Mannuronate, guluronate and guluronate tablet, capsule or ampoule preparation and preparation method thereof

Abstract

The present invention relates to tablet, capsule and ampoule formulations for oral and / or injectable use, said formulations comprising beta-D-mannuronic acid or alpha-L-guluronic acid or a mixture of beta-D-mannuronic acid and alpha-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts, the total amount of [beta]-D-mannuronic acid or [alpha]-L-guluronic acid or mixtures thereof, oligomers thereof, or pharmaceutically acceptable salts thereof is from 10% to 99.999% by weight, based on the total weight of the tablet or capsule formulation, or from 20% to 60% by weight, based on the total weight of the ampoule formulation; the tablet, capsule or ampoule formulation further comprises caffeic acid or a salt thereof, for example in powder form, in an amount preferably from 0.001 wt% to 1 wt%, more preferably from 0.01 wt% to 0.5 wt%, more preferably from 0.05 wt% to 0.3 wt%, based on the total weight of the tablet, capsule or ampoule formulation. Furthermore, the present invention relates to the oral and / or injectable use of tablet, capsule and ampoule formulations, preferably as supplements or medicaments, for use in methods for the treatment of neurodegenerative diseases, inflammatory responses, pain, cancer, aging, diabetes and / or heart diseases, as well as to methods of preparing such formulations.

Description

Technical Field

[0001] The present invention relates to tablet, capsule and ampoule preparations for oral and / or injectable use, wherein the preparations contain 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 thereof, wherein the total amount of β-D-mannuronic acid or α-L-guluronic acid or their mixture, their oligomers, or pharmaceutically acceptable salts thereof is 10% to 99.999% by weight, based on the total weight of the tablet or capsule preparation, or 20% to 60% by weight, based on the total weight of the ampoule preparation; the tablet, capsule or ampoule preparation further contains caffeic acid or a salt thereof, the content of which is preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and even more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule or ampoule preparation. Furthermore, the present invention relates to tablet, capsule and ampoule formulations, preferably for oral and / or injectable use as supplements or medicaments in methods for treating neurodegenerative diseases, inflammatory reactions, pain, cancer, aging, diabetes and / or heart disease, as well as methods for preparing such formulations. Background Art

[0002] Mannuronic acid and guluronic acid are natural uronic acids isolated and purified from various forms of alginates (polymers used as thickeners, adhesives, gelling agents or lubricants). The source of alginates can be brown algae (such as Phaeophyceae and Laminaria) and / or bacteria belonging to the genera Pseudomonas and Azotobacter. The properties of alginates vary depending on their source. Alginates mainly exist in the form of sodium salts, calcium salts and ammonium salts. Their monomer structures (mannuronic acid and guluronic acid) and the differences in the distribution, ratio and length of these monomer blocks determine the chemical and physical properties of alginate polymers and oligomers.

[0003] Mannuronic acid and guluronic acid are diastereomers of each other. Therefore, many of the physicochemical and biological properties of these two molecules, such as the molecular formula (C6H 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 highly similar.

[0004] The therapeutic properties of mannuronic acid in various animal models were first reported in 2004. These findings revealed the therapeutic efficacy and tolerability of mannuronic acid in vitro and in vivo. Mirshafiey et al. reported the potent therapeutic effects of mannuronic acid 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). Subsequent studies have been conducted to address the safety profile, potential cellular, molecular, and immunological mechanisms, and therapeutic efficacy at the level of human clinical trials. The results of multiple studies and clinical trials have confirmed that mannuronic acid is very safe and has a wide range of therapeutic effects on a variety of diseases, such as rheumatoid arthritis, ankylosing spondylitis, breast cancer, multiple sclerosis, and myelodysplastic syndrome (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 patient", Inflammopharmacology 2018; 26(3): 737-745;Rezaieyazdi Z, Farooqi A, Soleymani-Salehabadi H, et al., "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, et al., "A controlled, randomized phase II clinical trial for efficacy and safety evaluation of mannuonic acid in secondary progressive form of multiple sclerosis", Int J Neurosci. 2022; 132(4): 403-412; Ghaderi A, Nodehi SRS, Bakhtiari T, et al., "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 published relevant research results in 2015 (Afraei S, Azizi G, Zargar SJ, Sedaghat R, and Mirshafiey A., "New therapeutic approach by G2013 in experimental model of multiple sclerosis", Acta Neurol Belg., September 2015, 115(3):259-66). In addition, the safety and pharmacological and toxicological properties of guluronic acid have been studied, as well as its clinical efficacy in treating inflammatory diseases.

[0006] These studies indicate that these two uronic acids not only share many physicochemical properties but also possess identical or similar biological and medical properties. Summary of the Invention

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

[0008] Thus, in a first aspect, the present invention relates to a tablet, capsule or ampoule formulation for oral and / or injectable use, said formulation comprising:

[0009] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0010] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0011] (iii) 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 guluromannuronate,

[0012] 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 preparation, and / or 20% to 60% by weight based on the total weight of the ampoule preparation.

[0013] The tablet, capsule or ampoule further contains caffeic acid or a salt thereof (e.g., in powder form), and the content is preferably 0.001 to 1 weight %, more preferably 0.01 to 0.5 weight %, and even more preferably 0.05 to 0.3 weight %, based on the total weight of the tablet, capsule or ampoule preparation.

[0014] In various embodiments, the tablet, capsule or ampoule preparation is for oral and / or injection use, preferably for oral use, and the preparation comprises:

[0015] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0016] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0017] (iii) 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 guluromannuronate,

[0018] 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 preparation.

[0019] The tablet or capsule preparation further comprises caffeic acid or a salt thereof, such as caffeic acid or a salt thereof in powder form, and the content thereof is preferably 0.001 to 1 weight %, more preferably 0.01 to 0.5 weight %, and even more preferably 0.05 to 0.3 weight %, based on the total weight of the tablet or capsule preparation.

[0020] In various embodiments, the tablet, capsule or ampoule preparation is an ampoule preparation for oral and / or injection use, preferably for injection use, and the preparation comprises:

[0021] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0022] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0023] (iii) 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 guluromannuronate,

[0024] 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% to 60% by weight based on the total weight of the ampoule preparation.

[0025] The ampoule preparation further comprises caffeic acid or a salt thereof, such as caffeic acid or a salt thereof in powder form, with the content being preferably 0.001 to 1 wt %, more preferably 0.01 to 0.5 wt %, and even more preferably 0.05 to 0.3 wt %, based on the total weight of the ampoule preparation.

[0026] Preferably,

[0027] (i) β-D-mannuronate, its oligomers, or pharmaceutically acceptable salts thereof are β-D-mannuronates, more preferably selected from 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

[0028] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof are α-L-guluronates, more preferably selected from sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate or ammonium α-L-guluronate and combinations thereof, more preferably sodium α-L-guluronate.

[0029] In embodiments where a mixture of β-D-mannuronic acid and α-L-guluronic acid, their respective oligomers, or their respective pharmaceutically acceptable salts is used, the active (drug) agent may be gulaumannuronate;

[0030] Preferably, β-D-mannuronate and α-L-guluronate, their oligomers, or pharmaceutically acceptable salts thereof are mixed, and are preferably selected from sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate or ammonium β-D-mannuronate and sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate or ammonium α-L-guluronate and combinations thereof, most preferably sodium β-D-mannuronate and / or sodium α-L-guluronate; or

[0031] A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof (preferably guluromannuronate) is an alginate hydrolyzate (powder).

[0032] In various embodiments, the total amount of the following components in a tablet or capsule formulation is 30% to 100% by weight, preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule formulation, and / or the total amount of the following components in an ampoule formulation is 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, based on the total weight of the ampoule formulation:

[0033] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0034] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0035] (iii) a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof.

[0036] In various embodiments, the tablet, capsule, or ampoule formulation may further comprise at least one other supplement and / or medicament and / or at least one other ingredient, as described herein.

[0037] Preferably, the tablet, capsule or ampoule formulation is a supplement and / or a medicine. In various embodiments, the tablet, capsule or ampoule formulation is for oral and / or injectable use as the antioxidant described herein.

[0038] In a second aspect, the tablet, capsule or ampoule formulation is used for oral and / or injectable use in a method for treating (or preventing) the following:

[0039] (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or

[0040] (ii) an inflammatory response, preferably an inflammatory response in a rheumatic disease; and / or

[0041] (iii) pain, preferably joint and / or muscle pain; and / or

[0042] (iv) cancer, preferably breast cancer and prostate cancer; and / or

[0043] (v) aging; and / or

[0044] (vi) diabetes; and / or

[0045] (vii) heart disease, preferably arrhythmia.

[0046] In a third aspect, the present invention relates to a method for preparing the tablet, capsule or ampoule preparation of the present invention. Preferably, the tablet, capsule or ampoule preparation is an antioxidant tablet, capsule or ampoule preparation.

[0047] In various embodiments, the method is a method for preparing an antioxidant tablet, capsule or ampoule formulation, wherein the method comprises the following steps:

[0048] Provided are compositions comprising:

[0049] (a) comprising β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably β-D-mannuronate, in an amount of 10 to 100 wt% based on the total weight of the tablet or capsule preparation, and / or 20 to 60 wt% based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in an amount of preferably 0.001 to 1 wt%, more preferably 0.01 to 0.5 wt%, and even more preferably 0.05 to 0.3 wt%, based on the total weight of the tablet, capsule or ampoule preparation; or

[0050] (b) comprising α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salt, in an amount of 10 to 100 wt % based on the total weight of the tablet or capsule preparation, and / or 20 to 60 wt % based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in an amount of preferably 0.001 to 1 wt %, more preferably 0.01 to 0.5 wt %, more preferably 0.05 to 0.3 wt %, based on the total weight of the tablet, capsule or ampoule preparation; or

[0051] (c) comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably gulmanuronic acid, gulmanuronate or oligomers thereof, in an amount of 10 to 100 wt % based on the total weight of the tablet or capsule preparation, and / or 20 to 60 wt % based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in an amount of preferably 0.001 to 1 wt %, more preferably 0.01 to 0.5 wt %, and even more preferably 0.05 to 0.3 wt %, based on the total weight of the tablet, capsule or ampoule preparation.

[0052] These and other aspects, embodiments, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description and claims. Each feature of one aspect of the present invention may be applied to any other aspect of the present invention. Furthermore, the examples included herein are intended to illustrate and explain the present invention, not to limit it. In particular, the present invention is not limited to these examples. DETAILED DESCRIPTION

[0053] As used herein, "at least one" refers to more than one, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or more of the indicated substance. Similarly, as used herein, "more than one" refers to at least one, including 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. For a given substance, the term does not refer to the total number of molecules, but rather to the type of substance. For example, "at least one preservative" means that there may be one type of preservative or two or more different types of preservatives. For dosage, the term refers to the total amount of the indicated substance. For example, for a preservative, this means that the given dosage is the total amount of all preservatives in the composition / preparation.

[0054] As used herein, unless otherwise indicated, the singular forms "a," "an," and "the" include plural references. Thus, for example, reference to "an oligomer thereof" includes a plurality of oligomer molecules or oligomer types, for example, a mixture or combination of multiple oligomer types. Furthermore, unless otherwise indicated, references to plural forms, such as "an oligomer thereof" or "a pharmaceutically acceptable salt thereof," include references to the singular, for example, an oligomer or a salt.

[0055] Numerical values ​​without decimal places herein refer to the full value with one decimal place, for example, 99% means 99.0%, unless otherwise defined.

[0056] The term "about" in connection with numerical values ​​refers to a deviation of ±10%, preferably ±5%, relative to the given numerical value.

[0057] In the context of the present invention, the term "substantially free" is understood to mean that the content of the corresponding compound in the formulation is 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, wherein each content is ranked by decreasing preference. For example, 4% by weight is preferred over 5%, and 3% by weight is preferred over 4%.

[0058] All percentages given herein in connection with formulations are by weight (wt%) relative to the total weight of the corresponding formulation, unless expressly stated otherwise. Numerical ranges specified in the format "from x to y" include the specified values. If multiple preferred numerical ranges are specified in this format, it should be understood that all ranges generated by combining the different endpoints are also included.

[0059] Hereinafter, the term "tablet, capsule or ampoule preparation" is used to describe a tablet, capsule or ampoule preparation for oral and / or injectable use, preferably as a supplement and / or a medicine, in particular as an antioxidant.

[0060] The terms "tablet" and "tablet formulation" as well as "capsule" and "capsule formulation" are intended to encompass all types of solid dosage forms commonly used in the art, including lozenges, pills, film-coated tablets, compressed tablets and granules. These formulations are typically intended for oral administration.

[0061] In various embodiments, tablets are, for example, portioned powders, granules or matrices, compressed under pressure, preferably compressed powders. They may have any suitable shape and size, for example a biconvex shape.

[0062] In various embodiments, capsules, such as hard and soft capsules, microcapsules or enteric-coated capsules, can contain solid fillers, such as powders, granules, tablets or even smaller capsules, or liquid or pasty fillers, such as solutions, suspensions or emulsions. Preferably, the hard capsules contain solid fillers. The capsule coating can contain or consist of gelatin, cellulose, carrageenan, starch, glue or derivatives thereof or combinations thereof, but is not limited thereto.

[0063] 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.

[0064] In the context of the present invention, "ampoule preparation" is intended to encompass all types of injectable preparations commonly used in the art, for example, liquid or powder preparations in ampoule containers or vessels, preferably for oral and / or parenteral use, particularly for parenteral use. The ampoule container or vessel may be made of, but is not limited to, glass or plastic. If the preparation is a powder, it may be dissolved, for example, in water, before use. Ampoule preparations are typically intended for injection.

[0065] The preparation methods of tablets, capsules or ampoule preparations are known to those skilled in the art and can be prepared conventionally.

[0066] β-D-mannuronic acid has the following formula (I):

[0067]

[0068] α-L-guluronic acid has the following formula (II):

[0069]

[0070] Because mannuronic acid and guluronic acid are diastereomers, they share many physicochemical properties as well as biological and pharmaceutical characteristics, such as their role as antioxidants. Therefore, in the present invention, all concepts disclosed for β-D-mannuronic acid, its oligomers, or their pharmaceutically acceptable salts are also applicable to α-L-guluronic acid, its oligomers, or their pharmaceutically acceptable salts, or mixtures thereof, and vice versa.

[0071] Free radicals may play a role in various diseases, such as cancer, cardiovascular disease, atherosclerosis, arthritis, aging, depression, anxiety, and other conditions. These free radicals can be formed by the body itself during various metabolic processes, or they can be produced by harmful external influences, such as cigarette smoke, environmental toxins, or UV radiation from the sun. Antioxidants are substances that inhibit and / or reduce oxidation reactions. Oxidation is a chemical reaction that produces free radicals, triggering a chain reaction that can damage an organism's cells. Therefore, antioxidants can be used as both preventive and therapeutic agents.

[0072] According to the present invention, β-D-mannuronic acid or α-L-guluronic acid or a mixture thereof can be contained in a tablet, capsule or ampoule formulation in the form of a pharmaceutically acceptable salt. Preferably, these pharmaceutically acceptable salts are mannuronate, guluronate or a mixture thereof, more preferably β-D-mannuronate, α-L-guluronate or a mixture thereof (referred to as "gulomannuronate"). The counterion can be selected from sodium, potassium, magnesium, calcium, ammonium and other pharmaceutically acceptable cationic counterions.

[0073] Thus, in various embodiments, tablet, capsule or ampoule formulations for oral and / or injectable use may be:

[0074] (i) mannuronate tablets, capsules or ampoule preparations; or

[0075] (ii) guluronate tablets, capsules or ampoule preparations; or

[0076] (iii) Gulumannuronate tablet, capsule or ampoule preparation.

[0077] In various embodiments, the tablet, capsule, or ampoule formulation comprising β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof is a mannuronate tablet, capsule, or ampoule formulation. Specifically, in various embodiments, β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof may be β-D-mannuronate, more preferably selected from 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.

[0078] In various embodiments, β-D-mannuronate, preferably β-D-mannuronate, can also be added to the tablet, capsule or ampoule formulation in the form of a precursor selected from oligomers of β-D-mannuronate 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, especially sodium oligomannuronate.

[0079] In various embodiments, β-D-mannuronate, its oligomers, or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate) are selected from 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.

[0080] In various embodiments, the tablet, capsule, or ampoule preparation comprising α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is a guluronate tablet, capsule, or ampoule preparation. Specifically, in various embodiments, α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof may be α-L-guluronate, preferably selected from sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate, and combinations thereof, with sodium α-L-guluronate being particularly preferred.

[0081] In various embodiments, α-L-guluronic acid, preferably α-L-guluronate, can also be added to the tablet, capsule or ampoule preparation in the form of a precursor selected from oligomers of α-L-guluronic acid or α-L-guluronate, preferably (homo)oligomers of α-L-guluronate, in particular sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, ammonium oligoguluronate and combinations thereof, especially sodium oligoguluronate.

[0082] In various embodiments, α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof (preferably α-L-guluronate) are selected from sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate, sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, ammonium oligoguluronate, and combinations thereof, preferably sodium α-L-guluronate and / or sodium oligoguluronate.

[0083] In various embodiments, the tablet, capsule, or ampoule preparation comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof is a gulmanuronate tablet, capsule, or ampoule preparation. In particular, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts can be a mixture of β-D-mannuronate and α-L-guluronate, preferably selected from sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate or ammonium β-D-mannuronate or a combination thereof, and sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate or calcium α-L-guluronate, ammonium α-L-guluronate or a combination thereof, and particularly preferably a mixture of sodium β-D-mannuronate and sodium α-L-guluronate.

[0084] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, preferably guluromannuronate, can also be added to tablets, capsules or ampoule preparations in the form of a precursor selected from oligomers of β-D-mannuronic acid / β-D-mannuronate and / or α-L-guluronate, preferably β-D-mannuronic acid / β-D-mannuronate and / or oligomers of α-L-guluronate. (Homo)oligomers of α-L-guluronic acid / α-L-guluronate, in particular sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate, sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, ammonium oligoguluronate and combinations thereof, in particular sodium oligomannuronate and / or sodium oligoguluronate.

[0085] In various embodiments, β-D-mannuronic acid and / or α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof (preferably guluromannuronate) are selected from 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, oligomannuronate, Ammonium α-L-guluronate, sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate, sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, ammonium oligoguluronate and combinations thereof, preferably sodium β-D-mannuronate, sodium oligomannuronate, sodium α-L-guluronate, sodium oligoguluronate and combinations thereof.

[0086] In particular, the β-D-mannuronate oligomer or α-L-guluronate oligomer comprises 2 to 16 monomer units, preferably 3 to 6 monomer units, such as 3 or 4 or 5 or 6 monomer units.

[0087] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts (preferably guluronic acid salt) can be synthesized from sodium alginate and used in tablet, capsule or ampoule formulations in the form of an alginate hydrolysate (preferably an alginate hydrolysate powder, also referred to as guluronic acid salt). In particular, the alginate hydrolysate (guluronic acid salt) is a separated sodium alginate precipitate containing mannuronic acid / mannuronic acid salt and guluronic acid / guluronic acid salt. Therefore, in various embodiments, the tablet, capsule or ampoule preparation comprises or consists of: caffeic acid or a salt thereof (e.g., in powder form), 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 preparation; and alginate hydrolyzate (gulomannuronate), preferably,

[0088] In the tablet or capsule, the content of alginate hydrolysate (gulomannuronate) is 10 wt % to 99.999 wt %, more preferably 30 wt % to 99.999 wt %, more preferably 40 wt % to 99.999 wt %, more preferably 50 wt % to 99.999 wt %, based on the total weight of the tablet or capsule formulation, and / or

[0089] In the ampoule preparation, the content of alginate hydrolyzate (gulomannuronate) is 20% to 60% by weight, more preferably 30% to 60% by weight, more preferably 40% to 60% by weight, and more preferably 50% to 60% by weight, based on the total weight of the ampoule preparation.

[0090] Preferably, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts (preferably guluromannuronate) can be:

[0091] (1) A mixture of the individual ingredients β-D-mannuronic acid, its oligomers or their pharmaceutically acceptable salts (particularly β-D-mannuronate) (powder) and α-L-guluronic acid, its oligomers or their pharmaceutically acceptable salts (particularly α-L-guluronate) (powder); or

[0092] (2) Alginate hydrolyzate (powder).

[0093] In various embodiments, the total amount of the following components in a tablet or capsule formulation 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 formulation, and / or, in an ampoule formulation, the total amount of the following components 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 formulation:

[0094] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0095] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0096] (iii) a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof.

[0097] In various embodiments, the tablet or capsule, preferably the tablet, consists of:

[0098] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, and caffeic acid; or

[0099] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, and caffeic acid; or

[0100] (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 formulation contains no or substantially no other supplements, agents, and / or ingredients.

[0101] In one embodiment, the total amount of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof is: in a tablet or capsule formulation, preferably a mannuronate tablet or capsule formulation, from 20% to 99.999% by weight, preferably from 30% to 99.999% by weight, more preferably from 40% to 99.999% by weight, more preferably from 50% to 99.999% by weight, based on the total weight of the tablet or capsule formulation; or in an ampoule formulation, preferably a mannuronate ampoule formulation, from 30% to 60% by weight, preferably from 40% to 60% by weight, more preferably from 50% to 60% by weight, for example, 50% or 55% by weight, based on the total weight of the ampoule formulation.

[0102] In another embodiment, the total amount of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is: in a tablet or capsule preparation, preferably a guluronate tablet or capsule preparation, from 20% to 99.999% by weight, preferably from 30% to 99.999% by weight, more preferably from 40% to 99.999% by weight, more preferably from 50% to 99.999% by weight, based on the total weight of the tablet or capsule preparation; or in an ampoule preparation, preferably a guluronate ampoule preparation, from 30% to 60% by weight, preferably from 40% to 60% by weight, more preferably from 50% to 60% by weight, for example 50% or 55% by weight, based on the total weight of the ampoule preparation.

[0103] In another embodiment, the total amount of the mixture of β-D-mannuronic acid and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof is: in a tablet or capsule preparation, preferably a gulomonan salt tablet or capsule preparation, from 20% to 99.999% by weight, preferably from 30% to 99.999% by weight, more preferably from 40% to 99.999% by weight, more preferably from 50% to 99.999% by weight, based on the total weight of the tablet or capsule preparation; or in an ampoule preparation, preferably a gulomonan salt ampoule preparation, from 30% to 60% by weight, preferably from 40% to 60% by weight, more preferably from 50% to 60% by weight, for example, 50% or 55% by weight, based on the total weight of the ampoule preparation.

[0104] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably a guluromannuronate tablet or capsule formulation, preferably comprises or consists of: 0.01% by weight to 99.99% by weight of β-D-mannuronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof and 0.01% by weight to 99.99% by weight of α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, provided that, based on the total weight of the tablet or capsule formulation, the total amount of β-D-mannuronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof in the tablet or capsule formulation is at least 10% by weight and at most 99.999% by weight, preferably,

[0105] Based on the total weight of the tablet or capsule preparation, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1% to 99.9% by weight, more preferably 1% to 99% by weight, more preferably 10% to 90% by weight, and

[0106] Based on the total weight of the tablet or capsule preparation, 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.

[0107] In various embodiments, the weight ratio of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof to α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts 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.

[0108] In various embodiments, the mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts, preferably the guluromannuronate ampoule preparation, preferably 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, based on the total weight of the ampoule preparation, 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 preparation is at least 20% by weight and at most 60% by weight, preferably,

[0109] Based on the total weight of the ampoule preparation, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1% to 59.9% by weight, more preferably 1% to 59% by weight, more preferably 10% to 50% by weight, more preferably 20% to 40% by weight, and

[0110] Based on the total weight of the ampoule preparation, the total amount of α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1 wt % to 59.9 wt %, more preferably 1 wt % to 59 wt %, more preferably 10 wt % to 50 wt %, more preferably 20 wt % to 40 wt %.

[0111] In various embodiments, the weight ratio of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof to α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts 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.

[0112] According to the present invention, the tablet, capsule or ampoule preparation (especially the tablet or capsule preparation) contains caffeic acid or a salt thereof (e.g. in powder form), and the content is 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, for example 0.1 to 0.3% by weight, based on the total weight of the tablet, capsule or ampoule preparation (preferably based on the total weight of the tablet or capsule preparation).

[0113] Caffeic acid (3,4-dihydroxycinnamic acid, molecular formula C9H8O4) can be found in a variety of plants and foods. For example, coffee is the main source of caffeic acid in the human diet. However, it is also found in other foods, such as apples, pears, artichokes, and berries. In various embodiments, caffeic acid can be used in pharmaceuticals and / or supplements to enhance athletic performance, relieve exercise-related fatigue, and reduce weight. In particular, it has multiple benefits in humans, including antioxidant, anticancer, anti-inflammatory, neuroprotective, and photoprotective effects. Caffeic acid is commercially available, for example from Sigma Aldrich, or it can be isolated from coffee or other food sources.

[0114] Preferably, the formulation of the present invention can be used as an antioxidant drug or supplement.

[0115] In various embodiments, the tablet, capsule or ampoule formulation of the present invention may contain β-D-mannuronic acid or α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts or mixtures thereof (preferably β-D-mannuronate or α-L-guluronate or mixtures thereof) and caffeic acid, as well as other (preferably chemically pure) supplements, agents, drugs and / or herbs.

[0116] In various embodiments, the tablet, capsule, or ampoule formulation comprises at least one other supplement and / or pharmaceutical agent.

[0117] Supplements are nutrients that can be added, inter alia, to the medicaments or formulations of the present invention. In various embodiments, supplements are intended to supplement the diet of a subject in order to provide optimal nutrition for the body.

[0118] The pharmaceutical agent is preferably the active ingredient in a drug or formulation that is responsible for its pharmacological action.

[0119] In various embodiments, including but not limited to, at least one other supplement and / or at least one other pharmaceutical agent, particularly for tablet or capsule formulations, is selected from antioxidants, anticancer agents, vitamins, multivitamins, (pharmaceutical) minerals, (pharmaceutical) multiminerals, amino acids, fatty acids, herbs, carbohydrates, analgesics, anti-inflammatory agents and agents with anti-allergic properties or combinations thereof, but not limited thereto.

[0120] Suitable other antioxidants (from food) are, for example, beta-carotene, OPC, resveratrol, flavonoids, lycopene, anthocyanidins, zeaxanthin, chlorophyll and / or allicin, but are not limited thereto. Other suitable antioxidants may be thiols.

[0121] Vitamins that may be used as other supplements and / or medicaments are, for example, vitamin A, vitamin C, vitamin D, vitamin E or vitamin K (2), but are not limited thereto.

[0122] For example, the anticancer agent is curcumin, paclitaxel, or selenium, but is not limited thereto.

[0123] Suitable pharmaceutically acceptable minerals include, but are not limited to, calcium carbonate, calcium citrate, calcium malate, magnesium glycinate, magnesium citrate, magnesium gluconate, magnesium lactate, phosphorus-based substances, sodium chloride and / or potassium chloride.

[0124] In the context of the present invention, analgesics are defined as drugs that eliminate, relieve or reduce pain. Examples are, but are not limited to, methocarbamol, baclofen, nonsteroidal anti-inflammatory drugs (NSAIDs) and / or opioids.

[0125] According to the present invention, suitable anti-inflammatory agents refer to drugs that can reduce or eliminate inflammation or inflammatory reactions in the body, such as non-steroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors (coxibs), diclofenac, naproxen or ibuprofen, and / or corticosteroids, such as Cortisol, cortisone, prednisone and prednisolone, but are not limited to these.

[0126] Agents with anti-allergic properties, particularly those that can be added to tablet or capsule formulations for oral use, are safe anti-allergic or anti-allergic (desensitization) agents for human use, such as, but not limited to, antihistamines and diphenhydramine hydrochloride.

[0127] In a preferred embodiment, the tablet, capsule or ampoule formulation is used orally and / or by injection as a supplement and / or medicine.

[0128] In various embodiments, the tablet, capsule or ampoule formulation for oral and / or injectable use is an antioxidant formulation / supplement / drug, an anti-cancer formulation / supplement / drug, a vitamin formulation / supplement / drug, an analgesic formulation / supplement / drug, an anti-inflammatory formulation / supplement / drug, and / or a formulation / supplement / drug with anti-allergic properties.

[0129] In various embodiments, tablet, capsule or ampoule formulations for oral and / or injectable use may contain other ingredients, such as auxiliary agent(s) known to those skilled in the art and commonly used in such formulations.

[0130] For example, the following excipients can be used in the tablet, capsule or ampoule preparations (especially tablet or capsule preparations) of the present invention, but are not limited to these: particulate 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); sweeteners (e.g., aspartame, acesulfame potassium, sucralose, saccharin, neotame, advantame, alitame, glucose, fructose, galactose, inulin, isomalt, sorbitol).

[0131] In various embodiments, the at least one additional ingredient is selected from binders, fillers, builders, complexing agents, preservatives, coating agents, alkaline agents, acidulants, sweeteners, colorants, buffers, acids and bases, or combinations thereof.

[0132] According to the present invention, the tablet, capsule or ampoule formulation is administered orally and / or by injection, preferably to a subject in need thereof.

[0133] In a preferred embodiment, the subject is a mammal, particularly a human.

[0134] In a preferred embodiment, the tablet, capsule or ampoule formulation of the present invention is used for oral and / or injectable use in the following methods of treating (or preventing):

[0135] (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or

[0136] (ii) an inflammatory response, preferably an inflammatory response in a rheumatic disease; and / or

[0137] (iii) pain, preferably joint and / or muscle pain; and / or

[0138] (iv) cancer, preferably breast cancer and / or prostate cancer; and / or

[0139] (v) aging; and / or

[0140] (vi) diabetes; and / or

[0141] (vii) heart disease, preferably arrhythmia.

[0142] The term "neurodegenerative disease" may encompass all pathological processes that result in loss of nerve cell function and / or death. 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.

[0143] Tablets, capsules or ampoule formulations for oral and / or injection use can be used to treat or prevent any type of "cancer". As used herein, "cancer" preferably includes cancer (particularly cancer of epithelial origin), which is characterized by abnormal cell proliferation, which may manifest as tumor formation. The term covers cancers located within the tumor, as well as cancers that are not located within the tumor, such as cancer cells that undergo local reverse expansion from the tumor. In various embodiments, the present invention can be used 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, as well as sarcomas (such as fibrosarcoma or rhabdomyosarcoma), lymphoid or myeloid hematopoietic tumors or other tumors (including but not limited to melanoma, teratoma, neuroblastoma or glioma). Treatment.

[0144] In a preferred embodiment, the cancer includes, but is not limited to, leukemia, seminoma, 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 metastases thereof, preferably breast cancer and / or prostate cancer.

[0145] The term "aging" in the context of the present invention refers to any type of visible and invisible aging phenomenon of a subject's body. In various embodiments, the tablet, capsule, or ampoule formulation for oral and / or injectable use is used to treat, prevent, or reduce wrinkles, fine lines, and sagging skin and / or, for example, to provide the body with appropriate nutrients to treat, prevent, or reduce the aging phenomena and processes of the body or body cells.

[0146] "Heart disease" in the context of the present invention may refer to any heart disease or disorder, preferably arrhythmia.

[0147] In various embodiments, the tablet, capsule, or ampoule formulation is an antioxidant tablet, capsule, or ampoule formulation.

[0148] In other preferred embodiments, the (antioxidant) tablet, capsule or ampoule formulation of the present invention is administered orally and / or by injection to a subject in need thereof in a method for treating (or preventing) the following:

[0149] (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or

[0150] (ii) an inflammatory response, preferably an inflammatory response in a rheumatic disease; and / or

[0151] (iii) pain, preferably joint and / or muscle pain; and / or

[0152] (iv) cancer, preferably breast cancer and / or prostate cancer; and / or

[0153] (v) aging; and / or

[0154] (vi) diabetes; and / or

[0155] (vii) heart disease, preferably arrhythmia.

[0156] In such embodiments, the tablet, capsule or ampoule formulation preferably comprises at least one additional supplement and / or agent as described above, preferably at least one antioxidant, anticancer agent, vitamin, multivitamin, (pharmaceutical) mineral, (pharmaceutical) multimineral, amino acid, fatty acid, herb, carbohydrate, analgesic, anti-inflammatory agent and agent with anti-allergic properties or a combination thereof, but not limited thereto.

[0157] In another aspect, the present invention relates to a method for preparing the tablet, capsule or ampoule formulation of the present invention. Preferably, the tablet, capsule or ampoule formulation is a tablet, capsule or ampoule formulation for oral and / or injection use as described herein.

[0158] According to the present invention, the tablet, capsule or ampoule preparation obtained by the method of the present invention comprises:

[0159] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts 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 preparation, and / or 20% to 60% by weight, based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in an amount of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and even more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule or ampoule preparation; or

[0160] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salt, in a total amount of 10% to 99.999% by weight, based on the total weight of the tablet or capsule formulation, and / or 20% to 60% by weight, based on the total weight of the ampoule formulation; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in an amount 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 formulation; or

[0161] (iii) a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably gulmanuronic acid, gulmanuronate or oligomers thereof, in an amount of 10% to 99.999% by weight, based on the total weight of the tablet or capsule preparation, and / or 20% to 60% by weight, based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof (e.g., in powder form), in an amount of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and even more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule or ampoule preparation.

[0162] Preferably, the tablet, capsule or ampoule preparation of the present invention comprises:

[0163] (i) β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0164] (ii) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, or

[0165] (iii) 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,

[0166] 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 formulation, and / or

[0167] The content is 30 to 60 weight %, more preferably 40 to 60 weight %, more preferably 50 to 60 weight %, based on the total weight of the ampoule preparation.

[0168] In various embodiments, in the method of the present invention, caffeic acid and / or β-D-mannuronic acid, oligomers thereof or pharmaceutically acceptable salts thereof (preferably β-D-mannuronate) and / or α-L-guluronic acid, oligomers thereof or pharmaceutically acceptable salts thereof (preferably α-L-guluronate) are added in powder form.

[0169] In the embodiment where the obtained tablet, capsule or ampoule preparation is a gulaumannuronate tablet, capsule or ampoule preparation, the tablet or capsule preparation preferably comprises or consists of: based on the total weight of the tablet or capsule preparation, 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 and 0.01% to 99.99% by weight of β-D-mannuronic acid, its oligomers or its % to 99.99% by weight of α-L-guluronic acid, its oligomers or their pharmaceutically acceptable salts, provided that, based on the total weight of the tablet or capsule preparation, 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 tablet or capsule preparation is at least 10% by weight and at most 99.999% by weight, preferably,

[0170] Based on the total weight of the tablet or capsule preparation, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1% to 99.9% by weight, more preferably 1% to 99% by weight, more preferably 10% to 90% by weight, and

[0171] Based on the total weight of the tablet or capsule preparation, the total amount of α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1 to 99.9 weight %, more preferably 1 to 99 weight %, and even more preferably 10 to 90 weight %.

[0172] In various embodiments in which the obtained tablet, capsule or ampoule preparation is a gulaumannuronate tablet, capsule or ampoule preparation, the ampoule preparation preferably comprises or consists of: based on the total weight of the ampoule preparation, 0.001 wt% to 1 wt%, more preferably 0.01 wt% to 0.5 wt%, more preferably 0.05 wt% to 0.3 wt% of caffeic acid and 0.01 wt% to 59.99 wt% of β-D-mannuronic acid, low-dose thereof % to 59.99% by weight of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof and α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof, provided that, based on the total weight of the ampoule preparation, 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 ampoule preparation is at least 20% by weight and at most 60% by weight, preferably,

[0173] Based on the total weight of the ampoule preparation, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1% to 59.9% by weight, more preferably 1% to 59% by weight, more preferably 10% to 50% by weight, more preferably 20% to 40% by weight, and

[0174] Based on the total weight of the ampoule preparation, the total amount of α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1% to 59.9% by weight, preferably 1% to 59% by weight, more preferably 10% to 50% by weight, and more preferably 20% to 40% by weight.

[0175] In various embodiments, alginate hydrolyzate (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 guluronic acid tablets, capsules or ampoule preparations. Preferably, the total amount of alginate hydrolyzate (powder) used is:

[0176] In a tablet or capsule preparation, based on the total weight of the tablet or capsule preparation, the amount is 30% to 99.999% by weight, more preferably 40% to 99.999% by weight, more preferably 50% to 99.999% by weight, and / or

[0177] In the ampoule preparation, the total amount is 30 to 60 wt %, preferably 40 to 60 wt %, more preferably 50 to 60 wt %, based on the total weight of the ampoule preparation.

[0178] In various embodiments, β-D-mannuronate, its oligomers or pharmaceutically acceptable salts 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, among which sodium β-D-mannuronate and / or sodium oligomannuronate are particularly preferred in the form of mannuronate tablets, capsules or ampoule preparations.

[0179] In various embodiments, α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof, preferably α-L-guluronate, is selected from the group consisting of sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate and combinations thereof, and / or sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, ammonium oligoguluronate and combinations thereof, among which sodium α-L-guluronate and / or sodium oligoguluronate are particularly preferred in guluronate tablets, capsules or ampoule preparations.

[0180] In various embodiments, a mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or their pharmaceutically acceptable salts, preferably β-D-mannuronate and α-L-guluronate, is 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 sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, or ammonium α-L-guluronate, and Combinations, and / or their oligomers, preferably homopolymers thereof consisting of sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate, ammonium oligomannuronate, and sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate, ammonium oligoguluronate, and combinations thereof, wherein sodium β-D-mannuronate, sodium α-L-guluronate, sodium oligomannuronate, sodium oligoguluronate, sodium oligoguluronate, and combinations thereof are preferred in guluromannuronate tablets, capsules, or ampoule preparations.

[0181] In particular, the oligomannuronate or oligoguluronate 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, such as 3 or 4 or 5 or 6 β-D-mannuronic acid or α-L-guluronic acid monomers.

[0182] In a preferred embodiment, the tablet, capsule or ampoule preparation obtained by the process of the present invention may contain at least one other supplement and / or at least one other pharmaceutical agent, preferably selected from antioxidants, anticancer agents, vitamins, multivitamins, (pharmaceutical) minerals, (pharmaceutical) multiminerals, amino acids, fatty acids, herbs, carbohydrates, analgesics, anti-inflammatory agents and agents with anti-allergic properties or combinations thereof, but not limited to these, as described above.

[0183] Therefore, preferably, the method of the present invention is a method for preparing the following in various embodiments: antioxidant tablets, capsules or ampoule preparations, anti-cancer tablets, capsules or ampoule preparations, anti-aging tablets, capsules or ampoule preparations, analgesic tablets, capsules or ampoule preparations, and anti-inflammatory tablets, capsules or ampoule preparations, and / or tablets, capsules or ampoule preparations with anti-allergic properties, or combinations thereof, but not limited to these.

[0184] The tablet, capsule or ampoule preparation obtained by the process of the present invention may further comprise at least one other ingredient, for example, one or more auxiliary agents described herein.

[0185] All embodiments and examples described herein for the tablet, capsule or ampoule formulations for oral and / or injectable use of the present invention are also applicable to the tablet, capsule or ampoule formulations for oral and / or injectable use in methods for treating neurodegenerative diseases, inflammatory reactions, pain, cancer, aging, diabetes and / or heart disease, and methods for preparing such formulations, and vice versa.

[0186] Other embodiments are described in the following non-limiting examples.

[0187] Example

[0188] 1. A method for preparing mannuronic acid, guluronic acid and guluronic acid salt powders from sodium alginate.

[0189] Mannuronic acid, guluronic acid and guluronic acid salt were synthesized according to the WHO GMP standards for material production.

[0190] In order to synthesize "β-D-mannuronic acid", "α-L-guluronic acid" and "gulomannuronic acid salt (alginate hydrolysate)", sodium alginate salt (sodium alginate) was used. In the first step, sodium alginate (100 g) was gently dissolved in 1500 mL of 20% sulfuric acid at 0°C. The solution was stirred thoroughly at room temperature and then heated to 85°C until its color changed from cream to light brown. The hydrolyzate was cooled to room temperature and the precipitate was separated by centrifugation (3700 g). The precipitate can be used as gulomannuronic acid / gulomannuronic acid salt (alginate hydrolysate). The precipitate was redissolved by neutralizing it with 1 M Na2CO3 solution. The pH of the solution was then adjusted to 2.85 with 0.5 M HCl and the precipitate was separated again by centrifugation (3700 g). The precipitate was collected and washed once with distilled water. The precipitate (α-L-guluronic acid) is spread in a petri dish and dried to obtain α-L-guluronic acid in powder form. This powder can be used in guluronate tablets, capsules, or ampoule formulations, and / or in a mixture of β-D-mannuronic acid and α-L-guluronic acid in gulomomannuronic acid tablets, capsules, or ampoule formulations. The remaining supernatant of the L-guluronic acid precipitate is collected and its pH is adjusted to 1.0 with 0.5M HCl. After centrifugation (3700g), the precipitate is collected and washed once with distilled water. The resulting precipitate (β-D-mannuronic acid) is spread in a petri dish and dried to obtain β-D-mannuronic acid in powder form. It can be used in mannuronate tablets, capsules or ampoule preparations, and / or in a mixture of β-D-mannuronate and α-L-guluronate tablets, capsules or ampoule preparations. 13 C-NMR) spectroscopy confirmed the identity and purity of α-L-guluronic acid and β-D-mannuronic acid.

[0191] The provided powders (mannuronic acid) and (guluronic acid) are stored dry and sterile at room temperature (22 to 26° C.) to prepare tablets, capsules or ampoule formulations for oral and / or injectable use.

[0192] 2. Preparation of tablet or capsule preparations comprising mannuronic acid powder, guluronic acid powder or a combination of guluronic acid powder and caffeic acid powder.

[0193] To prepare tablets or capsules comprising a combination of caffeic acid and mannuronic acid / mannuronate, guluronic acid / guluronate, or gulmannuronic acid / gulmannuronate, 0.03 g (30 mg) of caffeic acid powder is added to 10 g of β-D-mannuronic acid powder or α-L-guluronic acid powder or a mixture thereof (gulmannuronate powder). The powder is preferably compressed into tablets.

Claims

1. A tablet, capsule or ampoule preparation for oral administration and / or injection, 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 and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in, 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 preparation, or 20% to 60% by weight based on the total weight of the ampoule preparation; The tablet, capsule or ampoule preparation further contains caffeic acid or a salt thereof, such as caffeic acid or a salt thereof in powder form. Based on the total weight of the tablet, capsule or ampoule preparation, the content of caffeic acid or a salt thereof is preferably 0.001 wt% to 1 wt%, more preferably 0.01 wt% to 0.5 wt%, and even more preferably 0.05 wt% to 0.3 wt%.

2. The tablet or capsule preparation for oral and / or injection use, preferably for oral use, according to claim 1, wherein 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 and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, Wherein, based on the total weight of the tablet or capsule preparation, 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, The tablet or capsule preparation further comprises caffeic acid or a salt thereof, such as caffeic acid or a salt thereof in powder form. Based on the total weight of the tablet or capsule preparation, the content of caffeic acid or a salt thereof is preferably 0.001 wt% to 1 wt%, more preferably 0.01 wt% to 0.5 wt%, and even more preferably 0.05 wt% to 0.3 wt%.

3. The ampoule preparation for oral administration and / or injection, preferably for injection, according to claim 1, wherein 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 and α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, Wherein, based on the total weight of the ampoule preparation, 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 wt % to 60 wt %, The ampoule preparation further comprises caffeic acid or a salt thereof, such as caffeic acid or a salt thereof in powdered form. Based on the total weight of the ampoule preparation, the content of caffeic acid or a salt thereof is preferably 0.001 wt % to 1 wt %, more preferably 0.01 wt % to 0.5 wt %, and more preferably 0.05 wt % to 0.3 wt %.

4. The tablet, capsule or ampoule preparation according to any one of claims 1 to 3, wherein (i) β-D-mannuronate, its oligomers, or pharmaceutically acceptable salts thereof are β-D-mannuronates, preferably selected from 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) α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof are α-L-guluronates, preferably selected from sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate, and combinations thereof, more preferably sodium α-L-guluronate; or (iii) a mixture of β-D-mannuronate and α-L-guluronate, their oligomers, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, selected from sodium β-D-mannuronate, potassium β-D-mannuronate, magnesium β-D-mannuronate, calcium β-D-mannuronate, ammonium β-D-mannuronate, and sodium α-L-guluronate, potassium α-L-guluronate, magnesium α-L-guluronate, calcium α-L-guluronate, ammonium α-L-guluronate, and combinations thereof, most preferably sodium β-D-mannuronate and / or sodium α-L-guluronate; or (iv) A mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably guluromannuronate, in the form of alginate hydrolyzate (powder).

5. The tablet, capsule or ampoule preparation according to any one of claims 1 or 4, wherein 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-guluronate.

6. The tablet, capsule or ampoule preparation according to claim 5, wherein Oligomers of β-D-mannuronate and / or α-L-guluronate: (i) a homo-oligomer of β-D-mannuronate and / or a homo-oligomer of α-L-guluronate; (ii) selected from sodium oligomannuronate, potassium oligomannuronate, magnesium oligomannuronate, calcium oligomannuronate or ammonium oligomannuronate and / or sodium oligoguluronate, potassium oligoguluronate, magnesium oligoguluronate, calcium oligoguluronate or ammonium oligoguluronate and combinations thereof, preferably sodium oligomannuronate and / or sodium oligoguluronate; and / or (iii) 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 preparation according to any one of claims 1 to 6, wherein The total amount of the following components in the tablet or capsule preparation is 30% to 99.999% by weight, preferably 50% to 99.999% by weight, based on the total weight of the tablet or capsule preparation; or the total amount of the following components in the ampoule preparation is 30% to 60% by weight, preferably 40% to 60% by weight, more preferably 50% to 60% by weight, based on the total weight of the ampoule preparation: (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, oligomers thereof, or pharmaceutically acceptable salts thereof.

8. The tablet or capsule preparation according to claim 7, wherein A mixture of β-D-mannuronic acid and α-L-guluronic acid, their oligomers, or pharmaceutically acceptable salts thereof, preferably a guluromannuronate preparation, comprising or consisting of: 0.01% by weight to 99.99% by weight of β-D-mannuronic acid, its oligomers, or pharmaceutically acceptable salts thereof and 0.01% by weight to 99.99% by weight of α-L-guluronic acid, its oligomers, or pharmaceutically acceptable salts thereof, provided that, based on the total weight of the tablet or capsule preparation, 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 preparation is at least 10% by weight and at most 99.999% by weight, preferably, Based on the total weight of the tablet or capsule preparation, the total amount of β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts thereof is 0.1% to 99.9% by weight, more preferably 1% to 99% by weight, more preferably 10% to 90% by weight, and Based on the total weight of the tablet or capsule preparation, 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.

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

10. The tablet, capsule or ampoule preparation according to any one of claims 1 to 9, wherein The tablet, capsule or ampoule preparation contains at least one other supplement and / or at least one other medicament, preferably, the tablet or capsule preparation contains at least one other supplement and / or at least one other medicament, and the other supplement and / or other medicament is selected from antioxidants, anticancer agents, vitamins, multivitamins, (pharmaceutical) minerals, (pharmaceutical) multiminerals, amino acids, fatty acids, herbs, carbohydrates, analgesics, anti-inflammatory agents and agents with anti-allergic properties or a combination thereof.

11. The tablet, capsule or ampoule preparation according to any one of claims 1 to 10, wherein The tablet, capsule or ampoule preparation further comprises at least one other ingredient, which is preferably selected from binders, fillers, builders, complexing agents, preservatives, coating agents, alkaline agents, acidulants, sweeteners, colorants, acids and bases or combinations thereof.

12. The tablet, capsule or ampoule preparation according to any one of claims 1 to 11, wherein The preparation is a supplement or a medicine, preferably an antioxidant tablet, capsule or ampoule preparation.

13. Use of the tablet, capsule or ampoule preparation for oral and / or injection use according to any one of claims 1 to 12 in a method for treating (or preventing) the following conditions: (i) neurodegenerative diseases, preferably MS and Alzheimer's disease; and / or (ii) an inflammatory response, preferably an inflammatory response in a rheumatic disease; 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. A method for preparing the tablet, capsule or ampoule preparation according to any one of claims 1 to 13, preferably, the method is used to prepare an antioxidant tablet, capsule or ampoule preparation, the method comprising the following steps: Provided are compositions comprising: (i) comprising β-D-mannuronic acid, its oligomers or pharmaceutically acceptable salts 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 preparation, or 20% to 60% by weight, based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof, for example, caffeic acid or a salt thereof in powder form, in an amount 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 preparation; or (ii) comprising α-L-guluronic acid, its oligomers or pharmaceutically acceptable salts thereof, preferably α-L-guluronic acid salt, in a total amount of 10% to 99.999% by weight, based on the total weight of the tablet or capsule preparation, or 20% to 60% by weight, based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof, for example, caffeic acid or a salt thereof in powder form, in an amount 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 preparation; or (iii) comprising a mixture of β-D-mannuronic acid and α-L-guluronic acid, oligomers thereof, or pharmaceutically acceptable salts thereof, preferably gulmanuronic acid, gulmanuronate or oligomers thereof, in an amount of 10% to 99.999% by weight based on the total weight of the tablet or capsule preparation, or 20% to 60% by weight based on the total weight of the ampoule preparation; and further comprising caffeic acid or a salt thereof, for example, caffeic acid or a salt thereof in powder form, in an amount of preferably 0.001% to 1% by weight, more preferably 0.01% to 0.5% by weight, and even more preferably 0.05% to 0.3% by weight, based on the total weight of the tablet, capsule or ampoule preparation.

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