodiments, the tablets and / or capsules may be dissolved prior to oral administration.

[0030] In the context of the present invention, "ampoules" are intended to include any type of injection commonly used in the art, such as liquid or powder formulations (preferably for oral and / or injection, especially for injection) contained in an ampoule container or dish. The material of the ampoule container or dish may be, but is not limited to, glass or plastic. If the formulation is a powder formulation, it may be dissolved, for example, in water, before use. Ampoule are generally intended for injection.

[0031] Methods for producing tablets, capsules, or ampoules are known to those skilled in the art, and they can be prepared according to conventional methods.

[0032] β-D-mannuronic acid has the following formula (I):

[0033] [ka] β-D-mannuronic acid ( 4 C1) (I)

[0034] α-L-guluronic acid has the following formula (II):

[0035] [ka] α-L-guluronic acid ( 1 C4) (II)

[0036] Because mannuronic acid and guluronic acid are epimers, they share many physicochemical and biological / pharmaceutical properties, e.g., as antioxidants. Thus, in this invention, all concepts disclosed for β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof are equally applicable to α-L-guluronic acid, its oligomers, pharmaceutically acceptable salts thereof, or mixtures thereof, and vice versa.

[0037] Radicals may play a role in various diseases, such as cancer, cardiovascular disease, atherosclerosis, arthritis, aging, depression, anxiety, and other disorders. These radicals are formed by the body itself during various metabolic processes, but they can also be generated by harmful external influences, such as cigarette smoke, environmental toxins, and solar ultraviolet radiation. Antioxidants are generally substances that inhibit and / or reduce oxidation, a chain reaction that generates radicals and can damage living cells. Therefore, antioxidants can be used as pharmaceuticals for both prevention and treatment.

[0038] According to the present invention, β-D-mannuronic acid or α-L-guluronic acid or a mixture thereof may be contained in a tablet, capsule, or ampoule as a pharmaceutically acceptable salt. Preferably, these pharmaceutically acceptable salts are mannuronate, guluronic acid, or a mixture thereof, more preferably β-D-mannuronate, α-L-guluronic acid, or a mixture thereof (referred to as "glumannuronate"). The counterion may be selected from sodium, potassium, magnesium, calcium, ammonium, and other pharmaceutically acceptable countercations.

[0039] Thus, in various embodiments, oral and / or injectable tablets, capsules or ampoules may contain: (i) mannuronate tablets, capsules, or ampoules; or (ii) guluronic acid salt tablets, capsules or ampoules; or (iii) Glumannuronate tablets, capsules or ampoules may be.

[0040] In various embodiments, the tablet, capsule, or ampoule containing β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a mannuronate tablet, capsule, or ampoule. Specifically, in various embodiments, the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof may be a β-D-mannuronate, more preferably selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, and combinations thereof, with sodium β-D-mannuronate being particularly preferred.

[0041] In various embodiments, β-D-mannuronic acid, preferably β-D-mannuronate, can also be added to the tablet, capsule or ampoule as a precursor selected from oligomers of β-D-mannuronic acid or β-D-mannuronate, preferably (homo)oligomers of β-D-mannuronate, in particular sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate and combinations thereof, in particular sodium oligomannuronate.

[0042] In various embodiments, the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably a β-D-mannuronate salt) is selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate, and combinations thereof, preferably sodium β-D-mannuronate and / or sodium oligomannuronate.

[0043] In various embodiments, the tablet, capsule, or ampoule containing α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a guluronic acid salt tablet, capsule, or ampoule. Specifically, in various embodiments, the α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof may be an α-L-guluronic acid salt, preferably selected from the group consisting of sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, ammonium α-L-guluronic acid, and combinations thereof, with sodium α-L-guluronic acid being particularly preferred.

[0044] In various embodiments, α-L-guluronic acid, preferably α-L-guluronic acid salt, can also be added to the tablet, capsule or ampoule as a precursor selected from oligomers of α-L-guluronic acid or α-L-guluronic acid salt, preferably (homo)oligomers of α-L-guluronic acid salt, in particular sodium oligoguluronic acid, potassium oligoguluronic acid, magnesium oligoguluronic acid, calcium oligoguluronic acid, ammonium oligoguluronic acid and combinations thereof, in particular sodium oligoguluronic acid.

[0045] In various embodiments, the α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (preferably an α-L-guluronic acid salt) is selected from the group consisting of sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, ammonium α-L-guluronic acid, sodium oligoguluronic acid, potassium oligoguluronic acid, magnesium oligoguluronic acid, calcium oligoguluronic acid, ammonium oligoguluronic acid, and combinations thereof, preferably sodium α-L-guluronic acid and / or sodium oligoguluronic acid.

[0046] In various embodiments, the tablet, capsule, or ampoule containing a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts is a glucanuronic acid salt tablet, capsule, or ampoule. In particular, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof may be a mixture of β-D-mannuronate and α-L-guluronic acid salts, preferably selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, or a combination thereof, and sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, ammonium α-L-guluronic acid, or a combination thereof, and particularly preferably a mixture of sodium β-D-mannuronate and sodium α-L-guluronic acid.

[0047] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, preferably glumannuronate, can also be added to the tablet, capsule or ampoule as a precursor selected from oligomers of β-D-mannuronic acid / β-D-mannuronate and / or α-L-guluronic acid / α-L-guluronic acid, preferably (homo)oligomers of β-D-mannuronic acid / β-D-mannuronate and / or α-L-guluronic acid / α-L-guluronic acid, in particular sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate, sodium oligoguluronic acid, potassium oligoguluronic acid, magnesium oligoguluronic acid, calcium oligoguluronic acid, ammonium oligoguluronic acid and combinations thereof, in particular sodium oligomannuronate and / or sodium oligoguluronic acid.

[0048] In various embodiments, β-D-mannuronic acid and / or α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably glucuronuronate) are selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate, α-L-glucuronic acid, The oligoguluronic acid salt is selected from the group consisting of sodium β-D-mannuronate, sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, ammonium α-L-guluronic acid, sodium oligoguluronic acid, potassium oligoguluronic acid, magnesium oligoguluronic acid, calcium oligoguluronic acid, ammonium oligoguluronic acid, and combinations thereof, and is preferably sodium β-D-mannuronate, sodium oligomannuronate, sodium α-L-guluronic acid, sodium oligoguluronic acid, and combinations thereof.

[0049] In particular, the β-D-mannuronate or α-L-guluronic acid oligomer comprises 2 to 16 monomer units, preferably 3 to 6 monomer units, such as 3 or 4 or 5 or 6 monomer units.

[0050] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts (preferably glumannuronate) may be synthesized from sodium alginate and used in tablets, capsules, or ampoules as an alginate hydrolysate (preferably alginate hydrolysate powder, also referred to as glumannuronate). In particular, the alginate hydrolysate (glumannuronate) is a separated precipitate of sodium alginate containing mannuronic acid / mannuronate and guluronic acid / guluronic acid. Thus, in various embodiments, the tablet, capsule, or ampoule comprises or consists of caffeic acid or a salt thereof (e.g., powdered form) and alginate hydrolysate (glumannuronate), preferably in an amount of 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule; preferably In the tablet or capsule, the content of alginate hydrolysate (glumannuronate) is 10% to 99.999% by weight, more preferably 30% to 99.999% by weight, more preferably 40% to 99.999% by weight, more preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule; and / or In the ampoule, the content of the alginate hydrolysate (glumannuronate) is 20% by weight to 60% by weight, more preferably 30% by weight to 60% by weight, more preferably 40% by weight to 60% by weight, and more preferably 50% by weight to 60% by weight, based on the total weight of the ampoule.

[0051] Preferably, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts (preferably glumannuronate) may be: (1) A mixture of the single component β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (especially β-D-mannuronate) (powder) with α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof (especially α-L-guluronic acid) (powder); or (2) Alginate hydrolysate (powder).

[0052] In various embodiments, the total amount of the following ingredients in the tablet or capsule is 20% by weight to 99.999% by weight, preferably 30% by weight to 99.999% by weight, more preferably 40% by weight to 99.999% by weight, more preferably 50% by weight to 99.999% by weight, based on the total weight of the tablet or capsule; and / or the total amount of the following ingredients in the ampoule is 30% by weight to 60% by weight, preferably 40% by weight to 60% by weight, more preferably 50% by weight to 60% by weight, for example 50% by weight or 55% by weight, based on the total weight of the ampoule.

[0053] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof.

[0054] In various embodiments, the tablet or capsule, preferably the tablet, comprises the following ingredients: (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, and caffeic acid; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, and caffeic acid; or (iii) a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, and caffeic acid In this case, the tablet or capsule is free or substantially free of additional supplements, drugs and / or ingredients.

[0055] In one embodiment, the total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof in a tablet or capsule, preferably a mannuronate tablet or capsule, is 20% to 99.999% by weight, preferably 30% to 99.999% by weight, more preferably 40% to 99.999% by weight, more preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule; or in an ampule, preferably a mannuronate ampule, is 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, for example 50% or 55% by weight, based on the total weight of the ampoule.

[0056] In another embodiment, the total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof in a tablet or capsule, preferably a guluronic acid salt tablet or capsule, is 20% to 99.999% by weight, preferably 30% to 99.999% by weight, more preferably 40% to 99.999% by weight, more preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule; or in an ampoule, preferably a guluronic acid salt ampoule, is 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, for example 50% or 55% by weight, based on the total weight of the ampoule.

[0057] In another embodiment, the total amount of a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof in a tablet or capsule, preferably a glumannuronate tablet or capsule, is 20% to 99.999% by weight, preferably 30% to 99.999% by weight, more preferably 40% to 99.999% by weight, more preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule; or in an ampule, preferably a glumannuronate ampule, is 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, for example 50% or 55% by weight, based on the total weight of the ampoule.

[0058] In various embodiments, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof (preferably the mixture in the glucanuronic acid tablet or capsule) preferably comprises or consists of 0.01% to 99.99% by weight of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts, and 0.01% to 99.99% by weight of α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts, provided that the combined amount of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts and α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts in the tablet or capsule is 10% to 99.999% by weight, based on the total weight of the tablet or capsule, and preferably The total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% by weight to 99.9% by weight, more preferably 1% by weight to 99% by weight, and more preferably 10% by weight to 90% by weight, based on the total weight of the tablet or capsule; and The total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is 0.1% to 99.9% by weight, preferably 1% to 99% by weight, and more preferably 10% to 90% by weight, based on the total weight of the tablet or capsule.

[0059] In various embodiments, the weight ratio of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof to α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 100:1 to 1:100, for example 10:1 to 1:10 or 5:1 to 1:5, preferably 3:1 to 1:3, 2:1 to 1:2, or about 1.5:1 to 1:1.5, and most preferably about 1:1.

[0060] In various embodiments, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts (preferably the mixture in the glucanuronic acid salt ampoule) preferably comprises or consists of 0.01% to 59.99% by weight of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts and 0.01% to 59.99% by weight of α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts, provided that the total amount of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts and α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts in the ampoule is 20% to 60% by weight, based on the total weight of the ampoule, and preferably The total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% by weight to 59.9% by weight, more preferably 1% by weight to 59% by weight, more preferably 10% by weight to 50% by weight, and more preferably 20% by weight to 40% by weight, based on the total weight of the ampoule; and The total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is 0.1% by weight to 59.9% by weight, more preferably 1% by weight to 59% by weight, more preferably 10% by weight to 50% by weight, and more preferably 20% by weight to 40% by weight, based on the total weight of the ampoule.

[0061] In various embodiments, the weight ratio of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof to α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 100:1 to 1:100, for example 10:1 to 1:10 or 5:1 to 1:5, preferably 3:1 to 1:3, 2:1 to 1:2, or about 1.5:1 to 1:1.5, and most preferably about 1:1.

[0062] According to the present invention, the tablet, capsule, or ampoule (particularly the tablet or capsule) contains caffeic acid or a salt thereof (e.g., powdered) in an amount of preferably 0.001 wt % to 1 wt %, more preferably 0.01 wt % to 0.5 wt %, more preferably 0.05 wt % to 0.3 wt %, for example 0.1 wt % to 0.3 wt %, based on the total weight of the tablet, capsule, or ampoule (preferably based on the total weight of the tablet or capsule).

[0063] Caffeic acid (3,4-dihydroxycinnamic acid, molecular formula CHO) can be found in a variety of plants and foods. For example, coffee is the primary source of caffeic acid in the human diet. However, it is also found in other food sources, such as apples, pears, artichokes, and berries. In various embodiments, caffeic acid can be used in pharmaceuticals and / or supplements aimed at improving athletic performance, alleviating exercise-related fatigue, and reducing weight, and exerts a variety of effects in the body, including antioxidant, anticancer, anti-inflammatory, neuroprotective, and photoprotective properties, among others. Caffeic acid can be purchased, for example, from Sigma-Aldrich, or isolated from coffee and other food sources.

[0064] Preferably, the formulation of the present invention can be used as an antioxidant medicine or supplement.

[0065] In various embodiments, tablets, capsules or ampoules according to the invention may contain β-D-mannuronic acid or α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof or mixtures thereof (preferably β-D-mannuronate or α-L-guluronic acid or mixtures thereof) and caffeic acid, as well as other (preferably chemically pure) supplements, drugs, medicines and / or herbs.

[0066] In various embodiments, the tablet, capsule, or ampoule contains at least one additional supplement and / or medication.

[0067] Supplements are nutrients that can be added specifically to the pharmaceutical preparations or formulations of the present invention. In various embodiments, supplements are intended to complement a subject's diet and provide optimal nutrition to the body.

[0068] The drug is preferably the active ingredient in a medicine or formulation that is responsible for its pharmacological action. In various embodiments, but not limited to, the at least one additional supplement and / or the at least one additional medication (particularly for tablets or capsules) is selected from the group consisting of, but not limited to, antioxidants, anti-cancer agents, vitamins, multivitamins, (medicinal) minerals, (medicinal) multiminerals, amino acids, fatty acids, herbs, carbohydrates, pain relievers, anti-inflammatory agents, and anti-sensitivity agents, or combinations thereof.

[0069] Suitable other antioxidants (food-derived) include, but are not limited to, beta-carotene, OPCs, resveratrol, flavonoids, lycopene, anthocyanins, zeaxanthin, chlorophyll, and / or allicin. Other suitable antioxidants may be thiols. Vitamins that can be used as additional supplements and / or medications include, but are not limited to, vitamin A, vitamin C, vitamin D, vitamin E, or vitamin K(2). Anti-cancer drugs include, but are not limited to, curcumin, taxol, or selenium.

[0070] Suitable medicinal minerals include, but are not limited to, for example, calcium carbonate, calcium citrate, calcium malate, magnesium glycinate, magnesium citrate, magnesium gluconate, magnesium lactate, phosphorus-based substances, sodium chloride and / or potassium chloride.

[0071] In the context of this invention, an analgesic is defined as a medication that eliminates, relieves, or reduces pain, including, but not limited to, methocarbamol, baclofen, nonsteroidal anti-inflammatory drugs (NSAIDs), and / or opioid medications.

[0072] According to the present invention, a suitable anti-inflammatory agent refers to a pharmaceutical agent that can reduce or eliminate inflammation or inflammatory responses in the body, such as, but not limited to, COX-2 inhibitors (coxibs), nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, naproxen or ibuprofen, and / or corticosteroids such as cortisol, cortisone, prednisone and prednisolone.

[0073] In particular, anti-sensitivity agents that can be added to oral tablets or capsules are any anti-allergy or anti-sensitivity (desensitizing) agents that are safe for human use. Examples include, but are not limited to, antihistamines and diphenhydramine hydrochloride.

[0074] In a preferred embodiment, the tablets, capsules or ampoules are used orally and / or by injection as a supplement and / or medicine.

[0075] In various embodiments, the oral and / or injectable tablets, capsules, or ampoules are antioxidant preparations / supplements / medicines, anti-cancer preparations / supplements / medicines, vitamin preparations / supplements / medicines, analgesic preparations / supplements / medicines, anti-inflammatory preparations / supplements / medicines, and / or anti-sensitivity preparations / supplements / medicines.

[0076] In various embodiments, the oral and / or injectable tablets, capsules or ampoules may contain additional ingredients known to those skilled in the art and commonly used in such formulations, such as one or more adjuvants.

[0077] For example, the tablets, capsules, or ampoules (particularly tablets or capsules) of the present invention may contain, but are not limited to, the following excipients: particle carriers (e.g., zinc oxide, starch, starch derivatives); antioxidants (e.g., allicin, β-carotene, flavonoids, vitamin E, ascorbic acid and its derivatives); fillers (e.g., microcrystalline cellulose, sorbitol); and sweeteners (e.g., aspartame, acesulfame K, sucralose, saccharin, neotame, advantame, alitame, glucose, fructose, galactose, inulin, isomalt, sorbitol).

[0078] In various embodiments, the at least one additional ingredient is selected from the group consisting of binders, fillers, builders, complexing agents, preservatives, coating agents, alkaline agents, acidifying agents, sweeteners, colorants, buffers, acids and bases, or combinations thereof.

[0079] According to the present invention, the tablets, capsules or ampoules are administered orally and / or by injection, preferably to a subject in need thereof.

[0080] In a preferred embodiment, the subject is a mammal, particularly a human.

[0081] In a preferred embodiment, the tablets, capsules or ampoules according to the invention are for oral and / or injectable use in methods for treating (or preventing) the diseases described below. (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or (ii) an inflammatory response, preferably an inflammatory response in rheumatic diseases; and / or (iii) pain, preferably joint and / or muscle pain; and / or (iv) cancer, preferably breast cancer and prostate cancer; and / or (v) aging; and / or (vi) diabetes; and / or (vii) Heart disease, preferably arrhythmia.

[0082] The term "neurodegenerative disease" may include any pathological process that results in the loss of function and / or death of nerve cells. Neurodegenerative diseases include, but are not limited to, various forms of multiple sclerosis (MS), Alzheimer's disease, or amyotrophic lateral sclerosis (ALS). In particular, neurodegenerative diseases include MS and Alzheimer's disease.

[0083] The oral and / or injectable tablets, capsules, or ampoules may treat or prevent any type of "cancer." As used herein, "cancer" preferably includes cancers characterized by abnormal cell proliferation and manifesting as tumor formation, particularly cancers of epithelial origin. The term encompasses cancers localized within a tumor, as well as cancers not localized within a tumor, such as cancer cells that locally grow back from a tumor. In various embodiments, the present invention is applicable as a general (systemic) and / or local control agent for tumor growth, such as bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, and gastric cancer, and as a therapeutic agent for sarcoma (e.g., fibrosarcoma or rhabdomyosarcoma), lymphoid or myeloid hematopoietic tumors, or other tumors, including, but not limited to, malignant melanoma, malignant teratoma, neuroblastoma, or glioma.

[0084] In a preferred embodiment, the cancer includes, but is not limited to, leukemia, seminoma, malignant melanoma, teratoma, glioma and / or colon cancer, rectal cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, pharyngeal cancer, nasal cancer, ear (ENT) cancer, kidney cancer, adrenal cancer, thyroid cancer, lymph node cancer, breast cancer, prostate cancer, uterine cancer, ovarian cancer, endometrial cancer, liver cancer, pancreatic cancer, skin cancer, brain cancer, lung cancer and metastatic cancers thereof, preferably breast cancer and / or prostate cancer. In the context of the present invention, the term "aging" refers to both visible and invisible types of aging phenomena in the body of a subject. In various embodiments, oral and / or injectable tablets, capsules, or ampoules are used to treat, prevent, or reduce wrinkles, fine lines, and sagging skin, and / or to provide the body with the appropriate nutrients to treat, prevent, or reduce, for example, aging phenomena and processes of the body or body cells.

[0085] In the context of the present invention, "heart disease" may refer to any disease or disorder of the heart, preferably arrhythmia.

[0086] In various embodiments, the tablet, capsule, or ampoule is an antioxidant tablet, capsule, or ampoule.

[0087] In another preferred embodiment, the (antioxidant) tablets, capsules or ampoules of the present invention are used to treat the following diseases: (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or (ii) an inflammatory response, preferably an inflammatory response in rheumatic diseases; and / or (iii) pain, preferably joint and / or muscle pain; and / or (iv) cancer, preferably breast cancer and prostate cancer; and / or (v) aging; and / or (vi) diabetes; and / or (vii) heart disease, preferably arrhythmia In a method for treating (or preventing) a disease, the compound is administered orally and / or by injection to a subject in need thereof.

[0088] In such embodiments, the tablet, capsule or ampoule preferably contains at least one additional supplement and / or drug as described above, preferably at least one antioxidant, anti-cancer agent, vitamin, multivitamin, (medicinal) mineral, (medicinal) multi-mineral, amino acid, fatty acid, herb, carbohydrate, analgesic, anti-inflammatory and anti-sensitivity agent or combinations thereof, but not limited to these.

[0089] In a further aspect, the present invention relates to a method for producing a tablet, capsule or ampoule according to the invention. Preferably, the tablet, capsule or ampoule is an oral and / or injectable tablet, capsule or ampoule as described herein.

[0090] According to the present invention, the tablets, capsules or ampoules obtained by the process of the present invention are (i) β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule, and / or 20% by weight to 60% by weight based on the total weight of the ampoule; and further containing caffeic acid or a salt thereof (e.g., in powder form) in a content of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salts, in a total amount of 10% to 99.999% by weight, based on the total weight of the tablet or capsule, and / or 20% to 60% by weight, based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in a content of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule; or (iii) A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronic acid, glumannuronate, or its oligomers, in a total amount of 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule, and / or 20% by weight to 60% by weight based on the total weight of the ampoule; and further containing caffeic acid or a salt thereof (e.g., in powder form) in a content of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule.

[0091] Preferably, the tablet, capsule or ampoule according to the invention comprises: The content is 30% to 99.999% by weight, more preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule; and / or The content is 30% by weight to 60% by weight, more preferably 40% by weight to 60% by weight, and more preferably 50% by weight to 60% by weight, based on the total weight of the ampoule. (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) Mixtures of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof. In various embodiments, the methods of the present invention include adding caffeic acid and / or β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate) and / or α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably α-L-guluronic acid) in powder form.

[0092] The resulting tablet, capsule, or ampoule is a glumannuronate tablet, capsule, or ampoule. In an embodiment, the tablet or capsule preferably contains, based on the total weight of the tablet or capsule, 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, more preferably 0.05% to 0.3% by weight of caffeic acid, 0.01% to 99.99% by weight of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof. and 0.01% by weight to 99.99% by weight of α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, provided that the total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof and α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof in the tablet or capsule is 10% by weight or more and 99.999% by weight or less, based on the total weight of the tablet or capsule, and preferably The total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% by weight to 99.9% by weight, more preferably 1% by weight to 99% by weight, and more preferably 10% by weight to 90% by weight, based on the total weight of the tablet or capsule; and The total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is 0.1% to 99.9% by weight, more preferably 1% to 99% by weight, and more preferably 10% to 90% by weight, based on the total weight of the tablet or capsule.

[0093] In various embodiments in which the resulting tablet, capsule or ampoule is a glumannuronate tablet, capsule or ampoule, the ampoule preferably comprises or consists of 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, more preferably 0.05% to 0.3% by weight of caffeic acid, 0.01% to 59.99% by weight of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, and 0.01% to 59.99% by weight of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, based on the total weight of the ampoule, with the proviso that the combined amount of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof in the ampoule is between 20% and 60% by weight, based on the total weight of the ampoule, and preferably The total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% by weight to 59.9% by weight, more preferably 1% by weight to 59% by weight, more preferably 10% by weight to 50% by weight, and more preferably 20% by weight to 40% by weight, based on the total weight of the ampoule; and The total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is 0.1% by weight to 59.9% by weight, preferably 1% by weight to 59% by weight, more preferably 10% by weight to 50% by weight, and more preferably 20% by weight to 40% by weight, based on the total weight of the ampoule.

[0094] In various embodiments, alginate hydrolysate (powder) (as a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof) can be used in gulumannuronate tablets, capsules, or ampoules. Preferably, the total amount of alginate hydrolysate (powder) used is: In tablets or capsules, the content is 30% to 99.999% by weight, more preferably 40% to 99.999% by weight, more preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule; and / or In ampoules, the content is 30% by weight to 60% by weight, preferably 40% by weight to 60% by weight, and more preferably 50% by weight to 60% by weight, based on the total weight of the ampoules.

[0095] In various embodiments, the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, is selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, and combinations thereof, and / or sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate, and combinations thereof, with sodium β-D-mannuronate and / or sodium oligomannuronate being particularly preferred in mannuronate tablets, capsules, or ampoules.

[0096] In various embodiments, the α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably α-L-guluronic acid, is selected from the group consisting of sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, ammonium α-L-guluronic acid, and combinations thereof, and / or sodium oligoguluronic acid, potassium oligoguluronic acid, magnesium oligoguluronic acid, calcium oligoguluronic acid, ammonium oligoguluronic acid, and combinations thereof, with sodium α-L-guluronic acid and / or sodium oligoguluronic acid being particularly preferred in guluronic acid tablets, capsules, or ampoules.

[0097] In various embodiments, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate and α-L-guluronic acid salts, is selected from the group consisting of sodium β-D-mannuronate or potassium β-D-mannuronate or magnesium β-D-mannuronate or calcium β-D-mannuronate or ammonium β-D-mannuronate and sodium α-L-guluronic acid or potassium α-L-guluronic acid or magnesium α-L-guluronic acid or calcium α-L-guluronic acid or ammonium α-L-guluronic acid, and combinations thereof, and / or oligomers thereof; Preferably, these homo-oligomers consist of sodium oligomannuronate or potassium oligomannuronate or magnesium oligomannuronate or calcium oligomannuronate or ammonium oligomannuronate and sodium oligoguluronic acid or potassium oligomannuronate or magnesium oligoguluronic acid or calcium oligoguluronic acid or ammonium oligoguluronic acid, and combinations thereof, and in glumannuronate tablets, capsules or ampoules, preferably sodium β-D-mannuronate, sodium α-L-guluronic acid, sodium oligomannuronate and sodium oligoguluronic acid, and combinations thereof. In particular, the oligomannuronate or oligoguluronic acid salt comprises 2 to 16 β-D-mannuronic acid or α-L-guluronic acid monomers, preferably 3 to 6 β-D-mannuronic acid or α-L-guluronic acid monomers, for example 3 or 4 or 5 or 6 β-D-mannuronic acid or α-L-guluronic acid monomers.

[0098] In a preferred embodiment, the tablet, capsule or ampoule obtained by the method of the present invention may contain at least one additional supplement and / or at least one additional drug, preferably selected from the group consisting of antioxidants, anti-cancer agents, vitamins, multivitamins, (medicinal) minerals, (medicinal) multiminerals, amino acids, fatty acids, herbs, carbohydrates, analgesics, anti-inflammatory agents and anti-sensitivity agents, or combinations thereof, as described above, but are not limited thereto.

[0099] Therefore, preferably, in various embodiments, the method of the present invention is a method for producing, but is not limited to, antioxidant tablets, capsules or ampoules; anti-cancer tablets, capsules or ampoules; anti-aging tablets, capsules or ampoules; analgesic tablets, capsules or ampoules; and anti-inflammatory tablets, capsules or ampoules; and / or anti-sensitivity tablets, capsules or ampoules; or combinations thereof.

[0100] The tablets, capsules or ampoules obtainable by the process according to the invention may further comprise at least one additional ingredient, such as one or more of the adjuvants described herein.

[0101] All embodiments and examples described herein relating to oral and / or injectable tablets, capsules or ampoules according to the invention also apply to oral and / or injectable tablets, capsules or ampoules in methods for treating neurodegenerative diseases, inflammatory responses, pain, cancer, ageing, diabetes and / or heart disease, and to methods for producing such formulations, and vice versa.

[0102] Other embodiments are included in the non-limiting examples below. [Example]

[0103] 1. Method for producing powders of mannuronic acid, guluronic acid and glumannuronate from sodium alginate Mannuronic acid, guluronic acid and glumannuronate were synthesized according to WHO GMP standards for the production of substances.

[0104] Sodium alginate (sodium alginate) was used to synthesize β-D-mannuronic acid, α-L-guluronic acid, and glumannuronate (alginate hydrolysate). First, sodium alginate (100 g) was slowly dissolved in 1500 mL of 20% sulfuric acid at 0 °C. After thorough stirring at room temperature, the solution was heated to 85 °C until the color changed from cream to light brown. The hydrolysate was cooled to room temperature and the precipitate was separated by centrifugation (3700 g). This precipitate was used as glumannuronic acid / glumannuronate (alginate hydrolysate). The precipitate was neutralized and redissolved in 1 M Na2CO3 solution. The pH of the solution was then adjusted to 2.85 with 0.5 M HCl, and the precipitate was again separated by centrifugation (3700 g). The precipitate was collected and washed once with distilled water. The precipitate (α-L-guluronic acid) was spread on a Petri dish and dried to obtain powdered α-L-guluronic acid. This powder can be used to prepare guluronic acid tablets, capsules, or ampoules, and / or a mixture of β-D-mannuronic acid and α-L-guluronic acid for glumannuronate tablets, capsules, or ampoules. The remaining supernatant of the L-guluronic acid precipitate was collected and its pH adjusted to 1.0 with 0.5 M HCl. After centrifugation (3700 g), the precipitate was collected and washed once with distilled water. The resulting precipitate (β-D-mannuronic acid) was spread on a Petri dish and dried to obtain powdered β-D-mannuronic acid. This powder can be used to prepare mannuronate tablets, capsules, or ampoules, and / or a mixture of β-D-mannuronic acid and α-L-guluronic acid for glumannuronate tablets, capsules, or ampoules. Fourier transform infrared (FT-IR) spectroscopy and carbon-13 nuclear magnetic resonance ( 13 The properties and purity of α-L-guluronic acid and β-D-mannuronic acid were verified by C-NMR spectroscopy.

[0105] The resulting powders (mannuronic acid) and (guluronic acid) were stored under sterile conditions in a dry place at room temperature (22-26°C) for the production of tablets, capsules or ampoules for oral and / or injectable use.

[0106] 2. Preparation of tablets or capsules containing mannuronic acid powder, guluronic acid powder, or a combination of glumannuronic acid powder and caffeic acid powder To prepare tablets or capsules containing a combination of caffeic acid and mannuronic acid / mannuronate, guluronic acid / guluronic acid, or glumannuronic acid / glumannuronate, 0.03 g (30 mg) of caffeic acid powder was added to 10 g of β-D-mannuronic acid powder, α-L-guluronic acid powder, or a mixture thereof (glumannuronate powder), and the powders were preferably compressed into tablets.

Claims

1. (i) β-D-mannuronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) Oral and / or injectable tablets, capsules or ampoules containing a mixture of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof and α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof, preferably glumannuronate, the total amount of β-D-mannuronic acid or α-L-guluronic acid or a mixture thereof, an oligomer thereof, or a pharmaceutically acceptable salt thereof is 10% to 99.999% by weight based on the total weight of the tablet or capsule, or 20% to 60% by weight based on the total weight of the ampoule; The tablet, capsule, or ampoule for oral and / or injection further contains caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, and the content of the caffeic acid or a salt thereof is preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule.

2. The formulation comprises: (i) β-D-mannuronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof with α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate; the total amount of β-D-mannuronic acid or α-L-guluronic acid, or a mixture thereof, an oligomer thereof, or a pharmaceutically acceptable salt thereof is 10% by weight to 99.999% by weight based on the total weight of the tablet or capsule; The tablet or capsule for oral and / or injectable use, preferably for oral use, according to claim 1, further comprising caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, and the content of the caffeic acid or a salt thereof is preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight, based on the total weight of the tablet or capsule.

3. The formulation comprises: (i) β-D-mannuronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) a mixture of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof with α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronate; the total amount of β-D-mannuronic acid or α-L-guluronic acid, or a mixture thereof, an oligomer thereof, or a pharmaceutically acceptable salt thereof is 20% by weight to 60% by weight based on the total weight of the ampoule; 2. The ampoule for oral and / or injection, preferably for injection, according to claim 1, further comprising caffeic acid or a salt thereof, for example powdered caffeic acid or a salt thereof, and the content of the caffeic acid or a salt thereof is preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, more preferably 0.05% by weight to 0.3% by weight, based on the total weight of the ampoule.

4. (i) the β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is a β-D-mannuronate salt, preferably selected from the group consisting of sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, and combinations thereof, more preferably sodium β-D-mannuronate; or (ii) the α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is an α-L-guluronic acid salt, preferably selected from the group consisting of sodium α-L-guluronic acid, potassium α-L-guluronic acid, magnesium α-L-guluronic acid, calcium α-L-guluronic acid, ammonium α-L-guluronic acid, and combinations thereof, more preferably sodium α-L-guluronic acid; or (iii) a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably the glumannuronate is selected from the group consisting of sodium β-D-mannuronate or potassium β-D-mannuronate or magnesium β-D-mannuronate or calcium β-D-mannuronate or ammonium β-D-mannuronate and sodium α-L-guluronic acid or potassium α-L-guluronic acid or magnesium α-L-guluronic acid or calcium α-L-guluronic acid or ammonium α-L-guluronic acid, and combinations thereof, most preferably sodium β-D-mannuronate and / or sodium α-L-guluronic acid; or (iv) A tablet, capsule or ampoule according to any one of claims 1 to 3, characterized in that the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers or their pharmaceutically acceptable salts, preferably glumannuronate, is an alginate hydrolysate (powder).

5. 5. The tablet, capsule or ampoule according to claim 1, wherein the β-D-mannuronic acid and / or α-L-guluronic acid, oligomers thereof or pharmaceutically acceptable salts thereof are selected from oligomers of β-D-mannuronate and / or α-L-guluronic acid.

6. The oligomers of β-D-mannuronate and / or α-L-guluronic acid are (i) homo-oligomers of β-D-mannuronate and / or homo-oligomers of α-L-guluronic acid; (ii) selected from the group consisting of sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate or ammonium oligomannuronate, and / or sodium oligoguluronic acid, potassium oligoguluronic acid, magnesium oligoguluronic acid, calcium oligoguluronic acid or ammonium oligoguluronic acid, and combinations thereof, preferably sodium oligomannuronate and / or sodium oligoguluronic acid; and / or (iii) A tablet, capsule or ampoule according to claim 5, characterized in that it comprises or consists of 2 to 16 β-D-mannuronic acid monomers and / or 2 to 16 α-L-guluronic acid monomers.

7. The tablet, capsule, or ampoule according to any one of claims 1 to 6, wherein the total amount of the following ingredients in the tablet or capsule is 30% by weight to 99.999% by weight, preferably 50% by weight to 99.999% by weight, based on the total weight of the tablet or capsule; or the total amount of the following ingredients in the ampoule is 30% by weight to 60% by weight, preferably 40% by weight to 60% by weight, more preferably 50% by weight to 60% by weight, based on the total weight of the ampoule. (i) β-D-mannuronic acid, an oligomer thereof, or a pharmaceutically acceptable salt thereof; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof; or (iii) A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof.

8. A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably a glumannuronate preparation, comprises or consists of 0.01% to 99.99% by weight of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and 0.01% to 99.99% by weight of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, provided that the total amount of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof in the tablet or capsule is 10% to 99.999% by weight based on the total weight of the tablet or capsule, and preferably The total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% to 99.9% by weight, more preferably 1% to 99% by weight, and more preferably 10% to 90% by weight, based on the total weight of the tablet or capsule; and 8. The tablet or capsule according to claim 7, wherein the total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is 0.1% to 99.9% by weight, preferably 1% to 99% by weight, and more preferably 10% to 90% by weight, based on the total weight of the tablet or capsule.

9. The mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably the glumannuronate preparation, comprises or consists of 0.01% by weight to 59.99% by weight of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts, and 0.01% by weight to 59.99% by weight of α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts, provided that the total amount of β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts and α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts in the ampoule is 20% by weight or more and 60% by weight or less, based on the total weight of the ampoule, and preferably The total amount of β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% by weight to 59.9% by weight, more preferably 1% by weight to 59% by weight, more preferably 10% by weight to 50% by weight, and more preferably 20% by weight to 40% by weight, based on the total weight of the ampoule; and The ampoule according to claim 7, wherein the total amount of α-L-guluronic acid, its oligomer, or a pharmaceutically acceptable salt thereof is 0.1% by weight to 59.9% by weight, preferably 1% by weight to 59% by weight, more preferably 10% by weight to 50% by weight, and more preferably 20% by weight to 40% by weight, based on the total weight of the ampoule.

10. 10. The tablet, capsule or ampoule according to any one of claims 1 to 9, wherein the tablet, capsule or ampoule comprises at least one additional supplement and / or at least one additional drug, preferably wherein the tablet or capsule comprises at least one additional supplement and / or at least one additional drug, the additional supplement and / or additional drug being selected from the group consisting of antioxidants, anti-cancer drugs, vitamins, multivitamins, (medicinal) minerals, (medicinal) multiminerals, amino acids, fatty acids, herbs, carbohydrates, analgesics, anti-inflammatory agents and anti-sensitivity agents or combinations thereof.

11. 11. The tablet, capsule or ampoule according to any one of claims 1 to 10, further comprising at least one additional ingredient, preferably selected from the group consisting of binders, fillers, builders, complexing agents, preservatives, coating agents, alkaline agents, acidifying agents, sweeteners, colorants, acids and bases or combinations thereof.

12. The tablet, capsule or ampoule according to any one of claims 1 to 11, characterized in that the formulation is a supplement or a medicine, preferably an antioxidant tablet, capsule or ampoule.

13. Use of an oral and / or injectable tablet, capsule or ampoule according to any one of claims 1 to 12 in a method for treating (or preventing) the following diseases: (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or (ii) an inflammatory response, preferably an inflammatory response in rheumatic diseases; and / or (iii) pain, preferably joint and / or muscle pain; and / or (iv) cancer, preferably breast cancer and prostate cancer; and / or (v) aging; and / or (vi) diabetes; and / or (vii) Heart disease, preferably arrhythmia.

14. 14. A method for producing a tablet, capsule or ampoule, preferably an antioxidant tablet, capsule or ampoule, according to any one of claims 1 to 13, comprising the steps of: (i) β-D-mannuronic acid, its oligomer, or a pharmaceutically acceptable salt thereof, preferably β-D-mannuronate, in a total amount of 10% to 99.999% by weight based on the total weight of the tablet or capsule, or 20% to 60% by weight based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, in a content of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, more preferably 0.05% to 0.3% by weight based on the total weight of the tablet, capsule, or ampoule; or (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salts, in a total amount of 10% to 99.999% by weight, based on the total weight of the tablet or capsule, or 20% to 60% by weight, based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, in a content of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule; or (iii) A method characterized by comprising the step of providing a composition comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably glumannuronic acid, glumannuronate, or their oligomers, in a total amount of 10% by weight to 99.999% by weight, based on the total weight of the tablet or capsule, or 20% by weight to 60% by weight, based on the total weight of the ampoule; and further comprising caffeic acid or a salt thereof, for example, powdered caffeic acid or a salt thereof, in a content of preferably 0.001% by weight to 1% by weight, more preferably 0.01% by weight to 0.5% by weight, and more preferably 0.05% by weight to 0.3% by weight, based on the total weight of the tablet, capsule, or ampoule.

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